Clinical Immunology_ Principles and Practice ( PDFDrive )

966 Part seven Organ-Specific Inflammatory Disease


8. Balasubramanyam A, Nalini R, Hampe CS, et al. Syndromes of 24. Couper JJ, Beresford S, Hirte C, et al. Weight gain in early life predicts
ketosis-prone diabetes mellitus. Endocr Rev 2008;29:292–302. risk of islet autoimmunity in children with a first degree relative with
9. Imagawa A, Hanafusa T, Miyagawa J, et al. A novel subtype of type 1 type 1 diabetes. Diabetes Care 2009;32:94–9.
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diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med islet autoimmunity (ENDIA): a pregnancy to early life cohort study in
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10. Imagawa A, Hanafusa T. Pathogenesis of fulminant type 1 diabetes. Rev 26. Knip M, Siljander H. The role of the intestinal microbiota in type 1
Diabet Stud 2006;3:169–77. diabetes mellitus. Nat Rev Endocrinol 2016;12:154–67.
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between humoral and cellular immunity to glutamic acid decarboxylase lifestyle” inflammatory diseases. Immunity 2014;40:833–42.
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human type 1 diabetes. Clin Exp Immunol 2009;155:173–81. transient pancreatic involution and hyperglycemia in weanling mice.
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e1002552. Lancet 2008;372:1746–55.

CHaPter 71 Type 1 Diabetes 966.e1


MUL t IPL e -CHOIC e QU est IO ns

1. Type 1 diabetes (T1D): C. Most newly diagnosed cases have a first- or second-degree
A. Is a genetic disease in which environment plays little or relative with the disease.
no role D. Most children who develop the disease have islet auto-
B. Is classified as type 1A or type 1B, depending on evidence antibodies after 5 years of age.
for an autoimmune basis (i.e., the presence of absence 3. In T1DA:
respectively of islet autoantibodies) A. The absence of islet autoantibodies excludes the diagnosis.
C. Cannot be diagnosed on the basis of clinical features alone B. Blood glycated hemoglobin (Hb A1c ) can be used to make
D. Is associated with increased diversity of gut bacterial the diagnosis children.
microbiota
C. Immune-modulating agents have been successful in stabiliz-
2. In T1DA: ing or reversing β-cell failure for at least 2 years after the
A. The dominant genetic contribution remains to be diagnosis.
established. D. Strict blood glucose control in pregnancy prevents fetal
B. The incidence has increased along with increased penetrance complications.
of lower-risk genetic alleles.

72









Immunological Lung Diseases



Joyce S. Lee, Andrew P. Fontenot







The lung serves as an interface between the environment and Macrophages and lymphocytes have also been localized to
the sanctuary of the body. The defense systems of the upper areas of pulmonary fibrosis in patients with immunological lung
airways clear the majority of inhaled particulates. Those that diseases, including idiopathic pulmonary fibrosis (IPF), systemic
1
evade the upper airway defenses are combated by the innate and sclerosis, and rheumatoid arthritis (RA). In the lung, macrophages
acquired immune responses. Essentially all autoimmune diseases can be divided, according to their location, into alveolar or
are dependent on the inappropriate activation of autoreactive CD4 interstitial macrophages. Resident alveolar macrophages are
T cells as well as autoreactive B cells responsible for pathogenic yolk-sac–derived cells that are dependent on interleukin-34
autoantibodies. Immunological lung diseases develop when the (IL-34), colony-stimulating factor 1 (CSF-1), and the transcription
2-4
normal mechanisms of immune self-tolerance fail. This chapter factor PU.1 for their development. These yolk-sac–derived
5
deals with the pulmonary manifestations of these disorders. macrophages are self-renewing, maintained at a stable number
throughout life, and are localized on epithelial surfaces and lining
INFLAMMATION IN THE PATHOGENESIS OF fluid of the alveoli and airways. With relatively poor antigen-
INTERSTITIAL LUNG DISEASE presenting ability, they function to remove inhaled particles and
bacteria. Conversely, interstitial macrophages are derived from
6
In the normal host, the resident alveolar macrophage is the hematopoietic stem cells (HSCs) and are located in the tissue
predominant cell type in fluid from bronchoalveolar lavage (BAL). spaces between the alveoli. In the context of lung injury, interstitial
Resident alveolar macrophages function to ingest and degrade macrophages greatly increase in number. Although interstitial
the inhaled antigenic load, to clear pulmonary surfactant, and macrophages have less phagocytic activity than alveolar macro-
to tonically suppress the development of inappropriate immune phages, they have increased ability to present antigens to T cells.
responses. Relatively few lymphocytes are present in the normal Upon activation, these macrophages express a variety of cytokines,
lung parenchyma. However, after stimulation by the relevant including tumor necrosis factor-α (TNF-α) and monocyte
antigen in the lung-draining lymph nodes, antigen-specific chemotactic protein-1 (MCP-1). In addition to antigen presenta-
lymphocytes migrate to the lung and participate in the inflam- tion to T cells, macrophages are important for lung fibrosis and
matory response. In addition to lymphocytes, other inflammatory tissue remodeling in immunological lung diseases through
and immune cells, including neutrophils, eosinophils, and other secretion of specific growth factors, such as transforming growth
mononuclear cells, accumulate in the lung of patients with factor-β (TGF-β), insulin-like growth factor-1 (IGF-I), platelet-
immunological lung disease, depending on the underlying disease. derived growth factor (PDGF), and fibroblast growth factor
Within the normal alveolus, the major cellular constituents are (FGF).
alveolar macrophages and epithelial cells. Resident dendritic cells T cells are also associated with lung fibrosis. For example,
(DCs) also project dendrites through the tight junctions of the T cells have been located in areas of interstitial fibrosis and
alveolar epithelium to sample the alveolar space. An initial insult honeycombing with relatively fewer in areas of normal lung
7
typically involves the alveolar epithelial cell. Damage to type I in patients with IPF. In connective tissue disease–associated
alveolar epithelial cells results in release of chemokines that recruit interstitial lung disease (ILD), T cells are diffusely distributed
8
and activate inflammatory cells, allowing for resolution of throughout the lung and within focal lymphoid aggregates.
inflammation and repair of injured tissue (Fig. 72.1). With either In animal models, depending on their phenotype, T cells can
prolonged exposure or failure to adequately clear an inhaled be either profibrotic or antifibrotic. γδ T cells decrease lung
9
antigen, persistent inflammation results in extracellular matrix inflammation and fibrosis in multiple mouse models. CD8 T
(ECM) deposition, culminating in tissue remodeling, progressive cells have been found in high proportion in BAL and surgical
collagen deposition, and pulmonary fibrosis. Impaired ventilation lung biopsy samples from patients with IPF, as well as patients
and gas exchange occur as a consequence of lung fibrosis, resulting with systemic sclerosis, but their role in these immunological
in patient morbidity and mortality. With destruction of type I lung diseases is not well understood.
alveolar epithelial cells, exposure of the underlying basement Different subsets of CD4 T cells (Chapter 16) have been
membrane can cause further inflammation. Proper restoration implicated in the pathogenesis of immunological lung diseases.
of the epithelial barrier is critical for resolution of lung inflam- T-helper type 1 (Th1) cells express interferon-γ (IFN-γ). Although
mation. Type II alveolar epithelial cells can serve as progenitor IFN-γ is a potent proinflammatory cytokine, it has antifibrotic
cells that migrate and differentiate into type I alveolar epithelial effects through inhibiting fibroblast proliferation and collagen
cells to reestablish an intact lung epithelium. expression. Th2 cells are defined by expression of IL-4, IL-5, and

967

968 Part Seven Organ-Specific Inflammatory Disease



Steady state Initiation of injury and repair Dysregulated repair
Alveolus
Type I epithelial cell
Monocytes
Dendritic cell Alveolar
macrophages
Lymphocytes Fibrosis
Type II epithelial cell
PMNs


ECM ECM
Resolution

Fibroblasts Fibroblasts
1. Denudation of barrier
2. Cytokine/chemokine expression
3. Recruitment of inflammatory cells
4. Proliferation of type II epithelial cells
5. DC maturation
6. Fibroblasts express ECM
FIG 72.1 Pathogenesis of Interstitial Lung Disease. In the healthy lung, the alveoli maintain an
antiinflammatory state to prevent unwanted inflammation. The predominant cells in the healthy
alveolus are macrophages and types I and II epithelial cells. Upon injury, there is denudation of
the epithelial barrier, resulting in the expression of cytokines/chemokines, recruitment of inflam-
matory cells, proliferation of type II epithelial cells, dendritic cell (DC) maturation, and expression
of extracellular matrix (ECM) by fibroblasts. This inflammatory milieu leads to the resolution of
inflammation and repair of lung injury. Conversely, in the presence of either prolonged antigen
exposure or an inability to clear antigen, persistent inflammation ensues, resulting in extracellular
matrix deposition with subsequent tissue remodeling, fibrosis, and permanent lung dysfunction.




IL-13. In contrast to IFN-γ, Th2 cytokines have been shown to KeY COnCePtS
promote lung fibrosis. Therefore the balance between Th1 and
Th2 T cells through expression of different cytokines affects the Classification of the Idiopathic
10
development of pulmonary fibrosis. Th17 cells express IL-17A Interstitial Pneumonias
and IL-17F, which are potent inflammatory cytokines important • The idiopathic interstitial pneumonias comprise a group of eight histologi-
for the recruitment of neutrophils to areas of inflammation. cally distinct disorders.
Th17 cells have been implicated in the development of lung • The distinction is important since response to treatment and prognosis
fibrosis in murine models. 11,12 Conversely, regulatory T cells differs:
(Tregs) suppress pathogenic T-cell responses that promote • Idiopathic pulmonary fibrosis (IPF) with histopathology labeled as
inflammation (Chapter 18). In patients with IPF, Tregs may be usual interstitial pneumonitis (UIP): the pathology of UIP can occur
in other diseases such as connective tissue diseases
less able to suppress expression of cytokines by Th1 and Th2 • Acute interstitial pneumonitis (AIP)
cells, suggesting that Tregs are important in regulating ILD and • Desquamative interstitial pneumonitis (DIP)
pulmonary fibrosis. 13 • Respiratory bronchiolitis–associated interstitial lung disease
(RB-ILD)
IDIOPATHIC INTERSTITIAL PNEUMONIAS • Nonspecific interstitial pneumonia (NSIP)
• Lymphocytic interstitial pneumonia (LIP)
• Cryptogenic organizing pneumonia (COP)
Idiopathic interstitial pneumonias (IIPs) are a group of diffuse
• Idiopathic pleuroparenchymal fibroelastosis (IPPFE)
inflammatory and/or fibrotic lung disorders that include IPF, • To differentiate between these diseases, a thoracoscopic lung biopsy
acute interstitial pneumonitis (AIP), desquamative interstitial is often required.
pneumonitis (DIP), respiratory bronchiolitis–associated interstitial
lung disease (RB-ILD), nonspecific interstitial pneumonia (NSIP),
cryptogenic organizing pneumonia (COP), lymphocytic interstitial
pneumonia (LIP), and idiopathic pleuroparenchymal fibroelastosis an underlying autoimmune disorder. However, these subjects
14
(IPPFE). The diagnosis of IIPs requires the exclusion of con- do not meet established criteria for a CTD. A joint European
nective tissue diseases (CTDs), drug toxicity, and environmental Respiratory Society and American Thoracic Society Task Force
exposures, and a thoracoscopic lung biopsy is often required. In recently proposed the term “interstitial pneumonia with auto-
addition, some patients with IIPs have clinical features suggesting immune features” (IPAF) as well as classification criteria for

CHaPter 72 Immunological Lung Diseases 969






























A B
FIG 72.2 Radiographic Manifestations of Idiopathic Pulmonary Fibrosis. (A) Chest radiograph
in a patient with idiopathic pulmonary fibrosis showing diffuse, coarse reticular opacities with a
lower lung zone predominance. Cystic radiolucencies, consistent with honeycombing, are evident.
(B) High-resolution computed tomography shows peripheral reticular opacities, honeycombing,
and traction bronchiectasis.



15
these subjects. Importantly, the distinction between these various insidious onset of exertional dyspnea and a dry, nonproductive
disorders is of clinical relevance, since response to treatment cough. Physical examination reveals dry, end-inspiratory crackles
and outcome differs. with clubbing present in 25–50% of patients.
Chest radiography typically shows diffuse reticular opacities,
Idiopathic Pulmonary Fibrosis predominantly in the peripheral lower lung zones. Ground-glass
IPF, also known as cryptogenic fibrosing alveolitis, is the most opacities, small cysts (honeycombing), and reduced lung volumes
common diffuse parenchymal lung disease of unknown etiol- may also be seen (Fig. 72.2A). These radiographic changes often
16
ogy. It is characterized by progressive clinical deterioration precede the onset of symptoms, and serial chest radiographs
despite available therapy. Although IPF has characteristic clinical, usually reveal progressive loss of lung volume. High-resolution
radiographic, and histological appearances, other ILDs, including computed tomography (HRCT) findings include bibasal periph-
the CTDs, drug reactions, and environmental exposures, can eral reticular opacities (see Fig. 72.2B). Honeycombing, traction
mimic these findings. bronchiectasis, and subpleural fibrosis can also be present.
The typical physiological abnormalities in IPF are those of a
Clinical Manifestations restrictive lung disease with a low diffusing capacity for carbon
monoxide and severe gas exchange abnormalities exacerbated
CLInICaL PearLS by exercise.
Idiopathic Pulmonary Fibrosis (IPF)
Histopathology
• IPF is one of the most common causes of diffuse parenchymal lung The gross appearance of the lungs in IPF shows a nodular pleural
disease of unknown etiology and is characterized by insidious onset surface, and histopathological examination reveals usual interstitial
of cough and dyspnea. 18
• The histopathological pattern of IPF is usual interstitial pneumonitis. pneumonitis (UIP). UIP is characterized by nonuniform and
• A confident diagnosis of IPF based on high-resolution computed variable distribution of the interstitial changes. At low magnifica-
tomography can only be made in one-third of cases. tion, alternating zones of interstitial fibrosis, inflammation,
• IPF is generally a fatal disorder, characterized by relentless progression honeycombing, and normal lung can be seen (Fig. 72.3A). At
and a 5-year survival of 30–50%. higher magnification, derangement of alveolar walls with edema,
• Pirfenidone and nintedanib appear to slow disease progression in IPF. fibrinous exudate, fibroblast proliferation, and fibrosis occur.
Honeycomb change refers to enlarged airspaces lined by metaplastic
The incidence and prevalence of IPF are uncertain, although bronchial epithelium and surrounded by walls thickened with
prevalence rates for men and women of 20.2 per 100 000 and collagen (see Fig. 72.3B). The earliest finding in UIP is the
17
13.2 per 100 000, respectively, have been reported. Both the fibroblast focus, a lesion consisting of distinct clusters of fibro-
incidence and prevalence of IPF increase with age, with most blasts and myofibroblasts in a loose connective tissue matrix
patients presenting between 50 and 70 years of age. Although the within the alveolar wall, with minimal interstitial inflammation
18
clinical features of IPF are variable, most patients present with the or intraalveolar macrophage accumulation (see Fig. 72.3C).

970 Part Seven Organ-Specific Inflammatory Disease


an interplay between immunological, genetic, environmental,
16
and viral factors (Fig. 72.4). Some cases of IPF are familial,
inherited as an autosomal dominant trait with variable penetrance.
Recently, dysregulated expression of a mucin gene, MUC5B, has
19
been associated with development of familial IPF. Mutations
in the telomerase ribonucleoprotein complex associated with
16
telomere shortening have also been linked with familial IPF.
In addition, surfactant protein C mutations have been rarely
associated with IPF.
In the normal lung, the interstitium is thin and delicate with
A few lymphoid cells and fibroblasts. Following the initiation of
the inflammatory process, damage to the alveolar epithelial cell
occurs, followed by vascular leak, fibroblast activation and
proliferation, ECM synthesis, and activation of the innate immune
16
system. The release of danger-associated molecular patterns
from dead or dying cells results in macrophage activation. Fol-
lowing activation, alveolar macrophages secrete IL-1, IL-8, tumor
necrosis factor-α (TNF-α), PDGF, and IGF-1. This cytokine
milieu promotes the activation and recruitment of neutrophils
and lymphocytes to the area of alveolitis.
T lymphocytes, which accumulate in the alveolar space and
interstitium, express an activated phenotype, including the
expression of human leukocyte antigen D-related (HLA-DR)
and IL-2 receptor. Following activation, CD4 T cells evolve into
three major subsets distinguished by the cytokines produced
B (Chapters 9 and 16). In IPF, T cells expressing a Th2-type
phenotype predominate, producing IL-4, -5, and -13. In addition,
the Th17 cytokine, IL-17A, has been linked to the development
of bleomycin-induced lung injury and collagen deposition. 11,12
Evidence also suggests that patients with IPF have oligoclonal
CD4 T-cell expansions that proliferate in response to antigens
20
present in diseased tissue. Treg function may be impaired in
13
patients with IPF. In addition, immune complexes have been
identified in the serum and lungs of patients with IPF. 21
In addition to their role as scavengers, alveolar macrophages
are vital in the repair phase of inflammation. However, the
distinguishing feature between a self-resolving inflammatory
process and a fibrotic response, as seen in IPF, is the accumulation
of collagen. Evidence suggests that the fibrotic process in IPF is
a consequence of dysregulation of both collagen synthesis and
degradation. Macrophage-derived growth factors, including
C
TGF-β, PDGF, and IGF-1, stimulate fibroblast proliferation and
22
FIG 72.3 Histopathology of Usual Interstitial Pneumonitis collagen deposition. Adequate resolution of an inflammatory
(UIP). (A) Low-magnification photomicrograph of UIP showing process requires matrix degradation. Matrix metalloproteases
the variegated appearance from one field of view to the next (MMPs) produced by macrophages and fibroblasts are involved
with areas of dense subpleural fibrosis (arrows) separated from in matrix degradation, and control of metalloprotease production
other areas of normal lung. (B) High-magnification photomicro- involves substances known as tissue inhibitors of metalloproteases
graph of UIP showing honeycomb change characterized by (TIMPs). TIMPs are elevated in the lungs of patients with IPF.
enlarged airspaces filled with mucin and separated by fibrosis. In addition, TGF-β can markedly augment TIMP production.
(C) Fibroblast focus in UIP is characterized by clusters of spindle- Thus there appears to be a loss of balance between the events
shaped fibroblasts (arrow) in a loose connective tissue matrix mediating resolution and those mediating perpetuation of the
within the alveolar wall. inflammatory response, setting the stage for lung injury, tissue
remodeling, and the development of irreversible pulmonary
fibrosis.

Tables 72.1 and 72.2 compare the clinical and pathological features Diagnosis
of UIP, DIP, RB-ILD, and NSIP. The diagnostic evaluation of a patient with diffuse parenchymal
lung disease includes a thorough history and physical examina-
Pathogenesis tion with particular attention to symptoms and signs that could
The pathogenesis of IPF is poorly understood, but current indicate a CTD, occupational and environmental exposures,
evidence suggests that fibrosis results from aberrant wound or medication and drug use. A careful family history is also
healing in response to repetitive injury and is mediated through important.

CHaPter 72 Immunological Lung Diseases 971



TABLE 72.1 Clinical Features of the Idiopathic Interstitial Pneumonias
UIP DIP rB-ILD aIP nSIP
Mean age (years) 57 42 36 49 49
Childhood No Rare No Rare Occasionally
Onset Insidious Insidious Insidious Acute Subacute, insidious
Mortality (mean survival) 68% (5–6 years) 27% (12 years) 0% 62% (1–2 months) 11% (17 months)
Response to steroids Poor Good Good Poor Good
Recovery possible No Yes Yes Yes Yes
AIP, acute interstitial pneumonitis; DIP, desquamative interstitial pneumonitis; NSIP, nonspecific interstitial pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung
disease; UIP, usual interstitial pneumonitis.
Adapted from Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathological classification. Am J Respir Crit Care Med 1998; 157: 1301.


TABLE 72.2 Histopathological Features of Genes? Environment? Infection?
the Idiopathic Interstitial Pneumonias
UIP DIP/rB-ILD aIP nSIP Persistent
Temporal Variegated Uniform Uniform Uniform sequential
appearance injury
Interstitial Scant Scant No Prominent
inflammation
Collagen/ Patchy Diffuse (DIP) No Diffuse
fibrosis Focal (RB-ILD) Epithelial and Inflammation Immune response
Fibroblast Fibroblast No Diffuse Rare endothelial injury (Th2>Th1)
proliferation foci
prominent
BOOP No No No Focal IL-4, IL-6, IL-8
Honeycomb Yes No No Rare
change
Intraalveolar Focal Diffuse (DIP) No Patchy TGF-β, IGF, PDGF
macrophages Focal (RB-ILD)
Hyaline No No Focal No Angiogenesis
membranes
AIP, acute interstitial pneumonitis; BOOP, bronchiolitis obliterans organizing Endothelin-1
pneumonia; DIP, desquamative interstitial pneumonitis; NSIP, nonspecific interstitial
pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease;
UIP, usual interstitial pneumonitis. Fibroproliferation Failure of apoptosis
Adapted from Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical
relevance of pathological classification. Am J Respir Crit Care Med 1998; 157: 1301.

Fibroblast Extracellular matrix
Myofibroblast deposition
Foci
KeY COnCePtS Lung remodeling
Pathogenesis of the Idiopathic Interstitial
Pneumonias (IIPs)
• Although the inciting event(s) is unknown in the different diseases, Fibrosis
a common result is a dysregulated fibroproliferative response (similar
to wound healing), which leads to excessive extracellular matrix (ECM) FIG 72.4 Events Hypothesized to Be Involved in the Patho-
production and lung remodeling. genesis of Idiopathic Pulmonary Fibrosis. The initiating event(s)
• A genetically determined inability to repair and reepithelialize the leading to persistent lung injury remains poorly understood. The
denuded basement membranes adequately may be a contributing interaction between genetic factors, environmental exposures,
factor and may relate to the familial occurrence of some cases of and infectious agents leads to epithelial and endothelial injury,
idiopathic pulmonary fibrosis (IPF). resulting in the secretion of macrophage-derived growth factors,
• The presence of a chronic stimulus (autoantigen), as is seen in the
pneumoconioses, may result in a persistent inflammatory and immune including transforming growth factor-β (TGF-β), insulin-like growth
response and lead to a failure in the normal healing process. factor-1 (IGF-1), and platelet-derived growth factor (PDGF). This
• The release of transforming growth factor-β (TGF-β) following epithelial cytokine milieu stimulates fibroblast proliferation and collagen
injury stimulates collagen synthesis and the prevention of apoptosis deposition. In addition, the resulting T-helper type 2 (Th2) immune
of proliferating fibroblasts in the lung and may impair collagen degrada- response stimulates extracellular matrix production and fibroblast
tion by inhibiting the production of metalloproteases. proliferation, resulting in lung remodeling and, eventually, lung
• A predominant T-helper type 2 (Th2) response in the lung and the fibrosis.
absence of interferon-γ (IFN-γ) favor the development of a fibrotic
response.

972 Part Seven Organ-Specific Inflammatory Disease


The history and physical findings in IPF are nonspecific.
However, extrapulmonary involvement does not occur; the pres-
ence of fever, arthralgias, myalgias, or pleuritis should suggest a
connective tissue disorder. Antinuclear antibodies (ANAs) and
rheumatoid factor are present in 10–20% of patients with IPF, but
titers greater than 1 : 320 should suggest an alternative diagnosis.
The majority of patients with IPF have abnormal chest
radiography results at the time of presentation. Basal peripheral
reticular opacities are the characteristic radiographic findings.
A confident diagnosis of IPF from HRCT of the lung requires
the presence of patchy, peripheral bibasal reticular abnormalities
23
with honeycombing. The presence of extensive ground-glass
opacities on HRCT should suggest an alternative diagnosis, such
as DIP, hypersensitivity pneumonitis, bronchiolitis obliterans
organizing pneumonia (BOOP), or NSIP.
A surgical lung biopsy is recommended in patients with FIG 72.5 Histopathology of Acute Interstitial Pneumonitis.
suspected IPF without a definitive HRCT appearance and who Diffuse thickening of the alveolar septum with an infiltration of
do not have contraindications to the procedure. This is especially mononuclear cells is the characteristic abnormality. The temporal
important in patients with atypical clinical or radiographic uniformity of this process is also apparent.
findings, which could suggest the possibility of one of the other
histological patterns of the IIPs and an improved prognosis.
Biopsy may be omitted in older patients with cardiovascular
disease, or those with evidence of extensive honeycomb change. affected. A viral prodrome is common, with symptoms that
Biopsy through video-assisted thoracoscopy (VATS) is the include fever, nonproductive cough, and dyspnea. Laboratory
preferred surgical technique and has been associated with less studies are nonspecific. Chest radiography and HRCT show
morbidity and a decreased length of hospital stay compared diffuse airspace opacities and ground-glass attenuation, respec-
with open lung biopsy. tively. A similar presentation may occur as the initial manifestation
of a CTD.
Treatment and Outcome
The usual course of IPF is relentless progression without spontane- Histopathology
ous remission, commonly with a fatal outcome. The most common AIP is characterized by diffuse interstitial fibrosis that is temporally
28
cause of death in patients with IPF is progression of the underlying uniform (Fig. 72.5). The changes are identical to the organizing
disease with two-thirds of deaths caused by respiratory failure phases of diffuse alveolar damage, as seen in ARDS. Within the
or cardiovascular complications. Other causes of death in IPF thickened interstitial space, there is active, diffuse fibroblast
include bronchogenic carcinoma, infection, and pulmonary proliferation similar to the focal fibroblast foci seen in UIP. If
embolism. Recent studies in patients with biopsy-proven IPF this is progressive, honeycomb change occurs. Other features of
24
indicate a poor prognosis (30–50% 5-year survival). Previously, acute lung injury, which are frequently seen in AIP, are intra-
there was no evidence to support the use of any specific therapy alveolar hyaline membranes.
in the management of IPF. However, recent clinical trials have
shown decreased decline in forced vital capacity (FVC) after use Diagnosis
25
26
of either pirfenidone or nintedanib. Thus for the first time, The diagnosis of AIP is based on a clinical syndrome of idiopathic
there are two drugs approved by the US Food and Drug Admin- ARDS and the presence of organizing diffuse alveolar damage
istration (FDA) for the treatment of IPF, with multiple other on lung biopsy. Lung biopsy is occasionally performed to establish
phase II and III clinical trials scheduled for completion in the the diagnosis and exclude other causes of acute ILD.
near future. Finally, lung transplantation should be considered
in patients who have progressive clinical and physiological Treatment and Outcome
deterioration and who meet established criteria. No effective therapy exists for patients with AIP. Glucocorticoids
are utilized in most cases, but no survival benefit has been shown.
Acute Interstitial Pneumonia Overall, the prognosis of patients with AIP is poor, with mortality
AIP is a fulminant form of IIP. Although it was previously thought rates in the range of 50–88%. Half the patients die within 6
to represent an acute phase of UIP, some studies have suggested months of disease onset. However, those who survive may have
18
that it is a distinct entity. However, patients with documented complete recovery of lung function, and AIP rarely recurs in
UIP/IPF experiencing acute exacerbations can have the pathology survivors.
of AIP superimposed on UIP. 27
Desquamative Interstitial Pneumonitis
Clinical Manifestations DIP represents fewer than 3% of all cases of interstitial lung
29
AIP presents with the abrupt onset of dyspnea followed by rapid disease. However, it is a distinct clinicopathological entity that
progression to respiratory failure. The clinical, radiographic, differs substantially from UIP.
physiological, and histological features are identical to those of
the acute respiratory distress syndrome (ARDS) but without Clinical Manifestations
any identifiable cause. Most patients are previously healthy DIP affects individuals in their fourth to fifth decades of life
individuals over 40 years of age. Men and women are equally with a male predominance. It predominantly occurs in cigarette

CHaPter 72 Immunological Lung Diseases 973























FIG 72.7 Histopathology of Desquamative Interstitial Pneu-
monitis. A high-magnification photomicrograph of desquamative
interstitial pneumonitis shows the uniform, diffuse accumulation
FIG 72.6 Radiographic Manifestations in Desquamative of macrophages within the alveolar space with associated
Interstitial Pneumonitis. High-resolution computed tomography thickening of the alveolar septum. These aggregates of macro-
scan in a patient with desquamative interstitial pneumonitis phages almost completely fill the alveolar spaces.
shows ground-glass attenuation in the periphery of the upper
and lower lung fields.


disease. A mortality rate of 28% with a mean survival of 12 years
smokers. Clinically, most individuals present with subacute onset has been reported compared with a 30–50% 5-year survival in
24
of a dry, nonproductive cough and dyspnea. Clubbing is present UIP. Of note, 22% patients improved spontaneously, and 60%
in approximately 50% of patients with DIP. Laboratory evaluation responded to glucocorticoid therapy. This picture is dramatically
is usually nonspecific. different from that of IPF, in which spontaneous improvement
Although the chest radiography results can be normal in up rarely, if ever, occurs. However, a significant minority of patients
to 20% of symptomatic individuals, it typically shows nonspecific with DIP fail to respond to treatment and progress to respiratory
bibasilar ground-glass opacities. Reticulonodular interstitial failure secondary to advanced fibrosis.
infiltrates have also been reported. HRCT confirms the presence
of ground-glass attenuation in the periphery of the lower lung Respiratory Bronchiolitis–Associated Interstitial
zones (Fig. 72.6). Pulmonary function testing shows a restrictive Lung Disease
defect with hypoxemia and a decrease in diffusion capacity. RB-ILD is a distinct clinical entity that occurs in current or
former cigarette smokers. It is unclear whether RB-ILD and DIP
Histopathology represent different diseases or different ends of the spectrum of
29
DIP is a misnomer. It was initially thought that the intraalveolar the same disease process. DIP occurs predominantly and RB-ILD
cells represented sloughed or desquamated alveolar epithelial occurs exclusively in cigarette smokers, suggesting a common
cells. However, DIP is pathologically characterized by uniform, pathogenesis related to cigarette smoke exposure.
diffuse accumulation of macrophages in the alveolar space (Fig.
72.7). At low magnification, the overall appearance is one of Clinical Manifestations
uniformity from one field of view to the next as opposed to the The mean age at presentation with RB-ILD is 36 years. Males
variegated appearance of UIP. In addition, there is scant interstitial are more often affected, and all individuals with RB-ILD are
inflammation with varying degrees of fibrosis of the alveolar cigarette smokers. Symptoms include a dry, nonproductive cough
septum. and dyspnea. Clubbing is absent in RB-ILD, whereas it is fre-
quently present in DIP. Laboratory evaluation is nonspecific.
Diagnosis Chest radiography typically shows diffuse, fine reticular or
The diagnosis of DIP requires tissue confirmation of the patho- nodular interstitial opacities with normal lung volumes. Additional
logical lesion. This is important since DIP has a better prognosis findings include bronchial wall thickening and a prominent
and response to therapeutic intervention compared with IPF. peribronchovascular interstitium. HRCT may reveal ground-glass
A DIP-like pattern is frequently seen in other IIPs as well as in opacification and emphysema.
pulmonary Langerhans cell histiocytosis, CTDs, and drug reac- Pulmonary function tests most commonly reveal a mixed
tions. Thus the diagnosis of DIP requires careful correlation of restrictive–obstructive pattern with a reduced diffusing capacity
pathological findings with clinical and radiological findings. and mild hypoxemia. The residual volume may be increased,
with no change in other spirometric parameters.
Treatment and Outcome
The primary intervention in DIP is smoking cessation. Since Histopathology
this is a rare condition with relatively few published cases, it is The pathology of RB-ILD is similar to that of DIP. However, in
unclear whether glucocorticoids alter the natural history of this RB-ILD, the intraalveolar macrophages accumulate primarily

974 Part Seven Organ-Specific Inflammatory Disease























FIG 72.8 Histopathology of Respiratory Bronchiolitis–Inter- FIG 72.9 Histopathology of Nonspecific Interstitial Pneumo-
stitial Lung Disease. An ectatic bronchiole with a thickened nitis. Low-magnification photomicrograph of cellular nonspecific
wall is shown, with a mononuclear infiltrate extending into the interstitial pneumonitis shows diffuse uniform thickening of the
immediately surrounding alveoli. alveolar septum as a result of the presence of a lymphoplasma-
cytic infiltrate.


within the peribronchiolar airspaces and are associated with
thickening of the alveolar septum in these areas (Fig. 72.8). The
differentiation of this lesion from DIP requires sparing of distal HRCT characteristically shows bilateral, patchy ground-glass
airspaces with the lesion confined to the peribronchiolar airspaces attenuation indistinguishable from DIP or RB-ILD. 23
in RB-ILD.
Histopathology
Diagnosis NSIP is characterized by varying, but temporally uniform, degrees
RB-ILD should be suspected in young individuals who have a of fibrosis and inflammation of the alveolar septum, without
history of cigarette smoking and complain of cough and dyspnea the histopathological features indicative of UIP, AIP, or DIP (Fig.
with chest radiography or HRCT showing nodular and/or reticular 72.9). NSIP has been divided into three groups, depending on
interstitial opacities. The diagnosis requires tissue confirmation the presence or absence of interstitial fibrosis: interstitial lympho-
of the pathological findings noted above. plasmacytic inflammation (48% of cases); inflammation and
fibrosis (38%); and fibrosis (14%). Although the changes are
Treatment and Outcome temporally uniform, they may be patchy with intervening areas
The key therapeutic intervention in RB-ILD is cessation of of normal lung.
smoking. The use of glucocorticoids has been associated with This temporal uniformity is in contrast to the variegated
favorable results. At present, the clinical course and progno- pattern seen in UIP. Fibroblast foci, the earliest lesions seen in
sis of patients with RB-ILD are unknown. In most clinical UIP, are found in 20% of patients with NSIP, making it difficult
series, patients either improved or stabilized, and mortality is to differente fibrotic NSIP from UIP. The key feature in this
uncommon. 29,30 circumstance is the temporal uniformity of the lesions in NSIP.
Nonspecific Interstitial Pneumonitis Treatment and Outcome
The term NSIP was first used to describe cases of interstitial Unlike patients with UIP, individuals with NSIP have a favorable
pneumonia that did not demonstrate a pattern of UIP, AIP, or prognosis. In the original description of the disease, 45% of
DIP. Currently, the term NSIP is applied to an IIP or to a similar subjects completely recovered, and the condition of another 42%
31
histological pattern that occurs in CTD, hypersensitivity pneu- remained stable or improved. Only 11% of patients died, with
monitis, infection, or drug-induced lung disease. Thus the a mean survival of 16 months. All of the individuals with an
diagnosis of NSIP should prompt investigation for a causative aggressive course were in the fibrotic group. Ten-year survival
18
agent. In fact, 16% of patients in the original description of in the cellular group was 90%, compared with 35% in patients
NSIP had one of the CTDs. 31 with the fibrotic pattern. Despite the worse prognosis of NSIP
with a fibrosing pattern, this is still significantly better than the
Clinical Manifestations 15% 10-year survival rate for patients with UIP. 32
Idiopathic NSIP occurs in middle-aged individuals, with a slight
female predominance. A dry, nonproductive cough and exertional Cryptogenic Organizing Pneumonia
dyspnea are the most common symptoms, although fever is COP is a specific clinicopathologic disorder of unknown etiology
present in 25% of patients. Symptoms are usually present for characterized by excessive proliferation of granulation tissue
33
6–10 months before diagnosis. As in other IIPs, the laboratory within the lumen of distal airspaces. The term COP is reserved
evaluation is nonspecific. for cases demonstrating bronchiolitis obliterans organizing
Chest radiography usually shows bilateral interstitial infiltrates, pneumonia (BOOP) without an obvious cause, since this his-
and sometimes the result can be normal in a symptomatic patient. tological appearance occurs in a variety of inflammatory lung

CHaPter 72 Immunological Lung Diseases 975


disorders, including CTDs, malignancy, infections, and those opacities can be migratory and usually have a peripheral distribu-
caused by medications. tion similar to those seen in chronic eosinophilic pneumonia.
Rarer radiographic manifestations include linear or nodular
Clinical Manifestations interstitial opacities and honeycombing. The presence of a pleural
The onset of disease is usually in the fifth to sixth decades of effusion or pleural thickening should suggest an associated CTD.
life; men and women are equally affected. Most individuals have HRCT shows patchy airspace consolidation, especially in the
symptoms for less than 2 months before diagnosis. The initial lung periphery with a lower-lung zone predominance (see Fig.
presentation is usually with a dry, nonproductive cough and 72.10B). Other findings include ground-glass attenuation, small
flu-like symptoms, including fever, sore throat, and malaise. This nodular opacities, and bronchial wall thickening.
is followed by progressive dyspnea, and routine laboratory As in other ILDs, a restrictive ventilatory defect is the most
evaluation is nonspecific. common pulmonary function abnormality. Gas exchange
Chest radiography shows diffuse, often patchy alveolar opacities abnormalities are common and are accompanied by decreased
in the setting of normal lung volumes (Fig. 72.10A). These diffusing capacity, widening of the alveolar–arterial gradient,
and exercise-induced hypoxemia.

Histopathology
The histopathology of COP is characterized by excessive prolifera-
tion of granulation tissue in the small airways and alveolar ducts
with associated chronic inflammation in the alveolar walls (Fig.
33
72.11). The intraluminal fibrotic buds (Masson bodies) consist
of loose collagen-embedding fibroblasts and myofibroblasts and
have a tendency to extend from one alveolus to the next, giving
a characteristic “butterfly” pattern. The lesions are patchy in
nature and have a uniform temporal appearance at low magnifica-
tion, with preservation of the underlying lung parenchyma. This
pattern has been described as the prototypical healing response
of the lung to a variety of insults.
Diagnosis
The presence of BOOP in a lung biopsy does not necessarily
represent COP, since COP is a diagnosis of exclusion. Organizing
pneumonia is a nonspecific response to many lung injuries and
can occur in conjunction with another pathological process or
A as a component of other primary pulmonary disorders, such as
infections, irradiation, CTD, hypersensitivity pneumonitis,
granulomatosis with polyangiitis, or chronic eosinophilic pneu-
monia (Table 72.3).























B
FIG 72.10 Radiographic Findings in Cryptogenic Organizing FIG 72.11 Histopathology of Cryptogenic Organizing Pneu-
Pneumonia. (A) Chest radiograph in a patient with cryptogenic monia. A photomicrograph of cryptogenic organizing pneumonia
organizing pneumonia shows bilateral patchy alveolar opacities shows intraalveolar fibroblast proliferation (arrows) and early
with a peripheral distribution in the setting of normal lung volumes. collagen production. In addition, thickening of the alveolar septa
(B) Chest computed tomography shows a dense right lower with a lymphoplasmacytic infiltrate consistent with cellular
lung consolidation with the presence of air bronchograms. nonspecific interstitial pneumonitis is present.

976 Part Seven Organ-Specific Inflammatory Disease



TABLE 72.3 Disorders associated With a TABLE 72.4 Pleuropulmonary
Bronchiolitis Obliterans Organizing Manifestations of Connective tissue
Pneumonia (BOOP) Pattern Diseases

Idiopathic BOOP (cryptogenic organizing pneumonia) SLe ra SSc
Connective tissue diseases
• Systemic lupus erythematosus Pulmonary hypertension + + +++
• Rheumatoid arthritis Vasculitis + ± ±
• Polymyositis/dermatomyositis Pleural disease +++ +++ +
• Sjögren syndrome Bronchiolitis obliterans ± ++ +
Hypersensitivity pneumonitis Aspiration pneumonia − − ++
Chronic eosinophilic pneumonia Diaphragmatic dysfunction ++ − −
Drug-induced Lung nodules − ++ −
• Gold Diffuse alveolar damage + ± ±
• Penicillamine BOOP ± + ±
• Amiodarone UIP + ++ +
• Bleomycin Capillaritis ++ + ±
• Sulfa drugs LIP + + +
Granulomatosis with polyangiitis (wegener granulomatosis) NSIP + ++ ++
Bone marrow transplantation BOOP, bronchiolitis obliterans organizing pneumonia; LIP, lymphocytic interstitial
Lung transplantation/rejection pneumonia; NSIP, nonspecific interstitial pneumonia; RA, rheumatoid arthritis; SLE,
Inhalational injury systemic lupus erythematosus; SSc, systemic sclerosis; UIP, usual interstitial
neoplasms pneumonitis.
Lung irradiation
virus-associated
• Human immunodeficiency virus (HIV)
• Influenza virus mainly affects young women (female-to-male ratio >8 : 1) and
• Adenovirus may involve virtually every organ system. Pleuropulmonary
involvement occurs at some point in the disease course in 38–89%
34
of cases. Thus the respiratory system is affected more commonly
in SLE than in any other CTD. However, infectious pneumonia
remains the commonest cause of pulmonary disease and death
Treatment and Outcome in these patients. Thus in patients with SLE presenting with a
Treatment with glucocorticoids usually offers dramatic clinical febrile illness and pulmonary infiltrates, a community-acquired
33
and radiographic improvement within days to weeks. Complete or opportunistic infection must be promptly excluded.
clinical, physiological, and radiographic recovery occurs in two-
thirds of cases. In the remainder, persistent disease progresses Acute Lupus Pneumonitis
to fibrosis. It is common for relapses to occur with glucocorticoid Acute lupus pneumonitis is an uncommon pulmonary manifesta-
34
tapering, followed by improvement with reintroduction of tion of SLE, occurring in fewer than 5% of cases. The clinical
treatment; consequently at least 6 months of therapy is recom- presentation mimics that of an infectious pneumonia with the
mended. The 5-year survival rate in COP is 73%, compared with abrupt onset of fever, cough, and dyspnea. Serum complement
5-year survival rates of 44% in patients with BOOP resulting levels are often low, and chest radiography typically shows diffuse
from other causes (e.g., CTD) or 30% for IPF. alveolar opacities. Acute lupus pneumonitis can be accompanied
by pericarditis and often pleuritis and pleural effusion.
LUNG INVOLVEMENT IN CONNECTIVE It can be difficult to distinguish acute lupus pneumonitis
TISSUE DISEASES from an infectious pneumonia. BAL followed by thoracoscopic
lung biopsy is recommended before instituting corticosteroid
CTDs are a heterogeneous group of systemic autoimmune diseases therapy. The histopathology varies and includes diffuse alveolar
that frequently involve the lungs. The pleuropulmonary mani- damage, BOOP, NSIP, or a combination of these.
festations of these diseases are diverse, affecting all parts of the There are no controlled trials of therapy for acute lupus
respiratory tract (i.e., airways, alveoli, blood vessels, and pleura) pneumonitis. Treatment includes high-dose glucocorticoids
(Table 72.4). Although pulmonary complications generally occur (1–2 mg/kg/day) with or without accompanying cytotoxic drugs,
in patients with well-established disease, occasionally the lung such as cyclophosphamide. Mortality rates as high as 50% have
involvement is the first manifestation of the autoimmune disorder. been reported. In those patients who fail to respond to treatment,
This section discusses the pleuropulmonary manifestations of respiratory failure is the usual cause of death.
systemic lupus erythematosus (SLE), RA, and systemic sclerosis
(SSc) (for a discussion of other manifestations in these diseases, Diffuse Alveolar Hemorrhage
see Chapters 51, 52, and 55). DAH occurs in fewer than 5% of patients with SLE, and it
represents the initial manifestation of disease in 11–20% of those
Systemic Lupus Erythematosus cases. However, most cases develop in individuals with well-
34
SLE is a disease of unknown etiology characterized by the presence established diagnoses of SLE, usually with preexisting lupus
of autoantibodies directed against various nuclear antigens. These nephritis.
autoantibodies and the resultant immune complexes mediate The symptoms of DAH mimic those of infectious pneumonia
34
many of the manifestations of SLE (Chapter 51). This disease and acute lupus pneumonitis. Hemoptysis is present in 42–66%

CHaPter 72 Immunological Lung Diseases 977


of patients at presentation. Therefore the absence of hemoptysis is the most common presentation. Most of the patients with
does not exclude the diagnosis, particularly in the setting of a SLE who have pulmonary hypertension are female, with 3- and
falling hematocrit, diffuse pulmonary infiltrates, and blood-stained 5-year survival rates of 45% and 17%, respectively, representing a
BAL fluid. DAH in SLE most often results from pulmonary worse prognosis compared with that for patients with idiopathic
capillaritis, but it can also be caused by diffuse alveolar damage. pulmonary hypertension. The vascular changes of SLE-associated
Immunofluorescence studies show granular deposits of immu- pulmonary hypertension are similar to those seen in idiopathic
noglobulin G (IgG) and C3 along alveolar walls, interstitium, pulmonary hypertension with intimal hyperplasia, smooth
and capillary endothelial cells. muscle hypertrophy, and medial thickening. Several pathological
There are no controlled trials for the treatment of alveolar mechanisms have been proposed for the development of pul-
hemorrhage in SLE. Glucocorticoids, cytotoxic drugs, and monary hypertension, including vasoconstriction, in addition to
plasmapheresis have been used in various combinations. The vasculitis and thrombosis associated with antiphospholipid and
mortality rate associated with DAH is approximately 50%. Poor anticardiolipin antibodies. Serum endothelin levels are elevated
prognostic factors include the need for mechanical ventilation, in patients with SLE-associated pulmonary hypertension and
presence of infection, and prior treatment with cyclophosphamide. correlate with pulmonary arterial pressures.
As the pulmonary hypertension advances, the central pul-
Lupus Pleuritis monary arteries enlarge. Pulmonary function testing shows an
The pleura are the most common site of respiratory involvement isolated decrease in the diffusing capacity for carbon monoxide.
in SLE, with pleurisy and pleural effusions occurring in 50–80% Patients with SLE-associated pulmonary hypertension may
of patients. Lupus pleuritis can be the presenting manifestation respond to immunosuppressive therapy. In a small study, five
of disease, but more commonly, it develops in patients with of 12 patients with SLE responded to monthly intravenous
established SLE. It is often recurrent. The clinical manifestations bolus doses of cyclophosphamide in addition to systemic
include chest pain, fever, and dyspnea, and chest radiography glucocorticoids. A positive response was indicated by sustained
typically shows bilateral pleural effusions. The pleural fluid is hemodynamic improvement after at least 1 year of treatment
serous or serosanguineous and exudative in nature. Compared without the need for additional pulmonary hypertension–specific
with effusions in RA, the glucose is higher, and the lactate therapies. Patients who responded to immunosuppression could
dehydrogenase level is lower. The most helpful measurement is be maintained on azathioprine or mycophenolate mofetil to avoid
a pleural fluid ANA titer greater than 1 : 160. Examination of potential adverse effects of cyclophosphamide. Patients with SLE
the pleura reveals infiltration with plasma cells and lymphocytes, who were treated with bosentan did not have clinical worsen-
36
accompanied by pleural thickening and fibrosis. Treatment with ing and showed an improvement in 6-minute walk distance.
nonsteroidal antiinflammatory drugs (NSAIDs) and/or gluco- Overall, the long-term survival of patients with SLE-associated
37
corticoids is usually effective for relief of pleural discomfort. pulmonary hypertension is poor, and the optimal treatment
regimen for SLE-associated pulmonary hypertension remains
Interstitial Lung Disease unknown.
The presence of ILD in SLE is uncommon, especially compared
with SSc or RA. However, minor interstitial abnormalities can Respiratory Muscle Dysfunction
be found on HRCT in approximately one-third of patients with The shrinking lung syndrome is caused by diaphragmatic weakness
SLE who have normal results of chest radiography and physiologi- as well as weakness of other respiratory muscles. This entity
cal testing. The significance and natural history of these subclinical accounts for the findings of dyspnea without evidence of inter-
findings are uncertain. The presence of anti-SSA (Ro) has been stitial infiltrates or pulmonary vascular disease. It occurs in 25%
noted in approximately 80% of patients who have lupus with of patients with SLE. Chest radiography typically shows elevated
interstitial changes. In addition, the prevalence of ILD is increased diaphragms and basilar atelectasis. The pathogenesis of respiratory
in a subset of patients with SLE who have sclerodermatous skin muscle weakness is unknown, but it is not associated with general-
changes. ized muscle weakness. Glucocorticoids are frequently ineffective
The diagnosis of SLE is usually well established in patients in the treatment of this syndrome. Improvement has been noted
who develop the insidious form of ILD. The disease course is with inhaled β-agonist and theophylline therapy. Despite a variable
characterized by progressive dyspnea and cough; chest radiography response to therapy, it is unusual for this manifestation of SLE
shows reduced lung volumes and reticular interstitial infiltrates. to be progressive.
A restrictive lung function pattern with reduced diffusing capacity
and exercise-induced hypoxemia are typical. The histopathology Rheumatoid Arthritis
of chronic interstitial disease in SLE resembles NSIP, although RA is an autoimmune disease associated with autoantibodies
cases of BOOP, LIP, and UIP have been described. Response to directed against citrullinated antigens and characterized by the
therapy depends on the underlying histopathology, with the presence of a symmetrical, inflammatory polyarthritis (Chapter
UIP-like form being least responsive. 52). It occurs more frequently in women, with a female-to-male
ratio of 2 : 1. Disease onset is most commonly in the fourth to
Pulmonary Vascular Disease fifth decades of life. The pleuropulmonary complications of RA
Although previously thought to be unusual, the development of occur more commonly in individuals with subcutaneous nodules,
pulmonary hypertension has been increasingly noted in SLE, with high titers of rheumatoid factor, and more severe chronic articular
an incidence ranging from 0.5–14%. Pulmonary hypertension in involvement. Although RA itself is more common in women,
SLE has been associated with the presence of Raynaud syndrome, the pleuropulmonary manifestations have a higher incidence in
35
serositis, digital vasculitis, and antiphospholipid antibodies. men. The pleuropulmonary complications of RA are numerous,
Dyspnea and fatigue, despite normal results on chest radiography, but the treatment-related lung toxicity and pulmonary infections

978 Part Seven Organ-Specific Inflammatory Disease


are difficult to differentiate from the primary pleuropulmonary occupational dust exposures have also been associated with this
manifestations of the disease. syndrome.
Pleuritis and Pleural Effusions Airway Disease
As in SLE, pleural abnormalities are one of the most common Airflow limitation is a common finding in patients with RA, being
pulmonary complications of RA. Pleural effusion is clinically present in approximately one-third of patients. The mechanism(s)
evident in approximately 5% of patients, and this can occur responsible for airway disease is poorly understood. The interplay
before the development of arthritis. Pleural disease is often of cigarette smoking and RA may play a role.
discovered as an incidental finding on routine chest radiography, A life-threatening complication of RA is upper airway
but nonspecific chest pain, dyspnea, and fever are not unusual. obstruction, resulting from synovitis of the cricoarytenoid joint.
The effusion can be unilateral or bilateral and can coexist with Common presenting complaints include a sore throat, hoarseness,
ILD. and fullness in the throat. It can progress to inspiratory stridor
Typically, the effusion is an exudate, with a glucose level less and upper airway obstruction. This complication occurs more
than 30 mg/mL in 70–80% of cases. The mechanism underlying commonly in women, particularly in those with advanced RA.
the low pleural fluid glucose is impaired membrane transport Seventy-five percent of patients were found to have cricoarytenoid
of glucose. A low pleural fluid pH is thought to occur secondary abnormalities when screening with direct or indirect laryngoscopy
to impaired carbon dioxide exit from the pleural space. If the and computed tomography (CT) was utilized. The treatment of
effusion is chronic, the cholesterol concentration can be increased, cricoarytenoid arthritis includes antiinflammatory medications.
and the pleural fluid can have a milky appearance (pseudochy- Bronchiolitis obliterans is a progressive form of obstructive
lothorax). Cytological examination reveals multinucleated giant lung disease that is being increasingly recognized as a complication
38
cells, spindle-shaped macrophages, and necrotic debris. of RA. This entity was thought to develop secondary to the
Most rheumatoid effusions are small and asymptomatic, thus use of penicillamine in the treatment of RA, but most cases
requiring no treatment. They resolve over several months without occur in the absence of this therapy. The histopathological lesion
complications. The use of glucocorticoids for active articular of bronchiolitis obliterans is constrictive bronchiolitis, which is
disease hastens the resolution of the pleural process. characterized by concentric submucosal and peribronchiolar
fibrosis resulting in extrinsic compression and obliteration of
the bronchiolar lumen. The typical clinical presentation is insidi-
CLInICaL PearLS ous onset of cough and dyspnea, with a normal or hyperinflated
Lung Involvement in Rheumatoid Arthritis (RA) chest on radiography. This complication occurs more commonly
in women than in men. Pulmonary function studies show airflow
• RA is more common in women, but pleuropulmonary complications limitation with hyperinflation and a reduced diffusing capacity.
occur more frequently in men. Expiratory HRCT shows multiple areas of air trapping (mosaic
• Factors associated with pleuropulmonary complications of RA include pattern). Some individuals respond to high-dose glucocorticoids
more severe articular involvement, subcutaneous nodules, and high
levels of rheumatoid factor. and cytotoxic drugs, but in most patients, bronchiolitis obliterans
• Pleural effusions are the most common complication, characterized progresses to respiratory failure.
by an exudate and a low glucose and low pH. Bronchiectasis occurs at an increased frequency in RA, usually
• The differentiation of rheumatoid nodules from malignant lesions can in individuals with long-standing articular disease. Productive
be difficult. cough and dyspnea are the most common respiratory symptoms.
• The rapid growth of a nodule should prompt aggressive investigation In most patients, bronchiectasis is not clinically significant.
for a malignant cause.
Recurrent pneumonia and respiratory failure are potentially fatal
complications of this problem.

Rheumatoid Nodules Interstitial Lung Disease
Rheumatoid or necrobiotic nodules are the only pleuropulmonary Although ILD is a common complication of RA, the incidence is
manifestation specific for RA. These nodules are most commonly difficult to determine, since different methods of detection have
seen in men with active articular disease, high rheumatoid factor been employed and dissimilar populations of patients have been
titers, and subcutaneous nodules. Most individuals are asymp- studied. However, clinically significant ILD occurs in approxi-
39
tomatic and are diagnosed on routine chest radiography. mately 14% of patients. The development of ILD in relation
Radiographically, these nodules can be singular or multiple with to the onset of arthritis is variable. Most often, the ILD develops
an upper to midlung zone predominance. Cavitation occurs in subsequent to arthritis, but in approximately 20% of patients,
approximately 50% of cases. HRCT indicates a higher frequency the lung disease precedes the onset of arthritis and is associated
of nodules than previously thought. Rarely, subpleural necrobiotic with cigarette smoking, presence of the shared HLA-DR4 epitope,
nodules can erode into the pleural space, resulting in a pneu- and RA-specific anticitrullinated protein antibodies.
mothorax with a complicating bronchopleural fistula. It can be The most common histopathologies identified in this patient
difficult to differentiate these nodules from malignant lesions, population are UIP, LIP, NSIP and BOOP. The clinical manifesta-
and open-lung biopsy is frequently necessary. Evidence of rapid tions of ILD in RA resemble those seen in idiopathic disease
growth on chest radiography should prompt an aggressive and include a dry, nonproductive cough and dyspnea on exertion.
diagnostic evaluation. Chest radiography and HRCT show increased reticular markings
Caplan syndrome refers to the rapid development of pulmonary with a predilection for the peripheral lower lung zones. Often,
nodules predominantly in the upper lung zone. This syndrome pleural abnormalities accompany the interstitial changes. With
was originally described in Welsh coalminers with RA. Histologi- advanced disease, progression to honeycomb lung occurs. LIP
cally, these nodules are identical to necrobiotic nodules. Other usually occurs in cases of RA complicated by Sjögren syndrome;

CHaPter 72 Immunological Lung Diseases 979


the presence of keratoconjunctivitis sicca and xerostomia in a Although the 5-year survival for patients with SSc and ILD is
patient with RA and ILD should suggest this histological type. 38–45%, it is better than that of patients with IPF.
In general, ILD in RA appears more indolent than in the IIPs.
Thus because of uncertain treatment benefits and possible adverse Pulmonary Vascular Disease
effects, the decision to institute therapy should be based on Pulmonary hypertension is a frequent complication of SSc,
clinical, radiographic, and physiological deterioration. occurring in approximately 30% of patients with diffuse sclero-
derma and in 10–50% of those with limited scleroderma (Chapter
Drug-Induced Lung Disease 55). It is a major cause of morbidity and mortality in systemic
Methotrexate and gold are the two main anti-RA drugs capable sclerosis and has also become part of the diagnostic criteria for
40
of causing lung injury. Methotrexate administered weekly the disease. Pulmonary hypertension can either be associated
(10–20 mg/week) is associated with the development of interstitial with interstitial fibrosis or result from involvement of small
changes in 1–5% of patients with RA. No correlation with age, and medium-sized arteries and arterioles with smooth-muscle
sex, disease duration, or cumulative dose has been identified. hyperplasia, medial hypertrophy, and intimal proliferation
The clinical presentation is subacute, with fever, cough, and (plexogenic). Direct involvement of the pulmonary circulation
dyspnea occurring 1–5 months after initiation of the drug. Chest is more common with limited scleroderma, whereas pulmonary
radiography shows mixed interstitial–alveolar infiltrates. Non- hypertension in patients with diffuse scleroderma is more likely
specific laboratory abnormalities include leukocytosis, sometimes associated with ILD.
with mild eosinophilia, and an elevated erythrocyte sedimentation The clinical presentation is characterized by the insidious
rate (ESR). In most cases, BAL reveals a lymphocytosis. Histologi- onset of fatigue and dyspnea on exertion. Physical examination
cally, cellular NSIP is seen with areas of organizing pneumonia. and chest radiography show signs typical of pulmonary hyperten-
Noncaseating, granulomatous inflammation similar to that seen sion, whereas a decreased diffusing capacity is seen on pulmonary
in hypersensitivity pneumonitis may also be present. The primary function testing. Risk factors for developing SSc-associated
treatment of methotrexate-induced pneumonitis is withdrawal pulmonary hypertension include limited skin involvement,
of methotrexate, as well as appropriate supportive care. duration of disease greater than 10 years, onset of SSc at older
Gold-induced pneumonitis occurs in fewer than 1% of patients age, and severity and duration of RP.
with RA who are treated with gold. Dyspnea and cough usually The pathogenesis of SSc-associated pulmonary hypertension
begin after 4–6 weeks of therapy; eosinophilia occurs in a minority is poorly understood. Vascular changes occur at an early stage
of patients. Chest radiography typically reveals mixed alveolar– in SSc and include apoptosis, endothelial cell activation with
interstitial opacities with a predilection for the upper lung zone. increased expression of cell adhesion molecules, inflammatory
The histology is similar to that seen in patients with RA-associated cell recruitment, intimal proliferation, and adventitial fibrosis
ILD. Thus the differentiation of gold-induced pneumonitis from leading to vessel obliteration. Endothelial injury is reflected by
RA-associated ILD can only be established when discontinuation increased levels of soluble cell adhesion molecules, disturbances
of the medication results in remission. of angiogenesis with increased levels of circulating vascular
endothelial growth factor (VEGF), and the presence of angiostatic
Systemic Sclerosis (Scleroderma) factors. To what extent dysregulated angiogenesis in SSc-associated
SSc is characterized by excessive deposition of ECM in the skin pulmonary hypertension is driven by an inflammatory process
and internal organs, and vascular involvement (Chapter 55). or other as yet unidentified mechanisms remains unclear.
The degree of visceral organ involvement determines morbidity Treatment of SSc-associated pulmonary hypertension has been
and mortality. Pulmonary involvement occurs in 70–100% of disappointing, with no therapy showing a significant survival
patients with SSc. There is no correlation with the degree of benefit. Calcium channel blockers are not usually indicated for
extrapulmonary disease. ILD is the most common pulmonary patients with SSc-associated pulmonary hypertension, although
manifestation of SSc. Of note, with the improved mortality often used at lower doses for RP. Continuous intravenous
41
associated with renal involvement in SSc, lung disease has become epoprostenol improves exercise capacity and hemodynamics.
the most important cause of morbidity and mortality. Randomized clinical trials with phosphodiesterase inhibitors,
including sildenafil, showed a modest effect on exercise capacity,
Interstitial Lung Disease hemodynamic parameters, and functional class after 12 weeks
The incidence of ILD in SSc depends on the method of detection. of treatment. Carefully selected patients may be considered for
Autopsy studies have reported an ILD incidence of 60–100% of heart–lung transplantation but are often excluded because of
cases, whereas studies based on chest radiography have noted the risk of postoperative complications arising from SSc-related
interstitial changes in 14–66% of cases. Cough and dyspnea on gastroesophageal reflux disease (GERD) and renal dysfunction.
exertion are the most common symptoms. Physical examina-
tion reveals bibasilar rales. Radiographic findings include basal CONCLUSIONS
reticulonodular infiltrates, enlargement of pulmonary arteries,
and progressive volume loss. Pulmonary function testing reveals ILDs comprise a diverse group of disorders ranging from
restrictive lung disease, preservation of flow rates, and decreased idiopathic etiologies to those related to an underlying autoimmune
diffusing capacity. A disproportionate decrease in diffusing condition. There is likely a complex interplay between the innate
capacity compared with lung volume changes should suggest and adaptive arms of the immune system and the profibrotic
pulmonary hypertension, especially in individuals with limited pathways that lead to the development of these various disease
scleroderma (calcinosis, Raynaud phenomenon [RP], esophageal states. Future work should focus on better understanding this
dysmotility, sclerodactyly, telangiectasia [CREST] syndrome). The relationship and, more importantly, translating these findings
predominant histopathologic abnormality is NSIP. Rarely, LIP to the clinical setting. The role of standard immunosuppressive
may complicate cases of SSc associated with Sjögren syndrome. approaches with the ongoing discovery of novel approaches to

980 Part Seven Organ-Specific Inflammatory Disease



On tHe HOrIZOn 16. Ahluwalia N, Shea BS, Tager AM. New therapeutic targets in idiopathic
pulmonary fibrosis. Aiming to rein in runaway wound-healing responses.
• Our understanding of the idiopathic interstitial pneumonias (IIPs) and Am J Respir Crit Care Med 2014;190:867–78.
autoimmune-related interstitial lung diseases (ILDs) has evolved over 17. Coultas DB, Zumwalt RE, Black WC, et al. The epidemiology of
time. With increased emphasis being placed on diagnosis, because of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967–72.
the implications for treatment and prognosis, we are more accurately 18. American Thoracic S, European Respiratory S. American Thoracic
phenotyping the diseases. This has led to a better understanding of Society/European Respiratory Society International Multidisciplinary
genetic associations, biological pathways, as well as more accurate Consensus Classification of the Idiopathic Interstitial Pneumonias. This
identification of risk factors for disease development and progression. joint statement of the American Thoracic Society (ATS), and the
• However, there are still many areas in need of further understanding European Respiratory Society (ERS) was adopted by the ATS board of
and research. In the future, determining whether risk factor identification directors, June 2001 and by the ERS Executive Committee, June 2001. Am
and modification can lead to primary and/or secondary prevention J Respir Crit Care Med 2002;165:277–304.
strategies in the treatment of immunological lung diseases will be 19. Seibold MA, et al. A common MUC5B promoter polymorphism and
essential.
• Testing if the novel antifibrotic therapies approved for idiopathic pulmonary fibrosis. N Engl J Med 2011;364:1503–12.
pulmonary fibrosis (IPF) are more broadly applicable to other forms 20. Feghali-Bostwick CA, et al. Cellular and humoral autoreactivity in
of ILDs, including autoimmune-related ILD, will be important. idiopathic pulmonary fibrosis. J Immunol 2007;179:2592–9.
• Other therapies that target the immune system also need to be more 21. Dreisin RB, Schwarz MI, Theofilopoulos AN, et al. Circulating immune
carefully studied in diseases outside of IPF. complexes in the idiopathic interstitial pneumonias. N Engl J Med
1978;298:353–7.
22. Lee CG, et al. Interleukin-13 induces tissue fibrosis by selectively
stimulating and activating transforming growth factor beta(1). J Exp Med
targeting the immune system as well as novel antifibrotic therapies 2001;194:809–21.
will need to be determined. 23. Lynch DA, et al. High-resolution computed tomography in idiopathic
pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med
Please check your eBook at https://expertconsult.inkling.com/ 2005;172:488–93.
for self-assessment questions. See inside cover for registration 24. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in
details. idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431–40.
25. King TE Jr, et al. A phase 3 trial of pirfenidone in patients with idiopathic
pulmonary fibrosis. N Engl J Med 2014;370:2083–92.
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1. Luzina IG, Todd NW, Iacono AT, et al. Roles of T lymphocytes in 27. Hyzy R, Huang S, Myers J, et al. Acute exacerbation of idiopathic
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2. Ginhoux F, et al. Fate mapping analysis reveals that adult microglia derive 28. Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A
from primitive macrophages. Science 2010;330:841–5. clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol
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throughout adult life with minimal contribution from circulating 30. Portnoy J, et al. Respiratory bronchiolitis-interstitial lung disease:
monocytes. Immunity 2013;38:792–804. long-term outcome. Chest 2007;131:664–71.
5. Yona S, et al. Fate mapping reveals origins and dynamics of monocytes 31. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis.
and tissue macrophages under homeostasis. Immunity 2013;38:79–91. Histologic features and clinical significance. Am J Surg Pathol
6. Schulz C, et al. A lineage of myeloid cells independent of Myb and 1994;18:136–47.
hematopoietic stem cells. Science 2012;336:86–90. 32. Travis WD, Matsui K, Moss J, et al. Idiopathic nonspecific interstitial
7. Parra ER, Kairalla RA, Ribeiro de Carvalho CR, et al. Inflammatory cell pneumonia: prognostic significance of cellular and fibrosing patterns:
phenotyping of the pulmonary interstitium in idiopathic interstitial survival comparison with usual interstitial pneumonia and desquamative
pneumonia. Respiration 2007;74:159–69. interstitial pneumonia. Am J Surg Pathol 2000;24:19–33.
8. Wells AU, et al. Fibrosing alveolitis in systemic sclerosis: increase in 33. Cordier JF. Cryptogenic organising pneumonia. Eur Respir J
memory T-cells in lung interstitium. Eur Respir J 1995;8:266–71. 2006;28:422–46.
9. Simonian PL, et al. Gammadelta T cells protect against lung fibrosis via 34. Kamen DL, Strange C. Pulmonary manifestations of systemic lupus
IL-22. J Exp Med 2010;207:2239–53. erythematosus. Clin Chest Med 2010;31:479–88.
10. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med 35. Hassoun PM. Pulmonary arterial hypertension complicating connective
2011;208:1339–50. tissue diseases. Semin Respir Crit Care Med 2009;30:429–39.
11. Sonnenberg GF, et al. Pathological versus protective functions of IL-22 in 36. Mok MY, et al. Bosentan use in systemic lupus erythematosus patients
airway inflammation are regulated by IL-17A. J Exp Med with pulmonary arterial hypertension. Lupus 2007;16:279–85.
2010;207:1293–305. 37. Qian J, et al. Survival and prognostic factors of systemic lupus
12. Wilson MS, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is erythematosus-associated pulmonary arterial hypertension: a
IL-17A dependent. J Exp Med 2010;207:535–52. PRISMA-compliant systematic review and meta-analysis. Autoimmun
13. Kotsianidis I, et al. Global impairment of CD4+CD25+FOXP3+ Rev 2016;15:250–7.
regulatory T cells in idiopathic pulmonary fibrosis. Am J Respir Crit Care 38. Schwarz MI, Lynch DA, Tuder R. Bronchiolitis obliterans: the lone
Med 2009;179:1121–30. manifestation of rheumatoid arthritis? Eur Respir J 1994;7:817–20.
14. Travis WD, et al. An official American Thoracic Society/European 39. Gabbay E, et al. Interstitial lung disease in recent onset rheumatoid
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multidisciplinary classification of the idiopathic interstitial pneumonias. 40. van den Hoogen F, et al. 2013 classification criteria for systemic sclerosis:
Am J Respir Crit Care Med 2013;188:733–48. an American college of rheumatology/European league against
15. Fischer A, et al. An official European Respiratory Society/American rheumatism collaborative initiative. Ann Rheum Dis 2013;72:1747–55.
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autoimmune features. Eur Respir J 2015;46:976–87. hypertension. Curr Opin Rheumatol 2014;26:637–45.

CHaPter 72 Immunological Lung Diseases 980.e1


MUL t IPL e -CHOIC e QU e S t IO n S

1. The most common pulmonary manifestations of systemic 3. Which of the following statement regarding systemic sclerosis
lupus erythematosus (SLE) is: (SSc) is correct?
A. Interstitial lung disease (ILD) A. Renal involvement and renal crisis remain the predominant
B. Diffuse alveolar hemorrhage (DAH) cause of mortality in SSc.
C. Pleural effusion B. Pulmonary hypertension is a newly added diagnostic criteria
D. Pulmonary hypertension for SSc.
C. The most common lung pathological lesion in SSc is
2. Idiopathic pulmonary fibrosis (IPF) is characterized by:
A. The pathological lesion of usual interstitial pneumonitis lymphocytic interstitial pneumonitis (LIP).
B. A relentless progression and a poor prognosis despite D. Calcium channel blockers are indicated for patients with
therapeutic intervention SSc-associated pulmonary hypertension.
C. The presence of interstitial opacities in a basilar and
peripheral distribution
D. All of the above

73









Sarcoidosis



Edward S. Chen, David R. Moller








Sarcoidosis is a systemic inflammatory disorder characterized of Japanese patients with sarcoidosis, but in only 10–25% of
by the presence of noncaseating granulomas and lymphocyte European and North American patients. Retrospective studies
1,2
inflammation. The disease most frequently involves lungs suggest that sarcoidosis is the direct cause of death in 1–6%
and thoracic lymph nodes, although any organ system can be of cases, usually from pulmonary, cardiac, or neurological
involved (Table 73.1). The manifestations and clinical course involvement. 10
3
of sarcoidosis vary greatly. An estimated 30–60% of patients
with sarcoidosis are asymptomatic, usually with isolated bilateral GENETICS
hilar adenopathy, and clearly some of these patients remain
unidentified. Symptomatic manifestations most frequently involve There is substantial evidence for a genetic predisposition to
the respiratory system, with symptoms of cough, dyspnea, and sarcoidosis, including higher concordance among monozygotic
chest discomfort. Löfgren syndrome is a distinct presentation of twins than among dizygotic twins and familial clustering in
acute sarcoidosis, with polyarthritis, bilateral hilar adenopathy, 5–16% of patients. A US-based multicenter study compared 706
erythema nodosum, and often uveitis. This form of sarcoid- newly diagnosed cases of biopsy-proven sarcoidosis to age-, sex-,
osis usually resolves completely. Other clinical manifestations and race-matched relatives and found an approximate fivefold
depend on the range and extent of extrapulmonary involvement. increased relative risk in siblings and parents of individuals with
More than one-third of patients will experience chronic active sarcoidosis. 11
disease, which is associated with considerable risk of long-term Major histocompatibility complex (MHC) class II alleles are
morbidity resulting from progressive organ dysfunction and major contributors to disease susceptibility across different ethnic
12
complications of immunosuppressive treatment. Given the populations. Human leukocyte antigen–D related 3 (HLA-DR3)
lack of validated biomarkers of disease activity, the manage- is associated with increased sarcoidosis risk in Scandinavian and
ment of sarcoidosis involves serial assessment of symptoms, European populations, whereas HLA-DR1 and HLA-DR4 alleles
radiographic imaging, and objective measurement of organ are associated with disease protection. A significant association
function. was found with HLA-DRB1*11:01 in African Americans and
Caucasians, whereas HLA-DRB1*15:01 was a risk factor only in
EPIDEMIOLOGY Caucasians. Residues forming pocket 4 of HLA-DR and pocket
9 of HLA-DQ seem to influence sarcoidosis risk, which suggests
Sarcoidosis is found worldwide, although there are striking specific antigenic peptides are involved in causing sarcoidosis.
differences in the prevalence of the disease in different geographi- HLA class I alleles (B*07, A*03) also confer risk for sarcoidosis,
4
cal areas and racial groups. In Europe and North America, the independently from HLA class II alleles. Together, these HLA
estimated prevalence ranges from 10 to 64 cases per 100 000, associations with sarcoidosis may reflect the effects of an 8.1
with higher rates in African-American populations. Although it ancestral haplotype (A1, B8, DR3, DQ2) that is linked to several
can occur at any age, over 80% of cases are diagnosed between other immune-related diseases; larger studies will be neces-
4,5
20 and 50 years of age, with a further peak after age 50 years. sary to determine the independent risks associated with each
Globally, there is a slight female preponderance. Sarcoidosis may allele.
6
present differently in men and women, and it presents differently HLA class I and II alleles are associated with clinical
7
in older people, complicating case identification. Recent studies course. HLA DRB1*03:01 and DQB1*02:01 are associated
have supported prior observations of worse outcomes in African with favorable outcomes, whereas DR14 and DR15 are associ-
American women compared with other demographic groups in ated with severe, chronic disease in European and Japanese
the United States. 8,9 populations, as are the closely linked alleles DRB1*1501:01 and
The frequency of clinical manifestations and disease severity DQB1*06:02.
varies among different groups. Löfgren syndrome has a par- Studies of non-HLA polymorphisms have yielded few clues
ticularly high frequency in the Scandinavian countries and in to the genetic basis of sarcoidosis. A meta-analysis found poly-
Ireland but occurs in <5% of African American patients with morphism of the gene for tumor necrosis factor-α (TNF-α)
sarcoidosis. Lupus pernio, a disfiguring nodular facial condi- associated with a 1.5-fold increased risk of developing sarcoid-
13
tion associated with chronic sarcoidosis, is more frequent in osis. Associations were reported between sarcoidosis and the
patients of African descent. Cardiac involvement occurs in >50% CC chemokine receptors CCR2 and CCR5 and the receptor for
981

982 Part seven Organ-Specific Inflammatory Disease



TABLE 73.1 Major Clinical Features of analysis suggested that T-helper 1 (Th1) and Th17 signaling
19
systemic sarcoidosis pathways are involved in sarcoid immunopathogenesis.
Organ system ENVIRONMENTAL FACTORS
(approx. %
Involvement) Major Clinical Features Environmental factors have been implicated in the etiology of
Pulmonary (90) Bilateral hilar adenopathy, restrictive and sarcoidosis with reports of time–space clustering and a higher
obstructive disease, fibrocystic disease, incidence of disease in the springtime months. Health care
bronchiectasis, mycetomas workers, military personnel, and firefighters may also have a
Upper airway (5–10) Hoarseness, laryngeal or tracheal obstruction, higher incidence of sarcoidosis.
nasal congestion, sinusitis, saddle nose The largest study of sarcoidosis etiology found weak positive
deformity
Ocular (25) Anterior and posterior uveitis, chorioretinitis, associations (odds ratio [OR] ≈1.5) with workplace exposure to
3
conjunctivitis, optic neuritis, glaucoma, insecticides, mold, mildew, and musty odors. Sarcoidosis was
lacrimal gland enlargement not associated with exposure to heavy metals, wood dusts, or
Skin (20–30) Cutaneous and subcutaneous nodules and rural residence, but smoking appeared to be protective. Studies
plaques, erythema nodosum, lupus pernio, of rescue workers and others exposed to the heavy dust burden
hypopigmented macules from the World Trade Center terror attack found an increased
Hepatic (10) Hepatomegaly, pruritus, jaundice, cirrhosis incidence of a sarcoidosis-like granulomatous pulmonary disease.
20
Cardiac (10–15) Arrhythmias, heart block, cardiomyopathy,
sudden death A significant proportion of these patients had extrapulmonary
Central nervous Cranial neuropathies (e.g., Bell palsy), aseptic manifestations, including chronic nonerosive polyarthritis,
system (5–10) meningitis, brain mass, seizures, suggesting that they fall within the spectrum of systemic
obstructing hydrocephalus, myelopathy, sarcoidosis. 21
polyneuropathy, mononeuritis multiplex,
small-fiber neuropathy Role of Infectious Agents
Salivary and parotid Salivary and parotid gland enlargement, sicca
gland (<10) syndrome Since the initial descriptions of sarcoidosis, investigators have
Hematologic (30–50) Lymphadenopathy, splenomegaly, looked for evidence of microbial infections in sarcoidosis because
hypersplenism, anemia, lymphopenia, of its clinical similarities to other infectious diseases, most
thrombocytopenia notably tuberculosis. Polymerase chain reaction (PCR) studies
Joints/ Polyarthritis, bone cysts, Achilles tendonitis, have shown microbial DNA in sarcoidosis tissues consistent
musculoskeletal dactylitis, heel pain, myopathy with prior exposure to mycobacteria. Overall mycobacterial
(10–20)
Endocrine (<10) Hypercalciuria (more common), DNA was detected 10–20-fold more often in sarcoidosis versus
22
hypercalcemia, hypopituitarism, diabetes control tissue. The Kveim reaction also suggests a transmissible
insipidus agent—intradermal inoculation with an extract from sarcoid-
Renal (<5) Renal calculi, nephrocalcinosis, renal failure, osis tissue induces epithelioid granulomas indistinguishable
23
epididymitis, testicular mass from those in sarcoidosis biopsies. Several groups have now
demonstrated lung and blood CD4+ and CD8+ T-cell responses
to multiple mycobacterial antigens in sarcoidosis, including
mKatG, Mycobacterium tuberculosis ESAT-6, Ag85, superoxide
dismutase, and heat shock proteins. 24,25 These studies suggest
that mycobacterial organisms trigger sarcoidosis in a subgroup
of patients.
advanced glycation end products (RAGE), but wider confirmation Studies from Japan report the presence of Propionibacterium
is lacking. Although strongly associated with early-onset sar- acnes or P. granulosum genomes in 80–98% of sarcoidosis tissues
26
coidosis in children, NOD2/CARD15/IBD1 has not been linked from Japan and Europe but also in up to 60% of control tissues.
14
with sarcoidosis in adults. No association has been found In animal models, P. acnes proteins have been shown to induce
between sarcoidosis and serum angiotensin-converting enzyme Th1-driven granulomatous inflammation, partly via Toll-like
(ACE), vitamin D–converting enzyme, or the NRAMP1 gene receptor 9 (TLR9) stimulation. Given that these are commensal
(linked to tuberculosis). organisms on normal skin and upper airways, their pathogenic
Genome-wide association studies (GWAS) in both familial role remains undefined.
and sporadic cases of sarcoidosis have identified chromosomal Although direct demonstration of an infectious etiology
regions both inside and outside the MHC region, which contribute remains unproven, most investigators favor the hypothesis that
to sarcoidosis susceptibility. The butyrophilin-like 2 (BTNL2) certain classes of microbial organisms trigger sarcoidosis in those
gene within the MHC locus is associated with sarcoidosis risk in with genetic susceptibility.
15
Caucasians and, to a lesser extent, African Americans. Despite its
proximity to the MHC locus, the BTNL2 rs206530 allele can confer AUTOIMMUNITY
increased risk for chronic active sarcoidosis in patients without
Löfgren syndrome. 16,17 BTNL2 belongs to the immunoglobulin Patients with sarcoidosis often have low-titer autoantibodies
(Ig) gene superfamily and is costimulatory for T-cell activation, that may be part of the generalized hypergammaglobulinemia
27
providing a hypothetical link with sarcoidosis. The gene encoding observed in many patients as a result of T-cell activation.
annexin A11 has also been associated with sarcoidosis, potentially No disease-specific autoantibodies have yet been identified,
affecting granuloma formation through its involvement in so it remains unknown whether autoimmunity plays a role in
18
apoptosis and cellular proliferation. A gene interaction network sarcoidosis.

CHaPter 73 Sarcoidosis 983


IMMUNOLOGY/PATHOGENESIS anergy. Subsequently, bronchoalveolar lavage (BAL) studies in
pulmonary sarcoidosis showed that there were, in fact, enhanced
KeY COnCePts cell-mediated immune processes at sites of granulomatous
inflammation with activated CD4 BAL lymphocytes. These BAL
Immunopathogenesis of Sarcoidosis T cells are CD4 with a CD45RO “memory” phenotype expressing
+
+
high levels of activation molecules DR and VLA-1 (very late
• Noncaseating epithelioid granulomas
• Genetic susceptibility primarily involving major histocompatibility antigen-1, CD49a). Direct evidence that sarcoidosis is an antigen-
complex (MHC) genes driven disorder comes from studies of T-cell receptor (TCR)
• Oligoclonal expansion of T-cell receptor specific T cells consistent gene expression. These studies document the expansion of
with antigen-driven inflammation oligoclonal populations of T cells expressing specific α/β or γ/δ
• T-helper 1 (Th1) polarization at sites of disease TCR in BAL, blood, or skin (Kveim biopsy). The most compelling
• Decrease in regulatory T-cell (Treg) function contributes to Th1- data were derived from HLA-DRB1*03:01-positive Swedish
mediated inflammation +
• Potential role of interferon (IFN)-γ–expressing Th17.1 cells patients who have greatly increased numbers of AV2S3 Th1
+
• Potential role of classical Th17 effector cells cells in the lung. The expanded oligoclonal αβ T-cell subsets
• Etiology involves microbial triggers in sarcoidosis often contain shared amino acid motifs in the
• Mycobacterial or propionibacterial organisms most commonly CDR3 region of their Vβ or Vα/Jα genes, consistent with an
implicated antigen-driven T-cell response. The antigenic specificities of these
• Role of innate immunity in macrophage activation and granuloma expanded T-cell clones remain to be identified.
formation
• Progressive accumulation of serum amyloid A (SAA) within granulomas Th1 Polarization in Sarcoidosis
may drive chronic disease
• Nidus for granuloma formation T cells at sites of disease show a highly polarized Th1 cytokine
29
• Feed-forward amplification of local Th1 responses in part through profile at the time of diagnosis (Fig. 73.2). BAL studies have
Toll-like receptor 2 (TLR2) demonstrated expression of interferon-γ (IFN-γ) and tumor
necrosis factor (TNF) in pulmonary sarcoidosis. Consistent with
a polarized type 1 process, Th1-promoting cytokines interleukin-12
The histological hallmark of sarcoidosis is the presence of (IL-12), -18, -2, -15, and -27 are upregulated in sarcoidosis-affected
discrete, compact noncaseating granulomas (Fig. 73.1). The tissues. Chemokines and chemokine receptors that are typically
dominant cell in the central core is the epithelioid cell, thought associated with Th1 responses, such as CXCR3, CCR5, MCP-1,
to be a differentiated mononuclear phagocyte. CD4+ T cells and RANTES, MIP-1, MIG, and osteopontin (early T-lymphocyte
mature macrophages are interspersed throughout the epithelioid activation protein), are upregulated in sarcoidosis, as are the
core, whereas CD4+ and CD8+ T cells are seen around the Th1-differentiation transcription factor signal transducer and
periphery of the granuloma. Multinucleated giant cells are scat- activator of transcription 1 (STAT1) and its phosphorylated form.
tered throughout the inflammatory locus. In the lung, granulomas Th1-associated gene expression signatures in sarcoidosis tissues
tend to form along areas that are rich in lymphatic vessels, such have linked CXCL9 with chronic disease activity. 30
as the bronchovascular, bronchial submucosal, and interlobular Other evidence of the importance of polarized Th1 immunity
septal regions. 28 in sarcoidosis comes from clinical experience with biological
Prior to the 1980s, sarcoidosis was thought to be a disease of therapies with Th1-promoting effects, such as IFN-α, IFN-γ,
immune depression with blood lymphopenia and cutaneous and IL-2, which have been associated with new or recrudescent

























A B
FIG 73.1 (A) Open lung biopsy showing typical noncaseating epithelioid granuloma, giant cells,
and lymphocytic infiltrates in lung parenchyma in sarcoidosis. (B) Lymph node biopsy showing
extensive replacement with well-defined epithelioid granulomas in a patient with sarcoidosis.

984 Part seven Organ-Specific Inflammatory Disease


Genetic/epigenetic +
Genetic/epigenetic +
Mycobacterial infection
Mycobacterial infection environmental factors
environmental factors
+ +
1. Innate response 2. Induces hyperpolarized Th1
2. Induces hyperpolarized Th1
1. Innate response

response to pathogenic microbial Ags
induces systemic and response to pathogenic microbial Ags
induces systemic and
intracellular SAA and SAA misfolding/aggregation
intracellular SAA
and SAA misfolding/aggregation
SAA mKatG
SAA
mKatG
MHC TCR SAA receptor
MHC
TCR
SAA receptor
T T
APC
APC
IFNg
+ + TNFa IFNg ? ?
TNFa
+ +
Treg
IL10
IL10 Treg
3. Misfolded/aggregated SAA “seeds” 4. SAA induces feed-forward
3. Misfolded/aggregated SAA “seeds”
4. SAA induces feed-forward
further SAA accumulation and amplification of local Ag-specific
further SAA accumulation and
amplification of local Ag-specific
release of soluble SAA peptides Th1 responses to trapped Ags
release of soluble SAA peptides

Th1 responses to trapped Ags
Inability to clear
Inability to clear Clearance ofClearance of
SAA and Ags leads to chronic
SAA and Ags leads to chronic SAA and AgsSAA and Ags
inflammation and fibrosis allows remission
inflammation and fibrosis
allows remission
FIG 73.2 Conceptual Model of the Immunopathogenesis of Sarcoidosis. Granuloma formation
in sarcoidosis results from stimulation by poorly soluble antigens that evoke a hyperimmune
T-helper 1 (Th1) response with stimulation of interferon (IFN)-γ, along with tumor necrosis factor
(TNF), interleukin (IL)-12, IL-10, and other cytokines from mononuclear phagocytes and dendritic
cells. As a consequence of this response, misfolded serum amyloid A (SAA) aggregates in an
amyloid-like process to provide a persistent poorly soluble nidus and a template for further SAA
aggregation within sarcoidosis granulomas. SAA and SAA peptides released from the granulomas
stoke a feed-forward stimulation of macrophages and T cells that amplifies polarized Th1 responses
to local tissue antigens. This course continues to progress unless there is removal of stimulating
antigen(s) and clearance of SAA, allowing remission of Th1-driven granuloma formation. The
model depicts mycobacterial organisms as the etiological trigger, although other microbes or
environmental agents might trigger a similar pathogenic pathway.
−
+
sarcoidosis. Conversely, low or undetectable levels of IL-4, IL-5, CD4 CD25 T cells to Tregs, suggesting that inhaled VIP might
36
and Th2-associated chemokines and chemokine receptors are be a treatment for sarcoidosis. Longitudinal studies will be
31
found in the sarcoidosis lung. Sarcoidosis has also been described necessary to confirm the relationship between T-cell subsets and
in patients with 5q-myelodysplasia with deletion of Th2 genes. the clinical course of sarcoidosis. Other studies find a reduced
+
Th17 effector responses may drive the granulomatous response number of immunoregulatory CD1d-restricted Vα24 natural
in sarcoidosis, although they are a minority of CD4 effector T killer T (NKT) cells in the blood of patients with nonremitting
cells. Most IFN-γ–producing cells in BAL from patients with sarcoidosis, suggesting that lack of these cells may play a role in
sarcoidosis bear a Th17 phenotype termed Th17.1, although chronicity.
32
their transcriptional profile remains to be studied. BAL cells
from patients with Löfgren syndrome strongly express transcrip- Innate Immunity in Sarcoidosis
+
+
33
tional regulators of Th1 (T-bet ) and Th17 (RORγT ). Further Far fewer studies have looked at innate immune mechanisms,
work is needed to assess whether and how a Th1/Th17 permissive but evidence is mounting that TLRs and other innate immune
environment affects clinical outcomes in sarcoidosis. receptors may be involved in sarcoidosis. For example, enhanced
CD4+ regulatory T cells (Tregs) show reduced numbers and responses to TLR2 stimulation, including induction of TNF, have
function in sarcoidosis. 34,35 This suggests that Treg deficiency been observed in the lung and blood cells of patients with
37
contributes to the imbalanced Th1 (and Th17) responsiveness sarcoidosis. TLR2 interacts with innate ligands as a heterodimer
+
+
in these patients. CD4 CD25 bright FOXP3 T cells (natural Tregs) with other TLR subunits. Analysis of the TLR10–TLR1–TLR6
accumulate at the periphery of sarcoidosis granulomas, in BAL gene cluster on chromosome 4 has suggested that the absence
fluid, and in the peripheral blood of patients with active disease of the common haplotype is associated with increased risk for
but are functionally deficient, with reduced ability to inhibit developing chronic active sarcoidosis. 38
34
granuloma formation in vitro. Nebulized vasoactive intestinal Patients with sarcoidosis also show increased responsiveness
peptide (VIP) has been shown to significantly reduce TNF to ligands for the TLR-2/1 heterodimer and decreased responses
37
production by lung cells in sarcoidosis and increased the frequency TLR-2/6 ligands. Together, these findings support a potential
+
+
-
of lung CD4 CD127 CD25 Tregs, possibly by converting naïve role for aberrant TLR2 responsiveness in sarcoidosis.

CHaPter 73 Sarcoidosis 985


A major conceptual challenge in sarcoidosis is understanding
how pulmonary fibrosis occurs in an environment dominated
by IFN-γ, which is known to inhibit collagen synthesis. Alter-
natively activated macrophages (M2) have been histologically
associated with myofibrosis in biopsy specimens of muscular
39
sarcoidosis. Although an M2 macrophage phenotype is often
associated with a Th2 cytokine environment (which has never
been identified in sarcoidosis, even in late fibrotic disease), a
fibrosis-promoting M2c macrophage phenotype could be induced
by IL-10 or CCL18, which are present in sarcoidosis tissues. 40,41
M2 macrophages can promote fibrocyte recruitment through
the expression of transforming growth factor (TGF), CCL18,
and CXCL12; M2 macrophages are also capable of differentiation
to fibrocyte-like cells that express collagen. It remains unclear
whether M2-like macrophages result from mechanisms inherent
to sarcoidosis or from generalized wound-healing responses.
Serum Amyloid A Aggregation Hypothesis
Although sarcoidosis is associated with prior exposure to myco-
bacterial or other microbial organisms, there is no clinical or
pathological evidence of active infection or reactivation of latent
microbial infection in sarcoidosis. This holds true in patients after
years of corticosteroid, immunosuppressive, or anti-TNF therapy.
The physicochemical properties of the Kveim reagent closely
resemble those of amyloid or prion proteins. Serum amyloid A
(SAA) can be detected in epithelioid macrophages in sarcoidosis.
This appears to be disease specific and several orders of magnitude FIG. 73.3 Stage II chest radiograph with bilateral hilar adenopathy
greater than in other granulomatous disorders. 42,51 SAA stimulates and reticulonodular infiltrates.
expression of TNF, Th1-related cytokines, and IL-10 via TLR2
in the lung cells of patients with sarcoidosis. Sarcoidosis may
therefore involve the induction, misfolding, and aggregation of
SAA as a result of an aberrant hyperpolarized Th1 response to Stage I is initially seen in 40–50% of cases. Typically, the hilar
specific microbial triggers (see Fig. 73.2). Misfolded SAA may adenopathy is discrete, symmetrical, and often accompanied by
promote progressive self-aggregation in an amyloid-like process, right paratracheal adenopathy. Stage II CXR, often with mid- or
with SAA and its peptides amplifying Th1 responses to pathogenic upper-zone infiltrates, is seen in 20–30% of presenting cases
tissue antigens present within sarcoidosis granulomas. This (Fig. 73.3). Stage III is seen in 10–20% of cases at presentation.
mechanism could explain the cardinal clinical feature of chronic Those with fibrotic changes are frequently placed in a separate
monophasic progressive inflammation in untreated sarcoidosis, subgroup, stage IV, in recognition of the poor outcome of this
in the absence of any tissue infection. 1 group of patients (Fig. 73.4). More unusual patterns of pulmonary
sarcoidosis include large, well-defined, nodular infiltrates; miliary
disease; or a pattern of patchy air-space consolidation with air
PATIENT EVALUATION AND bronchograms, termed “alveolar sarcoidosis.” Pleural effusions
DIFFERENTIAL DIAGNOSIS and pneumothorax are rare.
Computed tomography (CT) of the chest is more sensitive
Pulmonary Sarcoidosis than plain radiography in demonstrating enlarged lymph nodes
The most common symptoms of pulmonary sarcoidosis are and pulmonary infiltrates. Chest CT typically demonstrates
cough, progressive shortness of breath, and ill-defined chest nodular infiltrates that follow central bronchovascular structures
discomfort of variable severity (see Table 73.1). Chronic sputum (Fig. 73.5). Studies correlating the value of the CXR stage against
production and hemoptysis are more frequent in advanced objective assessments of chest CT are lacking. However, in child-
fibrocystic disease. Typically, there are few physical findings. Lung hood sarcoidosis, longitudinal scoring of the findings on high-
crackles are heard in <20% of patients, and clubbing is rare. resolution CT (HRCT) of the chest correlates with changes in
Pulmonary hypertension and cor pulmonale are important but pulmonary function. 43
underrecognized complications, associated with higher mortality Pulmonary function tests do not correlate well with CXR
rates. stage. In patients with stage I CXR, pulmonary function tests
Chest radiography (CXR) results are abnormal in over 90% are normal in about 80% of cases or show just isolated reduction
of sarcoidosis patients. By convention, the chest radiograph is in carbon monoxide diffusing capacity (DL co ). When pulmonary
divided into the following stages: infiltrates are present on CXR, 40–70% of cases show restrictive
0: Normal CXR impairment with reduced forced vital capacity (FVC) and forced
I: Bilateral hilar adenopathy expiratory volume per second (FEV 1 ), and/or reduced DL co .
II: Bilateral hilar adenopathy + interstitial infiltrates Obstructive impairment is found in 30–50% of patients with
III: Interstitial infiltrates only (nonfibrotic) abnormal CXR results, mainly in advanced fibrocystic sarcoidosis.
IV: Fibrotic interstitial lung disease Bronchial hyperreactivity is present in 10–30% of patients.

986 Part seven Organ-Specific Inflammatory Disease



Extrapulmonary Sarcoidosis
Most patients have clinically important involvement of more
than one organ, either with or without pulmonary sarcoidosis
(see Table 73.1).
Sarcoidosis of the Upper Respiratory Tract
Sarcoidosis can cause nasal congestion, crusting, epistaxis,
anosmia, rhinorrhea, sinusitis, or nasal septal perforation; a
“saddle nose” deformity, palatal perforation, or bone erosion
may occur. Laryngeal sarcoidosis occurs in 1–5% of patients,
with hoarseness, dysphonia, dysphagia, dyspnea, or, rarely, stridor
and acute respiratory failure.
Ocular Sarcoidosis
Unilateral or bilateral anterior uveitis is the most common
manifestation of ocular sarcoidosis, often in association with
bilateral hilar adenopathy. Chronic uveitis occurs in up to 20%
patients with chronic sarcoidosis, more frequently in Black
populations. Other manifestations include posterior uveitis,
granulomatous conjunctivitis, severe chorioretinitis, or optic
neuritis that can cause blindness (Chapter 74).
Cutaneous Sarcoidosis
Erythema nodosum, which is a feature of Löfgren syndrome, may
recur. Chronic skin sarcoidosis usually manifests as nontender,
nonpruritic plaques and subcutaneous nodules around the hair-
line, eyelids, ears, nose, mouth, and the extensor surfaces of arms
and legs. Lupus pernio is a disfiguring form of facial cutaneous
sarcoidosis, with violaceous plaques and nodules covering the
FIG 73.4 Stage IV chest radiograph of fibrocystic pulmonary nose, nasal alae, and malar areas and the area around the eyes.
sarcoidosis with typical upward hilar retraction and multiple cystic Cardiac Sarcoidosis
and bullous changes.
Cardiac involvement is clinically apparent in <5–10% of patients
with sarcoidosis in North America and Europe, although autopsy
studies have suggested that the prevalence may exceed 25%. In
Japan, cardiac involvement is more common, occurring in more
than 50% of patients. Complete heart block, bundle branch
blocks, ventricular arrhythmias, sudden death, cardiomyopathy,
supraventricular arrhythmias, and valvular dysfunction may
occur. Current advice is to screen for cardiac sarcoidosis at
presentation, via assessment of symptoms (palpitations, syncope),
electrocardiography (ECG), and echocardiography. 45
Hepatic Sarcoidosis
Symptoms of hepatic sarcoidosis include fever, tender hepato-
megaly, and/or pruritus. Characteristically, serum alkaline
phosphatase and γ-glutamyl transferase are elevated proportion-
ately higher than aspartate and alanine aminotransferases or
bilirubin, although all patterns can occur. “Abdominal sarcoidosis”
refers to a constellation of liver, spleen, and abdominal lymph
node involvement, which is often associated with hypercalcemia;
FIG 73.5 Computed tomography scan demonstrating bilateral pulmonary involvement may not be evident.
hilar, paratracheal, and paraaortic lymphadenopathy with interstitial
infiltrates in a dominantly central bronchovascular distribution. Joints and Bones
Arthralgias are common in multisystem sarcoidosis, although
Pulmonary hypertension is an underrecognized complication joint radiographs are usually normal. Acute, often incapacitating,
of pulmonary sarcoidosis affecting at least 5% patients and up polyarthritis involving the ankles, feet, knees, and wrists may
to 50% of patients with dyspnea that is not explained by the occur in Löfgren syndrome. Persistent joint disease with pain,
44
level of pulmonary function impairment. Screening for pul- swelling, and tenderness of the phalanges of the hands and feet
monary hypertension is indicated in patients with advanced lung is found in <5% of patients with chronic sarcoidosis. Joint
disease because of the associated increased mortality. radiographs may demonstrate “punched-out” lesions with cystic

CHaPter 73 Sarcoidosis 987


changes without erosive chondritis. Cystic lesions of the long female sex, lower socioeconomic status, poor access to care, and
bones, pelvis, sternum, skull, and vertebrae are rare. increased disease severity, but not with race.
Neurosarcoidosis
Neurosarcoidosis occurs in 5–15% of patients with sarcoidosis. KeY COnCePts
The most common manifestation is cranial neuropathy, most Clinical Relevance
frequently bilateral or unilateral seventh-nerve (facial) palsy. The
palsy may resolve spontaneously or with corticosteroids but • Multisystem disease with heterogeneous manifestations and clinical
sometimes recurs years later. Optic neuritis may result in blind- course
ness. Manifestations of central nervous system (CNS) involvement • Diagnosis based on consistent manifestations and biopsy showing
include mass lesions, aseptic meningitis, obstructive hydrocepha- typical pathology
• No useful biomarkers for diagnosis or prognosis
lus, and hypothalamic/pituitary dysfunction. Seizures, headache, • Differential includes infections (mycobacterial, fungal), malignancy
change in mental status, confusion, and diabetes insipidus may (e.g., lymphoma), immunoglobulin G4 (IgG4)–related disease;
be presenting symptoms. Myelopathy with paraparesis, hemi- interstitial lung diseases
paresis, and back and leg pain have been described. Peripheral • Association with T-helper 1 (Th1) –promoting therapies
neuropathies account for ≈15% of cases of neurosarcoidosis, • After treatment with interferon (IFN)-α, IFN-γ, and interleukin (IL)-2
and other biologicals
often presenting as mononeuritis multiplex or a primary sensory • After immune reconstitution in patients with human immunodefi-
neuropathy. Small-fiber neuropathies with or without autonomic ciency virus (HIV) infection undergoing highly active retroviral therapy
neuropathy are increasingly recognized in patients with sarcoid- (HAART)
osis, particularly those with pain and chronic disease. • Goal of treatment with immunosuppressive medications is to preserve
function of affected organs while improving quality of life
Salivary, Parotid, and Lacrimal Gland Sarcoidosis • Clinical trials needed to establish roles of individual therapies
• Benefit of anti–tumor necrosis factor (TNF) therapies point to a role
Parotid or lacrimal gland enlargement and sicca syndrome may
be the dominant clinical manifestations of sarcoidosis. Heerfordt for TNF in sarcoidosis
syndrome, also known as uveoparotid fever, manifests as fever,
parotid and lacrimal gland enlargement, uveitis, and bilateral
hilar adenopathy, sometimes with cranial neuropathies (usually Associated Conditions
facial palsy). Sarcoidosis and Pregnancy
Pregnancy usually has little effect on the course of sarcoidosis,
Hematological Sarcoidosis although some patients experience spontaneous improvement.
Peripheral lymph node enlargement occurs in 20–30% patients In those whose condition improves during pregnancy, exacerba-
as an early manifestation of sarcoidosis but then typically remits tions frequently follow several months after delivery. The tem-
spontaneously. Persistent, bulky lymphadenopathy occurs in porary clinical improvement may relate to suppressed Th1
<10% of patients. Splenomegaly occurs in <5% of cases. It is immunity during pregnancy.
occasionally massive and often associated with hepatomegaly or
hypercalcemia. Polyclonal hypergammaglobulinemia is present Th1-Promoting Therapeutics
in ≥25% of patients. Administration of Th1-promoting therapeutics, such as IFN-α,
IFN-γ, IL-2, and IFN-β, has been linked to initiation or recru-
Sarcoidosis Myopathy descence of sarcoidosis.
Although random muscle biopsy specimens at autopsy have
demonstrated muscle granulomas in most patients with sarcoid- Common Variable Immunodeficiency
osis, symptomatic myopathy with weakness and tenderness is Sarcoidosis is associated with common variable immunodeficiency
uncommon. Rarely, sarcoidosis can present as a polymyositis (CVID) in both adults and children. A high index of suspicion
with profound weakness and elevated serum creatine kinase and must be maintained for this in patients with sarcoidosis who
aldolase. have recurrent infections.
Hypercalcemia, Hypercalciuria, and Renal Disease IgG4-Related Disease
Hypercalcemia is present in 2–5% of patients; hypercalciuria is This lymphoproliferative disorder involves multiple organ systems
more common. Abnormal calcium regulation may cause kidney and can be mistaken for sarcoidosis, particularly when central
stones or nephrocalcinosis and is thought to result from enhanced or peripheral adenopathy are present. Distinguishing features
conversion of 25-OH vitamin D 3 to the active 1,25-(OH) 2 vitamin of IgG4-related disease include the presence of dense lympho-
D 3 by macrophages and epithelioid cells in granulomas expressing plasmacytic infiltrates on biopsy, autoimmune pancreatitis and
1α-hydroxylase (also known as cytochrome p450 27B1). Impor- other autoimmune phenomena, and the presence of fibrosis in
tantly, if patients with sarcoidosis are screened for vitamin D organs not commonly involved in sarcoidosis, such as the
deficiency, they may have low 25-OH vitamin D 3 levels and peritoneum, aorta, and thyroid gland.
elevated active 1,25-(OH) 2 vitamin D 3 levels, placing them at
risk of nephrocalcinosis with renal failure if they are given vitamin Human Immunodeficiency Virus
D supplements. Sarcoidosis may develop in patients infected by human immu-
nodeficiency virus (HIV) with immune reconstitution after
Psychosocial Manifestations starting antiretroviral therapy, perhaps from reconstituted Th1
Depression and/or fatigue have been found in 30–60% patients immunity. Granulomatous inflammation of skin or lungs is most
with symptomatic sarcoidosis. Depression is associated with often reported.

988 Part seven Organ-Specific Inflammatory Disease



CLInICaL PearLs
Autoimmune Disorders
Sarcoidosis has been described in association with autoimmune Tests Recommended for an Initial Evaluation of a
diseases, such as Crohn disease, ulcerative colitis, primary biliary Patient With Sarcoidosis
cirrhosis, scleroderma, Sjögren syndrome, autoimmune hemolytic • Chest radiography or chest computed tomography (CT)
anemia, and autoimmune endocrinopathies. These associations • Pulmonary function tests
could result from a common, predisposing altered Th1/Th17 • Spirometry
immunity. • Diffusing capacity
• Lung volumes
Cancer • Flow–volume loop (if suspected upper airway obstruction)
• Slit-lamp examination (to exclude subclinical uveitis)
Multisystem sarcoidosis may develop in patients with a recent • Blood tests
history of cancer or following chemotherapy treatment, perhaps • Comprehensive metabolic panel (calcium; liver and renal
related to a rebound in immunological responsiveness following functions)
successful treatment. • Complete blood count, including differential and platelet count
• Measurement of active 1,25-(OH) 2 vitamin D 3
Diagnosis • Electrocardiography
The diagnosis of sarcoidosis is based on a compatible clinical • Purified protein derivative skin test or blood test for latent
tuberculosis
picture, histological evidence of noncaseating granulomas, and
the absence of other known causes of this pathological response.
Chronic beryllium disease and hypersensitivity pneumonitis
must be excluded when there is a compatible history, and clinical
findings are confined to the lung. In the absence of defined MRI with gadolinium enhancement is the best way to detect
multisystem disease, sarcoidosis is a presumptive diagnosis, as the characteristic inflammatory lesions of CNS or spinal cord
local “sarcoid” reactions can occur in response to infection, tumor, sarcoidosis, particularly in the periventricular and leptomen-
or foreign material. Biopsy confirmation of sarcoidosis is not ingeal areas. A normal scan does not exclude neurosarcoidosis,
usually necessary in Löfgren syndrome, except in regions where particularly for cranial neuropathies or during corticosteroid
histoplasmosis is endemic. therapy. Cerebral spinal fluid characteristically demonstrates
In general, biopsy of the easiest, most accessible abnormal lymphocytic pleocytosis and/or elevated protein levels. Diag-
tissue site is used to confirm the diagnosis. Biopsy of a skin nosis of neurosarcoidosis is usually confirmed by biopsy of a
nodule, superficial lymph node, lacrimal gland, nasal mucosa, non-CNS site (e.g., lung or lymph node). Rarely, brain biopsy is
conjunctivae, or salivary gland (lip biopsy) helps establish a needed to exclude infectious or malignant disease. In suspected
diagnosis. cases of peripheral neuropathy or myopathy, electromyography
Biopsy by fiberoptic bronchoscopy is frequently used (EMG) or nerve conduction studies should be considered.
to diagnose pulmonary sarcoidosis because of its relative Small-fiber neuropathy can be confirmed by performing
safety and high yield. The yield of transbronchial biopsy is quantitative immunohistochemistry of appropriate skin biopsy
operator dependent but approaches 50–85% of patients when specimens.
pulmonary infiltrates are present. Endoscopic bronchial ultra-
sonography has improved the diagnostic yield of sampling Other Diagnostic Studies
intrathoracic lymph nodes in sarcoidosis. Mediastinoscopy or No noninvasive tests are useful in making a diagnosis of sar-
surgical lung biopsy is considered when lymphoma or other coidosis. Serum ACE levels are elevated in 40–90% of patients
intrathoracic malignancy cannot be excluded and less invasive with clinically active disease, but these are nonspecific and may
techniques have not given definitive answers. Imaging techniques, be found in other inflammatory and granulomatous diseases as
18
such as gadolinium-enhanced MRI, F-fluorodeoxyglucose well.
(FDG)-positron emission tomography (PET) scanning, or
67 gallium scanning, are nonspecific but may assist in assessing CLINICAL COURSE AND PATIENT MANAGEMENT
inflammation in the heart, brain, and bone or in directing
biopsy. The clinical course of sarcoidosis is highly variable. Overall,
Initial diagnostic evaluation of a patient with possible sar- 50–65% of patients undergo spontaneous remission, usually
coidosis should include tests for the presence and extent of within the first 2–3 years. Löfgren syndrome is associated with
pulmonary involvement and screening for extrathoracic disease. spontaneous remission in >70–80% of patients. Peripheral
If cardiac symptoms are present, echocardiography and Holter adenopathy, salivary and parotid gland enlargement, and Bell
monitoring should be performed. Cardiac magnetic resonance palsy generally subside spontaneously or with treatment and do
imaging (MRI) or cardiac PET have greater sensitivity in dem- not recur. Elevated serum liver function tests also may revert to
onstrating patchy inflammation or scarring compared with gated normal without treatment. Remission is observed in approximately
46
technetium( 99m Tc) sestamibi scanning or echocardiography. 50–80% of patients with a stage I CXR, 30–60% with a stage II
Endomyocardial biopsy is positive in <10–25% cardiac sarcoidosis CXR, and 20–30% with a stage III CXR. Patients with a stage
cases because of the patchiness of the granulomatous inflam- IV CXR with fibrocystic changes rarely (<5%) experience
mation, so a negative biopsy result never excludes the diagnosis. remission.
Diagnosis of cardiac sarcoidosis is usually made by histological Extrapulmonary disease that is severe at presentation tends
confirmation of sarcoid at a noncardiac site in association to persist and require treatment. Overall, mortality ranges from
with compatible cardiac imaging, conduction abnormalities, or 1–6%, with the major causes being advanced pulmonary, cardiac,
arrhythmias. and neurological involvement. 10

CHaPter 73 Sarcoidosis 989


The intensity of surveillance of sarcoidosis depends on the ALTERNATIVE CYTOTOXIC THERAPIES
severity of clinical presentation. When sarcoidosis undergoes
remission, the disease rarely recurs; exceptions often involve Corticosteroid-sparing therapies are frequently used for chronic,
neurological or ocular manifestations. No biomarkers have been progressive sarcoidosis when corticosteroid adverse effects sig-
found to be useful in management decisions. nificantly degrade quality of life. 2,47,48 Low-dose weekly methotrex-
ate (10–20 mg/week) is recommended for pulmonary, cardiac,
TREATMENT ocular (panuveitis), cutaneous, and neurological sarcoidosis
requiring higher doses of corticosteroids. Success rates range
from 50% to 70%, but it may take ≥6 months to be effective.
tHeraPeUtIC PrInCIPLes Potential serious complications include hepatotoxicity, oppor-
Indications for Corticosteroid Therapy in Patients tunistic infections, bone marrow suppression, and pulmonary
With Sarcoidosis toxicity. Azathioprine can also be useful in sarcoidosis with similar
response rates to methotrexate but a slightly increased risk of
• Pulmonary involvement infection. Mycophenolate mofetil and leflunomide have been
• Moderate or severe, symptomatic pulmonary disease used as steroid-sparing agents in small case series. Potential drug
• Progressive, symptomatic pulmonary disease toxicities for all four drugs include bone marrow suppression,
• Persistent pulmonary infiltrates or abnormal lung function for 1–2 gastrointestinal symptoms, skin rashes, and an increased risk of
years with mild symptoms to assess reversibility
• Advanced fibrocystic disease malignancy. Cyclophosphamide has been used in steroid-
• Extrapulmonary involvement recalcitrant sarcoidosis, particularly refractory neurosarcoidosis,
• Threatened organ failure: severe ocular, cardiac, or central nervous but its use is severely limited because of its oncogenic potential.
system (CNS) disease Calcineurin inhibitors suppress T-cell activation but do not work
• Posterior uveitis or anterior uveitis not responding to local in sarcoidosis.
steroids Clinical trials support the effectiveness of biological agents
• Persistent hypercalcemia
• Persistent renal or hepatic dysfunction targeting specific immunological pathways in sarcoidosis.
• Pituitary disease Infliximab (anti-TNF) had a small impact on pulmonary func-
• Myopathy tion over 6 months but was effective for many extrapulmonary
• Palpable splenomegaly or evidence of hypersplenism, such as manifestations. Case series have suggested that adalimumab may
thrombocytopenia also be effective in some patients with sarcoidosis. Etanercept,
• Severe fatigue and weight loss golimumab (anti-TNF), and ustekinumab (anti–IL12/IL23) were
• Painful lymphadenopathy ineffective in pulmonary sarcoidosis. Interestingly, there have been
• Disfiguring skin disease
some case reports of successful use of rituximab (anti–B cell) in
treatment-refractory sarcoidosis, particularly neurosarcoidosis,
47
Current therapies are nonspecific and largely unproven. If there although how it may work in sarcoidosis remains unclear. Further
is no organ-threatening involvement at presentation, a period studies are needed to define the role of biological agents (Chapter
of observation is usually indicated to evaluate whether the disease 89) in sarcoidosis, not least because these therapies carry risks
will remit spontaneously. of serious, life-threatening infections and malignancy.
Corticosteroids remain the mainstay of therapy for progressive
organ-threatening or life-threatening manifestations of sarcoidosis. SPECIFIC SITUATIONS
The optimal doses and duration of corticosteroid treatment have
not been established by rigorous clinical studies. For pulmonary Löfgren Syndrome
and cutaneous disease, initial treatment is usually with no more Nonsteroidal antiinflammatory drugs (NSAIDs) are recommended
than 20–40 mg/day of prednisone for 2–4 weeks, followed by a for relief of constitutional symptoms and joint pains. For disabling
slow tapering regimen over several months to a maintenance arthritis or severe constitutional symptoms, corticosteroids are
dose of 5–15 mg/day. Alternate-day therapy has been suggested, almost immediately effective and can generally be tapered over
although it may be ineffective in a subgroup of patients who a few weeks to months.
subsequently respond to daily dosing. Treatment is normally
continued for at least 6–12 months, as premature tapering is Mucocutaneous and Joint Sarcoidosis
likely to result in relapse. Recurrent, progressive pulmonary and Hypercalcemia
disease occurs in 16–74% of patients as corticosteroid therapy Hydroxychloroquine is often tried as a first-line treatment for
is tapered; patients with repetitive relapses usually need chronic cutaneous, joint, nasal, or sinus manifestations when corticoster-
suppressive therapy to minimize loss of lung function. Weight oids are not immediately needed. Hypercalcemia may also respond
gain, hypertension, hyperglycemia, glaucoma, and osteoporosis to hydroxychloroquine as maintenance therapy. Chloroquine
are serious potential complications. Bisphosphonate therapy is may be effective in some patients unresponsive to hydroxychlo-
recommended for patients on chronic corticosteroid therapy. roquine but has a greater potential for ocular toxicity and is
Inhaled corticosteroids may help reduce symptoms of cough or rarely used. Minocycline and doxycycline have been effective in
airway irritability but are not useful as sole agents in pulmonary a small number of patients with cutaneous sarcoidosis, but wider
sarcoidosis. experience shows that these drugs are rarely effective.
Pentoxifylline, a phosphodiesterase inhibitor, was shown to
be beneficial in one study of mild pulmonary sarcoidosis, although Ocular Sarcoidosis
wider experience suggests only very few patients respond to Anterior uveitis is usually treated with topical corticosteroids.
it. Gastrointestinal side effects often limit the dose that is Oral or intravenous corticosteroids are used initially for posterior
tolerated. uveitis, chorioretinitis, or optic neuritis.

990 Part seven Organ-Specific Inflammatory Disease


OPPORTUNITIES FOR PROGRESS IN SARCOIDOSIS
Pulmonary Hypertension
Small retrospective case series have suggested that pulmonary
vasodilator treatment can reduce pulmonary artery pressure On tHe HOrIZOn
and improve exercise dyspnea and 6-minute walk distance in • Diagnostic and prognostic tools based on:
49
patients with sarcoidosis who have pulmonary hypertension. • Genotyping
The benefit of vasodilator therapy on survival rates remains • Genomic/microbiome/proteomic and immunological signatures
uncertain. 50 • Improvements in imaging techniques to assist in assessment of organ
involvement
Cardiac Sarcoidosis • Multicenter clinical trials of immune-altering therapies for treatment
of sarcoidosis
Initial treatment consists of cardiac medications (antiarrhythmic
therapy, diuretics, and afterload-reducing agents) along with
corticosteroid therapy that may reverse heart block, reduce We have the necessary foundations for making rapid progress
arrhythmias, and improve cardiac function. Corticosteroids are in understanding sarcoidosis. Although there is considerable
recommended in moderate doses as some studies have found clinical heterogeneity, distinct clinical phenotypes are well
no difference in 5-year survival rates for patients treated with established, from acute sarcoidosis (Löfgren syndrome) to chronic
prednisone >30 mg/day versus <30 mg/day. Higher doses are progressive organ disease. It is known that the genetic basis of
often used initially for intractable arrhythmias or heart block. sarcoidosis predominantly resides within the MHC. Immunologi-
Cardiomyopathy may require long-term treatment, and cytotoxic cal hallmarks of the disease include noncaseating granulomas
drugs are often used for steroid sparing. Small case series have and highly polarized Th1 and Th17 immunity with proinflam-
suggested that TNF inhibitors may be useful, but caution is matory cytokines, such as TNF, at sites of disease, associated
advised with regard to their use, since these agents can worsen with reduced Treg activity. Evidence from multiple centers suggests
congestive heart failure in nonsarcoidosis cardiomyopathy. that mycobacterial and possibly propionibacterial organisms may
Automatic implantable defibrillators and/or pacemakers are trigger sarcoidosis. The recent identification of innate immune
indicated in patients at risk for sudden death from serious pathways, one of which involves SAA, suggests mechanisms that
arrhythmias or heart block, although their prophylactic use may explain the pathogenesis of chronic sarcoidosis in the absence
remains controversial. The effectiveness of radiofrequency ablation of active chronic infection. The challenge for the next 5–10 years
for prevention of arrhythmias in cardiac sarcoidosis remains is to translate these laboratory discoveries into clinical tools to
uncertain. assist the clinician in providing the diagnosis and prognosis for
individual patients. Newer therapies are sorely needed for the
Neurosarcoidosis treatment of patients with sarcoidosis, particularly those who
High doses of oral corticosteroids (60–80 mg/day) or high-dose have chronic disease and generally require long-term maintenance
pulse intravenous therapy are often used for serious CNS involve- therapy. The potential for curing this disease is suggested by a
ment. Tapering should be performed over several months after remission rate of >50%, although progress toward this goal awaits
confirming suppression of inflammation by objective criteria a better understanding of the mechanisms that allow remission
(e.g., serial MRI scans). With the exception of cranial neuropathies, to occur. Research that integrates assessment of clinical phenotype,
neurosarcoidosis tends to be chronic and requires long-term genetic background, and individual immunophenotypical and
therapy. environmental triggers in different subgroups of patients may
offer the best chance for rapid progress.
Depression/Fatigue/Pain
Small case series have highlighted the existence of small-fiber Please check your eBook at https://expertconsult.inkling.com/
neuropathy and autonomic neuropathy in sarcoidosis, particu- for self-assessment questions. See inside cover for registration
larly in patients with pain. A few case reports have suggested details.
that anti-TNF therapies may be beneficial in small-fiber
neuropathy, but their role in sarcoidosis remains undefined. REFERENCES
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CHaPter 73 Sarcoidosis 991.e1


MUL t IPL e -CHOIC e QU est IO ns

1. Is cardiac sarcoidosis a rare manifestation? 4. True or false, Sarcoidosis represents an immune deficiency
state.
2. True or false, sarcoidosis rarely results in airway obstruction.
5. True or false, calcineurin inhibitors are useful as treatment
3. True or false, stage IV sarcoidosis indicates advanced, wide- for sarcoidosis.
spread, multisystem disease.

74









Immunological Ocular Disease



James T. Rosenbaum, Phoebe Lin







The immune system can induce disease in virtually any portion triggers apoptosis of the Fas-bearing cell. FasL is constitutively
of the eye. Examples include conjunctivitis, keratitis, keratocon- expressed within the eye, being detected in normal cornea, anterior
junctivitis, uveitis, scleritis, optic neuritis, and orbital inflam- uvea, and retina. The importance of FasL to ocular immune
mation. The anatomy of the eye is depicted schematically in privilege has been demonstrated primarily in experimental models
Fig. 74.1. Uveitis is defined as inflammation of the uveal tract, of ocular inflammation. Corneal allografts from FasL-negative
which is the middle layer of the eye, divided into the anterior mice into recipients of normal phenotype are rejected in all
1
uvea (iris, ciliary body) and posterior uvea (choroid). The uvea cases, whereas approximately half of FasL-positive grafts survive.
is sandwiched between an outer layer (sclera) and an inner layer When injected into the eyes of FasL-deficient mice, herpes simplex
(retina). The anterior segment is separated from the posterior virus (HSV) causes a severe invasive infection. A similar procedure
segment by the lens. Two relatively common immunologically in normal phenotype control animals results in relatively minor
mediated ocular diseases, discussed elsewhere in this volume, inflammation. Levels of FasL in the aqueous humor during human
are sicca secondary to Sjögren syndrome (Chapter 54) and anterior acute anterior uveitis are capable of inducing apoptosis in Fas-
ischemic optic neuropathy secondary to giant cell arteritis positive lymphoid cells. In this self-limiting condition, as well
(Chapter 59). Before considering the various ocular inflammatory as in relevant rodent models, apoptosis of infiltrating T cells is
disorders, it is critical to review some unique considerations observed early in the course of the inflammation. In addition
related to ocular immunology. to FasL, the local expression of tumor necrosis factor (TNF)–
related apoptosis inducing ligand (TRAIL) by corneal endothelium
OCULAR IMMUNE PRIVILEGE also contributes to enhanced apoptosis and immune privilege
within the eye. 2
Many of the mechanisms that drive inflammation in the eye
are identical to those operating at other tissue sites. The major
difference between the immunopathology of intraocular inflam- CYTOKINES, NEUROPEPTIDES, AND COMPLEMENT
mation and that of systemic inflammatory disease relates to the IN THE PROMOTION AND REGULATION OF
fact that the eye, like the brain and the testis, is an immuno- OCULAR INFLAMMATION
logically privileged site. During uveitis, keratitis, and scleritis,
as well as following corneal transplantation, a variety of local The aberrant immune activation that occurs in uveitis appears to
immunosuppressive mechanisms act to limit the damage caused be caused by a combination of environmental triggers and genetic
by infiltrating leukocytes and, consequently, to influence the risk factors that tip the balance away from immune regulation
patient’s clinical course. One of the most important factors and toward inflammation. Inflammatory pathways of the adaptive
is the constitutive expression of Fas ligand (FasL) within the immune system that play a role in the pathogenesis of uveitis
eye. In addition, normal ocular tissues produce relatively high include T-helper 1 (Th1) lymphocytes (that produce interferon-γ
levels of immunomodulatory cytokines and immunosuppressive [IFN-γ], interleukin-2 [IL-2], and IL-12), and IL-23-responsive
neuropeptides, as well as complement. Other factors include the Th17 lymphocytes (that produce IL-17, IL-22, and IL-6).
blood–aqueous and blood–retinal anatomical barriers, limited An example of a subgroup of immune cells that keep the
major histocompatibility complex (MHC) expression, a paucity immune system in check are regulatory T cells (Tregs). Tregs
of lymphatic drainage channels within the eye, and, in the case produce antiinflammatory cytokines, such as IL-10, transforming
of the cornea, the complete absence of blood vessels. The term growth factor (TGF)-β, and IL-35. Tissues in both the anterior
anterior chamber–associated immune deviation (ACAID) describes and the posterior segments of the human eye constitutively
the suppression of a cell-mediated immune response when soluble express TGF-β. The concentration of TGF-β in the aqueous
antigen is directly injected into the aqueous humor. All of the humor is sufficient to inhibit T-cell activation and proliferation
3
above factors contribute to ACAID. in a variety of assays. As might be anticipated, significantly
lower levels of this activated cytokine are measured in the aqueous
FAS LIGAND humor of patients with a variety of uveitis syndromes compared
with levels present in normal eyes. Another antiinflammatory
Most immune cells, including neutrophils, monocytes, macro- cytokine, IL-27, is produced constitutively by resident cells in
4
phages, and lymphocytes, express Fas (CD95) on their surface. the retina, including retinal ganglion and photoreceptor cells.
4
The interaction between Fas and its receptor FasL (CD95L) IL-27 is upregulated by IFN-γ and suppresses Th17 cells.
993

994 Part seven Organ-Specific Inflammatory Disease


+
Vitreous humor and from γδ T cells; CD8 Tregs upregulate FasL, IL-10, and
Sclera TGF-β to promote FasL-mediated killing of T cells that recognize
the ocular antigen; TGF-β also induces ocular APCs to secrete
Iris Choroid IL-10 during antigen processing. Apoptotic T cells from the eye
pass in the bloodstream to the spleen, where they are phagocytosed
Lens Retina and induce activation of Th2-type CD4 T cells. The Th2-type
cells control Th1 function by secreting various immunomodula-
tory cytokines. T-cell receptor α-chain fragments from apoptotic
Cornea Vitreous Macula cells are presented in the class I pathway. This event generates
CD8 natural killer (NK) cells, which are capable of deleting the
Anterior Optic CD4 T cells that would otherwise mediate a delayed-type
chamber nerve hypersensitivity response. One study demonstrated that IFN-γ
appears to be important in CD8 Treg suppressive function.
Invariant natural killer T (iNKT) cells, which interact with
Conjunctiva
lipid antigens presented in the context of an MHC-like molecule,
FIG 74.1 Schematic representation of the eye. Cd1d, may play a role in the induction of ACAID in the thymus
and the spleen. In fact, one study showed that activation of iNKT
cells could suppress experimental autoimmune uveitis.
Furthermore, retinal pigment epithelial (RPE) cells are thought
to play an important role in inducing Tregs through the produc- IMMOBILITY OF DENDRITIC CELLS WITHIN THE
tion of retinoic acid in the presence of TGF-β. ANTERIOR CHAMBER
Several cytokines, such as IFN-γ or IL-17, can be either protec-
tive or inflammatory, depending on the context in which they The vast majority of cells that phagocytose foreign antigen within
are produced. For example, although IL-17 is recognized as an the iris fail to migrate after antigen uptake. This is clearly
inflammatory cytokine contributing to the pathogenesis of uveitis, demonstrable by intravital microscopy and correlates with the
one study showed that recombinant human IL-17 given systemi- failure of these antigen-bearing cells to migrate to the local lymph
9
cally protected against inflammation in two different animal nodes. The inability to migrate is consistent with the known
models of experimental uveitis. 5 lack of lymphatics within the eye and must mean that soluble
The inflammatory cytokine IL-1 has been implicated in antigen injected into the anterior chamber is not presented in
the pathogenesis of various ocular inflammatory diseases. IL-1 the regional lymph node in a manner that is comparable with
6
receptor antagonist (IL-1Ra) is expressed in normal cornea and what follows antigen exposure in other peripheral tissues.
retinal pigment epithelium, and this implies that this tissue
contains a control mechanism for responses mediated by IL-1. Role of the Commensal Microbiota in Ocular Immunity
Interestingly, topical application of IL-1Ra promotes experimental Although the eye is thought to be relatively devoid of microorgan-
corneal allograft survival. Furthermore, the aqueous humor isms, it is now known that there is a small number of normally
contains neuropeptides, including α-melanocyte stimulating residing ocular surface bacteria and viruses. 10,11 Perturbations
hormone, vasoactive intestinal peptide, substance P, and calcitonin in the ocular surface microbiota can result in infection and/or
7
gene–related peptide, which inhibit T cells and macrophages. manifest as sterile inflammation. For instance, the presence of
Complement is active at low levels in the healthy eye, regulated torque teno virus was very strongly associated with sterile
by complement regulatory proteins that are expressed both on endophthalmitis (a condition in which there is severe intraocular
intraocular cell membranes and within the intraocular fluid; inflammation usually associated with infection) and was also
12
this system may participate in the destruction of pathogens found in some cases of culture-positive bacterial endophthalmitis.
invading the eye. Interestingly, iC3b, generated because of this Whether torque teno virus was the causal factor, merely an
activation, appears to contribute to immune tolerance. 8 association, or indirectly causal via viral immune-modifying
effects is unknown. Deep DNA sequencing may uncover previously
ANTERIOR CHAMBER–ASSOCIATED unknown causes of uveitis.
IMMUNE DEVIATION
UVEITIS
ACAID is “a stereotypic, systemic immune response to antigens
placed in the anterior chamber (of the eye) in which delayed Uveitis as a Diagnostic Entity
hypersensitivity is avoided and suppressed.” The culmination of Uveitis is a spectrum of different diseases that includes infections
cellular events in ACAID leads to the production of two different and immune-mediated diseases (Table 74.1). It is the third leading
+
+
Treg populations, CD4 , CD25 Tregs that inhibit the afferent preventable cause of blindness worldwide. Inflammatory disorders
+
immune response, and CD8 Tregs that block the efferent phase of the retina (retinitis) and sclera (scleritis) frequently involve
characterized by previously sensitized CD4 T cells. The molecular the adjacent uvea. Mechanisms contributing to uveitis include
events that are responsible for ACAID include the following: an immune response to a sequestered self-antigen, molecular
entry of an antigen into the eye stimulates production of TNF-α, mimicry, immune complex deposition, or a toxin.
and hence the upregulation of cell adhesion molecules; antigens The differential diagnosis of uveitis is facilitated by identifying
processed by antigen-presenting cells (APCs) in the eye migrate characteristic clinical features. Uveitis can be classified by loca-
13
to the spleen and present to B cells in the marginal zone in the tion : anterior (iritis, iridocyclitis), intermediate (pars planitis,
+
context of a nonconventional MHC molecule; induction of CD8 vitritis), or posterior (retinitis, choroiditis, retinochoroiditis,
+
+
ACAID Tregs in the presence of IL-10 from CD4 , CD25 Tregs, chorioretinitis). Some forms of uveitis involve all portions of

CHaPter 74 Immunological Ocular Disease 995



TABLE 74.1 Diagnostic Categories
of Uveitis
Diagnostic Group Diagnosis
Infectious Viral Herpes simplex, Herpes zoster
causes Cytomegalovirus (CMV) infection
Chikungunya
Human T-lymphotropic virus 1
(HTLV-1) infection
Mumps
West Nile virus infection
Ebola
Zika virus infection
Bacterial or Atypical Mycobacterium infection
spirochetal Bacterial endocarditis
Bartonella infection
Brucellosis FIG 74.2 Fundus Fluorescein Angiogram Showing Cystoid
Leprosy
Leptospirosis Macular Edema. Fluorescein, which appears as a white stain,
Lyme disease should be absent from the center of this photograph because
Propionibacterium infection the macular area is avascular.
Tuberculosis
Leprosy
Syphilis
Whipple disease
Parasitical Acanthamoeba infection
(protozoan or Cysticercosis
helminthic) Onchocerciasis
Pneumocystis jiroveci infection
Toxoplasmosis
Toxocariasis
Fungal Histoplasmosis FIG 74.3 Spectral Domain Optical Coherence Tomography
Coccidioidomycosis
Candidiasis (SD-OCT) of Cystoid Macular Edema caused by Panuveitis.
Aspergillosis SD-OCT allows for precise quantification of macular thickening
Sporotrichosis and photoreceptor damage. Note the intraretinal fluid–filled cysts
Blastomycosis resulting in distortion of the foveal contour. This patient had
Cryptococcosis 20/100 visual acuity.
Immune-mediated Ankylosing spondylitis
Behçet disease
Crohn disease
Drug or hypersensitivity reaction
(e.g., to rifabutin or cidofovir)
Familial granulomatous synovitis with
uveitis
Interstitial nephritis FIG 74.4 Spectral Domain Optical Coherence Tomography
Juvenile idiopathic arthritis
Kawasaki disease (SD-OCT) Image of a Normal Eye. This is the same macula
Multiple sclerosis as seen in Fig. 74.3, after an intravitreal steroid implant was
Psoriatic arthritis placed. In this SD-OCT image, the macula shows a normal dimple
Reactive arthritis or indentation at the normal fovea.
Relapsing polychondritis
Rheumatic fever
Sarcoidosis the epithelium of the cornea) (Fig. 74.6); and by the appearance
Scleritis
Sjögren syndrome of inflammatory keratic precipitates on the endothelium of the
Sweet syndrome cornea within the eye (granulomatous, nongranulomatous) (Fig.
Systemic lupus erythematosus 74.7). Granulomatous diseases with large cellular concretions
Ulcerative colitis on the cornea or nodules within the iris include tuberculosis,
Vasculitis syphilis, sarcoidosis, Vogt-Koyanagi-Harada disease, and sym-
Vogt-Koyanagi-Harada syndrome
pathetic ophthalmia. The group of nongranulomatous diseases
includes ankylosing spondylitis, reactive arthritis, and juvenile
idiopathic arthritis. Table 74.2 shows how these parameters
the uveal tract (panuveitis). Uveitis can be classified by course contribute to the differential diagnosis.
(self-limiting, chronic, or recurrent); by onset (sudden, insidious); Additionally, ethnic and geographical considerations factor
by symmetry (unilateral, bilateral); by associated complications, into the differential diagnosis. For example, sarcoidosis, Behçet
such as glaucoma, cystoid macular edema (Figs. 74.2–74.4), syndrome, and Vogt-Koyanagi-Harada disease have strong ethnic
synechiae (e.g., adhesion of the iris to the lens) (Fig. 74.5), retinal predispositions, whereas certain infections, such as cytomegalovirus
detachment, or band keratopathy (the deposition of calcium in (CMV) in association with acquired immunodeficiency syndrome

996 Part seven Organ-Specific Inflammatory Disease



TABLE 74.2 Characteristic Features of
Common Forms of Uveitis
Parameter
Location Anterior: ankylosing spondylitis, reactive arthritis,
juvenile idiopathic arthritis
Intermediate: Pars planitis
Posterior: Vogt-Koyanagi-Harada syndrome (panuveitis
most common)
Onset Sudden: ankylosing spondylitis, reactive arthritis
Insidious: pars planitis, juvenile idiopathic arthritis
Symmetry Unilateral: ankylosing spondylitis, toxoplasmosis,
herpetic
Bilateral: pars planitis, lymphoma, juvenile idiopathic
arthritis
Course Self-limiting: toxoplasmosis
Recurrent: Behçet disease, ankylosing spondylitis
Chronic: pars planitis
FIG 74.5 Posterior Synechiae. The cloverleaf appearance of
the pupil is caused by the adherence of the iris to the lens
capsule.
TABLE 74.3 Likelihood of
Developing Uveitis in association With
a specific Disease

Diagnosis Likelihood (%)
Ankylosing spondylitis 30
Sarcoidosis 25–50
Behçet disease 80
Inflammatory bowel disease 1–9
Psoriatic arthritis 7
Juvenile idiopathic arthritis <2–53
Multiple sclerosis <1–2



(AIDS), leprosy, or onchocerciasis, vary in prevalence depending
on geographical area. Together with a medical history, sex, and
age, these findings help to narrow the differential diagnosis of
uveitis. For example, a 22-year-old man with low back pain and
a red painful eye caused by episodic, unilateral, sudden-onset
FIG 74.6 Band Keratopathy. Calcium deposition in the corneal anterior uveitis is highly likely to have a spondyloarthropathy
endothelium complicates the iridocyclitis in a patient with juvenile (Chapter 57). A 6-year-old girl with no ocular complaints but
idiopathic arthritis. bilateral band keratopathy and leukocytes in the anterior chamber
is likely to suffer from pauciarticular juvenile idiopathic arthritis
(Chapter 53).
The most obvious sign of uveal inflammation is the presence
of leukocytes in the anterior chamber or the vitreous humor of
the eye. Most patients with anterior uveitis will experience pain,
redness, photophobia, miosis, and a variable degree of visual
loss. In contrast, many forms of uveitis that affect the posterior
segment will cause no redness, pain, or change in pupil size.
Instead, ocular disturbances may vary from normal vision to
seeing floaters, flashing lights, or photopsia, blurred vision, or
blindness.
Epidemiology
The incidence and prevalence of the different types of uveitis
varies throughout the world, depending on numerous factors:
human leukocyte antigen (HLA) distribution, prevalence of
different infectious diseases, and the methodology employed
14
to evaluate and classify uveitis (Table 74.3). Gritz and Wong
FIG 74.7 Granulomatous Keratic Precipitates. Round white reported an incidence of 52.4 per 100 000 per year and a preva-
dots are scattered in a triangular shape. The dots represent lence of 115.3/100 000. Anterior uveitis is much more common
concretions of leukocytes adherent to the corneal endothelium. than intermediate or posterior uveitis.

CHaPter 74 Immunological Ocular Disease 997



Prevention and Patient Management
Uveitis can be the first sign of systemic disease (e.g., sarcoidosis,
syphilis, or central nervous system [CNS] lymphoma). It is
essential to identify the cause of uveitis as accurately as possible.
A targeted approach is preferable, with a limited workup guided
by the type and severity of uveitis and the presence of systemic
findings. The history is of great importance. The minimal workup
for uveitis of unknown etiology requires an extensive and careful
review of systems, a syphilis serology, and a chest X-ray. 15
Most practitioners use a stepladder approach to treat uveitis.
The first step is corticosteroids for all patients with noninfectious
uveitis (topical, especially for anterior uveitis, regional injection,
or systemic administration). A surgically implantable intravitreal
device to release fluocinolone for approximately 2.5 years is an
option that is limited by cost and complications, which can
include cataract, glaucoma, and scleral thinning. New delivery FIG 74.8 Hypopyon. Intense inflammation has resulted in a
approaches include injectable corticosteroids complexed with creamy exudate (pus), seen as whitening over the inferior portion
polymers to prolong the beneficial effects; iontophoresis to deliver of the anterior chamber. In this example, hypopyon was secondary
medication across the sclera; and small molecules, which seem to rifabutin, not ankylosing spondylitis.
to have a much broader biodistribution within the eye compared
with topical prednisolone. Systemic immunosuppressive therapy
should be used in cases of inadequate benefit from corticosteroids
22
or unacceptable steroid side effects. Immunosuppression is usually In frequently recurrent cases, therapy with sulfasalazine or TNF
reserved for bilateral forms of uveitis with a severity sufficient inhibitors is effective in reducing the frequency of the attacks. 23
to alter activities of daily living and is frequently chosen for eye Several studies have emphasized that spondyloarthritis may
involvement with Behçet disease. Immunosuppression may be be overlooked in patients with acute anterior uveitis (AAU). A
contraindicated by active infection in the eye or elsewhere. study from Ireland evaluated patients with AAU in the emergency
The role for therapy with biologics to treat uveitis is being room. About 40% had spondyloarthritis that had not been
24
assessed in randomized controlled trials. Antibodies to IL-1β recognized. A study from Spain included 798 patients who had
or to anti–IL-17A have proven disappointing in the treatment either HLA-B27–associated AAU or recurrent, HLA-B27–associ-
of uveitis. 16-20 However, adalimumab (an anti-TNF-α biologic) ated anterior uveitis. As in the Irish study, all patients with known
was shown to be effective in a randomized clinical trial for active spondyloarthritis were excluded. The study utilized the Assessment
18
25
17
uveitis and as a corticosteroid sparing agent in inactive uveitis. In of Ankylosing Spondylitis (ASAS) criteria. Fifty percent of this
an open label trial, infliximab has proven effective but had frequent large group had axial spondyloarthritis and close to an additional
19
severe toxicities for this indication. The authors frequently 20% had peripheral spondyloarthritis. 26
prescribe infliximab to treat Behçet disease (see below). Biologic
therapy for uveitis might also be guided by the underlying disease, Inflammatory Bowel Disease–Associated Uveitis
such as Crohn disease, juvenile idiopathic arthritis, or psoriatic Ocular manifestations of inflammatory bowel disease (IBD)
arthritis, all of which are particularly responsive to biologics. (Crohn disease and ulcerative colitis; Chapter 75) include anterior
uveitis, episcleritis, and scleritis (1–9% of all cases). Less common
Overview of the Most Common Uveitis Diagnoses ocular inflammatory manifestations include peripheral keratitis,
Ankylosing Spondylitis–Associated Uveitis intermediate uveitis, optic neuritis, and retinal vasculitis. Twenty
27
Ankylosing spondylitis (AS) is the most common systemic percent of patients with IBD may have sacroiliitis; 60% of them
diagnosis associated with uveitis in Western nations. A genetic are HLA-B27 positive. The anterior uveitis in patients with IBD
predisposition with the HLA-B27 allele is found in 88–96% of is often similar to that seen with the HLA-B27 spectrum of joint
patients. About 30–50% of patients with AS develop anterior diseases: sudden in onset, unilateral, and self-limiting. Like
uveitis transiently during their lifetime. Approximately 50% of sarcoidosis, it may result in intraocular inflammation that is
20
patients with sudden-onset anterior uveitis are HLA-B27 positive. insidious in onset, bilateral, posterior to the lens, chronic, or
In some studies, 80–90% of individuals with HLA-B27–associated associated with a retinal vasculitis. 28
iritis have spondyloarthritis. AS should be considered in any Crohn disease is a complex genetic disease—that is, multiple
patient with sudden-onset, primarily anterior, unilateral uveitis genes contribute to susceptibility. One of the best characterized
associated with redness and pain. Recurrent disease, fibrin in of these genes is NOD2. This gene functions as an intracellular
the anterior chamber, posterior synechiae, relatively brief inflam- Toll-like receptor (TLR) that recognizes muramyl dipeptide from
mation that resolves in <2 months, and lowered intraocular bacteria. The NOD2 gene is also implicated in autoinflammatory
pressure are additional hallmarks that help to distinguish diseases. A mutation in the portion of the NOD2 gene known
21
HLA-B27–associated iritis from other categories. Inflammation as the nucleotide-binding domain results in a rare autosomal
is sometimes so severe that a hypopyon (Fig. 74.8) develops. dominant form of uveitis known as Blau syndrome.
The posterior segment of the eye is not commonly involved in
this disease except for the development of a vision-reducing Psoriatic Arthritis–Associated Uveitis
cystoid macular edema (see Figs. 74.2 and 74.4). HLA-B27–associ- According to one study in the UK, 1–2% of the population have
ated anterior uveitis usually responds to topical corticosteroids. psoriasis (Chapter 64); roughly 10% of patients with psoriasis

998 Part seven Organ-Specific Inflammatory Disease


29
have arthritis ; and 7% of patients with psoriasis and arthritis
have uveitis. The diagnosis of psoriatic arthritis is made clinically
with the typical findings of cutaneous changes (erythematous,
hyperkeratotic rash) and joint disease. Patients with sacroiliac
disease and psoriatic arthritis are especially likely to develop
uveitis.
Sarcoidosis-Associated Uveitis
Ocular disease is the initial manifestation of sarcoidosis (Chapter
73) in 20% of patients. The systemic illness begins as ocular
inflammation almost as often as it initially presents as pulmonary
disease. Of the patients with sarcoidosis, 25–50% exhibit ocular
inflammation during the course of the illness. In most series,
sarcoidosis accounts for 3–10% of all patients with uveitis, second
to spondyloarthropathy as the most common systemic illness
associated with uveitis in North America and Europe. The
diagnosis of sarcoidosis should always be considered in any patient FIG 74.9 Fundus Photograph Showing Retinal Vasculitis. The
presenting with a uveitis of unknown etiology. Sarcoidosis occurs scattered hemorrhages are secondary to the vasculitis. The
in the United States 10 times more frequently among African patient has Behçet syndrome.
Americans than among whites. Because it can affect almost every
part of the eye, symptoms of ocular sarcoidosis vary widely.
Most commonly, patients have a bilateral chronic granulomatous may lead to blindness if ischemic optic neuropathy and retinopathy
30
anterior uveitis. The disease often regresses clinically, with are not adequately treated. Patients are often inadequately managed
two-thirds of patients becoming symptom free after 3 years. by corticosteroids alone: A regimen with immunosuppressive
Typical findings include “mutton-fat” keratic precipitates of the drugs (cyclosporine or azathioprine) has been proved useful.
34
cornea (see Fig. 74.7), Koeppe and Busacca iris nodules, posterior Some investigators advocate the use of IFN-α. Infliximab has
synechiae (see Fig. 74.5), and white clumps of cells (“snowballs”) demonstrated dramatic benefit in studies reported from Europe
35
in the inferior vitreous humor. Fundus findings include multifocal and Japan. It is now approved for this indication in Japan.
perivenular sheathing, typical punched out chorioretinal lesions,
and/or optic nerve head granulomata. Diffuse retinal vasculitis, Multiple Sclerosis–Associated Uveitis
predominantly of the retinal venules, can also be seen. A chest Although retrobulbar optic neuritis is the ocular inflammation
31
X-ray (or computed tomography [CT] scan of the chest ) should most associated with multiple sclerosis (MS), intermediate uveitis
be included in every basic workup of patients with uveitis of and bilateral granulomatous anterior uveitis are well described
36
unknown cause. The diagnosis is supported by a biopsy that in association with this disease (Chapter 66). Bilateral granu-
demonstrates the noncaseating granuloma in the absence of an lomatous uveitis may indicate a worse prognosis for the neurologi-
infection or beryllium exposure. Possible biopsy sites include cal disease. The HLA-DR2 antigen, strongly associated with MS,
lymph nodes, lung, skin, oral mucosa, and conjunctiva. Serological is also associated with uveitis.
abnormalities are not sufficiently unique to establish a diagnosis.
In general, the combination of uveitis and symmetrical hilar Juvenile Idiopathic Arthritis–Associated Uveitis
adenopathy is considered presumed sarcoidosis and can be treated Patients with juvenile idiopathic arthritis (JIA; Chapter 53) need
like sarcoidosis. Topical, periocular, and systemic corticosteroids special consideration as the disease often does not present with
are the mainstay of therapy. Steroid-sparing therapy can be a “red eye”: The uveitis often occurs as a smoldering, silent
required for more severe or chronic cases affecting the posterior inflammation in a quiet, white eye. In 20% of all JIA cases, the
segment, with the antimetabolites as first-line steroid-sparing joint involvement is pauciarticular (≤5 joints affected). Uveitis
agents, and TNF-α inhibitors as alternative treatment. 32,33 occurs far more commonly in this pauciarticular subset, and
these patients require routine ophthalmic screening every 3–4
Behçet Uveitis months. Girls are affected four times more often than boys,
37
Behçet syndrome is a generalized occlusive vasculitis of unknown although boys are more likely to develop complications. Eighty
cause (Chapter 58). It accounts for about 2.5% of patients at a percent of uveitis cases are positive for antinuclear antibodies
North American referral uveitis clinic and has a strong ethnic (ANAs) and negative for rheumatoid factor. The onset of ocular
relationship. It is most common in Japan (20% of patients with disease is usually within 5 years of arthritis but may precede
uveitis) and prevalent in Middle Eastern countries along the arthritis as well. Biomicroscopically, bilateral fine keratic pre-
Silk Road. cipitates, band keratopathy (see Fig. 74.6), flare and cells in the
The classic complex includes aphthous stomatitis, genital anterior chamber, posterior synechiae, glaucoma, and cataract
ulceration, and iritis, sometimes with hypopyon (30% of patients) formation can be found. Topical and periocular corticosteroid
and skin lesions. Ocular manifestations can range from a hypopyon treatment with a slow taper is the mainstay of therapy. Systemic
anterior uveitis to intermediate uveitis, retinitis, and occlusive therapy with antimetabolites, such as methotrexate or myco-
retinal vasculitis (Fig. 74.9). Extraocular manifestations include phenolate, can be used to spare corticosteroids and may be
arthritis, erythema nodosum, diarrhea (mimicking IBD), and indicated to reduce the morbidity of chronic corticosteroid use.
sterile meningitis. There is a strong tendency for symptoms to A TNF inhibitor, such as adalimumab, is useful in patients with
38
remit and exacerbate spontaneously. HLA-B51 is more commonly refractory disease. Cataract surgery is a special challenge and
found among patients with Behçet syndrome. Behçet syndrome may require intense perioperative immunosuppression.

CHaPter 74 Immunological Ocular Disease 999



KeY COnCePt TABLE 74.4 systemic Immune-Mediated
Diseases associated With scleritis
Unilateral, recurrent, acute anterior uveitis is one of the most common
forms of uveitis; it is frequently associated with spondyloarthritis. Rheumatoid arthritis
Granulomatosis with polyangiitis
Inflammatory bowel disease
Polyarteritis nodosa
Temporal arteritis/giant cell arteritis
CLInICaL PearL Systemic lupus erythematosus
Ankylosing spondylitis
It is important to rule out infectious causes of uveitis before initiating Relapsing polychondritis
immunosuppression for uveitis.




Advancements and New Treatments for Uveitis
As molecular diagnostics, such as next-generation deep sequencing
techniques and bioinformatics, are becoming refined and more
broadly available, additional etiological agents for uveitis may
be discovered. Additionally, with an increased understanding of
the cellular pathways involved in various uveitic entities, new
targets for therapy of uveitis may emerge. For instance, targeting
IL-6 with a biologic agent versus targeting lymphocyte trafficking
to the eye via an antibody against adhesion molecules may
represent emerging therapies. Additional local drug delivery
methods may improve ocular efficacy while lowering systemic
side effects.

On tHe HOrIZOn
FIG 74.10 Diffuse Anterior Scleritis. The red patch of vessels
Newer molecular diagnostic techniques will improve identification of temporally is secondary to scleritis.
etiological agents in uveitis, and potentially direct novel treatments both
locally and systemically for uveitis.


SCLERITIS
Description and Natural History
Scleritis is a relatively uncommon inflammation affecting the
sclera, the white tunic that encases the eye, and the overlying
episcleral tissues. Scleritis is usually presumed to represent a
vasculitis of the deep episcleral vessels that overly the sclera. At
least one-third of patients with scleritis will have clinical evidence
39
for a systemic vasculitis elsewhere in the body. The most
common systemic diseases are granulomatosis with polyangiitis
(GPA; Chapter 58), previously known as Wegener granulomatosis
(often in a limited form), or rheumatoid arthritis (RA; Chapter
52). The subset of patients with RA who develop scleritis are
especially likely to develop rheumatoid nodules, high-titer
rheumatoid factor, and pleuropericarditis, as well as small vessel FIG 74.11 Scleromalacia Perforans. Blue sclera is visible
vasculitis of the lower extremities. Other systemic diseases com- secondary to inflammation, resembling a rheumatoid nodule in
monly associated with scleritis are listed in Table 74.4. The the eye.
epidemiology of scleritis has not been adequately reported.
However, RA accounts for about one-third of all cases of scleritis.
Because only 1% of patients with RA develop scleritis, and about painful and persistent condition. Even with treatment, median
1% of the population has RA, one can estimate that the prevalence duration reaches 5 years.
of scleritis is 0.01 × 0.01 × 3, or 3/10 000.
Scleritis is frequently divided into five subsets based on the Genetic and Environmental Factors
clinical presentation: diffuse anterior (Fig. 74.10); nodular Genetic factors affecting scleritis have not been adequately studied.
anterior; necrotizing; scleromalacia perforans (Fig. 74.11); and Genes that affect the associated systemic diseases, such as RA,
40
posterior scleritis. Scleromalacia perforans is also known as GPA, and polyarteritis nodosa (PAN), presumably also influence
necrotizing scleritis without inflammation. The clinical presentation susceptibility to scleritis. Environmental triggers for scleritis have
will vary according to the type, but scleritis is usually a very not been defined, except that some cases of scleritis can be a

1000 Part seven Organ-Specific Inflammatory Disease


manifestation of infection, such as herpes zoster ophthalmicus, In choosing to treat with oral corticosteroid or an immunosup-
syphilis, Lyme disease, tuberculosis, or other bacterial and fungal pressive, the clinician will, of course, weigh the risk/benefit ratio.
infections. The rationale for aggressive therapy is much stronger if the disease
is bilateral and is affecting activities of daily living, because of
Immunology and Pathology pain or reduction in acuity.
Biopsy of the sclera entails some risk. Accordingly, many of the
published histological observations are based on end-stage or
extremely severe disease. In one pathology study of 55 examples CLInICaL PearL
of necrotizing scleritis, the histology was divided into four types: Although noninfectious scleritis may be considered a vasculitis of the
zonal necrotizing granulomatous scleritis; nonzonal diffuse deep episcleral vessels, oral nonsteroidal antiinflammatory drugs (NSAIDs)
scleritis; necrotizing scleritis with microabscesses; and sarcoidal are effective in its treatment, and when the disease is refractory, oral
41
granulomatous scleritis. Eighty-five percent of patients with corticosteroids, antimetabolites, or biologics can be quite effective.
zonal necrotizing granulomatous pathology had a systemic disease,
usually rheumatoid arthritis. The pathology associated with RA
was not distinct from other systemic diseases, such as GPA. None Evaluation and Differential Diagnosis
of 19 patients with nonzonal diffuse scleral inflammation had Patients with scleritis generally have characteristic findings that
a systemic disease. Just over half the patients with microabscesses allow an accurate diagnosis; scleritis can usually be readily
had an identifiable infection as the cause of scleritis. Only one distinguished from other causes of a red, painful eye. The most
patient had “sarcoidal granulomatous inflammation,” and that difficult distinction is between scleritis and episcleritis. The
patient had sarcoidosis. differences between scleritis and episcleritis are highlighted in
Table 74.5.
Prevention and Management The scleritis associated with a systemic vasculitis is often more
44
Topical medications are only slightly beneficial for most patients severe than scleritis not associated with a systemic illness. The
with scleritis. Topical nonsteroidal antiinflammatory drugs scleritis associated with GPA may be particularly destructive and
(NSAIDs), such as ketorolac, have not been proven efficacious. refractory to therapy. Scleritis in association with RA is often a
A topical corticosteroid can sometimes help in symptomatic poor prognostic sign. Before the routine use of disease-modifying
control but also has risk, especially the promotion of cataract antirheumatic drugs, the small subset of patients with scleritis
formation and elevation of intraocular pressure. The role for in association with RA had a shortened life expectancy compared
topical cyclosporine has not been adequately evaluated, but the with those without evidence for ocular involvement.
authors’ clinical experience has not been favorable. Posterior scleritis can be an extremely difficult disease to
Although most forms of scleritis represent a vasculitis, oral diagnose. If the anterior sclera is uninvolved, no redness is present.
NSAIDs can be immensely beneficial. Although not all patients Pain with posterior scleritis is much more variable. The examina-
derive adequate control from oral NSAIDs, a subset will benefit tion may show elevation of the adjacent retina and choroid. The
sufficiently such that no other medication is required. We speculate diagnosis can be confirmed with an ultrasound examination or,
that the subset responsive to an NSAID might have a pathogenesis less commonly, with CT of the orbit demonstrating thickening
other than vasculitis, but this hypothesis remains unproven. of the sclera.
Many patients with scleritis will not benefit adequately from
an NSAID and will require immunosuppression. In general, Pitfalls and Controversy
for those with an associated systemic disease, pharmacologic Some experts believe that scleritis can sometimes be a forme
control of that disease will control the scleritis. For those without fruste of GPA. In patients with scleritis, a positive antineutrophil
a systemic illness, oral corticosteroids are an accepted initial cytoplasmic antibody (ANCA) test and no other evidence for
approach to treatment. For example, therapy might begin with GPA has been described. 45
a dose of prednisone of 1 mg/kg bodyweight per day. The use With the exception of the ANCA test, laboratory studies are
of calcium and vitamin D, as well as other measures to preserve generally selected according to the history and general physical
bone mineral density, should be considered for any patient who examination. For example, although RA is associated with scleritis,
will be receiving corticosteroid on a chronic basis. If prednisone the patients almost always have long-standing severe RA. A
is not adequate for disease control or if the medication is poorly rheumatoid factor and/or anticyclic citrullinated peptide antibody
tolerated and cannot be safely tapered to a modest dose, it is titer would not be appropriate tests if no joint disease were
reasonable to add a steroid-sparing medication. There is consider-
able interest in the use of biologic agents as corticosteroid-sparing
agents in scleritis. Multiple recently published case reports and TABLE 74.5 Contrasting Features of
small case series have described the successful use of drugs, scleritis and episcleritis
including TNF blockers or rituximab, in some patients with
resistant disease. 42 scleritis episcleritis
Locally injected corticosteroids may be effective for uveitis, Pain Prominent Minimal
but they are contraindicated for patients with necrotizing scleritis. Duration Years Days to months
The corticosteroid might enhance the likelihood that the necrotic Association with systemic disease Frequent Uncommon
sclera will perforate. However, for nonnecrotizing anterior scleral Vessels blanch with topical No Yes
inflammation, there is accumulating evidence that subconjunc- vasoconstrictor
43
tivally injected corticosteroid is safe and may be highly effective. Associated ocular complications, Sometimes Rarely present
including visual loss
present
Scleral inflammation limited to the posterior sclera can probably Vessel color Violaceous Light pink
be safely treated with a periocular corticosteroid injection.

CHaPter 74 Immunological Ocular Disease 1001


present clinically. The findings from one study, however, do The cornea is divided into five layers: the epithelium facing
support screening patients with scleritis with serological tests to the atmosphere, Bowman membrane, the stroma, Descemet
46
detect RA. Similarly, systemic lupus erythematosus (SLE) can membrane, and the endothelium abutting the aqueous humor.
be associated with scleritis, but one would not diagnose SLE on Opacification of the stroma is known as interstitial keratitis.
the basis of a positive ANA result, scleritis, and the absence of Congenital syphilis and other infections, such as herpes simplex,
other findings to suggest SLE. An erythrocyte sedimentation are important causes of the latter. Cogan syndrome is defined
rate (ESR) can sometimes be helpful in ensuring that a systemic as an autoimmune disease of the eighth nerve combined with
47
process is not present. Other laboratory tests are largely dictated interstitial keratitis, presumably on an autoimmune basis. Some
by the medication that is chosen to treat the scleritis. ophthalmologists also recognize autoimmune eighth-nerve disease
associated with other forms of ocular inflammation, such as
KERATITIS uveitis, as examples of Cogan syndrome. The pathogenesis of
Cogan syndrome is presumed to be a vasculitis, and many patients
The cornea is the anteriorly situated window to the eye. Normally, will have evidence for vasculitis elsewhere in the body. The
it should be clear. It can become opacified as a result of trauma, treatment usually requires aggressive use of systemic immunosup-
exposure to toxins, infection, dryness, calcium deposition, or pressive medications.
genetic diseases, such as corneal dystrophies. The three main
immune-mediated diseases that affect the cornea are peripheral CORNEAL TRANSPLANTATION AND
ulcerative keratitis (PUK) (Fig. 74.12), Mooren ulcer, and Cogan TRANSPLANT REJECTION
syndrome.
Most patients with PUK have a systemic disease, most com- Corneal transplantation involves the repair of a diseased cornea
monly RA, but can have SLE, GPA, or PAN. PUK is usually with healthy cadaver tissue. Since the 1970s, advances in micro-
concomitant with scleritis. Treatment is similar to that for scleritis, surgical techniques and eye banking procedures have led to
with emphasis on controlling the underlying systemic illness widespread acceptance of this procedure. Currently, more than
and aggressive use of immunosuppression. A complication of 40 000 corneal transplantations are performed annually in the
uncontrolled PUK is corneal melt, which can lead to corneal United States alone. The usual indication for a full-thickness
perforation. This is usually treated with antimetalloproteinases/ corneal graft is poor vision from deep stromal scarring. The
collagenases and surgically with tissue adhesives, conjunctival most common medical conditions leading to corneal transplanta-
flaps, and possibly corneal transplantation, in addition to aggres- tion are keratoconus, a condition in which myopic astigmatism
sive systemic immunosuppression, such as with rituximab. PUK develops as the cornea becomes progressively more conical in
is fortunately a very rare disease. PUK must also be distinguished shape; corneal edema following intraocular surgery; and a failed
from other causes of corneal thinning, such as Terrien marginal previous corneal graft.
degeneration or senile marginal furrow, both of which are gener- Although the eye is an immune-privileged site, and corneal
ally more benign and rarely lead to perforation. transplants enjoy a 91% 1-year survival as shown by Kaplan-Meier
Mooren ulcer is clinically very similar to PUK, except survival analyses, only 62% of grafts are functional at 10 years.
that there is no accompanying scleritis and no evidence for a The most common cause of transplantation failure is immuno-
systemic illness. The superior cornea is especially likely to be logic rejection. Corneal allograft rejection rarely occurs within
involved. Mooren ulcer is too rare for therapeutic options to 2 weeks, and may occur as late as 20 years after surgery. Animal
be studied in randomized clinical trials. It may respond to oral studies using monoclonal antibodies (mAbs) directed against
immunosuppression, which is warranted if the severity threatens different T-cell subsets indicate that CD4 T cells play a critical
visual acuity because of impending corneal perforation. Some role in the rejection response. However, the mechanisms respon-
patients with Mooren ulcer have an autoantibody to calgranulin sible for this process are still being studied.
C. This antigen is expressed in the cornea, in neutrophils, and by Early recognition of a rejection episode is the most important
filarial nematodes. factor in achieving survival of the corneal transplant. In its most
florid form, the anterior eye is obviously inflamed, with intense
conjunctival injection, a cellular anterior chamber reaction, and
a Khodadoust line. This line, which is visible with the slit-lamp
biomicroscope, is a classic sign of corneal graft rejection. It appears
as a linear formation of inflammatory precipitates stretching across
the corneal endothelium and represents a wave of lymphocytes
marching across the cornea and destroying the endothelium
in their path. As endothelial pump function is lost, the cornea
becomes waterlogged and opaque. At an early stage of rejection,
the patient may be asymptomatic, but later, ocular redness,
photophobia, halos, and blurred vision are frequent complaints.
An intensive and extended course of topical corticosteroids
is the mainstay of treatment for a rejecting corneal graft, and
in severe cases intravenous and/or oral corticosteroids may also
be administered. Patients considered at high risk of transplant
rejection, such as those with corneal neovascularization or a
history of other anterior segment inflammation, are often given
FIG 74.12 Corneal Melt. A pie-shaped wedge of the cornea is perioperative systemic immunosuppression. The ideal prophylactic
thinned. The eye is red secondary to an associated scleritis. regimen has not been defined, although various combinations

1002 Part seven Organ-Specific Inflammatory Disease


of prednisone, cyclosporine, and azathioprine may be used. malignancy, ocular metastatic tumor spread and the effects of
Despite the critical influence of donor–recipient histocompat- drugs, including chemotherapy agents, must be excluded before
ibility matching for solid organ transplant survival, the chance CAR is diagnosed.
of corneal graft survival is not significantly improved by HLA The natural history of CAR is one of progressive visual loss,
matching. although this occurs over a variable period. Corticosteroid and
Corneal transplantation has traditionally been accomplished other immunosuppressive drugs have been successfully used to
51
by penetrating keratoplasty, in which all layers of the cornea are treat the ocular disease. It is suggested that serum antibody
simultaneously replaced. Many centers are increasingly performing levels can be monitored to guide therapy. In some cases, advanced
lamellar keratoplasty, in which layers of the cornea, such as the photoreceptor damage can be irreversible despite therapy.
endothelium and Descemet membrane, are selectively trans-
48
planted. Descemet membrane endothelial keratoplasty (DMEK) IMMUNOLOGIC ETIOLOGIC FACTORS IN
is an example of endothelial keratoplasty. Although technically “NONIMMUNOLOGIC” OCULAR DISEASE
more challenging, lamellar keratoplasty results in faster visual
recovery and a reduced likelihood of transplant rejection. Age-related macular degeneration (ARMD) is the leading cause
of irreversible visual loss in older persons in Western nations.
CANCER-ASSOCIATED RETINOPATHY A spectrum of pathologies can occur at the macula, ranging
from relatively benign lipid deposits, called drusen, to the
Cancer-associated retinopathy (CAR) is a rare paraneoplastic sometimes visually devastating retinal pigment epithelium atrophy
syndrome that is most commonly associated with small cell or subretinal/choroidalneovascular membranes. The pathogenic
49
carcinoma of the lung. In addition, the disease has been docu- stimulus for these age-related changes is unknown. Genetic
mented in association with various tumors of the female polymorphisms of the complement regulatory protein, comple-
reproductive tract, carcinoma of the breast, and neuroendocrine ment factor H, influences the susceptibility to ARMD, suggesting
52
bronchial carcinoma. For 50% of patients, CAR is the presenting that this disease is related to chronic inflammation. Subretinal
feature of their malignancy. Interestingly, there are now reports scar tissue removed from patients with advanced, neovascular
of retinopathy mimicking CAR but occurring in an apparently disease may contain immunoglobulins and complement com-
healthy individual. Melanoma-associated retinopathy is a related ponents. The histopathology of ARMD includes inflammatory
syndrome, occurring in patients with metastatic cutaneous cells, including lymphocyte subsets, and local cell populations
melanoma. can express class II MHC antigens. Inhibition of complement
Histopathological examinations of postmortem specimens activation is under study to treat or prevent ARMD.
taken from patients with CAR consistently demonstrate loss of
inner and outer segments of the retinal photoreceptors. This Please check your eBook at https://expertconsult.inkling.com/
destruction was initially attributed to the release of a hormone-like for self-assessment questions. See inside cover for registration
substance by malignant cells, but evidence has now accumulated details.
in support of an autoimmune etiology. Affected individuals
produce antibodies against one or more retinal photoreceptor
50
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corticosteroids (VISUAL II): a multicentre, double-masked, randomised, 39. Raiji VR, Palestine AG, Parver DL. Scleritis and systemic disease
placebo-controlled phase 3 trial. Lancet 2016;388:1183–92. association in a community-based referral practice. Am J Ophthalmol
18. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in Patients with Active 2009;148:946–50.
Noninfectious Uveitis. N Engl J Med 2016;375:932–43. 40. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol
19. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory 1976;60:163–91.
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2009;127:819–22. cases. Ophthalmology 1999;106:1328–33.
20. Brewerton DA, Caffrey M, Nicholls A, et al. Acute anterior uveitis and 42. Suhler EB, Lim LL, Beardsley RM, et al. Rituximab therapy for refractory
HL-A 27. Lancet 1973;302:994–6. scleritis: results of a phase I/II dose-ranging, randomized, clinical trial.
21. Rosenbaum JT. Acute anterior uveitis and spondyloarthropathies. Rheum Ophthalmology 2014;121:1885–91.
Dis Clin North Am 1992;18:143–51. 43. Albini TA, Zamir E, Read RW, et al. Evaluation of subconjunctival
22. Munoz-Fernandez S, Hidalgo V, Fernandez-Melon J, et al. Sulfasalazine triamcinolone for nonnecrotizing anterior scleritis. Ophthalmology
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23. Braun J, Baraliakos X, Listing J, et al. Decreased incidence of anterior rheumatoid arthritis and with other systemic immune mediated diseases.
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necrosis factor agents infliximab and etanercept. Arthritis Rheum 45. Hoang LT, Lim LL, Vaillant B, et al. Antineutrophil cytoplasmic
2005;52:2447–51. antibody-associated active scleritis. Arch Ophthalmol 2008;126:651–5.
24. Haroon M, O’Rourke M, Ramasamy P, et al. A novel evidence-based 46. Lin P, Bhullar SS, Tessler HH, et al. Immunologic markers as potential
detection of undiagnosed spondyloarthritis in patients presenting with predictors of systemic autoimmune disease in patients with idiopathic
acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool). Ann scleritis. Am J Ophthalmol 2008;145:463–71.
Rheum Dis 2015;74:1990–5. 47. Cogan DG. Syndrome of nonsyphilitic interstitial keratitis and
25. Rudwaleit M, van der Heijde D, Landewe R, et al. The Assessment of vestibuloauditory symptoms. Arch Ophthalmol 1945;33:144–9.
SpondyloArthritis International Society classification criteria for 48. Liu S, Veldman P. Evidence-based endothelial rehabilitation. Semin
peripheral spondyloarthritis and for spondyloarthritis in general. Ann Ophthalmol 2017;32:96–103.
Rheum Dis 2011;70:25–31. 49. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic
26. Juanola X, Loza Santamaria E, Cordero-Coma M, et al. Description and characterization of paraneoplastic and autoimmune retinopathies
Prevalence of Spondyloarthritis in Patients with Anterior Uveitis: The associates with antienolase antibodies. Am J Ophthalmol
SENTINEL Interdisciplinary Collaborative Project. Ophthalmology 2005;139:780–94.
2016;123:1632–6. 50. Thirkill CE, Keltner JL, Tyler NK, et al. Antibody reactions with retina
27. Salmon JF, Wright JP, Murray AD. Ocular inflammation in Crohn’s and cancer-associated antigens in 10 patients with cancer-associated
disease. Ophthalmology 1991;98:480–4. retinopathy. Arch Ophthalmol 1993;111:931–7.
28. Lyons JL, Rosenbaum JT. Uveitis associated with inflammatory bowel 51. Ferreyra HA, Jayasundera T, Khan NW, et al. Management of
disease compared with uveitis associated with spondyloarthropathy. Arch autoimmune retinopathies with immunosuppression. Arch Ophthalmol
Ophthalmol 1997;115:61–4. 2009;127:390–7.
29. Ibrahim G, Waxman R, Helliwell PS. The prevalence of psoriatic arthritis 52. Hughes AE, Bridgett S, Meng W, et al. Sequence and expression of
in people with psoriasis. Arthritis Rheum 2009;61:1373–8. complement factor H gene cluster variants and their roles in
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and mediastinoscopy in the diagnosis of sarcoidosis-associated uveitis.
Am J Ophthalmol 1998;126:132–4.

CHaPter 74 Immunological Ocular Disease 1003.e1


MUL t IPL e -CHOIC e QU est IO ns

1. What is anterior chamber–associated immune deviation B. Seldom associated with systemic disease
(ACAID)? C. Associated with spondyloarthritis without prior recognition
A. Uveal or lens proteins, when exposed to the immune system, 40% of the time
result in a robust reaction against these self antigens D. None of the above
B. When an autoimmune process only affects the eye, but E. A and C
no other tissue 3. Juvenile idiopathic arthritis (JIA)–associated uveitis:
C. Describes ocular immune privilege; antigens injected into A. Often presents with pain, redness, photophobia
the anterior chamber induce selective suppression of B. Causes a smoldering asymptomatic bilateral uveitis most
antigen-specific T-lymphocyte responses commonly
D. When viral infections affect only the anterior chamber C. Is typically associated with polyarticular arthritis in
but not the vitreous or retina
antinuclear antibody (ANA)–negative patients
2. Acute anterior uveitis is: D. Cannot be treated with anti–tumor necrosis factor (TNF)
A. Associated with human leukocyte antigen B27 (HLA-B27) treatment
positivity 50% of the time

75






Immunological Diseases of the

Gastrointestinal Tract



Peter J. Mannon






The gastrointestinal (GI) tract contains the largest mass of pylori infection (up to 30%) occur in PA, with antigastric antibod-
immune cells of any organ in the body. To manage the continuous ies present in up to 65% of patients with H. pylori infection
3
exposure to environmental and dietary antigens as well as (and none in noninfected patients with gastritis). In addition,
+
pathogens, commensal microbes, and their metabolic products, gastric mucosal CD4 T cells can display cross-reactivity to H -
+
4
the gut uses a number of strategies that support mucosal structural K -ATPase and H. pylori antigens. The actual identity of H.
integrity and immune regulation to maintain homeostasis. In pylori infection as the major causal link to PA has not been
spite of these defenses, the GI tract is susceptible to chronic established.
immune-mediated inflammation from pathogens, autoimmunity,
and immunodeficiency. This chapter discusses some of the most Helicobacter pylori Gastritis
frequent immunological diseases of the GI tract likely to be H. pylori infection of the gastric mucosa has been identified as the
encountered in the clinic, including autoimmune gastritis, chronic leading cause of peptic ulcer disease and is a WHO-designated
Helicobacter pylori gastritis, celiac disease, inflammatory bowel class I carcinogen for gastric carcinoma. Current data consistently
diseases (IBDs; Crohn disease, ulcerative colitis [UC], microscopic show that primary infection is largely acquired in childhood,
colitis, and eosinophilic esophagitis) and GI complications of at which stage in life poor sanitation enhances acquisition via
5
primary immunodeficiency. The coverage focuses on the clinical fecal/gastrooral pathways. Although acute infection can cause
presentation, mechanisms of disease, and approaches to diagnosis abdominal pain and dyspepsia, there is typically no clinical
and treatment of these conditions. recognition of acute infection. Rather, the burden of H. pylori
results from chronic infection of the stomach; H. pylori is uniquely
GASTRITIS adapted to the acidic environment of the stomach through
its ability to metabolize urea to ammonia, which provides a
Gastritis is a histological term that describes stomach inflam- buffered microenvironment that allows prolonged asymptomatic
mation resulting from toxic exposures, infection, idiopathic colonization.
inflammation, and autoimmunity. Although symptoms tend to The ability of H. pylori to confer risk of peptic ulcer disease
be very nonspecific, the etiology and treatment of gastritis can in 15% of chronically infected persons has been linked to H.
be extremely specific, particularly for H. pylori infection, which pylori infection lowering the mucus pH adjacent to the gastric
has important implications for outcomes and natural history. epithelium and increasing the permeability of the mucus to
hydrogen ions. In addition to inhibition of bicarbonate secretion
Atrophic Gastritis/Pernicious Anemia by the epithelium, expression of cytotoxins (vacuolating cytotoxin,
The most classic autoimmune disease of the GI tract is atrophic VacA) and upmodulation of the mucosal inflammatory response
gastritis characterized by antiintrinsic factor and antiparietal cell by virulence factors, such as CagA, may contribute to pathogenesis.
autoantibodies and an association with autoimmune thyroiditis, The recognition of H. pylori as a causative agent in the vast
1
vitiligo, and type I diabetes. Loss of acid-producing parietal cells majority of recurrent peptic ulcers and that its elimination could
leads to atrophic gastritis or “pernicious anemia (PA).” The age-old cure this disease led to the Nobel Prize in Medicine or Physiology
stereotype of the patient with atrophic gastritis/PA is an older to Marshall and Warren in 2005.
Caucasian woman with progressive effects of iron and vitamin The development of peptic ulcer disease and adenocarcinoma
B 12 deficiency. However, a female preponderance (approximately caused by chronic H. pylori infection correlates with the anatomi-
2 : 1) notwithstanding, 25% of cases are diagnosed below age 50 cal distribution of inflammation. When H. pylori chronic gastritis
years, and disease does occur in African and Asian ethnicities. affects the antrum predominantly, there is an association with
The detection of both antiintrinsic factor and antiparietal cell duodenal ulcers, increased serum gastrin levels and excess acid
6
serum antibodies has 73% sensitivity and 100% specificity for PA. 2 production, and no gastric mucosal atrophy. However, when
+
+
Murine models suggested that induced immunity to H -K - H. pylori affects the body and the antrum in a confluent or
ATPase (the parietal cell membrane protein that secretes H ions patchy manner, intestinal metaplasia develops, oxyntic mucosa
into the gastric lumen) may result in PA. Although potentially atrophies, and acid production decreases. This latter type of
+
+
pathogenic H -K -ATPase–responsive CD4 T cells can be isolated H. pylori chronic gastritis is associated with gastric ulcerations
from the gastric mucosa of patients with PA, it remains unclear and increased risk for adenocarcinoma and mucosa-associated
how these cells arise, but observations implicate a role for H. lymphoreticular tissue (MALT) B-cell lymphoma. Although
pylori infection. Antral inflammation (up to 92%) and mucosal eradication of H. pylori can reverse the mucosal atrophy and
atrophy (up to 30%) together with histological evidence of H. restore acid production in this setting, mucosal restoration occurs
1005

1006 Part seven Organ-Specific Inflammatory Disease


only in a minority of patients and does not necessarily reverse the On tHe HOrIZOn
intestinal metaplasia. Histologically, this form of atrophic gastritis
is differentiated from primary autoimmune atrophic gastritis by Gastritis
the presence of H. pylori organisms in the specimen (and concur- • Development of an ultimate Helicobacter pylori eradication treatment
rent involvement of the antrum). Specific immunohistochemical with easy global implementation yet without significant adverse effects
methods for detecting H. pylori are required when organisms or antibiotic resistance issues.
are not seen on hematoxylin and eosin staining, when intestinal
metaplasia occurs widely (H. pylori does not colonize intestinal
metaplasia heavily), or when confirming H. pylori eradication CELIAC DISEASE
7
after antibiotic treatment. Although there are many pieces of
evidence to support immune mechanisms for the persistence of Celiac disease (also known as gluten enteropathy) is the most
8
HP infection in the stomach, data suggest that pro-regulatory prevalent immune-mediated disease of the human GI tract. Gluten
effects of H. pylori infection, including local IL-10 production, peptide–specific T cells drive specific autoantibody formation,
increases in regulatory T cells (Tregs) in the gastric mucosa and small intestinal villus atrophy, and malabsorption caused by
increased antigen-presenting cell (APC) phagocytosis of apoptotic subsequent intestinal surface injury. The identification of the
cells all contribute to persistence of chronic H. pylori gastritis. 9-11 specific antigen-presenting human leukocyte antigen (HLA)
The indications for diagnosis and treatment of active H. pylori molecules and the gluten peptide cognate ligands that activate the
infection include active gastroduodenal ulcer disease, gastric MALT T cells have advanced the understanding of the pathophysiology
lymphoma, and, in highly endemic areas, dyspepsia symptoms and genetics of celiac disease and are driving innovative therapies.
(upper abdominal pain, bloating, early satiety, and nausea). Active
disease can be diagnosed with endoscopic biopsy, which has Presentation
high sensitivity and specificity, while simultaneously assessing The classic clinical presentation of celiac disease—chronic
12
peptic and malignant complications. Noninvasive testing for diarrhea, weight loss, and abdominal bloating—results from
H. pylori infection includes serum antibody detection (best used defective nutrient absorption by the small intestine as a result
in highly endemic areas to predict active infection), urea breath of inflammatory injury. However, patients with celiac disease
testing (limited by expense and possible false-positive results), are more likely to present with complications of nutrient
and fecal antigen testing (which has potential advantages in the deficiency (anemia, osteoporosis, failure to thrive in children)
setting of intestinal metaplasia and after antibiotic treatment). without overt GI complaints. Celiac disease can also present
Once H. pylori infection is diagnosed, there are many effective with a gluten-reactive skin eruption (dermatitis herpetiformis),
eradication therapies that need to be tailored to patients’ drug cerebellar ataxia, infertility and miscarriage, chronic fatigue, and
tolerance and allergy history as well as local antibiotic resistance associated autoimmune disorders, such as diabetes and thyroiditis,
patterns. In general, a 14-day course with a proton pump inhibitor Addison disease, Sjögren syndrome, autoimmune hepatitis, and
15
(histamine 2 [H2] blockers may be substituted) and two antibiot- primary biliary cirrhosis. A high frequency of nonspecific GI
ics (clarithromycin with amoxicillin or metronidazole) is recom- symptoms, such as abdominal pain and constipation, reported in
13
mended as first-line treatment. Alternative regimens, including over one-fifth of newly diagnosed subjects, complicates targeted
bismuth or sequential therapy, may be needed in cases of antibiotic disease screening. The variations of celiac disease presentation
resistance. Eradication of infection can be confirmed by either may reflect several features: (i) celiac disease severity follows
invasive or noninvasive (but not serum antibody) methods. In a dose effect of risk alleles; (ii) the actual occurrence of celiac
addition to the cure of recurrent gastroduodenal ulcer disease, disease requires genetic and environmental factors in addition to
eradication of H. pylori can cause regression of gastric MALT the well-characterized HLA molecules; (iii) celiac disease expres-
14
lymphoma in a majority of coinfected patients. Investigation sion depends on the quantity and quality of gluten exposure;
continues into enhancing eradication or preventing chronic and (iv) celiac disease complications reflect the severity of the
16
infection through targeting molecules critical for H. pylori survival inflammation and the length of involved bowel. The concept of
in the gastric environment as well as vaccine strategies. a vast subclinical celiac disease prevalence has led to an “iceberg
model,” where the visible tip is the group with symptomatic GI
disease and the characteristic gut mucosal lesion, and below the
KeY COnCePts surface are those with silent disease (no overt symptoms but gut
Gastritis mucosal lesions) and latent disease (no symptoms or mucosal
lesions but genetic susceptibility possibly with positive serology).
• Atrophic gastritis/Pernicious anemia results from loss of the acid- The key to diagnosing celiac disease is simply to consider it
producing cells of the gastric body and is associated with antiparietal in the differential diagnosis of classic gut malabsorption as well
cell antibodies, an intact antral gastric mucosa, and no evidence of as subtle manifestations of malabsorption (e.g., unexplained iron
Helicobacter pylori infection. deficiency anemia). Conversely, the differential diagnosis of villus
• However, H. pylori infection has been linked to atrophic gastritis/perni- blunting or intraepithelial lymphocytosis includes small-intestinal
cious anemia via increased rates of antigastric antibodies, autoantibodies
to H -K -adenosine triphosphatase (ATPase), and gastric mucosal CD4 bacterial overgrowth, tropical sprue, autoimmune enteropathy,
+
+
+
T cells with cross-reactivity to H -K -ATPase and H. pylori antigens. common variable immunodeficiency (CVID) enteropathy, and
+
• H. pylori infection of the stomach is chronic because of metabolic H. pylori gastritis, emphasizing that celiac disease is also not
and immune adaptations by the pathogen that allow persistence in solely a histological diagnosis.
the acidic gastric environment.
• H. pylori infection is a leading cause of peptic ulcer disease and a Immune Pathophysiology
World Health Organization (WHO) class I carcinogen because of its
link to gastric adenocarcinoma. Celiac disease results from the activation of T cells by gluten
peptide–MHC complexes on APCs in the lamina propria of the

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1007


gut (primarily the small intestine). In the absence of dietary specificity), it remains important for several reasons: (i) Currently,
gluten or the specific MHC molecules HLA-DQ2 or -DQ8, celiac the serologic markers should only be used as a screening test,
disease, theoretically, cannot occur. Dietary gluten, largely from identifying which patients are at highest risk for the disease and
wheat, barley, and rye, exists in polymeric (glutenin) and appropriate for biopsy confirmation; (ii) even in the presence
monomeric (gliadin) form and is incompletely digested to small of celiac-susceptible HLA genes, only a minority of persons will
peptides by gut luminal enzymes because of their high glutamine develop celiac disease (latent disease), so evaluating nonspecific
16
and proline content. These large gluten peptides cross the symptoms will require histological examination; and (iii) because
epithelial barrier and bind to the specific HLA-DQ2 or -DQ8 the treatment can be life altering, the most comprehensive
molecules. The enzyme tissue transglutaminase can deamidate information is needed to make a definitive diagnosis.
gluten peptides, and the resulting negatively charged gluten Beyond celiac disease, a true gluten-induced enteropathy, other
peptides actually have increased affinity for the HLA binding gluten-centric entities have been identified, namely, non–celiac
site. Gut microbes also can affect the immunogenicity of gluten disease gluten sensitivity and IgE-mediated gluten allergy.
17
peptides via their own proteolytic enzymes. The gluten peptide- Non–celiac disease gluten sensitivity includes a set of poorly
activated T cells produce proinflammatory cytokines interferon-γ characterized gut and extraintestinal symptoms that lack the
(IFN-γ), interleukin-18 (IL-18), tumor necrosis factor (TNFGr-), defining features of celiac disease yet respond to a gluten-free
22
and IL-21. The activated T cells also induce B-cell maturation diet (GFD). Increased levels of serum markers for bacterial
to plasma cells producing antibodies to gluten peptides as well translocation (lipopolysaccharide [LPS]-binding protein, soluble
as the tissue transglutaminase. The reason for tissue transglu- CD14) and epithelial damage (circulating fatty acid binding
taminase being targeted for autoantibody production and its protein 2) that is reversed following a wheat-free diet in a subset
role in disease is unknown. of subjects suggests altered gut permeability related to wheat and
According to animal models, the activated T cells are not cereal exposure may be a factor contributing to symptoms. 23
sufficient to induce the epithelial damage and villus blunting.
The characteristic villus atrophy is induced by gut APC- and Treatment
epithelial cell–produced IL-15, which enhances infiltration of The treatment of celiac disease is avoidance of gluten, specifically
CD8 T cells into the epithelium and upregulates NKG2D receptors foods containing wheat, barley, and rye. The expected response
on intraepithelial T lymphocytes (IELs) conferring cytotoxicity to gluten restriction is the resolution of symptoms and malabsorp-
against the epithelium. More recently, it was found that the IEL tion. Follow-up endoscopy to assess response to therapy should
signaling induced by NKG2D ligands MICA/B upregulated on be done only after 6–12 months of a strict GFD, although full
epithelial cells stimulates a leukotriene pathway (together with recovery of the villus mucosa may take several years. There are
IL-15 exposure) that itself produces cysteinyl leukotrienes (CystLT) no accurate biomarkers to monitor adherence to a GFD, although
that appear to drive the IEL-based killing. The impact of this one indication may be a fall in the pretreatment level IgA anti-TTG
observation is the possible use of montelukast, a CystLT inhibitor serum antibodies; therefore, follow-up endoscopy with biopsy
and drug widely used in allergic asthma, to treat celiac disease. 18 is needed to document restoration of the villus architecture.
Beyond the HLA associations with disease, genome-wide Symptom improvement, correction of malabsorption, and
association studies (GWAS) have linked over 30 disease susceptibil- regrowth of villi (seen by endoscopy or video capsule) may not
ity loci with non-HLA regions. One such locus is a polymorphism reflect complete full histological healing, yet the long-term risk
in lnc13, a long noncoding RNA, which affects its binding with of partial histological recovery is unknown.
a heterogeneous nuclear ribonucleoprotein to undo its repression About 5% of patients with celiac disease do not respond to
of other genes, including inflammatory mediators. 19 a GFD. Ensuring a strict adherence to a GFD is important to
identify the reasons for nonresponse, whether through inadvertent
Diagnosis gluten exposure or whether the inflammation is truly refractory
The diagnostic workup of celiac disease is initiated by both to a strict GFD. One group of patients with the so-called refractory
suggestive symptoms and signs (weight loss, chronic diarrhea) celiac disease with polyclonal IEL populations may respond to
as well as by atypical presentations, such as specific micronutrient corticosteroids and immunosuppressant treatment; another group
deficiencies or unexplained hyperamylasemia or hypertransami- with monoclonal IELs do not respond to such treatment and
20
nasemia. Initial tests include measuring serum immunoglobulin are at increased risk of lymphoma. 24
A (IgA) antibodies against tissue transglutaminase and endomysial The majority of patients with celiac disease respond positively
proteins, which have an estimated specificity/sensitivity of to a GFD with return of normal gut absorption. However, ongoing
21
95%/95% and 100%/>90%, respectively. It is necessary to inflammation is associated with risk of small bowel lymphoma,
measure a total serum IgA level at the same time to be certain so ensuring adherence to a GFD and documenting mucosal
that these IgA-based screening tests do not yield false–negative healing can affect the natural history of this disease. Finally,
results. However, in the setting of IgA deficiency (where celiac since first-degree relatives are at increased risk of celiac disease,
disease has an increased incidence), elevated IgG anti–tissue patients should be advised of serum antibody screening of these
transglutaminase (TTG) or deamidated gliadin levels and family members.
identification of celiac disease susceptibility HLA genes can help
determine the risk and presence of disease. CROHN DISEASE
In any case, an important part of celiac diagnosis is biopsy
of the upper small intestine mucosa (Fig. 75.1B,C); typically Crohn disease is a chronic idiopathic inflammation of the gut
three to four endoscopic biopsy specimens are obtained from characterized by transmural involvement of the bowel wall
both the duodenal bulb and the distal duodenum. Although the (mucosa, muscle layer, and serosa) (Fig. 75.1D). Although often
absolute requirement for histological diagnosis of celiac disease referred to as “terminal ileitis,” the majority of patients with
may be debated (and cannot be used alone because of lack of Crohn disease have colonic inflammation in addition or solely.

1008 Part seven Organ-Specific Inflammatory Disease












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&URKQ¶V GLVHDVH FRORQ 8OFHUDWLYH FROLWLV &9,' HQWHURSDWK\
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FIG 75.1 Gastrointestinal Histology in Health and Immune-Mediated Disease. (A) Normal
duodenal histology. (B) Celiac disease with blunted villus, increased plasma cell infiltrate, increased
intraepithelial lymphocytes. (C) CD3 staining in celiac disease showing increased intraepithelial
lymphocytes. (D) Crohn colitis showing mucosa expanded with lymphoplasmacytic infiltrate and
two granulomata. (E) Ulcerative colitis showing crypt dropout, cryptitis, crypt abscess, and
lymphoplasmacytic infiltrate. (F) Common variable immunodeficiency (CVID) enteropathy showing
villus blunting, increased intraepithelial lymphocytes, and epithelial apoptosis. (Photomicrographs
courtesy of Dr. Leona Council, Department of Pathology, University of Alabama at Birmingham,
Birmingham, Alabama, USA.)





KeY COnCePts Crohn disease typically runs a chronic, relapsing course often
Celiac Disease complicated by bowel obstruction as a result of fibrous strictures
as well as abscesses and fistulae caused by extension of inflam-
• Patients with celiac disease present more often with complications mation beyond the bowel wall. Most of these patients will require
of malabsorption than chronic diarrhea and weight loss. surgical treatment at rates up to 80% after 20 years’ disease
• Human leukocyte antigen (HLA)-DQ2 or -DQ8 alleles are necessary duration. Crohn disease is treated with corticosteroids and
but not sufficient for celiac disease to develop, as they are present immunosuppressants and more recently with antibodies targeting
in more persons unaffected by celiac disease. TNF-α and the integrin molecules α 4 and α 4 β 7 .
• Immunoglobulin A (IgA) antibodies to tissue transglutaminase and The cause of Crohn disease is unknown, but it is thought to
endomysial proteins should be used for screening only (not diagnosis) result from a dysregulated immune response to gut microbes.
and should be measured along with total IgA for validity.
• The goals of gluten-free diet treatment are relief of symptoms, reversal There is clear evidence for heritable disease susceptibility in twin
of malabsorption, and restoration of villi. and multiplex family studies, and several genes involved in innate
immune function, notably mutations in NOD2, have been linked
to Crohn disease risk. However, it seems clear that the complex
interactions of environmental exposures (including the gut
microbiome and its metabolome), innate and adaptive immune
On tHe HOrIZOn dysfunction, and complex genetic and epigenetic features are all
25
complicit in disease causation and expression.
Celiac Disease
Presentation
• Discovery of additional genetic and environmental factors (beyond
gluten) that strongly confer risk for celiac disease in the setting of Patients with Crohn disease most often come to medical attention
human leukocyte antigen (HLA)-DQ2 and -DQ8 alleles leading to because of abdominal pain, altered bowel habits, and rectal
strategies to modify or eliminate that risk bleeding. Abdominal pain may indicate bowel obstruction
• Novel therapies that modify gluten to nonimmunogenic forms or that (especially if the pain is postprandial), an inflamed viscus, or a
induce tolerance to gluten in persons at risk for or suffering from penetrating complication, such as an abscess or fistula. Diarrhea
celiac disease or are alternatives to a gluten-free diet is related to malabsorption and dysmotility secondary to the
• Identification of specific celiac disease–relevant components of the
microbiome that influence the expression of disease effects of inflammatory cytokines on gut function. Diarrhea can
also result from noninflammatory mechanisms (bile salt wasting,

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1009


small intestinal bacterial overgrowth, etc.). Conversely, constipa- IFN-γ, IL-12, IL-23, and IL-17. The anti–IFN-γ monoclonal
tion in Crohn disease can be a sign of stricturing of the bowel. antibody (mAb) fontolizumab showed no clinical efficacy in
Rectal bleeding results from mucosal friability and ulceration. Crohn disease (but did decrease C-reactive protein [CRP]
34
In addition, fever, unexplained weight loss, fatigue, anemia, and levels ). However, anti–IL-12/-23 p40 subunit mAbs targeting
growth retardation (in children) can accompany the GI complaints the Th1 and Th17 pathways resulted in clinical improvement
or even be the primary presentation. Extraintestinal manifestations that led to the current use of ustekinumab for Crohn disease. 35,36
of Crohn disease include arthritis, uveitis, inflammatory skin Unexpectedly, antibodies targeting IL-17A alone (secukinumab)
lesions (pyoderma gangrenosum and erythema nodosum), and or the IL-17AR receptor subunit (transducing IL-17A, -17E,
stomatitis. The arthritis can affect the axial (spine and pelvis) and -17F intracellular signals) either did not show clinical
and articular skeleton, with the latter more often mirroring the improvement (and was associated with increased fungal infec-
37
activity of the gut disease. The joint complaints range from usual tions ) or even induced clinical deterioration (the anti–IL-17AR
arthralgias to frank synovitis with swelling and tenderness antibody).
(without erosive joint destruction). The uveitis most commonly To date, it is estimated from multiple genome polymorphism
occurs as episcleritis and iritis. Many of these lesions will subside studies that over 160 IBD susceptibility loci exist, most associated
with effective therapy aimed at the gut, but they can also have with risk of both Crohn disease and UC, 30 loci associated only
independent courses that require site-targeted treatment. with Crohn disease, and 23 loci associated only with UC. However,
The incidence of Crohn disease in North American populations it was further estimated that all the loci together could account
has been estimated to be ≈3.1–14.6 cases/100 000 person-years. for no more than 13.6% of Crohn disease and 7.5% of UC
38
Ashkenazi Jewish heritage confers increased risk in Caucasians, disease risk. Although most of these loci are in the noncoding
whereas African Americans seem to have rates similar to those regions of genes thought to modulate gene expression, the actual
of non-Jewish Caucasians, and Hispanics and Asians have much genes implicated have roles in the immune response and epithelial
lower rates. 26,27 There is a genetic risk with up to 10-fold increased integrity, providing biological plausibility for their involvement
rates of IBD in relatives of patients with Crohn disease and a in IBD. Several examples stand out: (i) the NOD2 gene, encodes
28
30% concordance rate in monozygotic twin pairs. The typical an intracellular protein that binds muramyl dipeptide (MDP),
patient is diagnosed in his or her second or third decade, and a component of the bacterial cell wall TLR2 ligand peptidoglycan.
there is no significant gender preference. The only environmental Disease-associated mutations in the MDP-sensing leucine-rich
exposure that has been repeatedly linked to risk of Crohn disease repeat domain of NOD2 are associated with defective activation
has been tobacco use. of nuclear factor (NF)-κB. This disrupts the microbe recognition
The majority (up to 70%) of Crohn patients experience a pathway, but because NOD2 is also expressed by small intestinal
remitting and relapsing course, but some have chronically active epithelial Paneth cells, mucosal production of antimicrobial
symptoms refractory to medication. The recognized phenotypes defensins is decreased as well. (ii) The ATG16L1 autophagy gene
of disease include inflammatory (manifesting primarily as is important for the metabolism of autologous cell proteins as
intestinal edema and ulceration), fibrostenotic (luminal narrowing well as intracellular microbes. Expression of the Crohn disease–
by fibrous strictures dominate with symptoms of painful obstruc- associated Thr300Ala polymorphic ATG16L1 sequence in a colon
tion), and fistulizing (inflammatory tracts between the bowel cancer cell line showed in vitro inhibition of packaging of
and other intestines, the bladder, vagina, skin, and other struc- intracellular Salmonella into autophagosomes, supporting the
tures). Although the majority of patients have inflammatory hypothesis that this mutation could lead to impaired clearance
39
disease at the time of diagnosis, over time this phenotype changes of microbes and chronic inflammation. This ATG16L1 poly-
so that after 20 years of disease duration, up to 70% and 18% morphism provides a caspase cleavage site that enhances degrada-
40
of patients with Crohn disease report penetrating and fibrostenotic tion of this allele and leads to defective autophagy. (iii) A
29
complications, respectively. Accompanying this change in polymorphism in the coding region of the IL-23 receptor gene
phenotype is the need for surgical treatment in most patients (Arg381Gln) found in 14% of healthy controls is associated with
after 20 years of disease duration. protection from Crohn disease (less so UC) and is associated
with decreased Th17 cascade effector cells. 41
Immune Pathophysiology The emergence of the role of the commensal microbiota in
The current paradigm of Crohn disease inflammatory origins immune homeostasis has produced renewed interest in its role
is a dysregulated immune response to gut commensal microbial in IBD, where a number of studies show a dysbiosis compared
components (antigens and pathogen-associated molecular with the healthy gut microbiota. This change in the microbiota
patterns). Initial rodent colitis models showed a predominant in IBD has been characterized as a flipping of the Bacteroidetes-
42
T-helper cell-1 (Th1) inflammation, where the colitis could be to-Firmicutes phyla ratio with reduction in Firmicutes. In
blocked or reversed by treatment with anti–IL-12 antibodies. addition, Crohn disease has been associated with a reduction
Roles for IL-23 and IL-17 in Crohn disease were later supported in the butyrate-producing Faecalibacterium prausnitzii compared
by the IL-10–deficient mouse model of spontaneous colitis and with healthy controls, but it is not known whether this is a
the cell transfer model of induced colitis, where colitogenic naïve cause or effect of the gut inflammation. The roles of antibiot-
+
CD4 CD45RB high T cells from wild-type mice are infused into T ics, probiotics, prebiotics, or actively changing the microbiota
cell–deficient mice. 30,31 However, despite the important role of through fecal transplant have not been clarified sufficiently to
the IL-23/IL-17 axis in the transfer model of colitis, blockade of employ these strategies as conventional treatments in Crohn
32
IFN-γ activity also prevented development of gut inflammation. disease.
Although studies of Crohn disease confirm that production of
33
IL-12, IL-23, IFN-γ, and IL-17 are significantly elevated, the Diagnosis
hierarchy of cytokine control of inflammation in Crohn disease The diagnosis of Crohn disease is based on findings from
has been tested by clinical trials using agents that have targeted radiographic, endoscopic, and histological examinations. In

1010 Part seven Organ-Specific Inflammatory Disease


general, a combination of colonoscopy (with ileal intubation, if anti–TNF-α agents reliably exert long-term control of symptoms.
possible) and small bowel examination (barium small bowel In this way, they may be used for years as long as the disease is
follow-through, computed tomography [CT] or magnetic reso- responding. Currently, medically refractory inflammatory disease
nance enterography, and capsule video endoscopy) is usually may be treated with natalizumab, an anti-α 4 integrin antibody,
sufficient to demonstrate active inflammatory disease of the colon although this is being supplanted by vedolizumab, an anti-α 4 β 7
and small bowel. Endoscopically, mucosal ulceration and friability antibody inhibiting the trafficking of lymphocytes from the blood
in a patchy distribution separated by unaffected mucosa (“skip specifically into the gut lamina propria. Because of substantially
areas”) are hallmarks of the disease. Radiographically, evidence reduced concerns about a rare infectious side effect with vedoli-
of patchy bowel wall thickening, mucosal hyperemia, stricturing, zumab (progressive multifocal leukoencephalopathy has been
and penetrating complications, such as fistulae, abscesses, and associated with natalizumab), it is a more attractive antiintegrin
extraintestinal inflammatory masses involving the bowel, all therapy for IBD. An established approach to immunosuppres-
suggest Crohn disease. Histologically, although the appearance sant- and biological-naïve patients is to begin with a combination
of noncaseating granulomata is highly supportive of a diagnosis of azathioprine and infliximab, as this has been shown to be
of Crohn disease, in practice, they are not often detected by superior to either a single agent alone for inducing remission,
45
endoscopic biopsy, particularly in adults. More often evidence especially 1 year later. This “top-down” approach continues to
of chronic inflammation, such as architectural crypt distortion be studied for long-term efficacy as well as for identifying those
and basal lymphoplasmacytosis, are sought to differentiate the patients with Crohn disease with a pretreatment risk profile
inflammation from an acute, self-limiting colitis or enteritis. predicting more aggressive disease.
Other findings, such as fecal leukocytes or elevated fecal calpro- Surgery is required in cases of complications, such as
tectin, may indicate an inflammatory colitis but is not specific bleeding, pain/obstruction, and fistulae that are refractory to
for diagnosis of a chronic idiopathic IBD, such as Crohn disease medical therapy. Surgery typically involves resection limited to
or UC. In the setting of supportive findings through imaging inflamed segments of small intestine and colon; small strictures
or endoscopy, the measurement of certain serum antibodies can can be treated in situ by stricturoplasty. In addition, surgery is
further strengthen the diagnosis of Crohn disease and even help required for treatment of intestinal adenocarcinoma, which also
46
differentiate it from UC, but they should not be used by themselves complicates the chronic inflammation of the bowel. There is
43
as diagnostic tests. It has been shown that up to 68% of patients a high incidence of endoscopic and symptomatic recurrence
with Crohn disease are seropositive for antibodies targeting of inflammation by 2 years after surgery, but to date, there is
microbial antigens, such as anti–Saccharomyces cerevisiae antibody no consensus about who should routinely receive preventive
(up to 16% of patients with UC are seropositive). Additional therapy.
antimicrobial antibodies, such as anti-OmpC, anti-I2, anti-flagellin
3, X, and CBir, also develop in Crohn disease.
It goes without saying that prior to treatment, Crohn disease KeY COnCePts
may need to be differentiated from other similarly presenting Crohn Disease
conditions, including UC, chronic ischemic colitis, infectious
enteritis/colitis (amebiasis, Yersinia enterocolitica infection, • Crohn disease affects the full thickness of the bowel wall resulting
Mycobacterium tuberculosis infection), intestinal lymphoma, in fistulae and abscesses in 70% of patients by 20 years’ disease
duration.
celiac disease, diverticula-associated colitis, and radiation- • Crohn disease is a chronic, relapsing inflammation of the bowel, and
and nonsteroidal antiinflammatory drug (NSAID)–induced up to 80% of patients will require surgical treatment at some point.
enteropathy. • Several gene mutations and many genetic loci are associated with
disease risk, including NOD2 and ATG16L1, which are important in
Treatment innate immune function.
The treatment of Crohn disease includes medical and surgical • T-helper 1 (Th1) and Th17 cytokine pathways mediate disease in animal
approaches. Since there is no cure for Crohn disease, the principles models, but the hierarchy of these cytokine pathways in human disease
is still being tested by targeting strategies in clinical trials.
of therapy are to first make sure that symptoms are secondary
to the underlying idiopathic inflammation and not caused by
infectious or noninflammatory factors, such as coexisting irritable
bowel syndrome (IBS). The goal is to induce quick remission ULCERATIVE COLITIS
of symptoms and establish therapy to maintain the remission
with aggressive initial therapy commensurate with the extent UC also involves chronic idiopathic inflammation of the gut,
and activity of the disease. A traditional approach to therapy but this is limited to the mucosal layer of the colon (Fig. 75.1E).
has been to use short-term corticosteroids and mesalamine It can affect the rectum alone (ulcerative proctitis), the distal
preparations to start with in mild disease (these agents are not transverse colon to rectum (left-sided colitis), or the entire colon
useful for long-term maintenance of a clinical response), add (pancolitis). Because it lacks the transmural inflammation of
immunosuppressants (azathioprine, 6-mercaptopurine, or Crohn disease, penetrating complications, such as fistulae and
methotrexate) if symptoms persist or are moderate, and finally abscesses, are generally not features of UC. Oral and topical (per
44
start anti–TNF-α agents for recalcitrant or initially severe disease. rectum) mesalamine preparations are most often used to treat
Only corticosteroids and the anti–TNF-α agents are relied on UC, although patients also may require corticosteroids, immu-
for inducing clinical responses in short periods, within days to nosuppressants, and anti–TNF-α antibody agents to induce and
weeks. Therefore corticosteroid use may need to be prolonged maintain remission. Unlike Crohn disease, total colectomy
while immunosuppressants are begun concomitantly, since the eliminates the disease. However, there can be ongoing complica-
latter’s clinical effects may not be maximized until months later. tions of the surgery, such as pouchitis, when an ileal pouch–anal
For maintenance of remission, only immunosuppressants and anastomosis is performed. Over 40% of patients with UC require

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1011


surgery to treat medically refractory symptoms or development function, such as GNA12 for tight junction formation, CDH
of dysplasia over their lifetime. 47 for epithelial cadherin-1, and LAMB1 for the laminin con-
28
stituent of basement membranes. When specifically assaying
Presentation epithelial cells (vs whole tissue) for epigenetic markers associ-
The presentation of UC reflects the primary involvement of the ated with genomic risk loci, there is an enhanced association
rectum and extent of proximal colitis. Bloody stool and diarrhea supporting the epithelium as a primary target for dysfunction
(including nocturnal) are common symptoms, with proctitis- in UC. 54
specific complaints of rectal urgency and incomplete evacuation
also being prominent. As in Crohn disease, fever, unexplained Diagnosis
weight loss, fatigue, and anemia can accompany the GI complaints The diagnosis of UC is based on a colitis that typically involves
or be the primary presentation. Extraintestinal manifestations the rectum and adjacent proximal colonic segments in a confluent
may include arthritis, uveitis, inflammatory skin lesions, and inflammatory injury. This is best accomplished by colonoscopy
stomatitis. An interesting genetic connection exists between (ileal intubation can confirm that the inflammation is limited
UC and HLA-B27–positive spondyloarthropathy (Chapter to the colon). Biopsy specimens should contain histological
57), with 60% of patients with ankylosing spondylitis showing features of chronic inflammation, including crypt distortion,
inflammation on colonoscopy. UC is also closely associated with crypt dropout, and lymphoplasmacytosis. The presence of acute
primary sclerosing cholangitis (PSC; Chapter 76); up to 3% of inflammatory features alone (polymorphonuclear cells, crypt
UC patients develop PSC, and up to 75% of all patients with PSC abscess, and cryptitis) may also be seen but, when in isolation,
have UC. 48 these features suggest other etiologies, such as acute infectious,
With an incidence up to 20.3 cases per 100 000 person-years, drug-induced, ischemia, and toxic exposures. Although no blood
typically the diagnosis of UC is in the second or the third decade, test can be used to diagnose UC, the presence of high-titer
and there is no significant gender preference. Approximately perinuclear antineutrophil cytoplasmic antibodies (pANCAs)
6–15% of first-degree relatives of patients with UC have a can be seen in up to 70% of patients with UC; this information
history of UC, but in general, the genetic contribution to risk can help differentiate chronic indeterminate colitis when coupled
is lower than in Crohn disease. There is a higher incidence of with anti-Saccharomyces cerevisiae mannan antibodies (ASCAs;
UC in European and North American populations compared see above). At all times, acute infections from enteric pathogens,
with that in Asian and Latin American countries. The only including Clostridium difficile, should also be excluded, as these
environmental exposures linked to risk of UC are the protec- may also occur during active IBD treatment and mimic exacerba-
tive effect of tobacco use and appendectomy in the first decade tion of disease (evaluation for cytomegalovirus [CMV] infection
of life. should be performed in the setting of UC seemingly refractory
The natural history of UC shows that most patients experience to immunosuppressants). Once a diagnosis is established, eleva-
a remitting and relapsing course (60%), although some have tions in transaminases or alkaline phosphatase should prompt
prolonged remission after one episode of disease (20%), and an evaluation for PSC starting with magnetic resonance
others have chronically active symptoms refractory to medical cholangiopancreatography.
remission (20%). Total colectomy is performed to treat refractory
symptoms or development of epithelial dysplasia. Chronic Treatment
55
inflammatory UC (and Crohn colitis) is accompanied by an Treatment is tailored to the extent and activity of disease.
increased incidence of colorectal cancer (18% after 30 years’ For instance, mild to moderate proctitis can respond to topical
disease duration), so much so that recurring colonoscopic surveil- corticosteroids or mesalamine alone (enemas and/or supposi-
lance for dysplasia with biopsy is recommended starting 8–10 tories). Most often with more extensive colonic involvement,
years after diagnosis. oral mesalamine is required, which can be useful for induction
and maintenance of remission. In moderate to severe disease,
Immune Pathophysiology corticosteroids may be required to induce rapid responses, whereas
UC has been characterized as a Th2-like disease because of the immunosuppressants, such as azathioprine or 6-mercaptopurine,
increased IL-5 and IL-13 production in inflamed gut tissue seen are used for remission. Anti–TNF-α agents are used to induce
in an animal model of UC, oxazolone-induced colitis, as well as fairly rapid clinical responses and remission and may also be
49
from patient specimens. In this model, not only were mucosal used as maintenance therapy. Vedolizumab has been a recent
natural killer T (NKT) cells the source of excess IL-13, but the addition to conventional therapy as well.
colitis was reversed by immunoneutralizing anti–IL-13. 50,51 When Mesalamine-based drugs are a cornerstone of therapy in UC
translated to humans, patients with UC were found to have high and are generally included in most ongoing UC medical regimens.
capacity for IL-13 production, also by type II NKT cells. It turns Whether use of mesalamine even in quiescent disease confers
out that IL-13 is a biologically plausible effector cytokine in UC chemoprotection from developing dysplasia is still being debated,
injury because it disrupts the epithelial tight junction by upregu- but because of their generally low adverse event rate and high
lating claudin-2 and has a direct toxic effect on human gut tolerance, long-term use is a reasonable choice.
52
epithelial cells in vitro. However, results from a clinical trial As discussed, surgery has a definite role in treating medi-
using an anti–IL-13 antibody in UC did not show significant cally refractory disease or addressing dysplasia discovered by
treatment efficacy. 53 surveillance colonoscopy (dysplasia surveillance is done every
Data from genetic susceptibility studies in UC have provided 1–2 years after 8–10 years of disease by taking four-quadrant
less compelling examples of disease-specific mechanisms com- biopsy specimens every 10 cm). Total colectomy is performed, and
pared with those in Crohn disease, but there are associations with options include an ileal pouch–anal anastomosis or a permanent
HLA class II genes distinct from Crohn disease. Furthermore, end ileostomy. However, even the pouch can become chronically
other associated loci contain genes involved in epithelial barrier inflamed; generally antibiotic-responsive, this inflammation can

1012 Part seven Organ-Specific Inflammatory Disease


also become refractory and require steroid, immunosuppressant, with lymphocytosis of the colonic epithelium found in one-third
or biological therapy and even pouch removal. of patients with classic malabsorption symptoms and small-bowel
lesions of celiac disease. This may be a sequela of gluten antigen
KeY COnCePts reactivity extended to colonic epithelial responses, but it becomes
Ulcerative Colitis important to address as an independent process related to the
microscopic colitis itself if diarrhea and colonic lymphocytosis
• Ulcerative colitis is a chronic, relapsing inflammation of the colon that persist despite a GFD. Conversely, although celiac-like villus
is limited to the mucosa and is not transmural. blunting may be seen in <10% of patients with microscopic
• Animal models and human disease show the dominant cytokines to colitis, celiac serologies will not be positive, indicating that classic
be interleukin (IL)-5 and IL-13, suggesting a T-helper 2 (Th2)–like (without gluten enteropathy is not playing a role.
IL-4) inflammatory response, although IL-17 and interferon (IFN)-γ are There is no current information on the immune mechanism
also active. of microscopic colitis. Activated NF-κB is seen in the mucosa
• Although less strongly associated with genetic inheritance compared
with Crohn disease, several disease susceptibility loci have been of microscopic colitis, consistent with the general inflammatory
identified and are associated with epithelial barrier function. picture. Increased nitric oxide and prostaglandin production
• Over the course of the disease up to 40% of patients will undergo have also been measured, possibly contributing more to the
total colectomy for refractory symptoms or detection of epithelial diarrhea rather than the inflammation. Excessive transforming
dysplasia. growth factor (TGF)-β has also been measured in collagenous
colitis, consistent with its role in collagen production and fibrosis.
Interestingly, medications have been associated with microscopic
On tHe HOrIZOn colitis, including H2 blockers, proton pump inhibitors (PPIs),
Inflammatory Bowel Disease (IBD) selective serotonin reuptake inhibitors (SSRIs), and ticlopidine,
57
among others. Reports also suggest that long-term use of NSAIDs
• Establishment of new therapies targeting key cytokines and signaling may induce or sustain microscopic colitis.
pathways, especially anti-SMAD7 for transforming growth factor (TGF)-β The diagnosis of microscopic colitis relies on histology. The
enhancement, JAK/STAT inhibition, and immune cell–based sine qua non for microscopic colitis is increased numbers of
treatments intraepithelial lymphocytes (>20 lymphocytes/100 epithelial cells)
• Improvement in detection of dysplasia using molecular techniques on colonic mucosal biopsy. This can be accompanied by a chronic
for better understanding of the incidence, natural history, treatment,
and prevention of colonic epithelial dysplasia and neoplasia inflammatory infiltrate in the lamina propria and, less often, a
• Refining genome-wide association studies (GWAS) using large- limited appearance of neutrophils (especially cryptitis), the latter
scale fine-mapping to identify the actual polymorphisms in coding finding suggesting that the etiology of the microscopic colitis
and noncoding regions and to better test the mechanisms of IBD may actually be related to an injurious drug effect, such as NSAID
susceptibility exposure. In collagenous colitis, a prominent subepithelial collagen
• Defining whether the dysbiosis in IBD is a cause or effect and how band ≥10 µm is seen in addition to the intraepithelial
the microbiome is influenced by genetic background and inflammatory lymphocytosis.
status
As a general treatment approach to the patient with micro-
scopic colitis, the clinician should review and eliminate suspect
concomitant medications, such as NSAIDs. Coexisting celiac
OTHER IDIOPATHIC INFLAMMATORY disease should be considered, where appropriate, and addressed
BOWEL DISEASES with gluten withdrawal. Overall the choice of treatment begins
with low-risk medications in mild or moderate disease in an
Microscopic Colitis attempt to settle on a regimen that delivers the most relief of
58
Microscopic colitis is an increasingly recognized condition that symptoms with the lowest side effects. Therefore treatment
links chronic watery diarrhea with isolated intraepithelial can begin with antidiarrheals (loperamide, diphenoxylate/
lymphocytosis (lymphocytic colitis) or with increased subepithelial atropine), adding a trial of cholestyramine (bile salt malabsorption
collagen deposition (collagenous colitis). It differs from Crohn has been hypothesized to play a role in microscopic colitis) and
disease and UC because it does not display endoscopic mucosal even a trial of mesalamine. Bismuth subsalicylate has been
damage or show evidence of histological chronicity (no archi- reported to benefit a minority of patients with microscopic colitis;
tectural crypt distortion, lymphoplasmacytosis, or loss of Goblet three 262 mg tablets PO three times daily may result in long-term
cells). However, it causes significant morbidity and may require remission in some (some have reservations about the long-term
chronic immunosuppression for treatment. Although its etiology toxic effects of bismuth). In patients with initially severe symptoms
remains elusive, there are associations with autoimmune condi- or who are refractory to these first treatments, corticosteroids
tions as well as with certain drug exposures. have been very effective. In particular, oral budesonide 9 mg
The hallmark symptom of microscopic colitis is chronic, taken once per day has reliably improved diarrhea and induced
59
watery, nonbloody diarrhea that is frequently accompanied by remission, a result supported by placebo-controlled studies.
marked complaints of poor quality of life. Fatigue, arthralgias, The challenge is balancing relief of symptoms with the long-term
and weight loss may also be reported. Microscopic colitis has side effects of corticosteroid use (including budesonide) in
its typical onset in the sixth and seventh decades, has a female relapsing or steroid-dependent disease. In this case, emerging
predominance, and is associated with a history of autoimmunity strategies include use of lower doses of budesonide while monitor-
especially thyroid disease, rheumatoid arthritis, and CREST ing for side effects or using steroid-sparing immunosuppressive
(calcinosis, Raynaud phenomenon, esophageal dysmotility, medications, such as azathioprine and methotrexate, for long-term
56
sclerodactyly, and telangiectasia) syndrome. A connection maintenance. Reports of anti–TNF-α drugs for refractory
60
between microscopic colitis and celiac disease has also be observed, microscopic colitis have been published. Occasionally, patients

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1013


may need colectomy and ileostomy to manage refractory symp- been described in EoE, contributing more to dysphagia than to
toms or drug intolerance. strictures. 64
The pathogenesis of EoE seems to be linked to allergen
Eosinophilic Esophagitis hypersensitivity. Given a familial association of EoE, atopy, and
Eosinophilic esophagitis (EoE) is a more recently recognized food allergy, a genetic component may be contributing to disease
disease defined by symptomatic idiopathic eosinophilic inflam- susceptibility. Several candidate disease susceptibility gene/gene
mation in the absence of other known causes, especially chronic loci in EoE include the 3’ untranslated region of eotaxin (CCL26),
61
gastroesophageal reflux disease (GERD). Although its etiopathol- the TGF-β 1 promoter, a filaggrin (FLG) exon, and a thymic stromal
65
ogy is unclear, there are gene associations (FLG for epithelial lymphopoietin (TSLP) intron and TSLP receptor (CRLF2) exon.
barrier effects and eotaxin-3 and TSLP for immune response These associations are biologically plausible, since eotaxin is
effects), and data from animal models and human disease have excessively expressed in EoE mucosae, filaggrin is a structural
implicated central roles for loss of tolerance to food antigens skin protein that helps maintain barrier function (and is down-
involving Th2 cytokines IL-5 and IL-13. EoE is being recognized regulated by IL-13), and TSLP has been shown to stimulate IL-13
with increasing frequency against a background of increased production by innate helper cells in the lamina propria. Moreover,
incidence of inflammatory allergic diseases. the inflammation in EoE is characterized by increased IL-13 and
EoE is estimated to occur at 4–5 cases/10 000 children, has a IL-5 production; animal models of aeroallergen induction of an
male predominance (up to 70%), and peak incidence in neonates EoE-like lesion is blocked in both IL-13–deficient and signal
to 3-year-olds. Symptoms include failure to thrive and feeding transducer and activator of transcription 6 (STAT6)–deficient
difficulty in infants (e.g., food refusal, limited variety diet, (an intracellular molecule important for IL-13 receptor α 1 signal-
66
prolonged feeding times) and abdominal pain and vomiting in ing) animals. These data suggest that IL-13 secretion induces
older children and adolescents. In adults, the primary symptom production of eotaxin from epithelial cells, which, together with
is typically intermittent dysphagia, with the first presentation IL-5, drives the local eosinophilic infiltration. Finally, the associa-
possibly being an acute food impaction in the esophagus. Adult tion with food allergy has led to successful therapy of EoE by
patients may report GERD symptoms that do not respond to using strict elimination diets (sometimes informed by skin testing)
adequate acid-suppression therapy. Patients report a high rate or even the use of elemental diet tube feedings.
(>50%) of atopy (rhinoconjunctivitis, wheezing, or family history Given the strong association with food allergies, strict elimina-
of atopy) as well as food allergies (including positive skin prick tion of suspect foods or those identified by in vitro or skin prick
test, allergen-specific IgE test, or anaphylactic response to a testing may be restricted first. Lack of improvement in symptoms
62
dietary allergen). There is also an association of esophageal would lead to a trial of amino acid–based elemental liquid diet
disease (strictures or EoE) in the parents of up to 10% of necessitating nasogastric (or later percutaneous gastrostomy)
patients. placement, but this can be uncomfortable, impractical, and
The diagnosis of EoE requires endoscopic biopsy of the expensive. If this dietary approach is successful, then after
esophagus, since increased eosinophils in the esophageal epithe- several weeks, individual foods may be added back every 5–7
lium must be measured. The endoscopic appearance of the days. For patients not responding to dietary therapy or with
esophagus can show multiple thin rings (“feline esophagus”), no identifiable dietary allergens, corticosteroid treatment has
with linear longitudinal furrows and whitish papules that represent been used successfully. Both systemic oral and swallowed topical
eosinophilic microabscesses at the surface of the squamous corticosteroids (e.g., fluticasone propionate metered dose inhalers)
epithelium. Biopsy should show an infiltrate of eosinophils in for 4–6 weeks have been shown to relieve symptoms and resolve
the epithelium of at least 15—20 eosinophils/high-power field histological inflammation; one or the other may be more or
(hpf). These often concentrate just under the epithelial surface less effective based on body weight, dose, steroid resistance, or
and also form microabscesses in groups of ≥4 eosinophils. It is severity of the EoE. However, relapse rates are high over the
important to take at least three biopsy specimens, since involve- year following a course of steroids. Lastly, endoscopic therapy to
ment may be variable and patchy; in addition, it is advisable to treat strictures using dilation may incur higher risk of mucosal
take biopsy specimens from the distal and mid-to-upper esophagus tears so that conservative treatment (smaller dilators, assessment
(to help differentiate changes seen in GERD that can be limited for tears during the procedure before proceeding further) is
to the distal esophagus) and specimens from the gastric and encouraged.
duodenal mucosae (to show that the eosinophilic infiltration is Eosinophilic gastroenteritis encompasses an additional group
limited to the esophagus and does not represent a diffuse process, of infrequent conditions that link increased intestinal eosinophilia
such as that found in eosinophilic gastroenteritis or hypereo- (from mucosal to full-thickness intestinal wall infiltration) and
67
sinophilic syndrome). Systemic eosinophilia can be seen in over symptoms, such as abdominal pain, diarrhea, and malabsorption.
70% of patients with EoE. These are assumed to be primary inflammatory responses,
In terms of GERD, it is important to make sure that any although exclusion of parasitic infections, especially with hel-
excessive acid reflux is treated and controlled; persistent symptoms minths, is a necessary part of the workup.
(and persistent biopsy abnormalities) may prompt a 24-hour
ambulatory pH study of the distal esophagus to ensure that the GASTROINTESTINAL COMPLICATIONS OF
acid-suppression treatment results in a normal acid-contact time. PRIMARY IMMUNODEFICIENCIES
In fact, there seems to be a form of EoE that, while seeming to
be without excess exposure to gastric acid, does, in fact, respond Certain primary immunodeficiency diseases increase the risk
well to PPI treatment; this may be attributed to the non–acid- for GI complications. These complications fall into three main
suppressive effects of a drug, such as omeprazole, that can suppress categories: infectious, idiopathic inflammatory/autoimmune,
63
eotaxin-3 secretion from squamous mucosae. Multiple types and neoplastic. Common variable immunodeficiency (CVID)
of esophageal dysmotility, often reversible with treatment, have and chronic granulomatous disease (CGD) have some of the