Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 59 Large-Vessel Vasculitides 823


Calcium and vitamin D supplementation should be part of the Please check your eBook at https://expertconsult.inkling.com/
therapeutic regimen. for self-assessment questions. See inside cover for registration
In many, but not all, patients, immunosuppressive treatment details.
can be discontinued 18–24 months after diagnosis. Markers of
systemic inflammation may remain elevated, and continuous REFERENCES
monitoring for aortic involvement and recurrence of cranial
arteritis is recommended. 1. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J
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dose of 20 mg of prednisone per day. In some patients, 10 mg giant-cell arteritis. N Engl J Med 2002;347(4):261–71.
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for agents blocking TNF-α in patients with persistent disease potential role for neutrophils in giant-cell arteritis disease progression.
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of caring for patients with TA. Untreated hypertension leads to arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis
acceleration of atherosclerosis and cardiac insufficiency. In patients Rheum 2000;43(5):1041–8.
with upper-extremity involvement, obtaining accurate blood 12. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell
pressure measurements is a challenge and requires education of arteritis. N Engl J Med 2017;377:317–28.
the patient and caregivers. 13. O’Neill L, Rooney P, Molloy D, et al. Regulation of inflammation and
angiogenesis in giant cell arteritis by acute-phase serum amyloid A.
Revascularization Procedures Arthritis Rheumatol 2015;67(9):2447–56.
14. Weyand CM, Goronzy JJ. Immune mechanisms in medium and
Besides pharmacological therapy, revascularization procedures— large-vessel vasculitis. Nat Rev Rheumatol 2013;9(12):731–40.
including both surgical and endovascular interventions—have 15. Pryshchep O, Ma-Krupa W, Younge BR, et al. Vessel-specific Toll-like
vastly broadened therapeutic options in patients with TA and receptor profiles in human medium and large arteries. Circulation
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large-vessel GCA. To minimize the risk of complications, such 2008;118(12):1276–84.
as rapid reocclusion, an effort should be made to suppress vascular 16. Ma-Krupa W, Jeon MS, Spoerl S, et al. Activation of arterial wall dendritic
wall inflammation, ideally before subjecting the patients to cells and breakdown of self-tolerance in giant cell arteritis. J Exp Med
revascularization treatment. Conventional bypass grafts are still 2004;199(2):173–83.
considered the method of choice. Percutaneous transluminal 17. Krupa WM, Dewan M, Jeon MS, et al. Trapping of misdirected dendritic
angioplasty can be useful in managing renal artery stenosis or cells in the granulomatous lesions of giant cell arteritis. Am J Pathol
2002;161(5):1815–23.
other short-segment lesions. Bypass surgery is needed in patients 18. Weyand CM, Liao YJ, Goronzy JJ. The immunopathology of giant cell
with cerebrovascular ischemia in whom catastrophic strokes may arteritis: diagnostic and therapeutic implications. J Neuroophthalmol
be prevented by bypassing critical stenosis of cervical vessels 2012;32(3):259–65.
with grafts originating from the aortic arch. Reestablishing flow 19. Weyand CM, Wagner AD, Bjornsson J, et al. Correlation of the
in the upper- and lower-extremity arteries can be complicated topographical arrangement and the functional pattern of
by multiple and long-segment stenosis, and arterial reconstruc- tissue-infiltrating macrophages in giant cell arteritis. J Clin Invest
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alternative to obtain long-term patency. Placing of conventional 20. Weyand CM, Schonberger J, Oppitz U, et al. Distinct vascular lesions in
stents can be complicated by eliciting rapid restenosis, and it is giant cell arteritis share identical T cell clonotypes. J Exp Med
not known whether outcomes can be improved by drug-eluting 1994;179(3):951–60.
stents. Occlusive disease of the coronary arteries usually represents 21. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in
giant cell arteritis. Circulation 2010;121(7):906–15.
a challenging clinical scenario, and most physicians opt for 22. Watanabe R, Hosgur E, Zhang H, et al. Pro-inflammatory and
conventional bypass surgery. Depending on symptoms, patients anti-inflammatory T cells in giant cell arteritis. Joint Bone Spine 2016;pii:
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824 Part SIX Systemic Immune Diseases


23. Seko Y, Minota S, Kawasaki A, et al. Perforin-secreting killer cell 35. Achkar AA, Lie JT, Hunder GG, et al. How does previous corticosteroid
infiltration and expression of a 65-kD heat-shock protein in aortic tissue treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann
of patients with Takayasu’s arteritis. J Clin Invest 1994;93(2):750–8. Intern Med 1994;120(12):987–92.
24. Wen Z, Shimojima Y, Shirai T, et al. NADPH oxidase deficiency underlies 36. Jia L, Couce M, Barnholtz-Sloan JS, et al. Is all inflammation within
dysfunction of aged CD8+ Tregs. J Clin Invest 2016;126(5):1953–67. temporal artery biopsies temporal arteritis? Hum Pathol 2016;57:17–21.
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26. Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. JACC Cardiovasc Imaging. 2014;7(6):605–19.
Ann Intern Med 2003;139(6):505–15. 39. Goronzy JJ, Weyand CM. Understanding immunosenescence to improve
27. Brack A, Rittner HL, Younge BR, et al. Glucocorticoid-mediated responses to vaccines. Nat Immunol 2013;14(5):428–36.
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chimeras. J Clin Invest 1997;99(12):2842–50. arteritis using induction therapy with high-dose glucocorticoids: a
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Rheumatology 1990 criteria for the classification of giant cell arteritis. of glucocorticosteroid-induced remission of giant cell arteritis: a
Arthritis Rheum 1990;33(8):1122–8. randomized trial. Ann Intern Med 2007;146(9):621–30.
32. Dasgupta B, Cimmino MA, Kremers HM, et al. 2012 Provisional 43. Mahr AD, Jover JA, Spiera RF, et al. Adjunctive methotrexate for
classification criteria for polymyalgia rheumatica: a European League treatment of giant cell arteritis: an individual patient data meta-analysis.
Against Rheumatism/American College of Rheumatology collaborative Arthritis Rheum 2007;56(8):2789–97.
initiative. Arthritis Rheum 2012;64(4):943–54. 44. Liang P, Hoffman GS. Advances in the medical and surgical treatment of
33. Arend WP, Michel BA, Bloch DA, et al. The American College of Takayasu arteritis. Curr Opin Rheumatol 2005;17(1):16–24.
Rheumatology 1990 criteria for the classification of Takayasu arteritis. 45. Mason JC. Takayasu arteritis: surgical interventions. Curr Opin
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34. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern
Med 1994;120(11):919–29.

CHaPtEr 59 Large-Vessel Vasculitides 824.e1


MUL t IPLE CHOICE QUES t IONS

1. A 27-year old female presents with a 6-weeks history of C. Subclavian artery
intermittent fever, arthralgias and weight loss. She was admitted D. Renal capillaries
after she fainted in the emergency room. On physical examina- E. Arteries in the skin
tion she has no palpable peripheral pulse in her left upper 3. Extravascular GCA may result in the following laboratory
extremity, and Takayasu arteritis (TA) is added as a differential abnormalities. Identify the incorrect answer:
diagnosis. A. Elevated C-reactive protein
Which of the following statements is true: B. Autoantibodies to nuclear antigens
A. She should be scheduled for temporal artery biopsy, to C. Thrombocytosis
rule out giant cell arteritis. D. Elevated serum amyloid A
B. Laboratory tests, e.g. sedimentation rate will be of no use, E. Elevated alkaline phosphatase
as they can be non-specifically abnormal.
C. A pregnancy test should be performed.
D. A detailed physical examination will not be helpful.
E. If a diagnosis of TA is made, it will be a self-limited disease.
2. Giant cell arteritis and Takayasu arteritis have a stringent
tissue tropism. Which of the following vascular beds can be
involved? Identify all correct answers:
A. Aortic arch
B. Carotid artery

60









Systemic Autoinflammatory Syndromes



Catharina M. Mulders-Manders, Jeroen C.H. van der Hilst,
Jos W.M. van der Meer, Anna Simon





Autoinflammatory diseases, which are also known as periodic fever KEY CONCEPTS
syndromes, encompass a group of rare disorders characterized by
recurrent or persistent inflammation. Autoinflammation is a term Autoinflammation Versus Autoimmunity
that has been used since the late 1990s to illustrate the difference • Common features:
between autoimmune disorders and diseases characterized by • Inflammation due to excessive immune activation
exuberant inflammation. Typically, autoinflammatory diseases do • Phenotypes characterized by exacerbations and remissions
not show features of excess adaptive immune system activation, • Distinctive features:
and autoantigens or auto-antigen specific T-cells are not present • Autoinflammation: dysregulation of innate immunity, no high-titer
in these diseases. It is now recognized that autoinflammation and autoantibodies or autoantigen-specific T cells
autoimmunity form two ends of a spectrum of inappropriate • Autoimmunity: dysregulation of adaptive immunity, defect in
lymphocyte function, autoantibodies may be present.
immune system activation and share several common features. • Autoinflammation and autoimmunity form two ends of a continuous
Located at the autoinflammatory end of this spectrum are the spectrum of excessive immune system activation.
classic monogenic autoinflammatory diseases: familial Mediter- • Many diseases show overlapping features between autoinflammation
ranean fever (FMF), cryopyrin-associated periodic syndrome and autoimmunity.
(CAPS), mevalonate kinase deficiency (MKD; also known as
hyperimmunoglobulin D and periodic fever syndrome [HIDS]),
and tumor necrosis factor (TNF) receptor–associated periodic EPIDEMIOLOGY
syndrome (TRAPS). The number of autoinflammatory diseases
is increasing rapidly. New monogenic autoinflammatory diseases It is important to realize that the incidence of specific diseases
have been identified in the last decades. For many of the recently varies widely among ethnic groups. With more than 100 000
described autoinflammatory diseases, no genetic cause has been patients worldwide, FMF is the most prevalent monogenic
found yet. autoinflammatory disease. It is most common in individuals
It has also become clear that autoinflammation is at least originating from around the Mediterranean basin, such as Turks,
partially involved in the pathogenesis of other, more common Jews (primarily non-Ashkenazi), Arabs, and in Armenians. In
diseases, such as gout, Crohn disease, and ulcerative colitis. these selected populations, the carrier frequency of mutations
1
As it is impossible to discuss all autoinflammatory diseases in the MEFV gene can be as high as one in three individuals.
in detail here, the classic monogenic diseases FMF, CAPS, TRAPS, This may indicate a survival benefit for carriers of heterozygous
and MKD have been selected as the main focus of this chapter. mutations, possibly through protection against certain unknown
Their pathophysiological mechanisms are understood to a much infectious agents.
higher degree than in many newer autoinflammatory diseases, The first patients with MKD were described in 1984 in The
2
and their clinical presentations have been described precisely. Netherlands (then referred to as HIDS). Over 200 patients have
In addition, two other autoinflammatory diseases are discussed, now been identified, most of Western European and Caucasian
one with relatively high prevalence and the other because of its ancestry. This could be partly explained by increased awareness
interesting pathophysiological mechanism: (i) periodic fever, for this disease among physicians in that part of the world. An
aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome alternative explanation is a common founder effect with clustering
and (ii) Schnitzler syndrome. of carriers, illustrated by a carrier rate of 1 : 153 for the most
The cornerstone of diagnosing an autoinflammatory disease common mutation in the mevalonate kinase gene (MVK) (V377I)
is the clinical assessment of the patient. This includes a detailed in Dutch newborns. 3,4
medical and family history and direct observation of an inflam- TRAPS is seen in patients from around the world, although
matory episode. The first step in the diagnostic process is to most patients originate from northwestern Europe. A few dozen
exclude other more common causes of recurrent inflammation, families and over 200 sporadic cases have been reported.
including infections, malignancy and paraneoplastic phenom- The exact prevalence of the CAPS is unknown, but over 130
1
ena, and autoimmune disease. A first differential diagnosis cases have been recognized. Disease awareness and recognition
can be made on the basis of age of onset, associated signs and among clinicians have improved because of the availability of
symptoms, duration of inflammation, family history, and ethnic effective treatment for this disease.
5
background, (Table 60.1), and this can guide targeted diagnostic PFAPA syndrome was first reported at the end of the 1980s.
testing. It is difficult to estimate the incidence of PFAPA, as the level of
825

826 ParT SIX Systemic Immune Diseases



TABLE 60.1 Hereditary autoinflammatory Syndromes
FMF CaPS TraPS MKD
Mode of inheritance Autosomal recessive Autosomal dominant Autosomal dominant Autosomal recessive
Age of onset (years) <20 Generally <1, in MWS/FCAS <20 Variable, most <10 <1
possible
Main ethnic distribution Turks, Arabs, Jews, Europeans All Northwestern Europeans (Dutch,
Armenians French)
Gene involved MEFV NLRP3 TNFRSF1A MVK
Protein involved Pyrin NLRP3 TNF receptor type 1 Mevalonate kinase
Duration of typical attack 2–3 days Variable; hours–days or continuous Days–weeks HIDS: 4–6 days; MA: continuous,
inflammation flares possible
Distinguishing symptoms Peritonitis, pleuritis, Aseptic meningitis; sensorineural Severe myalgia, HIDS: lymphadenopathy, attacks
erysipelas-like skin deafness; bone lesions, periorbital edema induced by vaccination
lesions dysmorphic features MA: joint contractions, growth
May be cold-induced and developmental delay
Risk of amyloidosis a Up to 75% Up to 33% 25% <5%
Treatment Colchicine, combination IL-1 inhibition Mild disease: NSAIDs; IL-1 inhibition
with IL-1 inhibition Severe disease: IL-1
when resistant inhibition
a In patients with long-term uncontrolled inflammation.
CAPS, cryopyrin-associated periodic syndrome; FMF, familial Mediterranean fever; HIDS, hyperimmunoglobulin D and periodic fever syndrome; IL, interleukin; MA, mevalonic
aciduria; MKD, mevalonate kinase deficiency; TRAPS, tumor necrosis factor (TNF) receptor–associated periodic syndrome.


awareness of this disease seems to vary among clinicians. A single are very characteristic of FMF, but are only seen in 30% of patients.
pediatric center in the United States reported 122 patients fulfilling Less frequent symptoms of FMF include vasculitis, orchitis, aseptic
6
the criteria for PFAPA in 10 years, making it more common meningitis, and myalgia. Pericarditis is rare in FMF.
than any of the monogenic autoinflammatory diseases (with the There are no consistent triggers for FMF attacks. Emotional
exception of FMF in certain populations). In most patients with stress or menstruation may increase the frequency of attacks;
PFAPA, symptoms cease before or during adolescence. The cause some patients are able to report specific triggers for their attacks.
of this spontaneous resolution is unknown. The characteristic Attack frequency varies greatly among patients and during an
combination of symptoms of PFAPA has been described in adults, individual patient’s life. Attacks may be as frequent as 2–3 times
but it remains a matter of debate whether these patients suffer each month and as rare as less than once a year.
from true PFAPA syndrome. The literature on FMF is replete with genotype–phenotype
Schnitzler syndrome, first described by the French dermatolo- studies. The most consistent finding is that carriers of the M694V/
7
gist Schnitzler in 1972, is an acquired autoinflammatory disorder M694V genotype have more severe disease, with earlier onset
with a median age of onset of 51 years. Over 160 cases have been and higher frequency of arthritis and long-term complications.
reported worldwide. Life expectancy of patients with FMF depends on timely initia-
tion of appropriate treatment to prevent amyloidosis. Without
SIGNS AND SYMPTOMS amyloidosis, FMF patients have normal life expectancy.
Familial Mediterranean Fever Cryopyrin-Associated Periodic Syndrome
FMF is an autosomal recessive disease. Over 90% of patients CAPS is autosomal dominantly inherited. Originally, three separate
become symptomatic within the first two decades of life. Typically, clinical syndromes, all with their own clinical features, were
attacks are characterized by abrupt onset of high fever, peaking distinguished: familial cold autoinflammatory syndrome (FCAS),
soon after onset and lasting for 12 hours to 3 days. Subsequently, Muckle Wells syndrome (MWS), and neonatal onset multisystem
the fever subsides rapidly. Painful serositis accompanies the fever. inflammatory disease (NOMID), which is also known as chronic
Serositis can also be present without fever. Over 95% of patients infantile neurological, cutaneous and articular (CINCA) syn-
experience abdominal pain, which lasts up to 3 days. The pain, drome. With the discovery of NLRP3 mutations in all three
which is caused by sterile peritonitis, may initially be focal and diseases, it has become clear that the clinical phenotype of CAPS
progress to more diffuse pain. Before being diagnosed with FMF, is a continuous spectrum of severity, instead of distinct diseases.
a significant proportion of patients will have undergone explor- There is no genotype–phenotype association, suggesting a role
atory abdominal surgery under suspicion of appendicitis. At for other yet undiscovered disease modifying factors.
surgery, intraabdominal adhesions, a result of recurrent peritonitis, CAPS often manifests clinically soon after birth or in early
may be found. Pelvic adhesions can reduce fertility in female childhood. It is characterized by recurrent urticaria-like rash,
patients. Pleuritis, presenting as thoracic pain, is experienced by arthralgia, myalgia, headache, and fever. Ocular symptoms, in-
approximately 40% of patients. Synovitis with monoarthritis of cluding conjunctivitis and uveitis, are common. Some patients
knee, ankle, or wrist occurs in one-half to three-quarters of develop sensorineural hearing loss during adolescence or adult-
patients. An arthritic attack may have a more protracted course hood. At the severe end of the clinical spectrum, central nervous
compared with nonarthritic FMF, with fever lasting up to a week. system (CNS) symptoms, including chronic aseptic meningitis
Joint pain may persist when fever has already subsided. Synovitis that is characterized by chronic headache, increased intracranial
usually resolves completely without joint destruction. The skin pressure, hydrocephalus, mental retardation, and seizures, are
can be affected. Erysipelas-like skin lesions overlying the shins common. Papilledema with optic nerve atrophy can lead to loss

CHaPTEr 60 Systemic Autoinflammatory Syndromes 827


of vision. In severely affected patients, arthropathy, with distinct
radiographic findings of premature patellar and epiphyseal long Mevalonate Kinase Deficiency
bone ossification and osseous overgrowth, develops early in life. Before the discovery of the underlying genetic defect in the
If left untreated, this leads to growth retardation, severe joint mevalonate kinase gene, two distinct autosomal recessive diseases
contractures, and persisting disability. were distinguished, which are now known to form two ends of
The duration of attacks is variable and ranges from hours to a continuous spectrum: HIDS at the less severe end and mevalonic
days. At the severe end of the spectrum, patients have continuous aciduria (MA) at the most severe end.
inflammation. Attacks may be triggered by exposure to cold, HIDS is characterized by recurrent fever attacks that last for
minor trauma, or emotional stress. 4–6 days, starting in early childhood. The inflammatory attacks
In the past, patients with severe CAPS often died in childhood. occur on average every 4–6 weeks. Attack frequency varies in a
This changed after the introduction of anti–interleukin-1 (IL-1) single patient and among patients and tends to decrease later in
therapy, which is very effective in treating CAPS. Overall, patients life. Attacks often start with chills, followed by a rapid rise in
without neurological involvement are now believed to have a temperature. Factors that can provoke an attack are infections,
normal life expectancy. trauma, vaccination, and both physical and emotional stress,
although a clear trigger is often absent. Characteristic for HIDS
Tumor Necrosis Factor Receptor–Associated is the first attack being triggered by childhood vaccination.
Periodic Syndrome Fever is accompanied by cervical lymphadenopathy and
TRAPS is inherited in an autosomal dominant fashion. Age of abdominal pain with vomiting and diarrhea. The skin may show
onset varies widely. Many patients become symptomatic within erythema, papules, urticarial rash, or exanthema. The majority
the first years of life, with a median age of onset of 3 years, but of patients suffer from large-joint arthralgia or arthritis. Oral or
adult onset is also possible. The usual duration of fever in TRAPS genital aphthous ulcers may be present during attacks. Hepato-
is considerably longer than in the other classic autoinflammatory splenomegaly has been reported. Patients with HIDS appear to
syndromes: attacks persist for a minimum of 3 days but can last have normal life expectancy and experience no complications.
for several weeks. The interval between attacks in a single patient MA is located at the severe end of the MKD spectrum. This
can vary substantially. severe disease is present from birth and is characterized by
Localized myalgia, a deep cramping, and often severely dis- psychomotor retardation, ataxia, failure to thrive, cataracts, and
abling pain in a single limb resulting from monocytic fasciitis facial dysmorphia. Episodic fever or inflammation are present
and associated with fever is found in virtually all patients. The in MA. Many patients die in early childhood.
affected limb may show local erythema, which may migrate to In recent years, it has become clear that the spectrum of
the distal part of the extremity (Fig. 60.1). Almost all patients MKD comprises more than only these two diseases. Muta-
have abdominal pain, often accompanied by vomiting, constipa- tions in MVK have been found in the absence of typical MKD
tion, and bowel obstruction. Arthralgia and monoarthritis features in patients with retinitis pigmentosa and early-onset
involving hips, knees, or ankles are present in 25% of patients ulcerative colitis. Mutations in MVK have also been found in
at some point. Chest pain is frequent and can be caused by patients with the skin diseases disseminated superficial actinic
pleuritis or may be musculoskeletal in origin. Ocular symptoms porokeratosis and porokeratosis of Mibelli, cyclic neutropenia,
range from conjunctivitis and periorbital pain to severe uveitis and macrophage activation syndrome, but there is no evidence of
8
and iritis. Periorbital edema with conjunctival injection is a decreased mevalonate kinase activity in these patients. Mutations
distinctive, but infrequent, feature of TRAPS. Other less frequently in these diseases may overlap with mutations that may cause
observed symptoms are pericarditis and lymphadenopathy. MA and HIDS.
Periodic Fever, Aphthous Stomatitis, Pharyngitis,
and Adenitis Syndrome
PFAPA is primarily a childhood disease with a usual onset before
the age of 5 years. Patients suffer from recurring episodes of
fever that generally last for 3–6 days and recur with great regular-
ity. Additional symptoms include pharyngitis, cervical adenitis,
and aphthous stomatitis. Other symptoms may include headache,
vomiting and mild abdominal pain, arthralgia, and myalgia.
Between fever episodes, patients are symptom-free. In most
patients, attacks cease after several years, often before or during
adolescence.
Schnitzler Syndrome
A typical feature of Schnitzler syndrome is its late onset, at a
median age of 51 years. Patients typically present with chronic
recurrent and mostly nonpruritic urticarial rash. This can be
accompanied by fever, arthralgia or arthritis, and bone pain (Table
60.2). Symptoms progress over years. The presence of monoclonal
paraproteinemia, typically of immunoglobulin M (IgM), is char-
FIG 60.1 Migratory erythematous macular rash during an inflam- acteristic for Schnitzler syndrome. Presence of monoclonal IgG
matory attack in a patient with tumor necrosis factor recep- is less common and is sometimes referred to as variant Schnitzler
tor–associated periodic syndrome (TRAPS). syndrome. Onset of symptoms can precede paraproteinemia for

828 ParT SIX Systemic Immune Diseases



TABLE 60.2 Diagnostic Criteria for NLRP3
Schnitzler Syndrome a LRR NOD PYD
Major Criteria (≥1 present) FIIND PYD CARD ASC
(Chronic) urticarial rash
Monoclonal immunoglobulin M (IgM; or IgG: variant type) CARD CARD Pro-caspase-1
CARD
Minor Criteria (≥2 present) Caspase-1
Intermittent fever Caspase-1
Arthralgia or arthritis
Bone pain
Lymphadenopathy Pro-
Hepatomegaly and/or splenomegaly IL-1β IL-1β
Elevated erythrocyte sedimentation rate (ESR) and/or leukocytosis
Bone abnormalities (on radiological or histological examination) FIG 60.2 The Nucleotide-Binding Oligomerization Domain
(NOD)–Like Receptor P3 (NLRP3) Inflammasome. NLRP3 is
a Schnizler syndrome can be diagnosed only after exclusion of other causes. the central component of this inflammasome. NLRP3 contains
From: de Koning et al. Diagnostic criteria for Schnitzler syndrome. Semin Arthritis
Rheum 2007:37:137–148. three domains: a pyrin domain (PYD), NOD, and a domain of
leucine-rich repeats (LRR). Cryopyrin binds apoptosis-associated
speck-like protein containing a C-terminal caspase recruitment
domain (ASC) through its PYD domain and through the NOD
years, but only little is known about this. Symptom severity is domain. The association of these proteins ultimately leads to
unrelated to the level and type of paraproteinemia. the release of active caspase-1, which, in turn, activates
An important long-term complication of Schnitzler syndrome interleukin-1β (IL-1β) through the cleavage of pro–IL-1β.
is Waldenström macroglobulinemia, which, in a single study,
had an incidence of 15% 10 years after diagnosis. Patients with
Schnitzler syndrome have a normal life expectancy.
• Apoptosis
PATHOGENESIS PYD ? •NF-κB
Pyrin PYD
The common pathophysiological feature of most autoinflam-
matory diseases is overproduction of the proinflammatory ASC PYD CARD
cytokine IL-1β. This protein is produced as an inactive proform CARD
(pro–IL-1β), which must be cleaved to become activated. The
most common pathway of cleavage is by caspase-1. Like IL-1β, Caspase-1
caspase-1 is transcribed as an inactive proform (procaspase-1),
and it, too, must be cleaved by a multiprotein complex called
the inflammasome. Several inflammasomes have been identified,
of which the nucleotide-binding oligomerization domain Pro-
(NOD)–like receptor P3 (NLRP3) inflammasome has been studied IL-1β IL-1β
in greatest detail. FIG 60.3 Mechanism of Action of Pyrin. Pyrin contains a pyrin
The NLRP3 inflammasome consists of the central protein domain (PYD) that is able to bind to apoptosis-associated speck-
NLRP3, the adapter protein ASC, and the effector protein like protein containing a C-terminal caspase recruitment domain
procaspase-1. Upon activation of the inflammasome, procaspase-1 (ASC). ASC can recruit caspase-1 via its CARD domain leading
is converted into mature caspase-1, which is then able to cleave to production of mature interleukin-1β (IL-1β). Pyrin is also able
inactive pro–IL-1β to its active form (Fig. 60.2). to bind to the PYD domain of other proteins involved in inflam-

Familial Mediterranean Fever mation and apoptosis.
FMF is caused by mutations in the Mediterranean fever gene
(MEFV), which encodes the protein pyrin, primarily expressed in
peripheral blood leukocytes, especially neutrophils and monocytes. V726A, M680I, M694I, V694I, E148Q) cause approximately 80%
Pyrin is a member of the pyrin-domain (PYD)–containing pro- of cases. Recently, autosomal dominant mutations in MEFV were
teins, which are able to bind to the PYD domain of other proteins, described in four families with a colchicine-responsive FMF-like
including apoptosis-associated speck-like protein containing a phenotype. 9
C-terminal caspase recruitment domain (ASC). Binding of pyrin
to ASC leads to activation of ASC, with consequent recruitment Cryopyrin-Associated Periodic Syndrome
and activation of procaspase-1. Pyrin can also bind to the PYD CAPS is caused by mutations in the gene encoding NLRP3.
domains of other proteins that are able to initiate apoptosis or Previous to its discovery at the beginning of this century, the
activate nuclear factor (NF)-κB, including caspase-8 (Fig. 60.3). protein was unknown. It was named cryopyrin, in analogy with
These complexes are called pyrin inflammasomes. pyrin in FMF and to illustrate the influence of cold exposure in
So far, over 300 sequence variants in the MEFV gene have some patients with CAPS. Literature on this gene can be confusing,
been reported in the central online Infevers registry (http:// as the gene previously has also been referred to as NALP3, PYPAF1,
fmf.igh.cnrs.fr/ISSAID/infevers/), most of which are clustered and CIAS1. Mutations associated with CAPS are gain-of-function
in exon 10 of the gene. The six most prevalent mutations (M694V, (GOF) mutations, leading to increased NLRP3 activity.

CHaPTEr 60 Systemic Autoinflammatory Syndromes 829


There are two exceptional TNFRSF1A mutations: R92Q and
Tumor Necrosis Factor Receptor–Associated P46L. These mutations do not lead to receptor misfolding and
Periodic Syndrome are present in low frequency in the general population. They
Mutations in the gene TNFRSF1A are responsible for TRAPS. This may, however, cause a mild inflammatory phenotype.
gene encodes the TNF-receptor superfamily 1A (TNFRSF1A),
the main cell surface receptor for TNF. This receptor consists Mevalonate Kinase Deficiency
of three domains: an extracellular ligand-binding domain, a The genetic defect in MKD is located in MVK. Mevalonate kinase
transmembrane domain, and an intracellular effector domain. is a key enzyme in the isoprenoid pathway and is located directly
So far, over 100 TNFRSF1A sequence variants have been described, downstream from 3-hydroxy-3methylglutaryl-coenzyme A
and all TRAPS-associated mutations are located within the reductase (HMG-coA-reductase). The end products of the
extracellular domain of the protein. Upon ligand binding by the mevalonate kinase pathway are cholesterol and a number of
extracellular receptor domain, the TNFR forms trimers, triggering nonsterol isoprenoids, which are essential compounds in various
the recruitment of intracellular adaptor proteins, which initiate cellular functions. Mutations in MVK lead to reduced mevalonate
a downstream signaling cascade, leading to NF-κB and mitogen- kinase enzyme activity. In patients with mild disease, residual
activated protein kinase (MAPK) activation and caspase-induced mevalonate kinase activity is generally 5–15% of healthy controls
apoptosis. When the receptor is activated, the extracellular domain and is even lower in patients with the severe phenotypes.
of the TNFR is shed from the membrane. These shed receptors The mechanistic link between reduced mevalonate kinase
form an extracellular pool of soluble TNFRs, retain their affinity activity and autoinflammation is thought to be defective protein
for binding TNF, and are therefore able to mitigate the immune prenylation. Prenylation is a posttranscriptional modification,
response. Initially, it was hypothesized that TRAPS-associated in which nonsterol isoprenoids are coupled to proteins, influencing
mutations would lead to defective shedding of TNFR1 receptors, protein–protein and protein–membrane interactions.
but this hypothesis was discarded as the major pathogenetic In a human cellular model of MKD, deficiency of certain
mechanism for TRAPS after in vitro experiments showed misfold- isoprenoids were shown to lead to defective prenylation of RhoA,
ing and intracellular accumulation of mutated proteins. These with consequent activation of Rac1 and PKB, which are able to
aggregated receptors retain their normal signaling function and induce IL-1β secretion. 10-12 Defective prenylation with inactivation
can induce ligand-independent MAPK signalling and production of RhoA also impairs mitochondrial function. Mitochondria
of reactive oxygen species (ROS), resulting in inflammation. from patients with MKD are elongated and unstable. 12-–14
(Fig. 60.4) Normally, these abnormal mitochondria would be cleared from
the cytosol by autophagy, but in MKD, they accumulate in the
cytosol. Abnormal mitochondria release excessive amounts of
ROS, and mitochondrial DNA may directly activate NLRP3. 13,14
T
N Periodic Fever, Aphthous Stomatitis, Pharyngitis, and
F Adenitis Syndrome
α Little is known about the pathophysiology of PFAPA. No genetic
1 3 4 defect for PFAPA has been discovered as yet, and this is in agree-
ment with the absence of a clear hereditary pattern. It may be
linked to a complex genetic trait. A positive family history has
D been described, although not all of the patients with a family
D T T 15,16
R T R history were screened for other autoinflammatory diseases.
A R A During PFAPA flare-ups, upregulation of complement genes
D A D
D D D and genes in the IFN–IL-1 pathway are seen. Isolated peripheral
D blood mononuclear cells (PBMCs) and monocytes of patients
2 with PFAPA show increased IL-1β production without induction
of transcription of IL-1β RNA or caspase-1 induction upon
5 TRADD lipopolysaccharide (LPS) stimulation. This increased inflamma-
• NF-κB activation tory response can be abolished by a pan-caspase inhibitor,
• Apoptosis TRADD indicating the important role of the inflammasome in this
17
TRADD disease. Spontaneous apoptosis of polymorphous mononuclear
cells is significantly lower in patients with PFAPA compared
FIG 60.4 Pathophysiology of Tumor Necrosis Factor Recep- with healthy controls, and during fever episodes, increased
tor–Associated Periodic Syndrome (TRAPS). (1) Tumor production of ROS has been observed in vitro in patients with
necrosis factor (TNF) binds to the TNF receptor on the surface PFAPA. 18
of inflammatory cells (2). After receptor triggering, TNF receptor
type 1–associated DEATH domain (TRADD) is recruited, induc- Schnitzler Syndrome
ing a signaling cascade leading to apoptosis and production of The etiology of Schnitzler syndrome remains unknown. Involve-
proinflammatory cytokines (3). Receptors are shed from the ment of autoreactive antibodies has been suggested, but this
surface, leading to a pool of receptors that dampen immune finding could not be reproduced. A central role for IL-1β is
19
responses (4). Mutated TNF receptors form aggregates and are illustrated by the high efficacy of anti–IL-1β therapy in patients
retained intracellularly. These aggregated receptors are capable with Schnitzler syndrome. 19,20
of binding TRADD (5) and stimulate ligand-independent cytokine No causative genetic defect for Schnitzler syndrome has been
production. found, but somatic mosaicism of two different NLRP3 mutations

830 ParT SIX Systemic Immune Diseases


restricted to myeloid cells has been described recently in two For experienced physicians, it is not difficult to diagnose FMF
21
patients with Schnitzler syndrome. Strikingly, these patients in patients who have a medical history compatible with FMF
had the most severe phenotype in this cohort. Somatic mosaicism and who come from an ethnic group with high prevalence of
may be an explanation for the late onset of Schnitzler syndrome, FMF. In countries with a low incidence of FMF, several years of
and low-grade mosaicism may not be picked up by routine gene diagnostic delay are not unusual, as typical attacks remain
sequencing. Other genetic defects have also been described in unrecognized.
very small numbers of patients, but their role in the pathogenesis When FMF is suspected on clinical grounds, treatment with
of Schnitzler syndrome remains unclear. colchicine should be initiated immediately. A positive effect of
Schnitzler syndrome is regarded as a paraneoplastic syn- colchicine is confirmatory for the diagnosis FMF.
drome by some because of its association with Waldenström In populations with a low prevalence of FMF and in atypical
macroglobulinemia. cases, sequencing of the MEFV gene can be helpful in the
diagnostic workup.
LABORATORY TESTS Cryopyrin-Associated Periodic Syndrome

In classic monogenetic autoinflammatory diseases, an explicit CAPS is diagnosed on the basis of typical clinical features,
acute-phase response, with elevated inflammatory markers sometimes supported by a positive family history reflecting
(cross-reactive protein [CRP], erythrocyte sedimentation rate autosomal dominant inheritance. Detection of mutations in the
[ESR], serum amyloid A [SAA]) and leukocytosis, is invariably NLRP3 gene will confirm the diagnosis in most cases, but cases
present during symptomatic periods. In other autoinflammatory with “mutation-negative” CAPS have been described. Some of
diseases, this may be less evident. these patients may have somatic mosaicism. Reaction to treatment
During clinical disease remission, persistent subclinical inflam- is the same for these patients as for patients with proven NLRP3
mation can be found. Cold agglutinins, antinuclear autoantibodies mutation.
(ANAs), or cryoglobulins are usually not present but may be
found in low titers. Proteinuria (over 0.5 g of protein per 24 Tumor Necrosis Factor Receptor–Associated
hours) is highly suggestive for secondary AA amyloidosis. Periodic Syndrome
Elevated serum IgD can be present in MKD. It is discussed A set of clinical criteria for TRAPS has been proposed (Table
in detail in the respective section on the diagnosis of this disease. 60.4) but has not been validated. The cornerstone of the diagnosis
Similarly, the paraproteins encountered in Schnitzler syndrome of TRAPS is detection of mutations in the TNFRSF1A gene.
are discussed in the section on the symptoms of Schnitzler
syndrome. Mevalonate Kinase Deficiency
MKD can be suspected when characteristic clinical findings are
DIAGNOSIS present in combination with persistent elevated serum levels of
IgD >100 international unit per milliliter (IU/mL). Elevation of
Familial Mediterranean Fever serum IgD is not pathognomonic for MKD, as it may also occur
FMF is a clinical diagnosis. A validated set of clinical criteria for in other inflammatory conditions, including FMF and PFAPA.
the diagnosis of FMF has been defined (The Tel Hashomer criteria, Furthermore, in the very young, IgD may be normal, and in
Table 60.3). These criteria have high positive predictive value some of the affected individuals, IgD is never elevated. Elevated
and negative predictive value in populations with high pretest IgD is accompanied by elevated IgA in 80% of patients. The
probability, but their diagnostic accuracy is lower in other serum level of IgD does not correlate with disease severity, and
populations. elevated concentrations are present during asymptomatic periods.
Clinical suspicion of MKD can be confirmed by sequencing
of the MVK gene. During attacks, traces of mevalonic acid may
be found both in urine and serum and can be measured with
special techniques, which are, however, not commonly available.
TABLE 60.3 Tel Hashomer Criteria for the Measurement of mevalonate kinase enzyme activity is usually
Diagnosis of Familial Mediterranean Fever only done in the research setting and requires cell cultures.
Major Criteria (≥1 present)
a
Typical attack with abdominal symptoms
Typical attack with pleural symptoms
a
Typical attack with monoarthritis TABLE 60.4 Diagnostic Criteria for Tumor
a
Typical attack with only fever
a
Incomplete attack with abdominal symptoms Necrosis Factor receptor–associated
b
Periodic Syndrome (TraPS)
Minor Criteria (≥2 present) • Recurrent episodes of inflammatory symptoms spanning a period
Favorable response to colchicine of more than 6 months’ duration. Inflammatory symptoms include
Incomplete attack with monoarthritis fever, abdominal pain, myalgia, rash, conjunctivitis/periorbital
Exertional leg pain edema, chest pain, and arthralgia or monoarticular synovitis
• Episodes lasting ≥5 days
a Typical attacks are defined as at least three attacks with fever >38°C.
b Incomplete attacks are painful and recurrent attacks not meeting the criteria for • Responsiveness to glucocorticosteroids, but not colchicine
typical. • Affected family members (not always present)
The sensitivity and specificity of these criteria for the diagnosis of FMF are >95% and • Any ethnicity may be affected
>97%, respectively.
From: Livneh et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis From: Hull et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging
Rheum 1997;40:1879–85 concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002;81:349–68

CHaPTEr 60 Systemic Autoinflammatory Syndromes 831



TABLE 60.5 Diagnostic Criteria for As colchicine is the only drug with proven protection against
Periodic Fever, aphthous Stomatitis, the development of amyloidosis, all patients with FMF should
Pharyngitis, and adenitis (PFaPa) Syndrome be prescribed colchicine, regardless of disease severity and attack
frequency. When anti–IL-1 treatment is started, expert opinion
I Regularly recurring fevers with an early age of onset (<5 years of recommends continuation of colchicine in the highest tolerable
age) dose for the prevention of amyloidosis.
II Constitutional symptoms in the absence of upper respiratory The most common side effects of colchicine are diarrhea
infection, which include at least one of the following:
a) Aphthous stomatitis and abdominal pain. These are dose dependent. In patients with
b) Cervical lymphadenitis persistent diarrhea, dose reduction can be tried to reduce severity.
c) Pharyngitis Myopathy, neuropathy, and leukopenia are very rare, but severe
III Exclusion of cyclic neutropenia side effects occur primarily in patients with abnormal kidney
IV Completely asymptomatic interval between episodes or liver function or because of interaction with other drugs.
V Normal growth and development
High-dose colchicine has been shown to be teratogenic in
From: Thomas et al. Diagnostic criteria used for PFAPA Periodic fever syndrome in animals. However, multiple cohort studies have shown that
children. J Pediatr 1999;135:15–21 colchicine can be used safely during pregnancy and breastfeeding.
In therapeutic doses, colchicine does not have a negative effect
on sperm number and quality, and it has no negative effect on
male or female fertility.
As a general rule, there is no place for colchicine in the treat-
Periodic Fever, Aphthous Stomatitis, Pharyngitis, ment of autoinflammatory syndromes other than FMF. As an
and Adenitis Syndrome exception to this rule, patients with autoinflammation of unknown
There is currently no diagnostic test to prove PFAPA. It is origin may experience a favorable effect, especially if their disease
diagnosed based on clinical signs and symptoms. The modified shares characteristics with FMF. A small trial has demonstrated
criteria by Thomas et al. are used (Table 60.5) and may be supple- decreased attack frequency during colchicine treatment for
mented by numeric limits, such as minimum number of attacks PFAPA. 23
and duration of fever. Exclusion of other causes, including other
autoinflammatory syndromes, is important. Inhibition of Interleukin-1
Schnitzler Syndrome KEY CONCEPTS
Schnitzler syndrome is diagnosed on the basis of clinical criteria Interleukin-1β (IL-1β)
(see Table 60.2). Exclusion of other causes, particularly mono-
clonal gammopathy of undetermined significance (MGUS) and • IL-1β is a very potent proinflammatory cytokine, tightly regulated at
chronic idiopathic urticaria, is of paramount importance. multiple levels.
• The majority of autoinflammatory diseases is caused by dysregulation
Autoinflammation of Unknown Origin of IL-1β.
• Measurement of IL-1 β serum levels has no value in the diagnosis of
Regardless of the increasing number of autoinflammatory diseases autoinflammation or in assessing disease severity.
recognized and the increasing insights in the mechanisms of • IL-1 inhibition is the treatment of first choice for many autoinflammatory
autoinflammation, an increasing number of patients presenting diseases, and it has greatly improved quality of life in patients.
with an autoinflammatory phenotype cannot be assigned to
one of the known autoinflammatory diseases. These patients
are considered to suffer from autoinflammation of unknown
origin. It is likely that further research and newly developed
diagnostic techniques will identify new proteins, genetic defects, The detection of NLRP3 mutations in CAPS has illustrated the
and pathways in these patients, leading to recognition of new importance of IL-1β in the pathogenesis of autoinflammation.
diseases. In patients with autoinflammation of unknown The first inhibitor of IL-1 developed was the recombinant
origin, anti–IL-1 therapy can be tried both diagnostically and human IL-1 receptor antagonist anakinra, which is still the most
therapeutically. 21a commonly available IL-1 inhibitor. It competitively binds to the
IL-1 receptor, completely inhibiting the actions of both IL-1α
TREATMENT and IL-1β. Anakinra has a short half-life and needs to be given
as a once-daily subcutaneous injection.
Colchicine The selective anti-IL-1β monoclonal antibody canakinumab
Colchicine is the treatment of first choice for FMF. Although it has a longer half-life and is also injected subcutaneously. Standard
has been used since the 1970s, the mechanism of action of injection frequency is once per 8 weeks, but shorter intervals
colchicine in FMF is still unknown. It is highly effective in prevent- may often be necessary in severe disease.
ing attacks. Response to colchicine has been used as a diagnostic Rilonacept is a construct of two extracellular chains of the
criterion for FMF. IL-1 receptor complex fused to the Fc-portion of IgG. It is given
The average dose used is 1.0–1.5 mg/day. If tolerated, the as a weekly subcutaneous injection.
dose can be increased up to 3 mg/day in patients with insufficient Currently, there is evidence for the effectiveness of anti–IL-1
response. There are few patients with FMF that are unresponsive therapy in many autoinflammatory diseases, including FMF,
to colchicine. Others may not be able to tolerate an effective CAPS, TRAPS, MKD, PFAPA, and Schnitzler syndrome. Typically,
dose of colchicine because of side effects. These patients may anti–IL-1 treatment leads to instant abortion of inflammation
benefit from IL-1 inhibition. 22 with clinical response within the first hours to days after the

832 ParT SIX Systemic Immune Diseases


first injection. This vivid response to treatment is so characteristic
that IL-1 inhibition can serve as a diagnostic tool in the diagnosis Simvastatin
of these autoinflammatory disorders. Anakinra and canakinumab The finding of dysregulation of the mevalonate kinase pathway,
have both been approved for the treatment of CAPS by the US with cholesterol as its major end product, has led to the hypothesis
American Food and Drug Association (FDA) and the European that blockage of this pathway by HMG-CoA reductase inhibitors
Medical Association (EMA). These agents were given “orphan” (statins) would possible be beneficial in patients with MKD.
status for the treatment of TRAPS by the EMA. In 2016, the Small trials and case reports showed a statistically significant,
FDA and EMA approved the use of canakinumab in patients but clinically negligible, effect in some patients. Statins have,
with HIDS, TRAPS and colchicine-resistant FMF. Rilonacept is therefore, been abandoned as treatment for MKD in clinical
approved for the treatment of CAPS by the FDA but is not practice.
commonly used in Europe. 24
In patients with mild MKD and periodic symptoms with Other Immunosuppressive Drugs
long symptom-free intervals, anakinra can be used on demand. In the past, numerous immunosuppressive drugs were tried in
In these cases it can be started at the first signs of an attack and a trial-and-error approach to find an effective treatment for the
only be continued for a few days. 25 disabling symptoms of autoinflammation. The results have been
Side effects of IL-1 inhibition include painful injection-site mostly disappointing, and there is no strong evidence to support
reactions, which are most commonly seen with anakinra, and the use of other immunosuppressants in autoinflammation. When
increased frequency of infections, mostly mild upper respiratory other treatments are ineffective, some patients may, however,
tract infections. More severe infections are rarely seen. benefit from immunosuppressive drugs.
Inhibition of Interleukin-6 Other Treatments
Tocilizumab, a monoclonal antibody (mAb) against the IL-6 It remains a matter of debate whether adenotonsillectomy
receptor, has been registered for the treatment of rheumatoid effectively resolves symptoms in PFAPA. Few meta-analyses have
arthritis and systemic-onset juvenile idiopathic arthritis (SoJIA) focused on this subject; one of them found two small randomized
27
and is used with increasing frequency in autoinflammatory controlled trials of unclear risk–benefit ratio. A case cohort
diseases. It is available as an intravenous infusion or subcutaneous study on the use of the histamine type 2 receptor antagonist
injection. The most common dose is 8 mg/kg in children and cimetidine (150 mg twice daily) in PFAPA showed that this drug
6
adults, or 10 to 12 mg/kg in children with body weight under is able to resolve fever episodes in 25% of patients. There are
30 kg, with an interval of 2–4 weeks. Side effects of tocilizumab no clinical trials supporting this observation.
are increased susceptibility to infections, most commonly upper Several case reports on the positive effects of hematopoietic
respiratory tract infections, elevated liver enzymes, and hema- stem cell transplantation (HSCT) in patients with severe MKD
tological abnormalities. Bowel perforations have been reported. have been published. 28-30 Because of the severe side effects, HSCT
As IL-6 induces the production of CRP in the liver, anti–IL-6 should be considered the last resort.
therapy always normalizes CRP, making it impossible to use it
as a marker for disease activity. Tocilizumab has been shown to AMYLOIDOSIS
be effective in patients with anakinra-resistant Schnitzler syn-
drome, MKD, and TRAPS. Secondary or type AA amyloidosis is a serious complication of
all autoinflammatory syndromes. It is caused by tissue deposition
Inhibition of Tumor Necrosis Factor of insoluble degradation products of the inflammatory protein
Three widely used inhibitors of TNF are the mAbs infliximab SAA. Kidneys are most commonly affected. Since SAA is an
and adalimumab and the recombinant soluble TNF receptor acute-phase reactant, there is a close relationship between the
etanercept. The most common side effect of TNF inhibition is duration and level of inflammation and the development of
increased risk of serious infections. amyloidosis. The incidence of AA amyloidosis varies among
Originally, TNF inhibition was regarded the treatment of first autoinflammatory diseases. Patients with FMF are at highest
choice in patients with TRAPS unresponsive to nonsteroidal risk, with an incidence of up to 75% before the introduction of
antiinflammatory drugs (NSAIDs). However, TNF inhibition colchicine treatment for this disease. There is a strong correlation
induces complete response only in a minority of patients with between ethnicity and risk of amyloidosis in FMF, with increased
TRAPS and is therefore far less effective than anti–IL-1 treatment. 26 risk among Sephardi Jews.
Anti-TNF treatment may also be effective in MKD, but Up to 25% of patients with TRAPS will develop amyloidosis
responses are mostly partial. It may be tried in patients who if left untreated. There seems to be a strong familial predilection.
show unsatisfactory response to anti–IL-1 treatment. 24,26 In CAPS, approximately one-third of patients develop amyloidosis
in the absence of treatment. Patients with MKD and Schnitzler
Corticosteroids syndrome have a relatively small risk of amyloidosis, with only
Corticosteroids are very effective in PFAPA. Prednisone 1 mg/ a few patients with these diseases and amyloidosis known
19
kg is most commonly used during attacks, although lower doses worldwide. It is unclear why some patients with the same level
may also be effective. Use of corticosteroids may increase attack of inflammation may develop or never develop amyloidosis. This
26
frequency in PFAPA. Mild TRAPS can be treated with a short may be related to single nucleotide polymorphisms (SNPs) in
course of steroids (30 mg daily for 7 days), and patients experienc- the SAA gene or certain genotypes.
ing more severe attacks may respond to higher doses. The As proteinuria is often the first sign of AA amyloidosis, patients
beneficial effect of corticosteroids may decrease over time, with autoinflammation should be screened for it with regular
necessitating dose escalation. 24,26 Short-term corticosteroids may urine sampling. Amyloidosis can be confirmed by Congo red
also be effective in patients with mild MKD. 24,26 staining of the biopsy specimen of affected tissue. This will show

CHaPTEr 60 Systemic Autoinflammatory Syndromes 833























A B
FIG 60.5 Renal Biopsy From a Patient With Amyloid a (AA) Amyloidosis. Amyloid deposits
are visualized by staining with Congo red (A). Under polarized light microscopy amyloid deposits
show typical apple-green birefringence (B).




an apple-green birefringence under polarized light microscopy Since the introduction of the term autoinflammation at the end
(Fig. 60.5). Progression of amyloidosis is strongly dependent of the twentieth century, the clinical characteristics of the classic
on the ability to control the underlying inflammation. If the monogenic autoinflammatory diseases FMF, CAPS, MKD, and
SAA concentration can be kept under 10 mg/L, progression of TRAPS have been described in more detail. Many new diseases
amyloidosis can be halted in many cases. Some patients even have been identified. Research focused on their pathophysiological
show regression of amyloidosis during treatment. 31-34 A cohort mechanism has revealed new genes and pathways and provided
mainly consisting of patients diagnosed with amyloidosis before further insight into the mechanism of inflammation in general.
the availability of targeted therapy showed a median survival of The development of IL-1–targeting drugs has led to better quality
19 years after the diagnosis of amyloidosis. 33 of life for patients and to increased life expectancy in some of
these diseases by prevention of complications, such as secondary
CLINICaL PEarLS amyloidosis. Nevertheless, many patients with autoinflammation
A typical case of autoinflammation remain undiagnosed.
For the near future, further study of the mechanisms of
• An 18-year-old Western European woman was seen because of inflammation in patients with autoinflammatory diseases will
recurrent episodes of fever and skin rash. These attacks started 2 likely provide a deeper insight into the workings of innate
hours after birth when a systemic maculopapular skin rash appeared. immunity and will lead to the identification of even more diseases
The rash remained present on a daily basis but was not triggered or in the autoinflammatory spectrum. The search for new therapies,
exacerbated by cold exposure.
• At the age of 2 years, the patient developed episodes of fever, preferably oral drugs, for the treatment of autoinflammation
approximately 3 days each week. Typically, she had a single daily will continue.
fever spike up to 39°C, which usually occurred in the evening. There
was no hearing loss, and arthralgia/arthritis, dysmorphia, meningitis, Please check your eBook at https://expertconsult.inkling.com/
myalgias, abdominal pain, and lymphadenopathy were also absent. for self-assessment questions. See inside cover for registration
The family history was negative for autoinflammatory diseases. details.
• On the basis of the clinical presentation, cryopyrin-associated periodic
syndrome (CAPS) was suspected as a cause, and targeted gene analysis
was performed. This showed an R260W mutation of the NLRP3 gene. REFERENCES
Thus this patient was diagnosed with CAPS.
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activation. J Leukoc Biol 2013;93:289–99. 24. ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the
12. van der Burgh R, Pervolaraki K, Turkenburg M, et al. Unprenylated RhoA management of autoinflammatory diseases. Ann Rheum Dis
contributes to IL-1beta hypersecretion in mevalonate kinase deficiency 2015;74:1636–44.
model through stimulation of Rac1 activity. J Biol Chem 25. Bodar EJ, Kuijk LM, Drenth JP, et al. On-demand anakinra treatment is
2014;289:27757–65. effective in mevalonate kinase deficiency. Ann Rheum Dis
13. van der Burgh R, Nijhuis L, Pervolaraki K, et al. Defects in mitochondrial 2011;70:2155–8.
clearance predispose human monocytes to interleukin-1beta 26. Ter Haar N, Lachmann H, Ozen S, et al. Treatment of autoinflammatory
hypersecretion. J Biol Chem 2014;289:5000–12. diseases: results from the Eurofever Registry and a literature review. Ann
14. Tricarico PM, Kleiner G, Valencic E, et al. Block of the mevalonate Rheum Dis 2013;72:678–85.
pathway triggers oxidative and inflammatory molecular mechanisms 27. Burton MJ, Pollard AJ, Ramsden JD. Tonsillectomy for periodic fever,
modulated by exogenous isoprenoid compounds. Int J Mol Sci aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA).
2014;15:6843–56. Cochrane Database Syst Rev 2010;(9):CD008669.
15. Wurster VM, Carlucci JG, Feder HM Jr, et al. Long-term follow-up of 28. Arkwright PD, Abinun M, Cant AJ. Mevalonic aciduria cured by bone
children with periodic fever, aphthous stomatitis, pharyngitis, and marrow transplantation. N Engl J Med 2007;357:1350.
cervical adenitis syndrome. J Pediatr 2011;159:958–64. 29. Neven B, Valayannopoulos V, Quartier P, et al. Allogeneic bone marrow
16. Cochard M, Clet J, Le L, et al. PFAPA syndrome is not a sporadic disease. transplantation in mevalonic aciduria. New Engl J Med 2007;356:2700–3.
Rheumatology 2010;49:1984–7. 30. Chaudhury S, Hormaza L, Mohammad S, et al. Liver transplantation
17. Kolly L, Busso N, von Scheven-Gete A, et al. Periodic fever, aphthous followed by allogeneic hematopoietic stem cell transplantation for
stomatitis, pharyngitis, cervical adenitis syndrome is linked to atypical mevalonic aciduria. Am J Transplant 2012;12:1627–31.
dysregulated monocyte IL-1beta production. J Allergy Clin Immunol 31. van der Hilst JC. Recent insights into the pathogenesis of type AA
2013;131:1635–43. amyloidosis. ScientificWorldJournal 2011;11:641–50.
18. Sundqvist M, Wekell P, Osla V, et al. Increased intracellular oxygen radical 32. Lane T, Gillmore JD, Wechalekar AD, et al. Therapeutic blockade of
production in neutrophils during febrile episodes of periodic fever, interleukin-6 by tocilizumab in the management of AA amyloidosis and
aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Arthritis chronic inflammatory disorders: a case series and review of the literature.
Rheum 2013;65:2971–83. Clin Exp Rheumatol 2015;33:S46–53.
19. de Koning HD, Bodar EJ, van der Meer JW, et al. Schnitzler syndrome: 33. Lane T, Loeffler JM, Rowczenio DM, et al. AA amyloidosis complicating
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2007;37:137–48. 34. Yilmaz S, Cinar M, Simsek I, et al. Tocilizumab in the treatment of
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canakinumab treatment identifies IL-1beta as a pivotal mediator in Rheumatology 2015;54:564–5.
Schnitzler syndrome. J Allergy Clin Immunol 2011;128:1352–4.

CHaPTEr 60 Systemic Autoinflammatory Syndromes 834.e1


MULTIPLE-CHOICE QUESTIONS

1. Autoinflammatory diseases are characterized by: 3. What is the treatment of first choice for FMF?
A. Mutations in the NLRP3 inflammasome A. Acetaminophen
B. Spontaneous recurrent or persistent inflammation B. Colchicine
C. The presence of autoantibodies C. Interleukin (IL)-1 inhibition
D. Tonsillectomy
2. What is the MOST common monogenic autoinflammatory
disease worldwide? 4. What is the MOST common long-term complication of the
A. Cryopyrin-associated periodic syndrome (CAPS) monogenic autoinflammatory diseases?
B. Familial Mediterranean fever (FMF) A. Amyloid A (AA) amyloidosis
C. Mevalonate kinase deficiency (MKD) B. Chronic meningitis
D. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis C. Joint contractures
syndrome (PFAPA) D. Malignancy
E. Schnitzler syndrome
F. Tumor necrosis factor receptor–associated periodic syn-
drome (TRAPS)

61









Antiphospholipid Syndrome



Thomas L. Ortel, Doruk Erkan, Michael D. Lockshin







Diagnosis of the antiphospholipid syndrome (APS) requires that may bind directly to phospholipids and are rarely associated
a patient has both a clinical event (thrombosis and/or pregnancy with thrombosis.
loss) and persistent antiphospholipid antibody (aPL), documented
by a solid phase serum assay (anticardiolipin [aCL] or anti EPIDEMIOLOGY
β 2 -glycoprotein-I [β 2 GPI] enzyme-linked immunosorbent assay)
or an inhibitor of phospholipid-dependent clotting (lupus Low-titer aCLs occur in <10% of normal blood donors, and
1
anticoagulant [LA] test) or both (Table 61.1). Antiphospholipid moderate- to high-titer aCLs and/or a positive LA test occurs
syndrome occurs as an isolated diagnosis, referred to as primary in <1%. The prevalence of positive aPL tests increases with age;
APS, or is associated with other systemic rheumatic diseases because the differential diagnosis of vascular occlusion is broader
such as systemic lupus erythematosus (SLE). than it is in young adults, particular care is necessary in diagnosing
The primary antigen to which aPL binds is β 2 GPI (apoli- APS in older patients. Thirty to 40% of SLE patients and
poprotein H), a phospholipid-binding plasma protein. β 2 GPΙ approximately one-fifth of rheumatoid arthritis patients have
is normally present at a concentration of 200 µg/mL and is positive tests for aPL.
a member of the complement control protein family. An octapep- The strength of association between aPL and clinical events
tide in the fifth domain of the protein and critical cysteine bonds varies among studies. A study of healthy male physicians followed
are necessary for both phospholipid binding and antigenicity; a prospectively for 3 years showed that those with moderate to
first domain site is implicated in pathogenicity. In vivo, β 2 GPI high titers of IgG aCL have a risk for venous thrombosis or
binds, primarily as a dimer, to phosphatidylserine on activated pulmonary embolus that is eight times higher than that for men
or apoptotic cell membranes, including those of trophoblast, with negative tests. Although a number of studies have tried to
platelets, and endothelial cells, undergoing conformational estimate the annual thrombosis risk in asymptomatic aPL-positive
change and becoming antigenic. This binding may initiate cell patients, most of these studies have included predominantly
activation, clearance of apoptotic cells by macrophages, and/or patients with SLE. Despite the lack of well-controlled studies,
coagulation. 2 in aPL-positive individuals with no other systemic autoimmune
diseases or risk factors for thrombosis, the annual risk of first
thrombosis is probably very low (<1%/year). However, aPL-
KEY CONCEPTS positive patients with other systemic autoimmune diseases such
as SLE are at increased annual risk for first thrombosis (<4%/
• Antiphospholipid antibodies (aPL) exist as a family of autoantibodies year).
directed against phospholipid-binding plasma proteins, most commonly Approximately 10% of first-stroke victims have aPL, especially
3
β 2 -glycoprotein-I.
• The origin of aPL is unknown but is hypothesized to be an incidental those who are young, as do up to 21% of women who have
4
exposure to environmental agents inducing aPL in susceptible suffered three or more consecutive fetal losses.
individuals.
• In humans, although cross-sectional and prospective cohort studies ETIOPATHOGENESIS
demonstrate that aPL can predict future thrombosis, the pathogenic
mechanism is unknown; more than one mechanism may be involved. Antiphospholipid antibodies exist as a family of autoantibod-
• Concomitant prothrombotic risk factors may promote clotting in an ies directed against phospholipid-binding plasma proteins,
additive manner in aPL-positive patients.
most commonly β 2 GPI. Such proteins bind negatively charged
phospholipids (cardiolipin, phosphatidylglycerol, phosphati-
dylserine, phosphatidylinositol) but not zwitterionic or neutral
Autoimmune aPL binds β 2 GPI (β 2 GPI-dependent aPL), which phospholipids (phosphatidylethanolamine, phosphatidylcholine).
in turn binds negatively charged phospholipids. Drugs (such as Other phospholipid-binding plasma proteins are prothrombin,
chlorpromazine, procainamide, quinidine, and phenytoin), thrombomodulin, protein C, protein S, and annexins I and V.
malignancies (such as lymphoproliferative disorders), and infec- In vivo, the likely relevant phospholipid to which these proteins
tious agents (such as syphilitic and nonsyphilitic Treponema, bind is phosphatidylserine, which is normally sequestered on the
Borrelia burgdorferi, human immunodeficiency virus, Leptospira, inner cell membrane but is exteriorized during cell activation
or parasites) induce β 2GPI-independent transient aPL. β 2 GPI- and apoptosis. Annexins bind to exposed phosphatidylserine
independent aPLs are usually made up of low-titer aCLs, which and create a “remove me” signal on cells.

835

836 ParT Six Systemic Immune Diseases



TABLE 61.1 revised Sapporo TABLE 61.2 Possible Mechanisms of
Classification Criteria for the antiphospholipid antibody–induced
antiphospholipid Syndrome 1 Thrombosis

Clinical Criteria Endothelial Cells–antiphospholipid antibody
1. Vascular thrombosis a (aPL) interaction
(a) One or more clinical episodes of arterial, venous, or small- Endothelial cell damage or activation (via increased expression of
b
vessel thrombosis, in any tissue or organ. adhesion molecules)
c
2. Pregnancy morbidity: Coexisting antiendothelial antibodies
(a) One or more unexplained deaths of a morphologically normal aPL-induced monocyte adhesion to endothelial cells
fetus at or beyond the 10th week of gestation, or Increased tissue factor expression
(b) One or more premature births of a morphologically normal
neonate before the 34th week of gestation because of Platelet–aPL interaction
eclampsia, severe preeclampsia, or recognized features of Platelet activation
d
placental insufficiency or Stimulation of thromboxane production
(c) Three or more unexplained consecutive spontaneous abortions
before the 10th week of gestation, with maternal anatomical or Coagulation System–aPL interaction
hormonal abnormalities and paternal and maternal chromosomal Inhibition of activation of protein C by the thrombomodulin–thrombin
causes excluded.
complex
Inhibition of activation of protein C via its cofactor protein S
Laboratory Criteria e Interaction between aPL and substrates of activated protein C such as
1. Lupus anticoagulant present in plasma, on two or more occasions factors Va and VIIIa
at least 12 weeks apart, detected according to the guidelines of Interaction between aPL and an annexin V anticoagulant shield
the International Society on Thrombosis and Haemostasis.
2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or Complement activation
plasma, present in medium or high titer (i.e., >40 GPL or MPL, or >
the 99th percentile), on two or more occasions, at least 12 weeks
apart, measured by a standardized enzyme-linked immunosorbent
assay (ELISA).
3. Anti-β 2 glycoprotein-I antibody of IgG and/or IgM isotype in serum bacterial peptides, and heterologous β 2 GPI induces polyclonal
or plasma, (in titer > the 99th percentile) present on two or more aPL and clinical events associated with APS. β 2 GPI polymorphisms
occasions, at least 12 weeks apart, measured by a standardized influence the generation of aPL in individuals but have only a
ELISA.
Definite antiphospholipid syndrome (APS) is present if at least one of weak relationship to the occurrence of aPL-related clinical events.
the clinical criteria and one of the laboratory criteria are met. Persons congenitally lacking β 2 GPI as well as β 2 GPI knock-out
Classification of APS should be avoided if less than 12 weeks or mice appear normal.
more than 5 years separates the positive antiphospholipid antibody In humans, although cross-sectional and prospective cohort
(aPL) test and the clinical manifestation. In studies of populations of studies demonstrate that aPL can predict future thrombosis,
patients who have more than one type of pregnancy morbidity, the pathogenic mechanism remains unknown; more than one
investigators are strongly encouraged to stratify groups of subjects mechanism may be involved (Table 61.2). Because high-titer
according to a, b, or c above.
antibody can persist for years in asymptomatic persons and
a Coexisting inherited or acquired factors for thrombosis are not a reason for excluding because positive aPL tests can precede symptoms for years, it is
patients from APS trials. However, two subgroups of APS patients should be likely that vascular injury and/or endothelial cell activation will
recognized, according to (a) the presence, and (b) the absence of additional risk
factors for thrombosis. Indicative (but not exhaustive), such cases include age (>55 in immediately precede thrombosis in persons bearing the antibody.
men and >65 in women) and the presence of any of the established risk factors for Platelet activation followed by binding of aPL to platelet mem-
cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL brane phospholipid-bound annexins may initiate platelet adhesion
cholesterol, cigarette smoking, family history of premature cardiovascular disease,
body mass index ≥30 kg/m , microalbuminuria, estimated glomerular filtration rate and thrombosis. Antiphospholipid antibodies can inhibit
2
(GFR) <60 mL/min), inherited thrombophilias, oral contraceptives, nephritic syndrome, phospholipid-dependent reactions in the coagulation cascade,
malignancy, immobilization, and surgery. Thus patients who fulfill criteria should be such as protein C and protein S activation. Interaction between
stratified according to contributing causes of thrombosis.
b A thrombotic episode in the past could be considered as a clinical criterion, provided aPL and an annexin A5 anticoagulant shield is another potential
that thrombosis is proved by appropriate diagnostic means and that no alternative mechanism. Recent studies also demonstrate that aPLs induce
2
diagnosis or cause of thrombosis is found.
c Superficial venous thrombosis is not included in the clinical criteria. cellular activation through receptors such as annexin A2 and
d Generally accepted features of placental insufficiency include (i) abnormal or apoER2, and induce release of microparticles from endothelial
nonreassuring fetal surveillance test(s), e.g., a nonreactive nonstress test, suggestive cells. 6
of fetal hypoxemia; (ii) abnormal Doppler flow velocimetry waveform analysis
suggestive of fetal hypoxemia, e.g., absent end-diastolic flow in the umbilical artery; In experimental animal models, aPLs cause fetal resorption
(iii) oligohydramnios, e.g., an amniotic fluid index of 5 cm or less; or (iv) a postnatal (a proxy for recurrent fetal loss) and increase size and duration
birth weight less than the 10th percentile for the gestational age.
e Investigators are strongly advised to classify APS patients in studies into one of the of trauma-induced venous and arterial thrombi. Inhibiting
following categories: I, more than one laboratory criteria present (any combination); complement activation prevents experimental aPL-induced fetal
IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β 2-glycoprotein-I death, and C5 knock-out mice carry pregnancies normally despite
antibody present alone.
the presence of aPL, implying that a complement-mediated
effector mechanism is a requirement for fetal death to occur. 7
The commonly accepted hypothesis regarding the origin of In the “second-hit hypothesis,” a second trigger event (such
aPL states that an incidental exposure to environmental agents, as oral contraceptives or surgical procedures) may be necessary
the antigens of which contain β 2 GPI-like peptides, induces aPL for an asymptomatic aPL-positive individual to develop throm-
5
in susceptible individuals via molecular mimicry. In experimental bosis. Acquired and heritable risk factors for thrombosis may
animal models, passive or active immunization with viral peptides, increase the risk of thromboembolic events in aPL patients.

CHaPTEr 61 Antiphospholipid Syndrome 837


A proposed pathogenesis for aPL-mediated thrombosis and
placental injury begins with activation or apoptosis (by unknown
triggers, possibly infectious or traumatic) of platelets, endothelial
cells, or trophoblasts. Negatively charged phosphatidylserine
migrates from the inner to the outer cell membrane. Circulating
β 2 GPI binds to phosphatidylserine, which is followed by aPL
binding to a β 2 GPI dimer, activating a complement and, through
C5a, initiating a signaling cascade that induces cell surface tissue
factor (TF) expression and adhesion molecules (e.g., ICAM-1).
Other components of the innate immune system may also be
activated, leading to a milieu that promotes platelet activation
and thrombosis. In addition, aPL adversely affects formation of
a trophoblast syncytium, placental apoptosis, and trophoblast
invasion, all processes required for the normal establishment of
placental function. In vitro, pathogenic aPL induces adhesion
molecules and enhances adherence of leukocytes to cultured
endothelial cells.

DIAGNOSIS
Clinical Manifestations
The clinical manifestations associated with aPL represent a
spectrum from asymptomatic to catastrophic APS (Table 61.3).
The principal manifestations are venous or arterial thromboses
and pregnancy losses. Except for their severity, the youth of FiG 61.1 Livedo reticularis in a patient with primary antiphos-
affected patients, and unusual anatomical locations (Budd-Chiari pholipid syndrome.
syndrome, and sagittal sinus and upper extremity thromboses),
thromboses in APS do not clinically differ from thromboses
attributable to other causes. Stroke and transient ischemic attack TABLE 61.3 The Clinical Spectrum of
are the most common presentation of arterial thrombosis, whereas antiphospholipid antibodies
deep vein thrombosis and pulmonary embolism are the most a
common venous manifestations of APS. Glomerular capillary Asymptomatic antiphospholipid antibody (aPL)–positivity
Antiphospholipid syndrome with vascular events
endothelial cell injury or thrombosis of renal vessels (thrombotic Antiphospholipid syndrome with only pregnancy morbidity
microangiopathy) causes proteinuria without celluria or hypo- Asymptomatic aPL-positivity with noncriteria aPL manifestations
a
complementemia and may lead to severe hypertension and/or Catastrophic antiphospholipid syndrome
renal failure.
a No history of thrombosis or pregnancy morbidity as per the Sapporo Criteria. 1
Many patients have livedo reticularis (a lattice-like pattern of
superficial skin veins) (Fig. 61.1), cardiac valve disease (vegeta-
tions, valve thickening and dysfunction), or other nonthrombotic
manifestations described in several studies but not included in TABLE 61.4 Noncriteria Features of the
1
the revised Sapporo criteria due to nonspecificity or rarity (Table antiphospholipid Syndrome
61.4). These manifestations by themselves do not classify a patient
as having APS for clinical studies, but they add information to Type Features
the diagnosis of individual patients. The pathogenesis of cardiac Clinical Livedo reticularis
valve disease in APS is unknown; valve replacement may be Cardiac valve disease
necessary. A putative association of aPL and increased risk of Autoimmune hemolytic anemia 3
atherosclerosis may exist, but this is controversial; in studies Thrombocytopenia (usually 50 000–100 000/mm )
Multiple sclerosis–like syndrome and myelopathy
of atherosclerosis in patients with SLE, aPL protected against Nonfocal neurological symptoms
8
atherosclerosis. Some patients develop nonfocal neurological Chorea
symptoms such as lack of concentration, forgetfulness, and Laboratory IgA anticardiolipin and anti-β 2 -glycoprotein-I antibodies
dizzy spells. Small hyperintense lesions can be seen on magnetic Antiphosphatidylserine, phosphatidylinositol,
resonance imaging (MRI), primarily in the periventricular phosphatidylglycerol, phosphatidylethanolamine
antibodies
white matter, but do not correlate well with clinical symptoms Antiprothrombin antibodies
(Fig. 61.2). Antiphosphatidylserine-prothrombin antibodies
Pregnancy losses in patients with aPL typically occur after
10 weeks’ gestation (fetal loss), but early losses also occur
9
(preembryonic or embryonic losses). Patients with antiphos-
pholipid syndrome may develop severe early preeclampsia and Catastrophic APS (CAPS) is a rare, abrupt, life-threatening
HELLP (hemolysis, elevated liver enzymes, low platelets) syn- presentation. It consists of multiple thromboses of medium and
drome. Although placental infarction may be a cause of fetal small arteries occurring over a period of days, causing stroke;
growth restriction or death, nonthrombotic mechanisms of cardiac, hepatic, adrenal, renal, and intestinal infarction; and
placental dysfunction are likely more important. peripheral gangrene. Proposed diagnostic criteria for CAPS

838 ParT Six Systemic Immune Diseases



TABLE 61.5 Preliminary Criteria for the
Classification of Catastrophic
antiphospholipid Syndrome

1. Evidence of involvement of three or more organs, systems, and/or
tissues a
2. Development of manifestations simultaneously or in less than 1
week
3. Confirmation by histopathology of small-vessel occlusion in at least
one organ or tissue b
4. Laboratory confirmation of the presence of antiphospholipid
antibody (aPL) c

Definite Catastrophic antiphospholipid Syndrome (aPS):
• All 4 criteria
Probable Catastrophic aPS:
• Criteria 2–4 and two organs, systems, and/or tissues involved;
• Criteria 1–3, except no aPL confirmation 6 weeks apart due to the
early death of a patient not tested before catastrophic episode;
• Criteria 1, 2, 4; or
• Criteria 1, 3, 4, and development of a third event more than 1
week but less than 1 month after first despite anticoagulation.
a Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques
when appropriate. Renal involvement is defined by a 50% rise in serum creatinine,
severe systemic hypertension, and/or proteinuria.
b For histopathological confirmation, significant evidence of thrombosis must be
present, although vasculitis may coexist occasionally.
c If the patient had not been previously diagnosed as having APS, laboratory
confirmation requires that the presence of aPL must be detected on two or more
occasions at least 12 weeks apart (not necessarily at the time of the event),
FiG 61.2 Magnetic resonance imaging demonstrating multiple according to the proposed preliminary criteria for the classification of APS.
periventricular white matter hyperintense lesions.


reactions. Guidelines of the International Society on Thrombosis
11
are shown in Table 61.5. Early diagnosis can be a challenge, and Haemostasis for diagnosis of LA include the following:
especially in patients with no history of APS or aPL-positivity; Demonstration of a prolonged phospholipid-dependent coagula-
diagnostic algorithms are available to guide physicians for tion screening test such as activated partial thromboplastin
10
timely diagnosis. Acute adrenal failure may be the initial time (aPTT) or dilute Russell viper venom time (dRVVT);
clinical event, heralded by unexplained back pain and vascular Failure to correct the prolonged screening test by mixing the
collapse. Patients with CAPS often have moderate thrombocy- patient plasma with normal platelet-poor plasma, demonstrat-
topenia; fragmented erythrocytes can be seen, but they are less ing the presence of an inhibitor;
frequent than in hemolytic–uremic syndrome or in thrombotic Shortening or correcting the prolonged screening test by addition
thrombocytopenic purpura. Renal failure and pulmonary of excess phospholipid, demonstrating phospholipid depen-
hemorrhage may occur. Tissue biopsies show noninflammatory dency; and
vascular occlusions involving both small- and medium-sized Exclusion of other coagulopathies.
vessels. A positive screening coagulation test without confirmatory
Antibodies to prothrombin sometimes accompany aPLs and steps is not a positive LA test. Patients on anticoagulation may
may cause hemorrhage by depleting prothrombin (lupus anti- have false-positive or false-negative results for the LA test; thus
coagulant hypoprothrombinemia syndrome). when possible, the LA test should be ordered when the patient
is not receiving anticoagulation therapy. 11
Laboratory Tests Interpretation of positive tests should take into account the
In the presence of characteristic clinical events, APS is diagnosed following observations: moderate- to high-titer (>40 U) aCL or
when patients have persistent aPLs, including moderate- to aβ 2 GPI is more strongly associated with clinical events than is
high-titer IgG and/or IgM aCL, moderate- to high-titer IgG and/ low-titer; LA is a more specific but less sensitive predictor of
12
1
or IgM aβ 2 GPI, and/or positive LA test. Approximately 80% of thromboses than other aPL tests ; multiple positive aPL tests
13
patients with positive LA tests have aCL, but only 20% of patients impart a worse prognosis than does any single type of test ; and
positive for aCL have positive LA tests. Some patients are only positive aPL tests require a repeat test after 12 weeks to exclude
aβ 2 GPI positive. Patients with positive LA tests have higher risk transient aPL. 1
for thrombosis than patients with negative tests. Several studies Laboratory variability in these assays is moderately high: Assay
have shown that patients with positive aβ 2 GPI tests are also at stability in individual patients occurs over time in most patients.
higher risk for thrombosis, but this has not been consistently We showed that aPL results remain stable for at least three-quarters
observed. of subsequent tests during a mean follow-up of 2.4 years for the
LAs are detected in coagulation assays that detect the ability LA test, 3.5 years for the aCL test, and 1.0 year for the anti-β 2 GPI
14
of aPL to interfere with phospholipid-dependent coagulation test. Based on same-day specimens, the consistency of aCL

CHaPTEr 61 Antiphospholipid Syndrome 839


results among different commercial laboratories ranges from TREATMENT
64% to 88%, with moderate agreement for IgG and IgM, but
marginal agreement for aCL IgA. 14 Treatment recommendations for persistently aPL-positive patients
Antiphospholipid antibody tests developed based on phos- are determined by the specific clinical indication (Table 61.6).
phatidylserine, phosphatidylinositol, phosphatidylethanolamine,
or prothrombin are not well standardized or widely accepted; Asymptomatic Individuals
their clinical significance is unknown. IgA aCL can occur rarely The ideal strategy for primary thrombosis prevention in asymp-
as the only aPL in patients with APS. When positive, an IgA aCL tomatic, persistently aPL-positive individuals requires a risk-
may justify a diagnosis of APS in LA- and aCL-IgG/IgM test- stratified approach based on aPL profile, age, systemic autoimmune
negative patients with clinically typical disease. A false-positive diseases, traditional cardiovascular disease, or risk factors for
test for syphilis is not diagnostic for APS. venous thrombosis. Elimination of reversible risk factors for
Antinuclear and anti-DNA antibodies occur in approximately thrombosis (smoking, oral contraceptives) and prophylaxis during
45% of patients with APS who are not diagnosed as having SLE. high-risk periods (surgical interventions or prolonged immobiliza-
Thrombocytopenia occurs in APS and is usually modest (>50,000/ tion) is crucial for primary thrombosis prophylaxis in persistently
3
mm ); proteinuria and renal insufficiency occur in patients with aPL-positive individuals. The effectiveness of aspirin is not
thrombotic microangiopathy. Erythrocyte sedimentation rate supported by the literature; in a randomized, double-blind,
and hemoglobin and leukocyte count are usually normal in placebo-controlled trial, low-dose aspirin (81 mg) appeared to
patients with uncomplicated APS, except during acute thrombosis. be no better than placebo in preventing first thrombotic episodes
15
Complement levels are usually normal or only modestly low. in persistently asymptomatic aPL-positive patients. The general-
population cardiovascular disease (CVD) risk prediction tools
Imaging Studies and prevention guidelines formulated based on risk–benefit
MRI studies show vascular occlusion and infarction consistent calculations should play the primary role in decision making for
with clinical symptoms, without special characteristics, except aspirin therapy. Estrogen and estrogen-containing oral contracep-
that multiple otherwise unexplained cerebral infarctions in a tives are considered unsafe for asymptomatic women serendipi-
young person suggest the syndrome. Multiple small hyperintense tously known to bear high-titer antibody. There is no reliable
white matter lesions are common and do not unequivocally information regarding the safety of progestin-only contraception,
imply brain infarction (Fig. 61.2). Occlusions usually occur in “morning after” contraception, or raloxifene, bromocriptine, or
vessels below the resolution limits of angiography; hence angi- leuprolide in APS patients. However, progestin-only contraception
ography or magnetic resonance angiography is not indicated
unless clinical findings suggest medium- or large-vessel disease.
Echocardiography or cardiac MRI may show severe Libman-Sacks
endocarditis and intracardiac thrombi. TABLE 61.6 Treatment recommendations
in Persistently antiphospholipid
Pathological Studies antibody–Positive Patients

Clinical Circumstance recommendation
Asymptomatic No treatment a
CLiNiCaL PEarLS Venous or arterial Warfarin international normalized ratio
thrombosis (INR) 2–3.0 indefinitely
• The clinical manifestations of antiphospholipid antibodies (aPL) represent Recurrent thrombosis Warfarin INR 3–3.5 indefinitely ±
a spectrum (from asymptomatic to catastrophic antiphospholipid low-dose aspirin
syndrome [APS]); thus patients should not be evaluated and managed First pregnancy No treatment a
as having a single disease manifestation. Single pregnancy loss, No treatment a
• Stroke and transient ischemic attack are the most common presentation <10 weeks
of arterial thrombosis; deep vein thrombosis, often accompanied by Recurrent fetal loss or Prophylactic-dose heparin with
b
pulmonary embolism, is the most common venous manifestation of loss after 10 weeks; low-dose aspirin throughout the
APS. history of no pregnancy, discontinue heparin 6–12
• Pregnancy losses in patients with aPL typically occur after 10 weeks’ thrombosis weeks postpartum
gestation (fetal loss), but early losses also occur (preembryonic or Recurrent fetal loss or Therapeutic-dose heparin with low-dose
c
embryonic losses). loss after 10 weeks; aspirin throughout pregnancy, warfarin
• Catastrophic APS is a rare, abrupt, life-threatening complication of history of thrombosis postpartum
APS, which consists of multiple thromboses of medium and small Catastrophic Anticoagulation + corticosteroids +
arteries occurring over a period of days. antiphospholipid intravenous immunoglobulin or plasma
• APS diagnosis should be made in the presence of characteristic clinical syndrome (APS) exchange
manifestations and persistently (at least 12 weeks apart) positive aPL. Livedo reticularis No treatment
Valve nodules or No known effective treatment; full
deformity anticoagulation if emboli or intracardiac
thrombi are demonstrated
Skin, renal, and other tissues show noninflammatory occlusion Thrombocytopenia, No treatment
>50 000/mm
3
of all caliber arteries and veins, acute and chronic endothelial Thrombocytopenia, Prednisone and/or intravenous
injury and its sequelae, and recanalization in late lesions. The ≤50 000/mm 3 immunoglobulin
finding of inflammatory necrotizing vasculitis suggests con-
comitant SLE or other connective tissue disease. There are no a b Aspirin 81 mg/day may be given.
other diagnostic immunofluorescence or electron microscopical c Prophylactic dose such as enoxaparin 30–40 mg subcutaneously (SQ) once daily.
Therapeutic dose such as enoxaparin 1 mg/kg SQ twice daily or 1.5 mg/kg SQ once
findings. daily.

840 ParT Six Systemic Immune Diseases


is theoretically safer than estrogen-based contraception. A small immunoglobulin (IVIG), and plasmapheresis have theoretical
retrospective review of women undergoing artificial reproductive bases for efficacy and have all been used. There are no systematic
technology procedures demonstrated no thrombotic events. studies of treatment for CAPS. Detailed reviews conclude that
the most effective treatment combines full-dose anticoagulation,
Venous and Arterial Thromboembolism high-dose corticosteroids, plasma exchange, and IVIG.
Anticoagulation with unfractionated heparin or low-molecular-
weight heparin (LMWH) followed by warfarin is the treatment Pregnancy Morbidity
for APS patients with vascular events. Heparin inhibits comple- Pregnancy is a prothrombotic state; management strategies in
ment, a fact that makes it theoretically a preferred but impractical persistently aPL-positive patients should focus on prevention of
agent in most patients. For patients with a positive LA test that both pregnancy morbidity and maternal thrombotic complica-
9
prolongs the aPTT, monitoring heparin can be accomplished by tions. In pregnancy, heparin and low-dose aspirin combination
measuring antifactor Xa levels. increases fetal survival rate from 50% to 80% among women
Two prospective controlled studies concluded that recurrence who have had a fetal loss and tests positive for aPL. If patients
of thromboses in APS patients can be prevented with warfarin to fail this regimen, the next step is to add IVIG, an approach not
an international normalized ratio (INR) of 2.0–3.0. 16,17 Although supported by controlled studies. Most experts in the field use
these studies provide strong evidence for moderate-intensity LMWH (e.g., enoxaparin) due to lower risk of thrombocytopenia
anticoagulation after an aPL-related venous event, the intensity and osteoporosis—prophylactic doses for women who have had
of the anticoagulation is still debatable for APS patients with only pregnancy morbidity, or full anticoagulant doses for women
arterial events, since such patients constituted a minority in these who have had prior thromboses (Table 61.6). Treatment begins
studies. Although some APS patients may require high-intensity after confirmation of pregnancy, continues until 48 hours before
anticoagulation, in the absence of risk-stratified studies the anticipated delivery (to allow epidural anesthesia), and resumes
definition of high risk is based currently on clinical judgment. for 8–12 weeks postpartum (if no prior thromboembolism), or
Most aPL-positive patients receive warfarin after ischemic else the patient is transitioned to warfarin for continued therapy.
strokes; however, the Antiphospholipid Antibodies and Stroke No studies unequivocally justify treatment of women with aPL
Study (APASS) concluded that for selected aPL-positive patients during a first pregnancy, women with only very early losses, or
who have neither atrial fibrillation nor high-grade arterial stenosis, women whose aPL titers are low or transient. Nonetheless, it is
aspirin (325 mg/day) and warfarin (target INR 1.4–2.8) are common to offer such patients low-dose aspirin.
equivalent in efficacy and in association with major bleeding
18
complications. The generalizability of these results is limited, Other Clinical Manifestations of APS
as the study group had an average age of 60 years (higher than There is no consensus for the treatment of patients with non-
the average for APS populations), the aPL determination was criteria and/or nonthrombotic manifestations of aPL. Corticoster-
performed only once at study entry, and the cutoff for assigning oids and/or IVIG are the first-line treatments for platelet counts
3
a patient to the positive aCL group was very low. However, based less than 50 000/mm . An open-label phase IIa pilot study of aPL
on APASS results, aspirin is an option for older patients with a found that rituximab may be effective in controlling some but
single low positive aCL test who present with stroke. not all noncriteria manifestations of APS, although aPL profiles
Recently, four direct oral anticoagulants (DOACs) that target did not change with treatment. 21
thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, and
edoxaban) have been approved for the treatment of patients Perioperative Management
with venous thromboembolism. Use in patients with APS is Serious perioperative complications may occur despite prophy-
limited, and cases of therapeutic failure have been reported. A laxis. Patients with APS are at additional risk for thrombosis
prospective study investigated the use of rivaroxaban compared when they undergo surgery. Thus perioperative strategies should
with standard-intensity warfarin in patients with APS, using the be clearly identified before any surgical procedure or before
change in endogenous thrombin potential (ETP), a laboratory pharmacological and physical antithrombosis interventions are
parameter, as the primary outcome. Although the ETP did not vigorously employed; in addition, periods without anticoagulation
reach the noninferiority threshold, there was no increase in must be kept to an absolute minimum, and any deviation from
19
thrombotic events in patients taking rivaroxaban. The study a normal course must be considered a potential disease-related
was not powered for clinical outcomes, however, and other studies event. 22
are in progress.
Venous thrombosis in aPL-positive patients typically has a Additional Therapeutic Considerations
high recurrence rate if anticoagulation is discontinued, and There is experimental and clinical evidence in lupus patients
lifelong anticoagulation is usually recommended. A recent that hydroxychloroquine (HCQ) might decrease the incidence
systematic review of the literature revealed that the available of thrombosis, and recent in vitro studies have demonstrated
evidence in support of an association between the presence of that HCQ might protect endothelial cells and syncytialized
aPL and risk of recurrence is of low quality, however, suggesting trophoblast cell lines from the disruptive effect of antiphospho-
20
23
that indefinite anticoagulation may not be needed by all patients. lipid antibodies. In patients with systemic autoimmune diseases
For example, it is unknown whether patients whose event was (particularly lupus), HCQ is commonly employed for disease
triggered by an acquired, reversible risk factor for thrombosis control and should be considered independent of patients’ aPL
can discontinue anticoagulation or switch to aspirin when the status. However, further controlled studies are needed to determine
trigger factor is eliminated. Normalization of the LA or aCL the effectiveness of HCQ for primary prophylaxis in aPL-positive
tests is not an indication to discontinue anticoagulation. For patients.
well-anticoagulated patients who continue to have thromboses, Although statins have been used in primary and secondary
antiplatelet drugs, hydroxychloroquine, statins, intravenous cardiovascular disease prevention, no data exist for their use in

CHaPTEr 61 Antiphospholipid Syndrome 841


thrombosis prevention in aPL-positive patients. Experimental 5. Erkan D, Lockshin MD. What is antiphospholipid syndrome? Curr
evidence in APS mouse models and the clinical trials demonstrat- Rheumatol Rep 2004;6:451–7.
ing rosuvastatin’s protective effect against a first major cardio- 6. Betapudi V, Lominadze G, Hsi L, et al. Anti-β2GPI antibodies stimulate
vascular event and venous thrombosis in a general population endothelial cell microparticle release via a nonmuscle myosin II motor
protein-dependent pathway. Blood 2013;122:3808–17.
without hyperlipidemia but with elevated high-sensitivity 7. Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and
24
C-reactive protein levels justifies clinical studies of statins in neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin
nonpregnant aPL-positive patients. Invest 2003;112:1644–54.
Antiplatelet agents other than aspirin or long-term LMWH 8. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of
treatment, empirically used, have not been formally tested in accelerated atherosclerosis in systemic lupus erythematosus. N Engl J
clinical trials. Ongoing prospective, randomized clinical trials Med 2003;349:2399–406.
investigating the role of the direct oral anticoagulants in the 9. Ruiz-Irastorza G, Crowther M, Branch W, et al. Antiphospholipid
treatment of thromboembolism in patients with APS are eagerly syndrome. Lancet 2010;376:1498–509.
awaited, and other strategies, including complement inhibitors 10. Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid
and novel antithrombotic therapies, may be candidates for future syndrome: updated diagnostic algorithms. Autoimmun Rev 2010;10:74–9.
clinical trials. 11. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus
anticoagulant detection. Subcommittee on Lupus Anticoagulant/
Antiphospholipid Antibody of the Scientific and Standardisation
CONCLUSIONS AND TRANSLATIONAL RESEARCH Committee of the International Society on Thrombosis and Haemostasis.
J Thromb Haemost 2009;7:1737–40.
12. Galli M, Luciani D, Bertolini G, et al. Lupus anticoagulants are stronger
risk factors for thrombosis than anticardiolipin antibodies in the
ON THE HOriZON antiphospholipid syndrome: a systematic review of the literature. Blood
2003;101:1827–32.
Translational research in antiphospholipid Syndrome 13. Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic
• A better understanding of the cellular mechanisms of antiphospholipid event in asymptomatic carriers of high-risk antiphospholipid antibody
antibody (aPL) mediated clinical events that will help us design more profile: a multicenter prospective study. Blood 2011;118:4714–18.
specifically targeted treatments. 14. Erkan D, Derksen WJ, Kaplan V, et al. Real world experience with
• Identification of patients who are at risk for future aPL-related events. antiphospholipid antibody tests: how stable are results over time? Ann
• Controlled studies of theoretically useful medications such as hydroxy-
chloroquine, statins, complement inhibitors, or anti-B-cell therapies. Rheum Dis 2005;64:1321–5.
15. Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis
prevention in the antiphospholipid syndrome: a randomized,
double-blind, placebo-controlled trial in asymptomatic antiphospholipid
APS is a systemic autoimmune disease consisting of thromboses, antibody-positive individuals. Arthritis Rheum 2007;56:2382–91.
pregnancy losses, and persistent high-titer aPL. Inflammation 16. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities
and complement activation are established mechanisms of aPL- of warfarin for the prevention of recurrent thrombosis in patients with
related manifestations in murine models; however, definitive the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133–8.
studies in humans do not exist. The disease is too variable 17. Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of
high-intensity warfarin vs. conventional antithrombotic therapy for the
clinically, and its mechanisms too diverse, to expect that a single prevention of recurrent thrombosis in patients with the antiphospholipid
mechanism defined in a single model will apply to all aspects syndrome (WAPS). J Thromb Haemost 2005;3:848–53.
of this disease. Given that the mechanisms of aPL-induced 18. Levine SR, Brey RL, Tilley BC, et al. Antiphospholipid antibodies and
thrombosis are not well understood and that thrombosis is subsequent thrombo-occlusive events in patients with ischemic stroke.
multifactorial and that controversies exist about the strength of JAMA 2004;291:576–84.
association between aPL and clinical events, drug development 19. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to
specific for aPL-positive patients has been challenging. Antico- treat patients with thrombotic antiphospholipid syndrome, with or
agulation is the primary treatment today, but a future therapeutic without systemic lupus erythematosus (RAPS): a randomised, controlled,
approach will likely include immunomodulatory agents. open-label, phase 2/3, non-inferiority trial. Lancet Haematol
2016;3:e426–36.
20. Garcia D, Akl EA, Carr R, et al. Antiphospholipid antibodies and the risk
Please check your eBook at https://expertconsult.inkling.com/ of recurrence after a first episode of venous thromboembolism: a
for self-assessment questions. See inside cover for registration systematic review. Blood 2013;122:817–24.
details. 21. Erkan D, Vega J, Ramon G, et al. A pilot open-label phase II trial of
rituximab for non-criteria manifestations of antiphospholipid syndrome.
REFERENCES Arthritis Rheum 2013;65:464–71.
22. Erkan D, Leibowitz E, Berman J, et al. Perioperative medical management
1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus of antiphospholipid syndrome: hospital for special surgery experience,
statement on an update of the classification criteria for definite review of literature, and recommendations. J Rheumatol 2002;29:843–9.
antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. 23. Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the
2. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid annexin A5 anticoagulant shield from disruption by antiphospholipid
syndrome. N Engl J Med 2013;368:1033–44. antibodies: evidence for a novel effect for an old antimalarial drug. Blood
3. The Antiphospholipid Antibodies in Stroke Study (APASS) Group. 2010;115:2292–9.
Anticardiolipin antibodies are an independent risk factor for first 24. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of
ischemic stroke. Neurology 1993;43:2069–73. rosuvastatin in the prevention of venous thromboembolism. N Engl J
4. Stephenson MD. Frequency of factors associated with habitual abortion Med 2009;360:1851–61.
in 197 couples. Fertil Steril 1996;66:24–9.

CHaPTEr 61 Antiphospholipid Syndrome 841.e1


MULT i PLE-CHO i CE QUEST i ONS

1. Which of the following statements concerning treatment 3. Which of the following patients should be tested for possible
options for a patient with antiphospholipid antibodies is APS?
correct? A. A 65 year old man with a stroke
A. Aspirin is an effective thromboprophylactic strategy B. A 22 year old woman taking oral contraceptives with a
for asymptomatic individuals with antiphospholipid pulmonary embolism
antibodies. C. A 34 year old woman who presents with fetal demise at
B. Patients with arterial thromboembolism and APS should 34 weeks gestation
be treated with aspirin and a direct oral anticoagulant D. A 27 year old man new-onset seizures
C. Patients with venous thromboembolism and APS should
be treated with warfarin with a target INR of 2-3
D. A woman with prior pregnancy loss and APS should receive
intravenous immunoglobulin and steroids during subse-
quent pregnancies
2. A lupus anticoagulant is identified by which of the following
laboratory test results?
A. Elevated antibody levels to prothrombin
B. An antibody that interferes with phospholipid-dependent
coagulation reactions
C. An antibody that induces an increased thrombin potential
D. The presence of a specific factor inhibitor

62









Immunohematological Disorders



Jay N. Lozier, Pierre Noel




Congenital (primary) or acquired (secondary) immunodeficiencies, to cause renal failure from toxicities of hemoglobin to renal
medications, and lymphoproliferative and rheumatological epithelium.
disorders are frequently associated with immune-mediated A second less common mechanism develops primarily in
cytopenias. These processes can affect erythrocytes, leukocytes, patients receiving very high doses of penicillin (rarely used) for
and platelets (individually or in combination). In this chapter, at least 1 week. High-titer antipenicillin IgG develops and binds
we address immune-mediated cytopenias of each hematological to penicillin that is covalently attached to the RBC membranes.
component, discussing pathophysiology, clinical presentation, The resultant hemolysis is less acute than that caused by immune
differential diagnosis, and treatment options. complexes but can be life-threatening.
In a third mechanism, a drug stimulates the production of
IMMUNE-MEDIATED HEMOLYTIC ANEMIA an antibody that reacts with the patient’s RBCs independently
from the drug. Serologically, this antibody is indistinguishable
Immune-mediated hemolysis can be autoimmune, alloimmune, from an idiopathic autoantibody. This has become rare as the
idiopathic, or secondary to drugs or other diseases. Regardless use of the primary causal agent, methyldopa (an antihypertensive
of the underlying cause, immunoglobulin G (IgG) or IgM (rarely medication), has declined. Although these autoantibodies com-
IgA) antibodies are directed against antigens on the red blood monly cause positive clinical antibody tests (see below), they
1,2
cell (RBC) membrane (Table 62.1). These disorders can be rarely cause hemolysis in vivo, and when they do, it usually ceases
categorized on the basis of the underlying cause and the type within 2 weeks of discontinuing the drug.
of antierythrocyte antibody that mediates the process.
Cold Agglutinin Diseases
Autoimmune Hemolysis Mediated by Warm Antibody This type of hemolytic anemia is mediated predominantly by
Although warm-antibody autoimmune hemolytic anemia is rare, anti-I or anti-i IgM that agglutinates red cells at temperatures well
5
it increases in prevalence above the age of 50 years and tends to below 37°C. These antibodies engage the complement pathway
be more common in women than in men, as is typical of most resulting in C3b-mediated RBC phagocytosis mainly by Kupffer
autoimmune diseases. In this condition, IgG autoantibodies and cells, whereas membrane-associated complex is a minor mecha-
complement components are present on the RBC surface (see nism at low IgM titers. The severity of the clinical illness depends
below). Although the autoantibody target is most commonly on the concentration of the IgM and its “thermal amplitude.”
the Rh antigen, a variety of other targets are known. The specificity Thermal amplitude describes the temperature range over which
of the antibody, however, does not affect the clinical presentation it binds to RBCs: for example, antibodies that exclusively bind
or management of hemolysis. at 4°C are only active in vitro, whereas those that bind at >30°C
can bind to RBCs as they circulate in the periphery and begin the
Drug-Induced Immune Hemolysis process of complement fixation, which can persist even as the
3
Over 125 drugs have been associated with immune hemolysis. cells return to body core temperatures. The activity of the IgM is
Cefotetan, ceftriaxone, and piperacillin currently account for over also determined by its relative affinity for the I- and i-antigens,
80% of cases. The prognosis of drug-related immune hemolysis is which varies from one individual to the next.
much better than that of idiopathic hemolysis because the hemolysis Two general types of cold agglutinin disease are recognized:
stops once the offending drug has been removed. The drugs most a chronic idiopathic disease presenting in patients over age 50
commonly associated with fatal hemolytic anemia are cefotetan years, caused by monoclonal anti-I IgM, and a transient disease
3
(8%) and ceftriaxone (6%). Fludarabine and cladribine have been secondary to certain infections (e.g., mycoplasma, Epstein-Barr
associated with immune hemolysis. Following multiple courses virus [EBV], cytomegalovirus [CMV]), caused by polyclonal
of alkylating agents, fludarabine causes autoimmune hemolytic anti-i and anti-I (see Table 62.1). Avoidance of cold environments
anemia in 20% of patients with chronic lymphocytic leukemia is important in both categories of cold agglutinin disease. In
(CLL). The combination of fludarabine and cyclophosphamide addition, cold agglutinin disease can be associated with B-cell
with or without rituximab (FC, FCR) may protect against the lymphoproliferative disorders, and this typically is responsive
development of autoimmune hemolytic anemia. 3,4 to rituximab and/or rituximab combined with fludarabine. 6
Although the biochemical mechanisms of drug-related immune
hemolysis are not completely clear, several hypotheses are generally Paroxysmal Cold Hemoglobinuria
accepted. Most commonly, complexes of drug and IgG and/or Paroxysmal cold hemoglobinuria (PCH) is caused by anti-P IgG
IgM that adsorb to the RBC surface and fix complement. The that is very effective in fixing complement and producing
2
resultant intravascular hemolysis is acute and often severe enough intravascular hemolysis. Although rare, it is most common in
845

846 Part Seven Organ-Specific Inflammatory Disease



TABLE 62.1 Classification of Immune antibodies will be produced and can lead to significant hemolysis.
Hemolytic Disorders If the transplantation involves hematopoietic stem cells (HSCs),
this dilemma will resolve once the donor’s erythropoiesis pre-
autoimmune vails and the donor lymphocytes are no longer exposed to the
Warm Antibody-Mediated recipient RBCs.
Idiopathic
Secondary Immunopathogenesis
Drugs, lymphoid malignancies, infections
Other autoimmune diseases The antigens for antierythrocyte IgG are usually proteins, the
most clinically important of which are the Rh-associated glyco-
8
Cold Antibody-Mediated proteins (RhAG), D, C, c, E, and e. In contrast, antierythrocyte
Cold agglutinin disease IgM is directed at polysaccharides, which include the ABO and
Idiopathic I-antigens (I, i) found on the anion and glucose transporter
Secondary proteins in the RBC membrane. 9,10
Infection, lymphoid malignancies
Antibodies are distinguished by being “warm” and “cold”
Paroxysmal Cold Hemoglobinuria reactive, respectively, meaning that they bind antigens at core
Idiopathic body temperature (warm) or they bind antigens preferentially
Secondary to infections at lower temperatures (cold) in the peripheral circulation or ex
vivo. This distinction results from the different thermodynamics
alloimmune of binding to protein (hydrophobic) and polysaccharide (elec-
Secondary to red cell transfusions (alloantibodies, isoantibodies) trostatic) antigens. 10
Secondary to fetal-maternal hemorrhage IgG antibodies typically bind at warm temperatures and IgM
Secondary to transplanted lymphocytes antibodies typically bind at cold temperatures, although there
can be overlap and exceptions (e.g., the Donath-Landsteiner IgG
antibodies that are seen in paroxysmal cold hemoglobinuria).
children following a viral illness and can be managed by avoidance IgG and IgM also differ in their ability to fix complement, and
of cold. In the past, it was more commonly associated with syphilis this affects the resulting mechanism of hemolysis. To attach the
(see Table 62.1). There is also an autoimmune variety of PCH first component of the classical complement pathway, two IgG
that may require immunosuppression with corticosteroids. molecules must bind in close proximity on the RBC. However,
Splenectomy is not helpful as a consequence of the fact that the because of its pentameric structure, a single IgM molecule can
hemolysis is intravascular. initiate complement activation.
Erythrocyte-bound IgG becomes attached to the Fc receptors
Hemolytic Transfusion Reactions of splenic macrophages, which may engulf all or part of the cell
Because individuals with group O RBCs have preformed iso-anti-A or release lysosomal enzymes that digest its membrane (antibody-
11
and -B, they must only be transfused with group O cells. Similarly, dependent cell-mediated cytotoxicity [ADCC]). RBC fragments
individuals with group A RBCs with preformed anti-B isoantibod- escaping from this encounter lose more membrane than cytoplasm
ies must only receive group A RBCs, and individuals with group and become spherical (spherocytes) as a consequence of this
B RBCs must only receive group B RBCs. Because of the absence change in the surface-to-volume ratio. If IgG has initiated
of either group A or B antigens on the surface of group O RBCs, complement activation on the cell surface, binding of C3b to
such cells can be used in transfusion of A, B, or AB individuals splenic macrophages will augment erythrocyte phagocytosis in
in emergency situations. Failure to abide by these rules results the spleen. 12
in acute intravascular hemolysis that can cause renal failure, When IgM fixes complement, the process begins in the cooler
disseminated intravascular coagulation, and death. peripheral circulation, where IgM binds to RBCs. If the amount of
Other hemolytic transfusion reactions are caused by alloan- IgM bound is relatively high with at least some of it remaining on
tibodies, predominantly IgG. Therefore a multiply transfused the cell at 37°C (e.g., anti-A or anti-B isoantibodies), the cascade
patient is at risk for hemolysis from alloantibodies if the patient of complement activation goes to completion. Doughnut-shaped
receives incompatible blood. Multiparous women are at similar holes are formed in the cell membrane that allow the influx of
risk because of exposure to paternal fetal RBC antigens. Fortu- water and sodium, inducing intravascular osmotic rupture of
11
nately, for unclear reasons, most RBC antigens do not elicit an the cell. However, if the IgM elutes from the RBC as it returns
immune response although the Rh, Kell, Kidd, and Duffy antigens to body core temperature, the complement reaction attenuates.
are clearly immunogenic. Exposure particularly to Kidd or Duffy In this circumstance, the components remain on the cell but do
antigens may stimulate alloantibody formation that can rise to not cause intravascular hemolysis. Instead, the cells are cleared
sufficient titer to cause hemolysis with an onset typically delayed by hepatic macrophages via complement-binding sites. 13
by approximately 1 week. Such delayed transfusion reactions This has important implications for clinical tests for the pres-
may be subtle or cause an abrupt drop in hemoglobin with ence of antibody and complement on the RBC surface during
jaundice and hemoglobinuria. the workup of immune-mediated hemolysis. Antibody-mediated
hemolysis causes variable degrees of anemia and reticulocytosis.
Immune Hemolysis Associated With Transplantation Intravascular hemolysis releases hemoglobin into the circulation,
Any transplanted tissue may contain “passenger” lymphocytes but this is too small an amount to cause measurable hemoglo-
from the donor that will survive and proliferate in the recipient binemia, although it will result in consumption of haptoglobin,
7
if the recipient is sufficiently immunosuppressed. When the which is rapidly depleted. In contrast, when hemolysis results from
RBCs of the recipient carry A or B antigen and the donor is complement-mediated lysis, such as follows an ABO-incompatible
ABO incompatible, the transplanted lymphocytes will respond blood transfusion, hemoglobinemia becomes massive, overcom-
to the recipient RBCs as foreign, and allogeneic anti-A or anti-B ing the scavenging capacity of plasma hemoglobin binders

CHaPter 62 Immunohematological Disorders 847


(haptoglobin, hemopexin, albumin), resulting in hemoglobinuria. Antibody-coated red cells from patient Reagent anti-IgG
Because hemoglobin is toxic to the renal tubular epithelium,
renal function may become impaired. RBC membrane fragments
released by massive intravascular hemolysis are a rich source of
procoagulant phosphatidylserine and can precipitate disseminated
intravascular coagulation. +
In contrast, the consequences of extravascular hemolysis (i.e.,
via phagocytosis in the reticuloendothelial system of the liver
and the spleen) are much less severe. In macrophages, iron is
removed from the hemoglobin and recycled to the circulation
to support a compensatory reticulocytosis and the heme porphyrin
is metabolized to bilirubin.
Patients with immune-mediated anemia have an increased
incidence of venous thromboembolism, and detection of a lupus Visible red cell agglutination
anticoagulant in these patients places them at a particularly high
risk for this complication. 14
Diagnosis
With few exceptions, if the mechanism of hemolysis is immune
mediated, an anti-RBC antibody can be demonstrated, either
1,2
on the RBC surface, in serum, or both. With autoimmune
hemolysis, IgG or IgM and/or complement components can be
identified by a direct antibody test (DAT), originally known as
a direct Coombs test (Fig. 62.1). For this assay, a patient’s RBCs
are washed and suspended in buffer. Surface-bound IgG is detected
by adding anti-IgG antibody, which, being divalent, can bind to
IgG on adjacent RBCs and agglutinate them into visible aggregates.
Because of its pentameric structure, IgM on the cells can cause
agglutination without the addition of a second antibody. Even
when IgM has been previously eluted from the cell surface as a
result of warming in the central circulation, its earlier presence FIG 62.1 The Direct Antibody Test (DAT). The test is positive
in vivo can be detected by telltale remnants of complement that when immunoglobulin G (IgG: light blue triangles)–coated red
are fixed to the RBC. In this setting, detection requires the addition blood cells are cross-linked by anti-IgG antibody (dark blue tri-
of anticomplement (e.g., anti-C3dg) antibody. angles) to form visible cell aggregates. Cell-bound complement
Alloantibodies can also be detected by the DAT if allogeneic and/or IgM can be detected by using anticomplement or anti-IgM
RBCs from a previous transfusion are still circulating. If these reagent antibodies.
have been cleared, however, RBC antibodies can be identified
in the patient’s serum by adding the serum to a panel of RBCs
carrying different antigens. Agglutination is detected as described
above; this constitutes the indirect antibody test.

CLInICaL PearLS

In the workup of hemolytic anemia, the following clinical laboratory studies reticulocytes: Evaluation of the reticulocyte count indicates whether bone
provide important clues as to mechanism and may lead to a diagnosis of marrow is capable of making new erythrocytes in response to
an immune hemolytic anemia. hemolysis.
Direct antibody test (Dat): The presence of antibodies on the surface Lactic acid dehydrogenase (LDH): The LDH is typically elevated with
of red blood cells (RBCs) suggests an immune-mediated hemolysis. ongoing hemolysis, since LDH is an important housekeeping enzyme
The presence of antibody and complement on the surface of the RBC found in erythrocytes. LDH is found in cells from all tissues, each having
suggests drug-related hemolysis, whereas the presence of complement a characteristic isoenzyme form of LDH. It is rarely necessary to distinguish
alone may suggest an immunoglobulin M (IgM) or cold antibody-related LDH from RBCs from other tissue sources, but LDH isoenzyme 1 is
hemolysis. the predominant form found in RBCs.
Peripheral blood smear: Examination of the peripheral smear and various Bilirubin: As heme is released from RBCs, it is metabolized to bilirubin,
RBC indices (chiefly the mean corpuscular volume [MCV]) give mechanistic which is glycosylated and then excreted via hepatic metabolism. Initially,
clues to the etiology of the hemolytic process. Immune-mediated as large amounts of heme are released and metabolized, the bilirubin
hemolysis is characterized by spherocytosis, even microspherocytosis is predominantly indirect bilirubin (unconjugated), and then it is converted
in severe cases, as antibody-coated RBCs traversing the reticuloendothelial to direct (conjugated) bilirubin. This can be altered by cholestasis, either
system assume a spherical form, rather than that of a normal biconcave from biliary obstruction or hepatic disease or Gilbert disease, or hepatic
disc. The appearance of other pathological forms, such as schistocytes, immaturity in the premature infant or newborn.
sickle cells, targets, or tear drop forms (dacrocytes), suggest other causes Haptoglobin: Haptoglobin is extremely sensitive to even small amounts
of hemolysis, such as thrombotic thrombocytopenic purpura (TTP), or of hemolysis. Its absence merely confirms that there is a significant
mechanical, shear-induced hemolysis (e.g., aortic stenosis), sickle cell hemolysis, but not its extent. The presence of normal haptoglobin
disease, thalassemia, or extramedullary hematopoiesis from bone marrow effectively rules out significant hemolysis, and the return of measurable
fibrosis, metastasis, or failure. Nucleated RBCs can be seen in any form amounts of haptoglobin usually signals the end of hemolysis.
of hemolytic anemia if it is severe enough.

848 Part Seven Organ-Specific Inflammatory Disease

Therapy
TABLE 62.2 Causes of Immune
The first line of therapy is corticosteroids, and 80% of patients neutropenia
achieve a partial or complete response to 1 mg/kg/day of pred-
nisone (orally). Once a response is achieved, the prednisone Primary
dose is tapered slowly. Approximately 50% of patients require Isoimmune neonatal neutropenia
prednisone at a dose of 15 mg/day or less to maintain the Autoimmune neutropenia of childhood
Adult autoimmune neutropenia
hemoglobin level >10 g/dL, and it may take up to 3 weeks for
patients to achieve a response. Patients who do not respond in Secondary
3 weeks should be started on second-line therapy. It is estimated Systemic autoimmune disease
that long-term complete responses not requiring prednisone Rheumatoid arthritis (i.e., Felty syndrome)
can be achieved in 20% of patients. 15 Systemic lupus erythematosus
Sjögren syndrome
tHeraPeUtIC PrInCIPLeS Lymphoproliferative malignancy
Autoimmune Anemia Large granular lymphocyte (LGL) leukemia
Lymphoma
• Hemolytic anemia induced by “warm” antibody Drug-Induced
• Acute: corticosteroids, transfusion if severe
• Chronic: splenectomy, rituximab, immunosuppression Antiplatelets—ticlopidine
• Hemolytic anemia induced by “cold” antibody Inflammatory bowel disease drug—sulfasalazine
• Cold agglutinin disease: avoidance of cold; rituximab +/− fludarabine Antipsychotic—clozapine, phenothiazines
• Paroxysmal cold hemoglobinuria: avoidance of cold; corticosteroids Antithyroid medications—propylthiouracil, methimazole
• Hemolytic disease of the newborn Retrovirals
• Neonatal exposure to fluorescent light Antibiotics—beta-lactams, cefepime, trimethoprim-sulfamethoxazole,
• Intrauterine transfusion or exchange transfusion vancomycin, rifampicin, quinine/quinidine
Diuretics—furosemide, spironolactone
Antiepileptic—lamotrigine
Splenectomy and anti-CD20 antibody (rituximab) are Rituximab, infliximab, etanercept
considered second-line therapy. Splenectomy is associated with
short-term partial or complete responses in two-thirds of patients.
The overall response rate to rituximab is approximately 80%, but antibodies usually disappear within 12–15 weeks, but occasionally
rituximab is contraindicated in patients with untreated hepatitis it can persist as long as 24 weeks after delivery.
B. The rare, but most severe, long-term complication of rituximab
therapy is progressive multifocal leukoencephalopathy. 15 Primary Autoimmune Neutropenia
Danazol, a synthetic anabolic steroid, has been used as a Primary autoimmune neutropenia is an antibody-mediated
17
first-line agent in conjunction with prednisone; its effectiveness disease that presents commonly in early childhood. Patients
appears to be less in relapsed or refractory disease. The role of typically have normal blood counts at birth and develop neu-
high-dose intravenous immunoglobulin (IVIG) remains con- tropenia at 3–36 months of age. Children presenting at <2 years
troversial; its effectiveness remains to be determined in larger of age most commonly recover spontaneously within 2–3 years
trials. Third-line therapy consists of immunosuppressive agents of diagnosis. Nevertheless, some children, particularly those
(e.g., azathioprine, cyclophosphamide, alemtuzumab, mycophe- presenting at older ages or manifesting other autoimmune
nolate mofetil, cyclosporine). 1,15 findings, develop a chronic neutropenia disorder. Primary immune
neutropenia (in the absence of other disease manifestations) is
IMMUNE-MEDIATED NEUTROPENIA less common in adults. Rigorous incidence data are lacking, but
a small retrospective study in Sheboygan County, Wisconsin,
Immune neutropenia constitutes a heterogeneous group of found an annual incidence of 5–10 cases of primary or secondary
acquired diseases in which the immune system responds to neutropenia per 100 000 people.
circulating neutrophils, selectively reducing their level to below
3
1500 cells/mm (Table 62.2). Neutropenia Associated With Systemic Autoimmune or
Lymphoproliferative Diseases
KeY COnCePtS Most patients with active systemic lupus erythematosus (SLE)
Immune Neutropenia develop neutropenia as part of a more global leukopenia (Chapter
18
51). Separately, a smaller subset develops severe neutropenia,
• Immune neutropenia in children is caused by antineutrophil antibodies presumably mediated by ANAs. Sjögren syndrome (Chapter 54)
(ANAs). and other systemic autoimmune diseases are also sometimes
• Immune neutropenia in adults has a more complex etiology. complicated by immune neutropenia. Lymphoproliferative
• Immune complex-mediated neutrophil clearance and cell-mediated disorders, such as chronic lymphocytic leukemia (Chapter 78),
suppression of myelopoiesis often play a major role.
can occasionally be complicated by immune neutropenia as well.
Isoimmune Neonatal Neutropenia Felty Syndrome
Transient neutropenia analogous to neonatal immune hemolysis Immune neutropenia develops in about 1% of patients with
or thrombocytopenia develops when IgG antineutrophil antibod- rheumatoid arthritis, most commonly (but not exclusively) in
ies (ANAs) from an allosensitized or autoimmune mother cross association with splenomegaly, a combination designated as Felty
19
16
the placenta and destroy fetal neutrophils. Neutropenia is syndrome. Patients typically express human leukocyte antigen–
typically present at birth and resolves spontaneously, as maternal DR4 (HLA-DR4) and have long-standing seropositive rheumatoid

CHaPter 62 Immunohematological Disorders 849


have been attempts in the past to classify this pattern as
pseudo-Felty syndrome, but the clinical findings and course
are often indistinguishable from “classic” Felty syndrome.
2. About half the patients with clinically apparent T-LGL leukemia
have circulating rheumatoid factor and immune complexes
in their blood; about a third, usually patients expressing
HLA-DR4, develop clinically significant arthritis, sometimes
requiring antiinflammatory agents.
Although the reason why clonal T-LGL disorders and autoim-
munity often coexist is unclear, the tendency toward overlap is
clear. Since the pathophysiology and therapy of both conditions
are similar, these problems in classification usually have little
impact on the initial management of neutropenia. When a patient
with “Felty syndrome” develops aggressive T-LGL leukemia or
a patient with T-LGL manifests severe rheumatological symptoms,
FIG 62.2 The Large Granular Lymphocyte (LGL) Is a Moderate- the clinician must be prepared to alter therapy, as needed, to fit
Sized Lymphocyte Containing Several Distinctive Azurophilic the clinical picture.
Granules. Additional immunophenotyping is required to distin- Although some clinicians have attempted to develop criteria
guish the CD3 , CD8 , CD57 T-LGL associated with neutropenia for distinguishing Felty syndrome from T-LGL with pseudo-Felty
+
+
+
from CD16 , CD56 natural killer (NK)–LGL. syndrome, there is now substantial evidence that clonal T-LGL
+
+
disorders are commonly found in rheumatology patients and
that patients with clonal disorders seldom develop a progressive,
arthritis complicated by erosive joint disease, subcutaneous neoplastic disorder. Conversely, although patients with T-LGL
nodules, and/or leg ulcers. The natural history is often marked leukemia have a malignancy, it is typically quite indolent and in
by repeated infection, with 5-year mortality rates of >30% these cases, the clinical course is often dominated by rheuma-
reported in some studies. The complex pathophysiology of this tological complication and/or neutropenia and not by progressive
disorder is discussed elsewhere in detail (Chapter 52). neoplastic disease.
T-Cell Large Granular Lymphocyte Leukemia Drug-Induced Immune Neutropenia
22
Large granular lymphocytes (LGL) are medium to large lymphocytes A wide variety of medications cause neutropenia. In some
recognizable on light microscopy by their distinctive azurophilic cases, it may be antibody-mediated (see Table 62.2 for common
granules (Fig. 62.2). These cells normally constitute <15% of examples); in others, it may be a direct toxic effect on marrow
circulating leukocytes and are composed of two major subsets. precursors. Often, the mechanism for neutropenia is unclear. A
One is the natural killer (NK) LGLs that express CD2, CD16, and detailed discussion of this topic is beyond the scope of this chapter,
CD56 and is not linked to neutropenia. The other, T-cell (T) LGLs, but drug-induced neutropenia must always be considered in
expresses CD2, CD3, CD8, and CD57 with or without CD16, a the differential diagnosis of acquired neutropenia. Rituximab
phenotype typical of antigen-stimulated mature CD8 effector T (anti-CD20) is occasionally associated with late-onset neutropenia
23
cells. Polyclonal and transient monoclonal expansions of these (LON). LON is typically self-limiting and of no significant clinical
cells sometimes appear in response to viral infection or other consequence; the occurrence and severity of LON may be associ-
immune stimuli without adverse effect. However, some patients ated with the total dose of rituximab and the myelotoxicity of
develop an indolent lymphoproliferative disease characterized by the accompanying chemotherapy administered. LON appears to
the accumulation of an autonomous T-LGL clone in blood and in coincide with post-rituximab B-cell recovery. In patients receiving
other lymphoid organs, particularly bone marrow, the liver, and/ DA-EPOCH (dose-adjusted etoposide/vincristine/doxorubicin/
or the spleen. Patients with this disease have a remarkably high cyclophosphamide/prednisone regimen) chemotherapy for
incidence of immune neutropenia. 20,21 Even in the absence of gross lymphoma, the incidence of LON was 8%, the median time of
marrow involvement, over 80% have a neutrophil count of <2000/ onset was 175 days (range of 77–204 days), and the duration was
3
mm at presentation, and at some point 30–40% develop severe 11–16 days. A list of the most common agents associated with
3 20,21
neutropenia with <500 neutrophils/mm . The pathophysiology drug-induced neutropenia is included in Table 62.2.
resembles Felty syndrome in many respects.
Immunopathogenesis
Clinical Overlap Between Felty Syndrome Regulation of Antineutrophil Antibody Production
and T-LGL Leukemia Isoimmune ANA production in pregnant women represents
At the extremes these syndromes are easily separable. Patients an “appropriate” immune response to foreign antigens. The
with classical Felty syndrome have severe rheumatoid arthritis, production of autoimmune ANAs in other settings reflects
usually requiring antiinflammatory therapy, incidentally com- immune dysregulation. Older studies attributed primary
plicated by late neutropenia. This is quite different from the immune neutropenia of childhood to delayed maturation of
pattern in patients with isolated T-LGL leukemia with neutropenia T cells responsible for regulating B-cell responses. In this view,
in the absence of clinical autoimmune disease. Nonetheless, the spontaneous recovery usually observed reflects the eventual
confusing overlap can occur in two settings: appearance of mature regulatory or inhibitory T cells. However,
1. More than half the patients with a clinical Felty syndrome this hypothesis is not well supported with clinical laboratory
may have detectable T-LGL clones in their blood when studied data; the cause of antibody production in other autoimmune
20
with sensitive flow cytometric or molecular techniques. There diseases remains unclear.

850 Part Seven Organ-Specific Inflammatory Disease


this antibody probably is not specific for neutropenia, since it is
also present in patients with autoimmune disease who do not
have neutropenia.
Patterns of Autoantibody Specificity
Isoimmune neonatal neutropenia is associated with maternal
IgG iso- or autoantibodies that can be generated in response to
each of the polymorphic alloantigens noted above, particularly
polymorphisms affecting FcγRIIIb.
Platelets with bound IgG Macrophage with FcRγIIA receptor Immune neutropenia in childhood is most commonly
FIG 62.3 Antibody-Bound Platelets Are Cleared From the associated with IgG directed against the autoantigens HNA-1a
26
Circulation by Binding of the Fc Domain of Immunoglobulin and/or HNA-1b. Sera from affected patients often also bind
G (IgG) to FcγIIIA Receptors on Macrophages and Other Cells. (albeit more weakly) to neutrophils expressing the alternative
The cross-linking of the macrophage receptors sets off a cascade allele, and in some series, more than half the patients with this
of internal signaling that leads to increased expression of the entity were shown to produce antibodies capable of binding to
inhibitory FcγIIB receptors (not shown). nonpolymorphic elements within FcγRIIIb. Using monoclonal
antibody (mAb)–specific immobilization of granulocyte anti-
gens (MAIGA) to search for antibodies directed against other
neutrophil surface molecules, more complex patterns can be
recognized. In one study, autoantibodies against FcγIIIb were
Antibody Specificity seen in 27%, against CD11b/CDI8 (CR3) in 21%, against CD35
27
The most important target for antibody responses is the Fcγ (CR1) in 14%, and FcγRII in 2% of patients’ sera. Prognostically,
receptor IIIb (FcγRIIIb), a low-avidity granulocyte-specific Fcγ patients with antibody responses confined to HNA-1a and/or
receptor that binds IgG immune complexes (Fig. 62.3). This cell HNA-1b are more likely to have uncomplicated, self-limiting
surface protein, a glycosyl phosphatidylinositol-linked variant disease; patients with specificity for nonpolymorphic determinants
of CD16 selectively expressed on neutrophils, contains several on the FcγRIIIb molecule and other antigens more often have a
26
highly immunogenic polymorphisms. 24 generalized immune disorder and more persistent neutropenia.
Human neutrophil antigen 1a (HNA-1a) and HNA-1b (previ- Although antineutrophil assays are not highly quantitative, a
ously designated NA1 and NA2) are two related polymorphic recent retrospective study has suggested that patients with low
forms of FcγRIIIb. Antigenic differences are attributed to a cluster levels of ANAs may have a more favorable long-term prognosis. 28
of five base substitutions, all found within exon 3. The two In adults, it is often difficult clinically to distinguish immune
products can be distinguished because two of the base substitu- neutropenia from nonimmune idiopathic neutropenia. Conse-
tions in HNA-1a disrupt sites of N-linked glycosylation, thereby quently, the sensitivity and specificity of antibody assays in this
lowering the size of the protein by ~30 000 Daltons (Da). The setting are uncertain. In general, antibodies against HNA-1a or
frequency of the gene for HNA-1a (FCGR3B) varies from 0.3 HNA-1b are less common, and antibodies against surface recep-
to 0.55 in different ethnic groups. tors, such as CD11b/CD18 (CR3), are more common in older
HNA-1c (previously designated SH) is another immunogenic children and adults than in young children.
20
21
polymorphism related to FcγRIIIb. This antigen, present in 5% Sera from patients with Felty syndrome and T-LGL leukemia
of northern Europeans, is attributable to an amino acid poly- are often positive in ANA assays. Interpretation of these results
morphism at position 266 in a (reduplicated) copy of the HNA-1b is complicated by the high incidence of nonspecific immune
allele of FcγRIIIb. complexes in these populations, which may bind nonspecifically
FcγRIIIb-null phenotype, present in 0.1% of the northern through Fc and complement receptors to the neutrophil surface.
European population, occurs in individuals homozygous for an Indeed, because it is difficult to distinguish these two types of
extensive gene deletion involving all of FcγRIIIb. Because affected binding, the incidence of “true” ANAs in these syndromes remains
individuals have never been exposed to endogenous FcγRIIIb, uncertain. Detectable antineutrophil antibodies are low in titer or
they often develop a broad antibody response after neutrophil absent in most patients carefully studied with either diagnosis. 20,21
exposure through transfusion or pregnancy.
25
Other HNAs have also been identified. Perhaps most Impact of Antibodies and Immune Complexes on
clinically relevant is HNA-2a (previously NB1), a neutrophil Neutrophil Survival
glycoprotein designated CD177. Antibodies against this target There is good experimental evidence that both ANAs and immune
have been reported in isoimmune and autoimmune neutropenia. complexes can induce neutropenia in vivo. The relative importance
HNA-3a (previously 5b) and HNA-4a (previously MART), an of reversible sequestration and neutrophil destruction in inducing
epitope on CD11b, are also immunogenic, but antibody formation neutropenia varies with the experimental model, the character
against these is seen primarily in heavily transfused individu- of the antibody/immune complex, spleen size, and presumably
als and not in autoimmune neutropenia. As described below, other factors as well.
individuals with chronic immune neutropenia may develop The detection of antineutrophil antibodies in serum, however,
antibodies against other surface antigens, including CD11b/CDI8 does not automatically predict accelerated immune clearance of
and CD35. 26 neutrophils in vivo. Some antibodies bind well to neutrophils
Using a sophisticated antigen discovery strategy, patients under in vitro assay conditions, without provoking neutrophil
29
with Felty syndrome were found to have a high incidence of destruction in vivo. In part, this reflects the inability of these
antibodies against an intracellular antigen eukaryotic elongation crude assays to distinguish effective from ineffective binding of
factor 1A-1 (eEF1A-1). Although the finding has been confirmed, immunoproteins.

CHaPter 62 Immunohematological Disorders 851


which might suggest an alternative diagnosis. The marrow
Myelopoiesis in Immune Neutropenia examination may also be helpful in confirming T-LGL leukemia. 30
In primary immune neutropenia, bone marrow is typically Detection of antineutrophil antibodies. Antibodies are assayed
normocellular or mildly hypercellular with an increased propor- clinically using indirect assays (i.e., by measuring the binding
tion of early myeloid forms (particularly myelocytes and pro- of antibodies from patient sera to fixed granulocytes from
myelocytes) and decreased mature forms (neutrophils, bands, unrelated individuals). The granulocyte immunofluorescence
and metamyelocytes), a pattern designated maturation arrest. test (GIFT), which exploits flow cytometry for detection, is most
Although maturation arrest can also be seen in a number of commonly used because of its high sensitivity. The granulocyte
other diseases, in this setting, it suggests an expansion in immature agglutination test (GAT) is less sensitive but is particularly valuable
precursors with early release of mature components into blood. used in conjunction with GIFT to detect antibodies against
Rigorous kinetic studies in children with primary neutropenia HNA-3a or HNA-1b. Once the presence of an antibody has been
are not available, but the available data suggest myelopoiesis in confirmed, MAIGA is a valuable technique in identifying the
this setting is increased. target molecule recognized by the antibody, information that
The findings are more complex in Felty syndrome and T-LGL may be very helpful in identifying antibody specificity and in
leukemia. In vivo neutrophil kinetic studies and in vitro assays distinguishing granulocyte-specific antibodies from alloantibodies
of marrow function often document reduced myelopoiesis in directed against HLA determinants. More precise epitope typing
these settings. 20,21 This has been attributed to T-cell–mediated still requires a panel of granulocytes of varied phenotype.
and cytokine-mediated suppression. T-LGL leukemia cells Unfortunately, to date, granulocyte panels are both difficult to
constitutively express Fas ligand on their surface and also release prepare and impossible to store. Consequently, antibody typing
significant quantities of soluble Fas ligand into plasma in vivo. remains a laborious, difficult task. At the second international
Reduced myelopoiesis in T-LGL leukemia and some patients granulocyte serology workshop, 12 centers independently tested
with Felty syndrome may be linked to apoptosis instigated by a series of unknown sera. Many laboratories could detect strong
the binding of Fas ligand expressed on the abnormal cells to Fas HNA-1a antibodies, but the success rate was much lower in
21
expressed on the surface of myeloid precursors. Whatever the defining HNA-1b or HNA-2a antibodies, and individual labo-
precise mechanism, reductions in myelopoiesis appear to be a ratories varied greatly in their proficiency. 25
common element in patients with these forms of secondary Clinical use of antineutrophil antibody studies. In young
immune neutropenia. children with neutropenia, a positive result is very helpful in
distinguishing between immune-mediated and congenital causes.
Diagnosis Isoimmune and congenital disease may be apparent from birth,
Clinical Presentation and the former usually resolves within 2–6 months. Using GIFT
Isoimmune neutropenia presents at birth and may persist for or GAT assays, ANAs can be detected in more than 70% of
up to 6 months. Self-limiting primary autoimmune neutropenia children with primary immune neutropenia. When both are
typically presents in early childhood. In older children and adults, used in tandem the yield increases further. A strong positive
neutropenia is more commonly associated with other systemic result strongly supports the diagnosis of immune neutropenia.
autoimmune disease, especially rheumatoid arthritis and SLE However, a negative result does not exclude the diagnosis. 28
or T-LGL leukemia. Drug-induced neutropenia must always be Primary autoimmune neutropenia in adults is difficult to
considered in patients taking medications. distinguish from the ill-defined entity chronic idiopathic neu-
1
tropenia. Because there is no “gold standard” for distinguishing
Laboratory Findings immune disease from nonimmune disease in this setting, the
Blood counts typically demonstrate isolated neutropenia, diagnostic sensitivity and specificity of the ANA assays are unclear.
sometimes with monocytosis. More generalized leukopenia, Assays are positive in perhaps a third of adults referred with
anemia, and/or thrombocytopenia suggest concurrent SLE or a chronic neutropenia, and a positive result in the absence of other
primary bone marrow disorder, especially aplastic anemia or systemic autoimmune disease certainly supports a diagnosis of
myelodysplasia. immune neutropenia. Again, a negative result does not preclude
Examination of the blood film for evidence of abnormalities an immune etiology, but it is more consistent with chronic
in other cell lines or increased numbers of LGL is essential. The idiopathic neutropenia.
3
persistent presence of >2000 LGL/mm for 6 months in itself is In patients with systemic autoimmune disease or T-LGL
diagnostic of T-LGL leukemia; however, normal LGL counts leukemia, hyperglobulinemia and circulating immune complexes
in blood do not preclude this diagnosis. Perhaps a quarter of greatly complicate laboratory evaluation. ANA assays are fre-
patients with T-LGL leukemia and immune neutropenia have quently positive even in the absence of neutropenia. Since the
3
21
fewer than 500 monoclonal LGL/mm in blood. The evaluation specificity of a positive result is low, its diagnostic value is very
of patients with small T-LGL clones detected in blood on flow limited, and the clinician must be vigilant for other possible
cytometric or molecular testing without clear tissue infiltration causes, especially drug-induced neutropenia.
remains problematic. At least some of these patients probably
have self-limiting “T-cell gammopathies of unknown origin” Therapy
(Chapter 80) unassociated with overt lymphoproliferation or Overview
3
autoimmunity. All patients with neutrophil counts below 1000/mm have some
Bone marrow findings in immune neutropenias (as briefly increased risk of infection, but some remain asymptomatic even
3
reviewed above) can vary substantially. Perhaps the most impor- with absolute neutrophil counts of 500/mm or less. Growth
tant function of the bone marrow examination is to rule out factors can usually improve neutropenia and reduce the risk of
hypoplasia/aplasia, myelokathexis, marked megaloblastic dysplastic infection, but given their expense, inconvenience, and possible
changes, or abnormal infiltration with nonhematopoietic cells, side effects, they should be reserved for use in patients with a

852 Part Seven Organ-Specific Inflammatory Disease


very low count, or a previous pattern of frequent infection. The IMMUNE-MEDIATED THROMBOCYTPENIAS
indications for immunosuppressives, steroids, and splenectomy
are more complex. Immune Thrombocytopenia
tHeraPeUtIC PrInCIPLeS KeY COnCePtS
Immune Neutropenia Immune Thrombocytopenic Purpura
• Palliative treatment of neutropenia is reserved for patients with a • Antibody-mediated destruction or decreased production of platelets
neutrophil count below 500/mm or recurrent infection. • Both B and T cells important in etiology
3
• Recombinant granulocyte–colony-stimulating factor (G-CSF) is the most • Clearance of platelets mediated by Fcγ receptors
effective single agent for palliating neutropenia. • Diagnosis depends on:
• Immunosuppressive agents, steroids, and splenectomy are reserved • Clinical presentation of low platelets
for patients with persistent or refractory neutropenia or with other • Exclusion of other causes of thrombocytopenia
detrimental manifestations of systemic autoimmunity.
Colony-Stimulating Factors Immune thrombocytopenia (ITP) is an autoimmune syndrome
31
Controlled trials are lacking in this disease setting, but involving antibody and cell-mediated destruction of platelets.
granulocyte–colony-stimulating factor (G-CSF) or granulocyte ITP can occur in the absence of an identified predisposing factor
macrophage–colony-stimulating factor (GM-CSF) usually enhance (primary ITP) or in association to drug exposure or other
neutrophil counts in each of the clinical groups discussed. Because identified cause (secondary ITP). Recent recommendations from
of their safety, speed, and efficacy, they have replaced steroids an international working group recommend that a platelet count
9
and splenectomy as first-line symptomatic therapy. They should of <100 × 10 /L be required for diagnosis. 32
be used at the lowest effective dose, with particular caution in
patients with systemic autoimmune disease, as they are prone ITP During Pregnancy and the Neonatal Period
to leukocytoclastic vasculitis as a complication of therapy. 18 Gestational thrombocytopenia is the most common cause of
thrombocytopenia in pregnancy, affecting 5% of all pregnan-
Immunosuppressive Agents cies and accounting for 75% of cases of pregnancy-associated
Because disease is usually self-limiting and responsive to G-CSF, thrombocytopenia. Gestational thrombocytopenia develops in
immunosuppressive agents are seldom used in children with the late second or third trimester and is not associated with
primary immune neutropenia. Chronic low-dose methotrexate an increased incidence of pregnancy-related complications or
is considered first-line therapy for patients with Felty or LGL the delivery of thrombocytopenic offspring. Preeclampsia and
leukemia–associated neutropenia. Cyclophosphamide and HELLP (hemolysis, elevated liver enzymes, and low platelet count)
cyclosporine are considered second-line therapy for LGL leukemia, syndrome are also present in the third trimester and are associated
and purine analogues, splenectomy, and alemtuzumab are with thrombocytopenia. Thrombotic thrombocytopenic purpura
considered third-line therapy for LGL leukemia. (TTP) and hemolytic uremic syndrome need to be considered in
the differential diagnosis of thrombocytopenia of pregnancy. ITP
Other Therapy accounts for 5% of pregnancy-associated thrombocytopenia.
33
Each of the following treatments can be effective in reversing Lack of hypertension, fever, hemolytic anemia, uremia, and liver
neutropenia, but their use has diminished considerably in recent function abnormalities serve to distinguish ITP from these other
years. IVIG can temporarily reverse neutropenia, particularly conditions.
in children, probably by blocking Fc receptors responsible for
triggering neutrophil destruction. However, G-CSF, which is more Neonatal Alloimmune Thrombocytopenia and
convenient to administer and at least as effective, has largely Posttransfusion Purpura
replaced use of IVIG. Neonatal alloimmune thrombocytopenia (NAT) caused by
Splenectomy and steroids can each reduce immune destruc- antihuman platelet antigen 1a (HPA-1a) antibodies occurs in
tion by suppressing the body’s capacity to clear IgG- and 1 : 1250 pregnancies in the Caucasian population. Severe hemor-
complement-coated cells. Over a longer time frame, these rhage occurs in 1 : 12 500–1 : 25 000 pregnancies. NAT is caused
treatments can also suppress antibody production, in the first by maternal antibodies against paternally derived antigens on
case by removing a major site of production and in the second fetal platelets, most commonly HPA-1a. These antibodies cross
by reducing antineutrophil antibody production and blocking the placenta and sensitize fetal HPA-1a–positive platelets, which
T-cell–mediated myelosuppression. They can reverse neutropenia are then removed in the spleen. Two percent of Caucasian women
in many patients, but their long-term impact on outcome remains carry the less frequent HPA-1b and can be immunized against
unclear. Given their risk and side effects, both modalities are HPA-1a during pregnancy (25%) or at the time of delivery
generally reserved for patients resistant to CSFs and low-dose (75%). The HPA-1a antigen is most efficiently presented by
immunosuppressives. HLA-DRB3*0101; 35% of the women at risk (with HPA-1b and
34
HLA- DRB3*01:01) are immunized. In most circumstances,
Prophylactic Antibiotics first-time cases of NAT are identified following the birth of a
Where recurrent infection is a problem, oral trimethoprim– markedly thrombocytopenic neonate; antenatal management
sulfamethoxazole (TMP-SMX) is commonly used for prophylaxis, is, thus, only possible in subsequent pregnancies. Screening all
particularly in children. This approach is very reasonable, given pregnancies for NAT is under evaluation in several countries.
its success in other immunocompromised groups, but it has not Treatment of NAT consists of maternal administration of high
been tested in a controlled trial. Immunization with pneumococcal doses of IVIG and corticosteroids. 35
vaccine is also recommended in situations where therapeutic Platelet transfusions can induce antibodies to either HPA or
splenectomy has been used or is being planned. antigens encoded by the major histocompatibility complex

CHaPter 62 Immunohematological Disorders 853


(MHC). Eight percent of transfused patients mount detectable antibodies following infections. Human immunodeficiency virus
antibodies to HPA antigens and 45% to HLA antigens. Platelet (HIV), hepatitis C virus (HCV), and Helicobacter pylori infections
antibodies cause rapid clearance of transfused platelets and lead have been associated with ITP. H. pylori CagA antigen appears
36
40
patients to become refractory to platelet transfusions. Post- to cross-react with platelet antigens, which may explain the
transfusion purpura (PTP) can follow transfusion with platelets association with ITP and H. pylori infection. Interestingly, empiric
or RBCs (in which platelets are found in numbers sufficient to treatment of Helicobacter infection with amoxicillin, clarithro-
sensitize the recipient). mycin, and proton pump inhibitors in patients suspected of
infection leads to 53% remission of ITP whether or not Helico-
Drug-Induced Thrombocytopenia bacter is eradicated, suggesting immunomodulatory effects of
Drug-induced thrombocytopenia (DITP) is an idiosyncratic treatment that do not involve elimination of the bacterial antigen
41
immune-mediated reaction. The drug-dependent antibodies bind with cross-reactivity to platelet antigens. Patients who are not
to specific epitopes on platelet surface glycoproteins only in the infected with H. pylori but are treated empirically with antibiotics
presence of the sensitizing drug. The drugs bind noncovalently and do not have a significant platelet response rate (6.5%), which
reversibly to platelets, commonly to GPIIb-IIIa and GPIb-V-IX, suggests that empiric therapy is not useful in the absence of a
and also to the antibody. The Fab domains of the antibodies documented infection. 41
bind to the drug-platelet epitope. Drug-dependent antibodies NAT is caused by maternal antibodies against the HPAs that
inducing thrombocytopenia typically develop 1–2 weeks after the fetus carries but which the mother lacks (most commonly
exposure to a drug; exceptions to this rule include eptifibatide, HPA-1a). It is more likely to cause intracerebral hemorrhage
tirofiban, and abciximab, as naturally occurring antibodies to (10–20% of cases) than is maternal ITP, and it is very likely to
42
these drugs can cause thrombocytopenia within a few hours of the recur if it has occurred in a previous pregnancy. IVIG and
first exposure. Thrombocytopenia with platelet counts frequently platelet transfusions using maternal platelets (to ensure that the
9
below 20 × 10 /L develops acutely, recovery occurs 1–2 days offending antigen is not present in the transfused product) are
after discontinuation of the drug and is usually complete after often necessary.
1 week, but rarely thrombocytopenia persists for several weeks. Antibodies against human platelet antigens are also responsible
Quinidine, quinine, rifampin, tegretol, TMP-SMX, vancomycin, for PTP, in which the recipient has an acquired antibody directed
danazol, acetaminophen, abciximab, eptifibatide, tirofiban, and against a platelet antigen on the donor platelets. It is not under-
gold salts are the most common culprits. Treatment consists stood why the antibodies also destroy the patient’s own “antigen-
of discontinuing the offending drug; platelet transfusions are negative” platelets. Treatment consists of IVIG and corticosteroids,
34
sometimes necessary. 37,38 and sometimes plasma exchange. Transplantation-mediated
Heparin-induced thrombocytopenia (HIT) is a special case alloimmune thrombocytopenia (TMAT) may occur as the result
that is caused by antibodies to platelet factor 4 (PF4)–heparin of donor-origin antibodies produced by passenger B cells directed
complexes. It can be associated with life-threatening thrombosis. against the recipient platelet alloantigen (HPA-1a). 43
The antibody–PF4–heparin complex activates platelets, resulting The most common epitopes for platelet antibodies in ITP
44
39
in a high risk of both arterial and venous thrombotic events. are the platelet GPIIb/IIa and GPIb-IX receptors. The autoan-
Thrombocytopenia occurs as a result of clearance of platelet tibodies serve as opsonins resulting in the clearance of platelets
aggregates induced by the antibody and usually appears 5–7 by FcγR-bearing cells in the reticuloendothelial system (see Fig.
days after treatment with heparin (or low-molecular-weight 62.3). There is upregulation of genes involved in cell-mediated
+
+
45
heparin) unless a patient has been previously exposed to heparin. cytotoxicity via CD3 CD8 T lymphocytes, with T-helper 1
46
In the event of prior exposure, especially within the last 100 (Th1)–associated cytokines predominating. Regulatory T cells
48
47
days, thrombocytopenia can occur within 1 day of heparin (Tregs) are decreased, and B-cell activation is increased. There
administration. Even small doses of heparin given as “flushes” is evidence of suppression of megakaryopoiesis by both T
50
49
to maintain intravenous catheter patency can be sufficient to cause lymphocytes and ITP plasma/IgG. In addition, megakaryocyte
HIT with thrombosis. In cases of suspected HIT, all heparins and platelet production are dependent on thrombopoietin signal-
should be stopped, and an alternative anticoagulant agent, such as ing through binding to the Mpl receptor, and patients with ITP
the direct thrombin inhibitors argatroban and lepirudin, should have reduced thrombopoietin levels despite the presence of low
be used. Fondaparinux is an anticoagulant synthesized from the platelet counts. 51
pentasaccharide core of the heparin molecule and may be another 52
option for the treatment of HIT, since it binds to HIT antibodies Laboratory Diagnosis
but does not activate platelets and cause thrombosis. In cases of Peripheral blood smear examination is important to evaluate
confirmed or strongly suspected HIT, anticoagulation should be for the presence of schistocytes, leukocyte adhesion bodies in
continued for 3 months because the risk of thrombosis persists in MYH-9-related disease, and giant or large platelets in inherited
this group of patients. Coumadin is generally used for long-term thrombocytopenias and to exclude ethylenediaminetetraacetic
anticoagulation; it should be started concomitant with a heparin acid (EDTA)–dependent platelet agglutination.
alternative because of the increased risk of thrombosis during Bone marrow aspirate, biopsy, flow cytometry, and cytogenetics
the initial depletion of anticoagulant factors (proteins C and S) should be considered in patients older than 60 years of age and
by warfarin (Coumadin). The role of direct oral anticoagulants in patients with systemic symptoms. The detection of H. pylori
that target thrombin or activated factor X remains to be defined. with the urea breath test is recommended in adults, and testing
in children is recommended in high prevalence areas. Routine
Pathogenesis serological evaluation for HIV and HCV is recommended in
In the majority of patients the underlying defects leading to adults. Baseline Igs (IgG, IgA, IgM) should be measured in both
autoantibody production remain unclear. In some patients, ITP adults and children to diagnose such conditions as common
follows exposure to viral or bacterial antigens. Molecular mimicry variable immunodeficiency and selective IgA deficiency (Chapter
appears to play a role in the development of self-reactive platelet 34), in which ITP is a common complication.

854 Part Seven Organ-Specific Inflammatory Disease


Antiplatelet antibody testing to specific platelet glycoproteins TRAs. Initial dosing of eltrombopag should be reduced by 50%
is not routinely recommended; the test is neither sensitive nor in patients of Southeast Asian origin. Danazol is an attenuated
specific for ITP. Routine testing for anticardiolipin antibodies androgen administered orally and has been used, with some
is not recommended in the absence of symptoms of antiphos- success, as a steroid-sparing agent. Third-line therapy is reserved
pholipid syndrome. DAT should be obtained if hemolytic anemia for patients who are unresponsive to or ineligible for first- and
is suspected and in patients in whom anti-D antiglobulin treat- second-line therapies. These agents include cyclophosphamide,
ment is considered. Blood group Rh(D) typing should be obtained azathioprine, mycophenolate mofetil, cyclosporine, alemtuzumab,
if anti-D antiglobulin treatment is considered. and vinca alkaloids. One novel approach to ITP consists of
Where a microangiopathic process is evident, especially with blockade of the FcγIIIA receptors on macrophages in the spleen
concomitant renal failure, fever, or cognitive impairment, measure- that mediate uptake of antibody-bound platelets. Prior attempts
ment of ADAMTS13 (ADintegrin-like And Metalloprotease with at FcγIIIA receptor blockade to ameliorate ITP using mAbs to
ThromboSpondin type 13 motifs) is warranted to rule out TTP. FcγIIIA have improved platelet counts in half the patients refrac-
tory to other treatments but were abandoned because of nausea,
Therapy of ITP 53 vomiting, fever, and rarely anaphylaxis that were presumed to
be caused by immune stimulation from cross-linking of FcγIIIA
tHeraPeUtIC PrInCIPLeS receptors by bivalent IgG. Preclinical studies suggest monovalent
anti-FcγIIIA fused to albumin (to prolong the half-life) may
Immune Thrombocytopenic Purpura (ITP) block the FcγIIIA receptor without stimulating the immune
system, and this approach may be tested clinically, again. 54
• Primary goal—prevent bleeding
• Treatment not usually necessary if platelets >30 000/µL Therapy of ITP During Pregnancy and the
• Prednisone and/or intravenous immunoglobulin (IVIG) usual first
medications Neonatal Period
9
• Anti-D may avert/delay splenectomy Patients with ITP with platelet counts higher than 20–30 × 10 /L
• Treat refractory ITP with immunosuppressives usually do not require treatment during the first and second
• Mycophenolate mofetil, cyclosporine, alemtuzumab, cyclophospha- trimesters of pregnancy; platelet counts should be monitored
mide, rituximab (not approved by the US Food and Drug Administra-
tion [FDA] for this use) more closely as delivery approaches. Obstetrical anesthesiologists
9
• Splenectomy for persistent disease (immunize patient with pneu- recommend a minimum platelet count of 75 × 10 /L to allow
mococcal vaccine before surgery) administration of spinal or epidural anesthesia. A platelet count
9
of at least 50 × 10 /L is generally considered adequate to allow
a Cesarean section. 52
In most circumstances, the goals of therapy are to keep the platelet First-line therapy consists of prednisone and IVIG. Prednisone
9
count above 30 × 10 /L and to minimize toxicity. In the absence is initiated at a low dose (10–20 mg) and then adjusted to the
of hemostatic comorbidity, trauma, or surgery, intracranial minimum dose that produces a hemostatically effective platelet
hemorrhage is rare in patients with a platelet count above 20 × count. Corticosteroids may exacerbate hypertension, diabetes,
9
10 /L. Treatment of ITP should be individualized, but first-line and osteoporosis during pregnancy and are associated with weight
therapy usually consists of corticosteroids supplemented with gain and psychosis. Corticosteroid use in the first trimester has
either IVIG or anti-Rh(D) in Rh(D)-positive, nonsplenectomized been associated with congenital anomalies, such as orofacial clefts,
patients. Intravascular hemolysis, disseminated intravascular and low-dose corticosteroids have no impact on the fetal platelet
coagulation, and renal failure have been reported with the use count. IVIG is an effective means of increasing the platelet count
of anti-Rh(D). Anti-Rh(D) should be avoided in patients with rapidly and is preferred over prednisone in this setting. The
underlying hemolysis or a positive result of the DAT that is not American Society of Hematology (ASH) guidelines consider
the result of prior therapy. Several uncontrolled studies suggest IVIG to be an appropriate first-line agent for severe thrombo-
that bolus oral therapy with oral dexamethasone for 1–4 cycles cytopenia or for thrombocytopenic bleeding in the third trimester.
increases response rates and prolongs remission duration. Anti-Rh(D) is safe and effective for the mother and fetus in
Second-line therapy should be initiated if there is absence of nonsplenectomized Rh(D)-positive patients. 33,52
a robust response at 1 month or once significant steroid related Second-level therapy before delivery may require utilizing
toxicity supervenes. Two-thirds of patients obtain a durable higher doses of corticosteroids combined with IVIG to achieve
long-term remission following splenectomy, and these patients an adequate platelet count. Splenectomy is an option for patients
should receive immunizations with the pneumococcal, Hae- who fail corticosteroids and IVIG. Remission of ITP is achieved
mophilus influenzae type b, and the quadrivalent meningococcal in 75% of patients. Splenectomy is optimally performed during
vaccines before splenectomy. A single course of rituximab the second trimester. The risk of inducing premature labor is
2
(anti-CD20) (375 mg/m weekly for 4 weeks) is associated with high during the first trimester, and the enlarged uterus renders
40% complete remission at 1 year and 15–20% complete remission the procedure difficult if not impossible during the third trimester.
at 5 years. Patients who relapse after an initial response usually Vinca alkaloids, rituximab, danazol, thrombopoietin receptor
respond to a second course. Rituximab is contraindicated in agonists, and immunosuppressive drugs (other than azathioprine)
patients with active hepatitis B. Cases of multifocal leukoen- should be avoided during pregnancy. 33,52
cephalopathy have been reported in HIV-negative patients treated Management of parturition is based on the finding that there
with rituximab. The thrombopoietin receptor agonists (TRAs) is no correlation between platelet counts or ITP status of the
romiplostim and eltrombopag have shown significant sustained mothers and the development of neonatal thrombocytopenia.
activity in patients with ITP. Romiplostim is administered The most reliable predictor of neonatal thrombocytopenia is a
33
subcutaneously and eltrombopag orally. Increased bone marrow history of thrombocytopenia at delivery in a prior sibling. In
9
reticulin fibrosis has been described in some patients receiving a large meta-analysis, fetal platelet counts below 50 × 10 /L were

CHaPter 62 Immunohematological Disorders 855


9
observed in 10.1%, and fetal platelet counts below 20 × 10 /L 6. Berentsen S, Randen U, Vagan AM, et al. High response rate and durable
42
were observed in 4.2%. The risk of intracranial hemorrhage remissions following fludarabine and rituximab combination therapy for
is below 1%, and the risk of fetal platelet count determination chronic cold agglutinin disease. Blood 2010;116:3180–4.
by either fetal scalp sampling or umbilical blood sampling likely 7. Petz LD. Immune hemolysis associated with transplantation. Semin
Hematol 2005;42:145–55.
exceeds the risk of fetal intracranial hemorrhage, negating its 8. Avent ND, Reid ME. The Rh blood system: a review. Blood
clinical utility. The mode of delivery has no impact on the 2000;95:375–87.
incidence of intracranial hemorrhage. 9. Mollison PL, Engelfriet CP, Contreras M. Immunology of red cells. In:
Platelet counts should be monitored for 1 week following Mollison PL, Engelfriet CP, Contreras M, editors. Blood transfusion in
delivery. In a study of 61 patients, 66% of neonates had a further clinical medicine. 10th ed. London: Blackwell Science; 1997. p. 60.
drop in platelets following delivery; the nadir occurred at day 10. Hughes-Jones NC. Red-cell antigens, antibodies and their interaction.
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2, and the counts stabilized or began to rise at day 7. ASH Clin Haematol 1975;4:29–43.
guidelines recommend that children with a platelet count below 11. Petz LD, Garratty G. Mechanisms of immune hemolysis. In: Petz LD,
9
20 × 10 /L or those with hemorrhage be treated with IVIG. The Garratty G, editors. Immune hemolytic anemias. 2nd ed. Philadelphia,
concurrent use of corticosteroids is controversial because of the PA: Churchill Livingstone; 2004. p. 133.
risk of neonatal sepsis. Neonates with platelet counts below 50 12. Kurlander RJ, Rosse WF, Logue GL. Quantitative influence of antibody
and complement coating of red cells on monocyte-mediated cell lysis. J
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× 10 /L should have brain imaging performed to detect occult Clin Invest 1978;61:1309–19.
intracranial hemorrhage. 13. Frank MM, Schreiber AD, Atkinson JP, et al. Pathophysiology of immune
hemolytic anemia. Ann Intern Med 1977;87:210–22.
On tHe HOrIZOn 14. Moise KJ. Red blood cell alloimmunization in pregnancy. Semin Hematol
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• For many years immunosuppressive therapy for immune thrombocy- 15. Lechner K, Jager U. How I treat autoimmune hemolytic anemias in
topenic purpura (ITP) has consisted of corticosteroids and infusions adults. Blood 2010;116:1831–8.
of intravenous immunoglobulins (IVIGs), and more recently anti-Rh 16. Maheshwari A, Christensen RD, Calhoun DA. Immune-mediated
antibodies (in suitable candidates), and/or rituximab in patients whose neutropenia in the neonate. Acta Paediatr Suppl 2002;91:98–103.
disease is refractory to first-line therapy. Splenectomy may be indicated 17. Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary
in those who fail medical therapy altogether.
• All ITP seems to be mediated by interaction of antibody-coated platelets autoimmune neutropenia. Arthritis Res Ther 2005;7:208–14.
with Fc receptors in the reticuloendothelial system of the spleen (and 18. Starkebaum G. Chronic neutropenia associated with autoimmune disease.
the liver). Many investigators have sought to interrupt the interaction Semin Hematol 2002;39:121–7.
between immunoglobulin (Ig)–coated platelets and Fcγ receptors by 19. Balint GP, Balint PV. Felty’s syndrome. Best Pract Res Clin Rheumatol
use of monoclonal antibodies to the Fcγ receptor itself. However, the 2004;18:631–45.
use of traditional murine monoclonal antibodies (mAbs) to Fcγ has 20. Mohan SJ, Maciejewski JP. Diagnosis and therapy of neutropenia in large
been associated with adverse events, perhaps as a result of cross-linking granular lymphocyte leukemia. Curr Opin Hematol 2009;16:27–34.
of Fcγ receptors on the surface of macrophages, resulting in undesirable 21. Lamy T, Loughran TP. How I treat LGL leukemia. Blood
immune stimulation and even anaphylaxis. One strategy to circumvent 2011;117:2764–74.
these problems would be to use monovalent Fab fragments that 22. Tesfa D, Keisu M, Palmblad J. Idiosyncratic drug-induced agranulocytosis:
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on the design of a monovalent fusion protein composed of the single 23. Grant C, Wilson WH, Dunleavy K. Neutropenia associated with
chain variable region (scFv) of the anti-FcγRIIIA antibody, fused to rituximab therapy. Curr Opin Hematol 2010;18:49–54.
human serum albumin so as to increase its size and prolong its half-life. 24. Bux J. Molecular nature of granulocyte antigens. Transfus Clin Biol
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in larger animal models, it may be eventually tested for use in humans 26. Bruin MC, von dem Borne AE, Tamminga RY, et al. Neutrophil antibody
with ITP. Further, in theory this approach could be applied to other specificity in different types of childhood autoimmune neutropenia.
diseases, such as autoimmune hemolytic anemia.
Blood 1999;94:1797–802.
27. Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of
autoimmune neutropenia in infancy: analysis of 240 cases. Blood
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details. detection of anti-neutrophil antibodies in children with chronic
neutropenia. Blood 2002;99:3468–71.
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CHaPter 62 Immunohematological Disorders 856.e1


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

1. Which of the following treatments is LEAST likely to improve 3. Hemolytic anemia of the newborn:
+
platelet counts in an patient with type A- blood and immune a. Usually occurs when the mother of the infant is Rh and
thrombocytopenic purpura (ITP)? the father is Rh −
a. Rituximab 375 mg/m2 IV b. Is more likely in a first pregnancy than subsequent pregnan-
b. Prednisone 1 mg/kg PO cies between the same two parents
c. WinRho 250 IU/kg (50 micrograms/kg) IV c. May be prevented by administration of RhoGam at week
d. IVIG, 2 g/kg continuous IV infusion over 48 hours 28 of pregnancy when the parents are Rh incompatible
d. Is more common if the parents are ABO incompatible
2. Which is true of hemolysis caused by a “cold” antibody elicited
by exposure to drugs? 4. Neutropenia associated with administration of rituximab:
a. Usually caused by immunoglobulin G (IgG) antibody a. Is usually self-limiting
against Rh antigens b. Precludes future use of rituximab
b. Usually accompanied by a direct antibody test (DAT) c. Typically occurs 7–10 days after administration of
(Coombs test) that is positive for IgM and IgG and negative rituximab
for complement d. Does not respond to administration of granulocyte–colony-
c. Usually accompanied by a DAT (Coombs test) that is stimulating factor (G-CSF)
negative for IgM and IgG and positive for complement
d. Usually caused by a Donath-Landsteiner IgG against Rh
antigen on the surface of the red blood cell (RBC)

63






Bullous Diseases of the Skin and

Mucous Membranes



Adela Rambi G. Cardones, Russell P. Hall III







PEMPHIGUS In the early 1960s, investigators found IgG antibodies bound
to the epithelial keratinocyte cell surface in the skin of patients
Pemphigus is a group of cutaneous autoimmune blistering diseases with PV and showed that the serum of these patients contained
characterized by intraepidermal blistering of the skin and mucous IgG antibodies that bound in an identical pattern to normal
5
membranes. Pemphigus comprises four distinct conditions: human skin. These findings demonstrated that PV is an
pemphigus vulgaris (PV), pemphigus foliaceus (PF), paraneo- autoimmune disease directed against a normal component of
plastic pemphigus, and immunoglobulin A (IgA) pemphigus. stratified squamous epithelium.
Pemphigus Vulgaris Pemphigus Foliaceus
The most common and most severe form of pemphigus, PV is PF is characterized by blisters within the epidermis, resulting in
still a rare disease, with an incidence estimated at 0.5–1.6 per superficial erosions with scaling and crusting (Fig. 63.3). In
1-3
100 000. PV presents most often in the fourth to sixth decades contrast to patients with PV, patients with PF rarely develop
but can occur at any age. PV is characterized by the presence of mucous membrane lesions. Because the blisters are superficial,
flaccid blisters and erosions of the skin and mucous membranes many patients present with erythematous, scaling, and crusted
(Fig. 63.1). Virtually all patients with PV develop oral erosions plaques, which occur principally on the head, neck, and trunk
at some point during the course of their disease. Most present (Fig. 63.4). The prognosis for patients with PF is markedly better
with oral erosions, and for many, these are their only disease than that for patients with PV, although patients with severe PF
manifestation for months to years (Fig. 63.2). These erosions do occasionally die as a result of infections and/or the side effects
are often persistent and shaggy; they can involve all areas of the of therapy.
oral mucosa and extend into the esophagus. In severe cases, the An unusual variant of PF is the endemic form of the disease,
conjunctiva, nasal, anal, cervical, or urethral mucosae may be fogo selvagem (FS) (which is the Portuguese term for “wild
affected. fire”). Although clinically identical to the sporadic form of PF,
PV blisters are flaccid and easily ruptured; they can occur on FS only occurs in certain rural areas of South America and North
6
inflamed or noninflamed skin. Once broken, these blisters leave Africa. The epidemiology suggests an infectious etiology, and
large, nonhealing erosions. Blisters can occur on any area of an arthropod vector may be involved in spreading the disease.
skin, most often beginning on the head, neck, or trunk. General- Pemphigus erythematosus, or Senear-Usher syndrome, is
ized blistering is not uncommon, especially if diagnosis and/or another PF variant. These patients have typical features of PF
treatment have been delayed. with additional characteristics suggestive of systemic lupus
Pemphigus vegetans is an unusual variant of PV, in which erythematosus (SLE) (Chapter 51), such as malar involvement
lesions develop mainly in the axilla, groin, and other flexural and antinuclear antibodies. The clinical course tends to parallel
areas. The characteristic lesions are plaques of hypertrophic that of PF, and most patients do not develop SLE. The patho-
granulation tissue with occasional pustules. These can occur de genesis of this form of PF is poorly understood.
novo or after healing of PV lesions. The etiology of this unusual PF can also be associated with drugs. The most common
clinical presentation is unknown. agents that induce pemphigus are D-penicillamine and
7
Before the advent of glucocorticoids, PV was almost uniformly angiotensin-converting enzyme inhibitors. Although these drugs
fatal, with patients developing large areas of denuded skin and can induce a PV-like picture, the clinical manifestations are most
dying from overwhelming sepsis. Since the introduction of often similar to PF. Patients with drug-induced pemphigus have
systemic glucocorticoids, the mortality rate has fallen to approxi- autoantibodies directed against the keratinocyte cell surface; the
mately 10%. The residual mortality is largely due to the side mechanism(s) causing these antibodies are unknown, but reactive
effects of the high doses of glucocorticoids required to treat the sulfhydryl or amide groups on the drugs are thought to be
disease, particularly in debilitated or older patients. 4 responsible. 7
Histologically, PV is characterized by intraepithelial blisters, Histological examination of PF blisters reveals intraepidermal
with acantholysis (breaking apart of the suprabasilar portion of blisters with acantholysis of the most superficial portion of skin
the epidermis). Biopsy of early PV lesions shows that basal (the granular cell layer), resulting in blisters with an epithelial
epidermal cells remain attached to the dermis, forming a “row base rather than the basal cell layer as seen in PV.
of tombstones,” with loss of attachment of individual keratinocytes The immunohistological features of PF are indistinguishable
to each other, resulting in intraepidermal blisters. from those of PV (Fig. 63.5). Cell-surface IgG deposits are present,

857

858 Part SEVEN Organ-Specific Inflammatory Disease






























FIG 63.3 Patient with pemphigus foliaceus showing superficial
erosions and crust formation on the head and neck.



FIG 63.1 Patient with pemphigus vulgaris showing ulcerative
plaques and crust involving the back.




















FIG 63.4 Patient with pemphigus foliaceus showing involvement
of the scalp with erosions and adherent crust with alopecia. The
patient’s hair regrew fully after initiation of treatment.









FIG 63.2 Patient with pemphigus vulgaris showing ulceration
of the soft palate.



FIG 63.5 Direct immunofluorescence of perilesional normal-
appearing skin from a patient with pemphigus foliaceus using
antibodies directed against human immunoglobulin G (IgG).
Cell-surface IgG deposits are seen on the epidermal keratinocytes.
A similar pattern is seen in patients with pemphigus vulgaris.

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 859


and serum from patients with PF contains IgG antibodies, which IgA deposition mainly in the upper epidermis. The IEN subtype
bind to normal stratified squamous epithelium. Although the is characterized by pustules deeper in the epidermis, with intercel-
immunofluorescence patterns of PF and PV are virtually identical, lular IgA deposition throughout the epidermis. Circulating IgA
the antigenic targets of these autoantibodies are different (see antibodies to intraepidermal structures are present in ~50% of
below). cases. Desmocollin 1 (a desmosomal cadherin) has been identified
as a target autoantigen in most cases with the SPD phenotype.
Paraneoplastic Pemphigus In some IEN-type cases, desmoglein-1 (Dsg1) and Dsg3 are
Anhalt described a series of patients with severe oral erosions autoantibody targets, but in most IEN cases the autoantigen
and polymorphic skin lesions suggestive of coexistent PV and remains unknown. Patients of both types commonly present
8
erythema multiforme. All these patients had associated malignan- with flat pustules, often on a slightly erythematous base, which
cies, which were mostly lymphoreticular, including lymphoma, tend to coalesce to form annular patterns. IgA pemphigus mainly
chronic lymphocytic leukemia, and thymoma. The histological affects the trunk, axillae, and groin but not the mucosa. Histology
features of the skin lesions in these patients resembled PV, of lesional skin reveals subcorneal or intraepidermal blisters,
including suprabasilar blister formation, but with additional with acantholytic cells and a neutrophilic infiltrate. 9
keratinocyte cell necrosis as found in erythema multiforme. Skin
biopsies from these patients revealed IgG bound to keratinocyte Pathogenesis
cell surfaces, and granular–linear deposits of IgG and C3 at the The antigenic targets in pemphigus have been identified as
basement membrane. Serum contained circulating IgG antibodies, components of desmosomes, key structures involved in kerati-
which bound to normal keratinocyte cell surfaces of squamous nocyte adhesion (Table 63.1). IgG from patients with PF binds
epithelium. Although initial reports suggested that these antibodies to a 160-kilodalton (kDa) glycoprotein, Dsg1. IgG from patients
bound to stratified and nonstratified squamous epithelium, this with PV with only mucosal lesions binds predominantly to Dsg3,
is not always the case. The antigenic targets of these antibodies an epithelial cadherin with significant homology to Dsg1. Patients
were also distinct from both PV and PF (see below). with PV who have both skin and mucosal diseases have IgG
10
antibodies directed against both Dsg1 and Dsg3. In paraneo-
IgA Pemphigus plastic pemphigus, IgG antibodies bind to members of the plakin
IgA pemphigus presents as an annular, vesiculopustular eruption family of desmosomal/hemidesmosomal proteins (desmoplakin
characterized by intraepidermal blisters with numerous neutro- I, desmoplakin II, envoplakin, periplakin, plectin, and BPAG1)
phils. Intercellular deposits of IgA are present. This entity is also as well as to Dsg1 and Dsg3. 8
known as intraepidermal neutrophilic IgA dermatosis, intercellular It has been clearly shown that these autoantibodies are
IgA vesiculopustular dermatosis, and intercellular IgA dermatosis. 9 pathogenic. Neonatal mice injected with IgG from patients with
IgA pemphigus is a distinct clinical entity with two subtypes PV, PF, or paraneoplastic pemphigus develop cutaneous blisters,
that differ in histology and epidermal IgA deposition patterns: histological changes, and immunofluorescence findings consistent
subcorneal pustular dermatosis (SPD) and intraepidermal with pemphigus. 8,11
neutrophilic IgA dermatosis (IEN). Biopsy specimens from SPD The causes of the autoimmune response remain unknown.
show subcorneal acantholysis and pustules, with intercellular An increased frequency of human leukocyte antigen (HLA)-DR4




TABLE 63.1 Immunopathology of autoimmune Blistering Diseases
Disease Direct IF (Patient’s Skin) Indirect IF (Patient’s Serum) antigen(s)
Pemphigus vulgaris IgG keratinocyte cell surface IgG binds keratinocyte cell surface (normal Dsg3, +/− Dsg1
stratified squamous epithelium)
Pemphigus IgG keratinocyte cell surface IgG binds keratinocyte cell surface (normal Dsg1
foliaceus stratified squamous epithelium)
Paraneoplastic IgG keratinocyte cell surface; C3, IgG binds keratinocyte cell surface Plakin proteins, Dsg1,
pemphigus granular/linear at epidermal basement Dsg3
membrane (normal stratified and
nonstratified squamous epithelium)
Bullous pemphigoid Linear IgG, C3 at epidermal basement IgG binds in linear pattern normal stratified 180-kDa, BPAG2
membrane squamous epithelium basement 230-kDa, BPAG1
membrane (epithelial side)
Herpes gestationis Linear C3 at epidermal basement IgG binds in linear pattern normal stratified 180-kDa, BPAG2
membrane (in 30–50% of patients squamous epithelium basement
linear IgG also seen) membrane (epithelial side)
Linear IgA bullous Linear IgA at epidermal basement IgA binds in linear pattern normal stratified 97-kDa protein (portion of
dermatosis membrane squamous epithelium basement BPAG2)
membrane (epithelial side)
Epidermolysis Linear IgG epidermal basement IgG binds in linear pattern normal stratified Type VII collagen
bullosa acquisita membrane (IgA rarely) squamous epithelium basement (noncollagenous domain)
membrane (dermal side)
Dermatitis Granular IgA dermal papillary tips Negative Epidermal TGase-3
herpetiformis
Dsg, desmoglein; IF, immunofluorescence; Ig, immunoglobulin; kDa, kilodalton; TGase-3, transglutaminase-3.

860 Part SEVEN Organ-Specific Inflammatory Disease


and HLA-DR14 is found in patients with PV, although the in many patients, in others, PV may flare up during corticosteroid
individual susceptibility gene differs with ethnic origin: PV therapy taper and require additional immunosuppression.
is associated with PV HLA-DRB1*04:02 in Ashkenazi Jews; Azathioprine, mycophenolate mofetil, cyclophosphamide,
DRB1*14:01/04 and DQB1*05:03 in non-Jewish patients of methotrexate, and cyclosporine are the additional immunosup-
European or Asian descent. T cells from patients with PV have pressive agents most often utilized. Azathioprine and cyclosporine
been observed to secrete high levels of interleukin-4 (IL-4) and have steroid-sparing effects in long-term treatment, but adding
IL-10 in response to specific Dsg3 peptides presented by these agents to steroids does not induce long-term remission
19
DRB1*04:02. T cells reactive against Dsg3 are found in patients any better than steroids alone. In small trials, mycophenolate
with PV and also in some normal healthy subjects with HLA mofetil, used alongside prednisone, induced disease control more
DRB1*04:02. Which additional factors are required for HLA- quickly compared with prednisone alone. However, a recent larger
20
susceptible individuals to develop clinical disease remains study of this failed to show statistical significance. Because of
unknown. its relatively low toxicity, azathioprine (1–3 mg/kg/day) is fre-
Both the sporadic and endemic (FS) forms of PF are associated quently chosen for adjuvant immunosuppression. Other possible
with HLA class II alleles. Susceptibility has been correlated with adjunctive therapies include parenteral gold, plasmapheresis, and
the presence of DR4, DR14, and DR1 alleles, but no single DR4 extracorporeal photochemotherapy. Treatment for PF is similar
or DR14 allele has been associated with the disease. The to that for PV, but therapy can be less aggressive, as PF is usually
HLA-DRB1 alleles DRB1*04:04, *14:02, *14:06, or *01:02 have less severe than PV and rarely fatal. Dapsone is used for intraepi-
12
9
been identified as risk factors for FS (relative risk >14). These dermal IgA neutrophilic dermatosis. Occasionally, systemic
alleles all share a common sequence in the third hypervariable glucocorticoid therapy is needed, either alone or with dapsone.
domain of the DRB1 gene. Therapy for paraneoplastic pemphigus has been disappointing
Environmental factors have been implicated in FS, the endemic and usually unsuccessful.
form of PF. Healthy people living in endemic areas in South Various biological agents, including etanercept, infliximab,
America have anti-Dsg1 IgG antibodies. The proportion of normal high-dose intravenous immunoglobulin (IVIG), and rituximab,
individuals with anti-Dsg1 IgG decreases with distance from the have been tried in pemphigus, with some success. Trials with
13
endemic focus of FS. In addition, normal controls and patients etanercept showed mixed results with heterogeneous responses. In
with FS from endemic areas have IgM against the nonpathogenic a trial comparing infliximab plus prednisone versus prednisone
21
extracellular domain of Dsg1. This is uncommon in other alone, neither group achieved their primary endpoints, but at
pemphigus phenotypes or in patients with FS who have migrated 26 weeks, three of 10 patients given infliximab showed positive
to urban centers, suggesting exposure to an environmental antigen responses, compared with none who received prednisone alone.
14
that may share epitopes with Dsg1. An IgG4 response seems Median anti-Dsg1 and anti-Dsg3 levels were lower in the infliximab
important: In endemic areas, both normal subjects and those group at 18 and 26 weeks. A single course of IVIG was effective
with preclinical disease or in remission had anti-Dsg1 antibodies in a double-blind study of patients with steroid-refractory PV. 22
15
that were predominantly IgG1 ; in those with active disease, There are numerous case reports of successful use of rituximab
anti-Dsg1antibodies were predominantly IgG4. 15 in severe or recalcitrant pemphigus. In most cases, rituximab
FS has been linked to bites from bloodsucking black flies was added to systemic corticosteroid therapy. Three prospective
found in the endemic areas of Brazil. Pathogenic IgG4 antiDsg1 studies of rituximab in pemphigus, alongside corticosteroids or
antibodies from patients with FS cross-react with the LJM11 other immunomodulatory agents, have reported dramatic
sand fly salivary gland antigen. 12,16 This suggests that FS may be improvement or total clearance in most patients. 23,24 The mean
triggered in HLA-susceptible individuals by an immune response time to achieve disease control, with re-epithelialization of
24
that is cross-reactive with Dsg1. mucosal and cutaneous erosions, was 3 months. The response
Although autoantibodies are clearly important in pathogenesis, to rituximab appears durable, with 58% of patients remaining
the mechanism by which they cause acantholysis is unknown. in complete remission 6 years after therapy. 24
Complement components (C3, C1q) are often present in lesional
skin, but autoantibodies can induce acantholysis in vitro and in
neonatal mice without complement activation. Overall, it seems KEY CONCEPtS
that complement may augment acantholysis, but pemphigus Pemphigus
IgG on its own can bind keratinocytes and induce loss of cell–cell
adhesion. It has been suggested that urokinase plasminogen Clinical presentations correlate with the antigenic target of the
activator is necessary for skin lesions to develop, but pemphigus autoantibodies.
antibodies remain pathogenic in plasminogen-activator knock-out Pemphigus foliaceus presents with superficial intraepidermal blisters
and antibodies directed against Dsg1 alone.
17
mice. Acantholysis may be triggered by intracellular signaling Pemphigus vulgaris with only oral mucosal lesions most often has anti-
after antibodies bind to cell-surface desmogleins: p38MAPK bodies against Dsg3.
inhibition prevents disease in the mouse model. 18 Pemphigus vulgaris with skin and mucosal lesions most often has anti-
bodies against both Dsg1 and Dsg3
Therapy
Before the introduction of glucocorticoid therapy, pemphigus
was uniformly fatal. The introduction of high-dose systemic BULLOUS PEMPHIGOID
glucocorticoids and improvements in wound care have markedly
reduced mortality caused by PV, but it remains a serious condition. Clinical Features
Most blistering can be controlled with prednisone (1–2 mg/kg/ Bullous pemphigoid (BP) is characterized clinically by extremely
day, usually in divided doses). The dose can be slowly tapered pruritic, tense blisters on inflamed or noninflamed skin. These
toward alternate-day therapy. Although this will control disease lesions range from small (1–5 mm) vesicles to large bullae several

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 861





















FIG 63.6 Patient with bullous pemphigoid showing erythematous
plaques with tense subepidermal bullae.





centimeters in diameter (Fig. 63. 6). Patients with BP can also
present with other skin lesions, including urticarial or eczematous
dermatitis. Blisters can occur anywhere on skin, but often on FIG 63.7 Direct immunofluorescence of perilesional normal-
skin in the extremities, groin, and axillae. appearing skin from a patient with bullous pemphigoid using
Oral and ocular mucosal lesions are infrequent in BP, in antibodies directed against human immunoglobulin G (IgG). A
contrast to patients with mucous membrane pemphigoid (see linear band of IgG is present at the basement membrane.
below), in which mucosal lesions predominate.
Most patients with BP are over 60 years of age, although it
can develop at any age. BP has been reported in association
with other diseases, including neurological disease, diabetes
mellitus, psoriasis, autoimmune diseases, and malignancy. Recent
studies have suggested that only neurological disease is actually
more prevalent, being over two-fold more common in patients
25
with BP. Drug-related BP is recognized, with furosemide and
phenacetin being the most frequent offenders. BP has also been
linked to ultraviolet light and therapeutic radiation. In general,
the prognosis for BP is good, with a 1-year survival rate of 90% in
the United States. Higher mortality rates are reported in Europe,
but the reasons for this difference are not currently understood.
Biopsy of an early lesion of BP can show several different
patterns consistent with the polymorphic appearance of the
eruption. The classic finding is a subepidermal blister with a
dermal inflammatory infiltrate, comprised predominantly of
eosinophils with some lymphocytes, histiocytes, and neutrophils. FIG 63.8 Direct immunofluorescence sample from a patient
The epidermis over this blister is often intact with minimal with bullous pemphigoid after incubation with 1 mol/L sodium
abnormality, whereas the blister cavity is filled with inflammatory chloride (NaCl), showing localization of immunoglobulin G (IgG)
cells. Sometimes neutrophils predominate, or there may be immunoreactants to the roof (epidermal side) of the blister cavity.
cell-poor lesions with very few inflammatory cells.
Occasionally, there may only be mild epidermal edema, with
eosinophil infiltration but no blister. The polymorphic histology Although the immunofluorescence findings in patients with
of BP means the diagnosis is not based solely on the histological BP are characteristic, they are not diagnostic. Other blistering
and clinical findings. diseases, such as bullous lesions in SLE, pemphigoid gestationis
The diagnosis of BP can be confirmed by direct immuno- (PG), and epidermolysis bullosa acquisita (EBA), can have similar
fluorescence of perilesional skin. Over 90% of patients with BP patterns of immunoreactivity. Saline treatment splits skin within
have linear C3 deposits at the dermal–epidermal junction (DEJ), the lamina lucida: IgG from patients with BP binds predominantly
whereas 70–90% have linear IgG deposits at the DEJ (Fig. 63.7). to the epidermal side, whereas antibodies from patients with
In some patients, only C3 is seen in the skin. In 70–90% of EBA bind only to the dermal side. Saline-treated skin from patients
patients with BP, circulating IgG is present and binds in a linear with BP also shows that IgG is deposited in vivo on the epidermal
pattern at the DEJ of normal human skin. Anti-BP180 (BPAG2) side of the split skin (Fig. 63.8).
antibody titers indicate disease activity, especially at disease onset.
Anti-BP230 (BPAG1) antibodies are a fairly sensitive and specific Pathogenesis
diagnostic marker but do not correlate strongly with disease Immunofluorescence microscopy demonstrates IgG in the lamina
activity. lucida of the basement membrane. The target antigens are

862 Part SEVEN Organ-Specific Inflammatory Disease


components of hemidesmosomes. These are the major attachment normal HLA-DQB1*03:01 showed similar T-cell reactivity but
sites of epidermal basal cells and where cytoskeletal proteins produced only T-helper-1 (Th1-type) cytokines, whereas T cells
link through the plasma membrane to the dermis. Two pre- from patients with BP produced both Th1-type and Th2-type
dominant antigens have been identified: 230-kDa and 180-kDa cytokines. These results suggest that the ability to mount Th2-
proteins. These have been cloned and sequenced, confirming pattern responses to BP antigen(s) may be critically important.
that they are distinct proteins, associated as a complex within
the hemidesmosome. The 230-kDa BP antigen (BPAG1) is an Therapy
intracellular protein with sequence homology to desmoplakin The mainstay of therapy for BP is treatment with systemic
I, a member of an adhesion junction plaque protein family. The glucocorticoids: most patients respond rapidly to oral prednisone
180-kDa BP antigen (BPAG2) contains both intracellular and (0.5–2.0 mg/kg/day), but starting prednisone at doses >0.75 mg/
extracellular domains joined by a transmembrane region. The kg/day confers no advantage. Mild or localized disease can
extracellular portion of BPAG2 has alternating collagen and sometimes be managed with potent topical corticosteroids
noncollagen domains and has been termed type XVII collagen. (confirmed in controlled trials). 31
Epitope mapping studies of BPAG2 have identified an immuno- When new blister formation has stopped and healing has
dominant epitope on an extracellular noncollagen linker domain begun, systemic steroids can be tapered slowly. The speed of
that is also targeted by IgG antibodies in PG. tapering is dictated by the severity of the patient’s initial disease
Although patients with BP have antibodies against BPAG1 and any flare-ups that occur during tapering. Most patients can
and BPAG2, the pathogenic role of these autoantibodies remains stop systemic steroids completely within 6–18 months, but
uncertain. Targeted disruption of the gene encoding BPAG1 did recurrence of disease activity is not uncommon. Flare-ups should
not result in blister formation or epidermal–dermal adhesion be managed with the lowest dose of systemic steroids possible;
abnormalities. This suggests that anti-BPAG1 antibodies may occasionally topical corticosteroids are enough. Usually, BP is
not directly inhibit the function of BPAG1 but may maintain or self-limiting, lasts between 1.5 and 5 years, and responds promptly
enhance the inflammatory response in BP. Interestingly, targeted to systemic glucocorticoids. 31
knockout of BPAG1 in mice causes progressive deterioration in A minority of patients requires prolonged high-dose systemic
motor function and sensory neurodegeneration. Additionally, glucocorticoids. In these individuals, adding azathioprine,
certain portions of BP230 (BPAG1n1 and BPAG1n3) seem to cyclophosphamide, or methotrexate will often allow tapering or
play important roles in organizing cytoskeletal networks in discontinuation of systemic steroids, but data on which is best
26
31
vivo. These findings complement prior studies implicating for steroid sparing are limited. Other unproven adjunctive
BP230 (BPAG1) in the function of the central nervous system of therapies that may help in some patients include dapsone,
humans and may explain the overlap between BP and neurological cyclosporine, and rituximab. Our preferred options for additional
diseases. 27 therapy are azathioprine (1–2 mg/kg/day) or mycophenolate
Patients with BP (and PG) develop antibodies against a mofetil (1000–2000 mg/day). 32
28
noncollagenous, extracellular portion of BPAG2. Serum levels A recent review of IVIG for BP concluded that 70% of patients
of BPAG2 autoantibodies correlate with disease activity in patients experienced some improvement but there was no clinical benefit
with BP. Interestingly, patients with an inherited form of skin in the remainder. IVIG 2 g/kg over 5 days at monthly intervals
blistering (generalized atrophic benign epidermolysis bullosa) for 3 months has been commonly used; typically more than one
have a mutation in BPAG2 resulting in a dysfunctional or missing cycle is needed to prevent recurrence. In some patients, IVIG
protein. 29 appears to be steroid sparing. IVIG was ineffective if patients
In an animal model of BP, rabbits were immunized to produce received low-dose IVIG or only a single infusion.
+
antibodies directed against mouse BPAG2. Passive transfer of Rituximab eliminates CD20 B cells through complement-
this rabbit IgG to newborn mice resulted in blisters, an inflam- dependent and antibody-dependent cell-mediated cytotoxicity,
matory infiltrate, and deposition of immunoreactants. In this as well as by inducing structural changes and apoptosis. The
model, complement activation, mast cell degranulation, and targeted B cells remain absent from the circulation for 6–12
neutrophil infiltration are important in blister formation. months. Several groups have reported clinical success with the
Complement activation and other extracellular mediators are use of rituximab for pemphigus, but it has only had limited
also implicated in the pathogenesis of BP skin lesions. Comple- success in the treatment of BP. 33
ment and the terminal components of the complement cascade An open-label trial of anti-IgE (omalizumab) demonstrated
34
are present in the skin of patients with BP. Early lesions in these benefit in 5 of 6 patients with BP, albeit with varying degrees
patients contain eosinophil granule proteins and eosinophil- of success.
derived gelatinase, suggesting an early role for eosinophils in the
lesion development. Taken together, these findings suggest that
IgG autoantibody binds, most likely, to BPAG2 and activates
complement and local cytokine production. This attracts KEY CONCEPtS
eosinophils and neutrophils that release enzymes leading to blister
formation. IgE antibodies against BPAG2 have also been found Bullous Pemphigoid
in sera from patients with BP and are implicated in the early Most common autoimmune blistering disease that presents in older
lesions of BP, the development of eosinophilic infiltration, and adults
degradation of the basement membrane zone. 30 Severely pruritic with clinical presentations, including urticarial lesions,
The factors that induce development of autoantibodies in small vesicles, and/or large tense vesicles
patients with BP are unknown. T cells from these patients Linear immunoglobulin G (IgG) and C3 present at the epidermal basement
membrane, binding to the epidermal side of “1 M NaCl split” skin
respond in vitro to the extracellular region of BPAG2; this Disease activity correlates best with IgG anti-BP 180 antibodies
reactivity is restricted by HLA-DQB1*03:01. Subjects with

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 863



EPIDERMOLYSIS BULLOSA ACQUISITA in BP. Linear deposits of C3, IgM, IgA, and fibrinogen have also
35
been reported. However, in EBA, these deposits are localized
EBA is a chronic subepidermal blistering disease that typically exclusively below the lamina lucida. Direct immunofluorescence
presents in the fourth to sixth decades. There are two forms of of saline-split perilesional skin shows IgG in the blister floor in
EBA—a noninflammatory type with blisters on distal extremities EBA (Fig. 63.10); in BP, IgG is in the blister roof.
and an inflammatory type that closely resembles BP. Patients Indirect immunofluorescence using normal human skin shows
with non-inflammatory EBA have peripherally distributed blisters circulating anti–basement membrane zone antibodies in 30–50%
that heal with scarring and milia formation. Their skin is extremely of patients with EBA. However, IgG antibody can be detected
fragile, often resulting in numerous erosions in areas of mechanical in 85% of patients when using saline-split skin, which is the
trauma, such as hands, feet, elbows, and knees. Lesions are often more sensitive and specific substrate. As expected from the in
seen on oral mucous membranes, sometimes including the vivo deposition pattern, IgG from patients with EBA localizes
esophagus. Patients with classic EBA may also develop ocular, to the blister floor. Sera from these patients recognize the 300-kDa
vaginal, urethral, and rectal mucosal lesions. Ocular changes are protein, type VII collagen, primarily targeting its immunodomi-
common, clinically resembling mucous membrane pemphigoid nant NC1 domain.
(MMP). Other cutaneous manifestations include scarring alopecia
and variable degrees of nail dystrophy. Patients with nonclassic Pathogenesis
(inflammatory) EBA often present similarly to those with BP, Immunoelectron microscopy of EBA biopsy specimens has shown
with widespread tense bullae on an erythematous base, which immunoglobulin deposits localized to the lamina densa zone of
heal without scarring (Fig. 63.9). 35 the basement membrane, below the lamina lucida. Transmission
EBA has been associated with several diseases, particularly electron microscopy of lesional EBA skin shows decreased or
inflammatory bowel disease (IBD) and bullous SLE. These absent anchoring fibrils. Anchoring fibrils are implicated in
associations may partly result from the association of EBA with epidermal–dermal adherence via linkage of the hemidesmosome
HLA-DR2. 36 through the basement membrane, and their absence may explain
Skin biopsies of early lesions from patients with EBA show the observed skin fragility. The lack of inflammatory infiltrate
subepidermal blisters with variable degrees of inflammation. In in many patients with EBA suggests that autoantibodies may
patients with classic EBA, lesional skin biopsies often have minimal disrupt the interaction between anchoring fibrils and dermal
inflammatory cell infiltrate. In contrast, patients with inflam- matrix proteins.
matory EBA may have substantial collections of mononuclear The target antigen for the IgG autoantibodies present in the
cells, neutrophils, and eosinophils in the superficial dermis. sera of patients with EBA is type VII collagen, a 300-kDa gly-
Direct immunofluorescence of perilesional skin biopsies from coprotein composed of a 145-kDa noncollagenous domain (NC1)
patients with EBA shows linear deposits of IgG at the DEJ, as at the amino-terminal end, an 18-kDa noncollagenous domain
(NC2) at the carboxy terminus, and a central collagenous domain.
IgG antibodies from patients with EBA appear specific for epitopes
within the NC1 noncollagenous domain. Type VII collagen is
the major structural component of anchoring fibrils and is
produced by both epithelial keratinocytes and dermal fibroblasts.
Passive transfer experiments in mice and active immune models



























FIG 63.10 Direct immunofluorescence sample from a patient
FIG 63.9 Patient with epidermolysis bullosa acquisita showing with epidermolysis bullosa acquisita (EBA) after incubation with
extremity involvement with tense bullae. Note the similarity to 1 mol/L sodium chloride (NaCl), showing localization of immu-
lesions of bullous pemphigoid, with somewhat less inflammation noglobulin G (IgG) immunoreactants to the floor (dermal side)
surrounding the base of bullae. of the blister cavity.

864 Part SEVEN Organ-Specific Inflammatory Disease


have provided additional support for the critical role of anti-type relationship to herpes virus infections. The term pemphigoid
35
VII collagen antibodies in the pathogenesis of EBA. In experi- gestationis eliminates this confusion and emphasizes the patho-
mental mouse-model EBA, induction of specific types of antibod- physiological similarity of PG to BP.
ies is linked to the MHC haplotype suggesting future work may PG is rare, occurring in <1 in 50 000 pregnancies in North
37
identify non-MHC EBA susceptibility genes. Utilizing a four-way, America. It usually presents in the third trimester or in the
autoimmune-prone, advanced mouse intercross line immunized immediate postpartum period. Disease flare-ups beyond the
with a COL7 fragment to induce EBA, investigators identified immediate postpartum period do occur, and patients have been
quantitative trait loci (QTLs) on chromosomes 9, 12, 14, and reported to develop blisters when menses return or when oral
19 associated with disease development and QTLs on chromo- contraceptives are used. Although PG may recur in subsequent
4
somes 1, 15, and 19 associated with maximum disease severity. pregnancies, this is not absolute.
In this model, gene–microbiota interactions appear to promote PG presents as tense blisters, often on an urticarial base,
38
disease development. Finally, identification of other mediators ranging in size from small (3–5 mm) vesicles to large (1–2 cm)
in inflammatory EBA, such as heat shock protein-90 (HSP-90), bullae. The blisters often begin on the abdomen, although the
granulocyte macrophage–colony-stimulating factor (GM-CSF), entire body can be involved. Pruritus is common and can be
chemokine ligand-1 (CXCL1), CXCL2, or IL-1, suggests other severe.
possible candidates for therapeutic targeting. 38 PG is associated with maternal and fetal morbidity. In the
mother, morbidity mainly relates to skin disease, with extensive
Treatment itching and blister formation. Recent data indicate a better
Spontaneous resolution is infrequent in EBA, and management prognosis for the fetus than previously reported, with a 20%
is difficult. The main goals of therapy are to minimize blistering risk for premature delivery. Small-for-gestational-age birth weight
and scar formation, with particular attention to ocular and oral and spontaneous abortion are only marginally increased in
mucosal lesions. Systemic glucocorticoids are the mainstay of frequency. Similar effects have been found in pregnant women
therapy, especially for patients with inflammatory EBA. Unfor- receiving systemic corticosteroid treatment for allergy, asthma,
tunately, even high-dose systemic steroids do not usually improve inflammatory bowel disease, and so on. Low birth weights and
skin fragility and trauma-induced blister formation. Mucosal prematurity are significantly associated with early onset of PG
lesions often respond to systemic steroids (prednisone 0.5–1.5 mg/ (in first or second trimester), rather than exposure to corticoster-
40
kg/day) but may recur with tapering and/or discontinuation oids during pregnancy. Up to 10% of children born to mothers
of steroids. Several adjunctive agents, including azathioprine, with PG develop skin lesions similar to those in the mother,
cyclophosphamide, colchicine, dapsone, hydroxychloroquine, likely as a result of transplacental crossing of maternal autoan-
and plasmapheresis, have been proposed, but none has been tibodies. The typical presentation is an erythematous urticarial
consistently effective. Cyclosporine has been used to treat patients or vesicular rash; yellowish plaques on erythematous base and
with EBA with some success, although toxicity can limit therapy. frank bullae have also been reported. The disease is generally
Photopheresis, IVIG, and rituximab have also been reported mild and resolves spontaneously over days to weeks as maternal
35
to be effective in some patients with refractory EBA. Mucous antibodies are cleared.
membrane lesions can prove particularly difficult to manage The histopathology of PG lesions is not diagnostic. Subepi-
and may require systemic therapy. Patients with ocular lesions dermal blisters are seen with necrotic basal keratinocytes and a
need ophthalmologist review and may require systemic gluco- perivascular infiltrate containing eosinophils, neutrophils,
corticoids to prevent conjunctival scarring. Oral mucous lymphocytes, and monocytes.
membrane lesions can sometimes be managed with frequent Direct immunofluorescence studies of the skin of patients
application of potent topical steroid ointments or gels (0.05% with PG shows linear deposition of C3 at the DEJ. In addition,
clobetasol propionate, 0.05% fluocinonide). If this fails and the 30–50% of patients have linear IgG deposits in a similar pattern.
degree of oral erosions inhibits appropriate nutrition, systemic Occasionally IgA, IgM, C1q, C4, properdin, factor B, and C5
glucocorticoid therapy may be required. Clinicians should also may be present in the lamina lucida. Indirect immunofluorescence
be aware of possible involvement of esophageal mucosa and/or reveals circulating IgG antibodies directed against the epidermal
tracheal mucosa and involve appropriate specialists to monitor basement membrane in only ~30% of patients. In contrast,
and treat these potentially severe complications. 50–75% of patients have IgG antibody directed against epithelial
As well as therapies targeting B cells, novel therapeutic targets basement membrane as shown by complement fixation techniques.
addressing autoreactive T cells are being studied in the treatment This IgG anti–basement membrane antibody fixes complement
39
of EBA. These include inhibitors of the stress-inducible HSP-90. in vitro but is not detected by routine indirect immunofluores-
Strategies targeting other features of EBA, such as neutrophil cence because of its low concentration. These autoantibodies
recruitment and complement activation, are also being explored. can cross the placenta: Infants born to mothers with PG often
The management of chronic skin wounds is vital in EBA. have C3 deposits at the DEJ, but without any clinical skin disease.
Protection of skin from trauma and early use of topical and These IgG antibodies bind the epithelial side of saline-split skin,
systemic antibiotics are critical to improving the rate of healing. as seen in BP.
The development of new biological dressings for chronic ulcers
has also proven helpful in the management of these wounds. Pathogenesis
Sera from most patients with PG bind to BPAG2 but do not
PEMPHIGOID GESTATIONIS react with BPAG1. The role of pregnancy and other hormonal
factors in the development of PG is not understood.
PG is a rare, itchy, blistering disease of pregnancy and the Patients with PG have an increased frequency of HLA-DR3;
puerperium characterized by linear deposits of IgG and C3 at the greatest relative risk is when HLA-DR3 and HLA-DR4 are
the DEJ. Formerly known as “herpes gestationis,” PG has no both present. Patients with PG have an increased frequency of

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 865


anti-HLA antibodies compared with multiparous control subjects. normal human skin. A BP180 C-terminal domain enzyme-linked
Some studies have suggested that paternal haplotype is important immunosorbent assay (ELISA) has been evaluated as a method
in PG pathogenesis, but further prospective studies are needed. of characterizing MMP, although direct immunofluorescence
Patients with PG also have increased frequency of the C4 null remains the most sensitive test for diagnosing BP-180 MMP. 43
allele, although this may just secondary to the increased frequency
of HLA-DR3. 41 Pathogenesis
Understanding the pathogenesis of MMP has been hampered
Treatment by the heterogeneous clinical presentation and the relative lack
Therapy of PG is directed at relieving pruritus and preventing of antibodies in serum. The presence of different immunoglobulin
the development of new blisters. If the extent of disease is limited, classes at the basement membrane on immunofluorescence and
patients can be managed with topical glucocorticoids and the variable localization of these immunoglobulins on immu-
antihistamines. However, most patients with PG have extensive noelectron microscopy support the hypothesis that MMP is a
disease and need systemic glucocorticoids. Prednisone 20–60 mg/ heterogeneous disease, in which a variety of basement membrane
day is usually sufficient to control both pruritus and new blister zone proteins are targeted. In a group of patients with immune-
formation; once control has been achieved, the dosage should mediated subepithelial blistering disorders of the mucous
be reduced to the lowest possible effective dose. Occasionally, it membranes, immunoreactants were found on direct immuno-
may be possible to stop prednisone before delivery. However, fluorescence in about 90% with both skin and mucous membrane
44
PG often flares up in the immediate postpartum period. Only lesions or with mucous membrane lesions alone. In contrast,
rarely do patients require therapy beyond the initial postpartum only 40% of patients with isolated ocular disease had C3 and/
period. In patients who do require prolonged therapy after or IgG deposits. This may reflect the difficulty encountered in
delivery, immunosuppressive agents should be considered, as in biopsy of inflamed conjunctiva. On indirect immunofluorescence,
the case of the other blistering diseases. Patients being treated 11 of 14 (81%) patients with skin and mucous membrane disease
with systemic steroids or immunosuppressive drugs should be had circulating IgG anti–basement membrane zone antibodies,
counseled regarding breastfeeding restrictions. of which nine were identified as having BPAG1 and BPAG2 by
immunoblot and/or immunoprecipitation. In contrast, only 3
MUCOUS MEMBRANE PEMPHIGOID of 24 patients with only oral mucosal lesions or ocular lesions
had positive results on indirect immunofluorescence, and one
MMP, formerly termed cicatricial pemphigoid, is a rare, chronic, of the sera reacted with the BP antigens.
scarring blistering disease that predominantly affects the oral Sera from some patients with MMP react with BPAG2, whereas
and conjunctival mucosae. Conjunctival involvement ranges from others have antibodies against type VII collagen. Sera from patients
mild conjunctivitis to severe inflammation leading to symblepha- with ocular MMP react with a 205-kDa protein that has homology
ron formation, entropion, trichiasis, corneal scarring, and, in with the cytoplasmic domain of β 4 integrin and a 45-kDa protein.
some cases, to blindness. Oral lesions include gingivitis, often Some patients have antibodies against epiligrin (laminin 5), a
with erosions and desquamation, as well as erosions and ulcer- ligand for major keratinocyte integrins (α 3 β 1 and α 6 β 4 ). Patients
ations on the buccal and palatal mucosa. Esophageal and laryngeal with MMP who have anti-epiligrin antibodies need a careful
45
involvement is rare but can cause scarring and stenosis. MMP workup, as they have an increased risk of malignancy. Addition-
can also affect the genitalia, rectum, and nasopharynx. Cutaneous ally, >80% of patients with anti-epiligrin antibodies show laryngeal
46
involvement occurs in 10–25% of patients, although it is often involvement, something seen in <10% of all patients with MMP.
limited in extent and predominantly on the scalp, back, or face. 42 These data suggest that the clinical presentation of MMP is
Mucosal biopsy reveals subepidermal blisters with a cellular associated with diverse autoantibodies that react with multiple
infiltrate, usually consisting of lymphocytes and plasma cells. antigens of the skin basement membrane zone. The different
Increased numbers of neutrophils and/or eosinophils have also clinical presentations may therefore result not only from different
been reported. Skin biopsy specimens of lesions in patients with target antigens but also perhaps from different antibody-binding
MMP are indistinguishable from those of BP. sites on these antigens.
Direct immunofluorescence of perilesional skin or mucosal MMP has been linked to many different HLA class II alleles.
samples reveals linear deposition of immunoreactants at the It has been suggested that HLA-DR4 substantially increases the
basement membrane zone. In most patients with MMP, these risk of ocular disease. An increased prevalence of HLA-DQB1*03:01
46a
are IgG and C3, although IgA, IgM, and fibrin deposits have also was described in patients with isolated ocular MMP, but this
been reported. In patients who have ocular or oral mucosal MMP allele was later found to be associated with all clinical sites of
but no skin lesions, undirected skin biopsy for immunofluores- involvement and possibly to anti–basement membrane IgG
cence is unhelpful. Similarly, conjunctival biopsy can yield negative production as well as overall disease severity.
immunofluorescence in patients with otherwise typical MMP.
This may be attributed to conjunctival inflammation. Careful Therapy
evaluation for mucosal lesions and biopsy of perilesional mucosae Treatment of MMP is difficult and directed at minimizing
is often diagnostic. On immunoelectron microscopy, immuno- the scarring and resultant ocular complications. Dapsone
reactants have been found in the lamina lucida and the lamina (100–200 mg/day) is effective at controlling the early inflammatory
densa. response. Tetracyclines can also control MMP and are often
Circulating anti–basement membrane zone antibodies may combined with nicotinamide. If these are unsuccessful, treatment
be present in low titers but are usually absent in patients with with systemic glucocorticoids (1–2 mg/kg/day) may be needed,
MMP. The diagnostic yield of indirect immunofluorescence is often with adjunctive immunosuppressive therapy, such as with
not improved by using different tissue substrates, including oral azathioprine, mycophenolate mofetil, or cyclophosphamide. IVIG
and conjunctival mucosae, normal human skin, and saline-split may be useful: It starts to work rapidly and is especially helpful

866 Part SEVEN Organ-Specific Inflammatory Disease


in patients with progressive ocular MMP whose vision is threat- monomeric and not of gut origin. Immunoelectron microscopy
ened. In some patients, IVIG has arrested the progression of eye most often reveals IgA deposits in the lamina lucida; but IgA
disease, maintaining vision and preventing blindness. However, deposits have also been seen below the lamina densa. Circulating
no controlled studies have yet been performed. Case reports IgA antibodies against the basement membrane zone of stratified
suggest some benefit with plasmapheresis, etanercept, and squamous epithelium are detected in only 10–30% of both adult
infliximab. Growing numbers of case series have suggested that and pediatric patients with linear IgA deposits. Other immuno-
rituximab may effective, with most patients showing complete reactants, especially IgG and C3, have been found in 30–40%
response after a single course, but, again, no controlled trials of patients.
47
have been published. A retrospective study of MMP patients
given rituximab showed that all patients achieved disease control, Pathogenesis
compared with 40% of those who received conventional therapy. 48 The paucity and heterogeneity of circulating antibody has made
The clinical course of MMP is difficult to predict, and the it difficult to determine the antigenic target in LABD. Sera from
response to treatment is often suboptimal. Some patients achieve adults and children with linear IgA deposits within the lamina
long-lasting remissions, but MMP frequently recurs, and patients lucida reacted with a 97-kDa protein that is identical to part of
50
in remission should be monitored closely. BPAG2. In patients with LABD or linear IgA disease of childhood
Ocular mucosal lesions are often severe in MMP and can with IgA deposits below the lamina densa, antibodies have been
cause significant morbidity. Consultation with an ophthalmologist identified reactive to type VII collagen and an unknown 285-kDa
50
is important in managing the potentially severe ocular complica- dermal protein. These findings support the hypothesis that
tions. Physicians should also be aware of the risk of esophageal there are heterogeneous target antigens in LABD and linear IgA
and tracheal involvement; patients with severe disease often need disease of childhood. Regardless of the location of IgA deposits
consultation with relevant specialists. Oral mucosal lesions can or the specific antigenic target, the mechanism of lesion formation
often be managed with frequent application of potent topical in patients with LABD remains unknown.
corticosteroids (0.05% clobetasol propionate or 0.05% fluoci-
nonide). In severe cases, dapsone or systemic glucocorticoids Therapy
may also be needed. Patients with limited skin disease can often Dapsone (25–200 mg/day) is the mainstay of therapy of patients
be managed with topical therapy alone. If this fails, treatment with all forms of LABD. Although dapsone is well tolerated by
as for BP is usually successful. most patients, it has significant pharmacological and idiosyncratic
adverse effects. Occasionally, patients do not respond to dapsone
LINEAR IGA BULLOUS DISEASE alone. In these cases, adding low doses of prednisone (10–20 mg/
day) may result in significant improvement.
Linear IgA bullous disease (LABD) is a clinically heterogeneous
blistering disease in which direct immunofluorescence of peri- tHEraPEUtIC PrINCIPLES
lesional skin biopsies reveals linear deposition of IgA at the
basement membrane zone. The majority of patients with LABD Treatment of Autoimmune Blistering Diseases
presents with pruritic vesicles and papules, localized primarily Systemic corticosteroids are the initial mainstay of treatment.
to the extensor surfaces, similar to the clinical pattern seen in Dapsone is the mainstay of therapy for linear immunoglobulin A (IgA)
patients with dermatitis herpetiformis (DH). Patients with LABD dermatosis and dermatitis herpetiformis.
do not, however, have associated gluten-sensitive enteropathy, Steroid-sparing agents, including azathioprine, mycophenolate mofetil,
their disease is not improved on a gluten-free diet, and they do methotrexate, and intravenous immunoglobulin (IVIG), are often needed
not have the characteristic HLA associations of patients with DH. for treatment.
Other patients with linear IgA deposits present a clinical picture Rituximab and other anti-CD20 biologics have been proven to be very
effective as steroid-sparing agents in clinical studies.
more suggestive of BP, with pruritic tense blisters on an
erythematous base. Other clinical presentations have been
described, with clinical, histological, and immunopathological DERMATITIS HERPETIFORMIS
overlap among patients with LABD, MMP, and EBA. Children
can develop a subepidermal blistering disease with linear IgA Clinical Features
basement membrane deposits, a condition previously termed DH is an intensely pruritic blistering disease that typically presents
chronic bullous disease of childhood. In these juvenile cases, blisters in the second or third decade with erythematous papules and/
occur mainly in flexural surfaces, around the genitalia, and on or vesicles over extensor surfaces (Fig. 63.11). Patients often
the face, especially the perioral region. A drug-induced form of present with a broad spectrum of lesions. The severe pruritus
LABD can occur, mainly in association with vancomycin, but leads to scratching, resulting in erosions that may be the presenting
also with other medications. 49 feature. Patients can also present with urticarial plaques or, less
Histopathology of lesional skin of patients with LABD reflects commonly, frank bullae. Lesions are usually symmetrically
the clinical heterogeneity seen in these patients. Biopsy usually distributed over the extensor surfaces, especially the elbows, knees,
reveals collections of neutrophils in the dermal papillary tips in buttocks, back, and posterior hairline. Symptomatic mucous
a pattern virtually identical to DH. However, subepidermal blisters membrane lesions are rarely present. Extreme pruritus is a clinical
with eosinophils may also be seen, as in BP. hallmark of DH. Patients characteristically report severe burning
Direct immunofluorescence of perilesional skin in patients or stinging 12–24 hours before the appearance of lesions, which
with LABD reveals a linear band of IgA, almost exclusively IgA1, persists until vesicles break and crusts form. DH is generally
at the basement membrane zone. These IgA skin deposits contain considered a life-long dermatosis, although clinical remission
51
both κ and λ light chains, indicating that the antibodies are can occur in as many as 12% of patients. The wide variety of
polyclonal. J chain is not present, suggesting that the IgA is clinical presentations of DH often suggests a long differential

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 867



























FIG 63.12 Direct immunofluorescence of normal-appearing
FIG 63.11 Patient with dermatitis herpetiformis showing perilesional skin of a patient with dermatitis herpetiformis using
erythematous papules with crusts on the elbows. Rare intact antibodies against human immunoglobulin A (IgA). Granular
vesicles are present. deposits of IgA are present at the dermal–epidermal junction.




diagnosis, including erythema multiforme, PG, BP, transient Most patients with DH have no GI symptoms. Only 10% of
acantholytic dermatitis, papular urticaria, scabies, bug bites, and DH patients have typical symptoms of isolated GSE, such as
neurotic excoriations. bloating, diarrhea and malabsorption, while 20–30% have mild
The frequency of DH varies in different ethnic groups. It is steatorrhea. However, many patients with DH have asymptomatic
between 10 and 39 per 100 000 in Anglo-Saxon and Scandinavian abnormal intestinal function, as shown by abnormal absorption
populations, but up to 75 per 100 000 in Finland, although its of D-xylose, iron, folate, glucose, water, and bicarbonate.
incidence in the UK appears to be decreasing. 52,52a DH occurs GSE clearly plays a critical role in the pathogenesis of DH.
much less frequently in other populations (e.g., those of Asian Patients with DH who adhere to gluten-free diets can control
or African descent). This relates, in part, to differing frequencies their skin disease, normalize the morphological changes of the
of the DH-associated HLA antigens in different populations, as small intestine and, after years of gluten avoidance, lose their
detailed below. cutaneous IgA deposits. However, the exact relationship between
Biopsy of early DH lesions reveals neutrophilic infiltration the skin disease, cutaneous IgA deposits and GSE remains
of dermal papillae with fibrin, neutrophilic fragments, edema, unknown.
and variable numbers of eosinophils. This histological pattern HLA-DR3 is expressed in 90–95% of patients with DH,
is not specific and has been reported in BP, linear IgA disease, compared with ~23% controls. In addition, 95–100% of patients
bullous eruption in SLE, and leukocytoclastic vasculitis. with DH express HLA-DQ2 (which is in linkage disequilibrium
Granular IgA deposits can be found at the DEJ on direct with HLA-B8 and HLA-DR3), compared with 40% of controls.
immunofluorescence of DH skin biopsy specimens (Fig. 63.12). The HLA-DR and HLA-DQ alleles involved in the pathogenesis
These granular deposits of IgA at the DEJ are specific for DH of DH are DQB1*02:01, DQA1*0501, and DRB1*03:01, which
and have not been found in gluten-sensitive enteropathy (GSE, are essentially identical to those associated with isolated GSE.
also known as celiac disease; Chapter 75) without DH or in Patients with DH also have an increased frequency of gastric
53
asymptomatic relatives of patients with DH. Although some atrophy and gastric hypochlorhydria. Thyroid abnormalities,
patients with DH have circulating antibodies against tissue including hypothyroidism, hyperthyroidism, thyroid nodules,
transglutaminase, identification of granular IgA deposits at the and thyroid cancer, also occur more frequently in these patients.
DEJ remains the gold standard for diagnosing DH. To maximize Various other autoimmune diseases, including SLE, dermato-
the diagnostic yield, biopsies for direct immunofluorescence myositis, myasthenia gravis, Sjögren syndrome, and rheumatoid
studies should be taken from normal-appearing perilesional skin. arthritis, have also been reported in patients with DH. It is thought
A gastrointestinal (GI) abnormality similar to that seen in that many of these associations relate to the high frequency of
54
isolated GSE was identified in 60–70% of DH patients. This the HLA-B8, HLA-DR3, and HLA-DQ2 haplotypes in these
abnormality was reversible by avoiding dietary gluten, confirming patients. A five- to sixfold increased incidence of non-Hodgkin
that DH was a gluten-sensitive disease. Small bowel histological lymphoma has been reported among patients with DH, without
changes in DH include flattening of the normal villous architecture any increased mortality. 55,56
of the jejunal epithelium, with elongation of intestinal crypts
and mononuclear cell infiltrates within the lamina propria and Pathogenesis
epithelium. These findings are often patchy and less severe than The pathogenesis of DH rests on three distinct associations: (i)
in isolated GSE. In effect, all patients with clinical DH and granular granular deposits of IgA in the skin at the DEJ; (ii) gluten-sensitive
IgA deposits have associated GSE. enteropathy (albeit often asymptomatic); and (iii) increased

868 Part SEVEN Organ-Specific Inflammatory Disease


frequency of the HLA-DR3/DQ2 haplotype. Attempts to under- reduction in patients on gluten-free diets. Strict adherence to a
stand DH must integrate all these factors. gluten-free diet controls the cutaneous manifestations of DH in
The mechanism of IgA binding to DH skin is uncertain. most patients, reverses the morphological changes in the small
Circulating antibodies that bind to normal human skin in vitro intestine and, after many years, may result in disappearance of
have not been detected in DH. Also, the IgA deposits do not the cutaneous IgA deposits. Cutaneous IgA has been shown to
appear to be caused by IgA-containing circulating immune return after rechallenge with dietary gluten. 59
complexes. Another mechanism by which IgA might bind to Rarely, patients with DH fail to respond to a gluten-free diet
DH skin is that IgA produced in the gut, in response to wheat despite what appears to be total dietary compliance. This has
or other dietary antigens, may reach the circulation, where it also been reported in patients with isolated GSE and other dietary
could bind to wheat protein deposited in skin or cross-react factors have been postulated to play a role. In support of this
with normal skin structures or molecules. DH sera contain IgA concept, the skin lesions and GI changes of DH may also respond
antibodies against endomysium, a connective tissue element to an elemental diet, often within only 2–3 weeks of starting the
surrounding smooth muscle, and are directed against tissue diet. These results imply that other proteins besides gluten play
57
transglutaminase. Patients with DH also have IgA antibodies a role in the DH pathogenesis. Although a gluten-free diet is an
against epidermal transglutaminase, with higher avidity compared attractive alternative to medication for many patients, it is difficult
with those found in patients with isolated GSE. The IgA deposits to maintain. Gluten is present in most common grains (wheat,
in DH skin colocalize with epidermal transglutaminase, suggesting rye, barley) but not in rice and maize. Eating oats appears to be
epidermal transglutaminase-3 (eTG3) is the IgA target in the safe for patients with DH, but oat products may be contaminated
skin of patients with DH. Development of IgA anti-eTG3 antibod- with wheat protein. Patients should be informed that the success
ies is associated with prolonged periods of gluten exposure, or failure of the diet cannot generally be assessed until they have
suggesting that these antibodies result from epitope spreading. been on the diet for at least a year.
In a mouse model in which normal human skin is grafted onto
SCID mice, human IgA anti-eTG3 antibody binds in a pattern TRANSLATIONAL RESEARCH
identical to that seen in patients with DH. These observations
suggest that IgA anti-eTG binds and slowly accumulates in the
dermis, resulting in the pathognomonic IgA deposits seen in ON tHE HOrIZON
patients with DH. 58
The presence of an ongoing mucosal immune response in Precise characterization of the antigenic targets of autoantibodies and
patients with DH has been shown to result in systemic signs of correlation with clinical presentations and outcomes
inflammation, including elevated serum levels of soluble IL-2 Identification of markers or disease activity and response to therapy
receptor and IL-8, increased neutrophil expression of CD11b, Specific immunoabsorption therapy with faster responses and less
treatment-associated morbidity
59
and increased expression of endothelial cell E-selectin in skin. Increased use of targeted biologic therapy (e.g., anti–B-cell therapy) to
These findings suggest that the mucosal immune response results provide rapid, long-lasting remission while minimizing morbidity and
in a proinflammatory environment in skin, which, when coupled mortality.
with cutaneous IgA deposits, can result in development of typical
DH skin lesions. The next 5–10 years should see further advances in the treatment
of autoimmune blistering skin diseases. Anti–B-cell therapies,
Therapy such as rituximab, offer a more targeted, steroid-sparing approach,
DH can be treated either with dapsone or a gluten-free diet; the and we can expect to see the development of more efficient ways
choice of therapy should be individualized to each patient. The of delivering these therapies. Translational studies of immunologi-
treatment of choice for most patients with DH is dapsone or cal changes among patients successfully treated with anti–B-cell
sulfapyridine because of the lack of GI symptoms in most cases therapies will yield insights into the role of different B-cell
and difficulty adhering to a strict gluten-free diet. Dapsone populations in the pathogenesis of autoimmune blistering disease.
(100–200 mg/day) is sufficient to control cutaneous eruptions We can expect to see more precise determination of the antigenic
in most cases, with minimal side effects. Dapsone therapy results targets of the autoantibodies and correlation with clinical pre-
in almost immediate cessation of DH skin symptoms, but it sentations, response to therapy, and clinical outcomes.
does not affect the GI mucosal defect or symptoms. Patients An improved understanding of the clinical response to biolog-
with DH who are on dapsone therefore have ongoing (albeit ics and the mechanisms of those responses will lead to discovery
low-grade) GSE. Dapsone is potentially toxic, and if the disease of new combinations and earlier initiation of biological therapy.
flares up, patients should not increase the dose without consulting Early or immediate use of specific biological therapies, such as
their physician. rituximab, may allow shorter courses of systemic corticosteroid
Strict adherence to a gluten-free diet will also control DH therapy, long-lasting remissions, and potentially lead to “cures”
skin lesions. Nearly 80% of patients with DH who follow such of these severe autoimmune diseases.
a diet can stop or substantially reduce the dose of dapsone required Please check your eBook at https://expertconsult.inkling.com/
59
to control their skin disease. Patients may need to be on a for self-assessment questions. See inside cover for registration
gluten-free diet for at least 5 months before being able to reduce details.
their dose of dapsone; being on this diet for 8–48 months is
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CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 870.e1


MUL t IPLE-CHOICE QUES t IONS

1. In the evaluation of a patient with suspected autoimmune 3. Patients with pemphigus vulgaris are characterized by (may
blistering skin disease diagnosis requires which of the following have more than one correct answer):
(may have more than one correct answer): A. Subepidermal blister with eosinophils by routine
A. Direct immunofluorescence testing of lesional skin histology
B. Routine histology of lesional skin B. Oral mucosal ulcerations are common either alone or in
C. Direct immunofluorescence testing of normal appearing combination with skin lesions
perilesional skin C. Immunoglobulin G (IgG) antibodies can be found against
D. A and B desmoglein-1 (Dsg1) and/or Dsg3
E. B and C D. Occurs in older adults more frequently and may be associ-
ated with neurological disease
2. Which of the following statements regarding bullous pem-
phigoid are correct? May have more than one correct answer. E. Recent evidence suggests that therapy directed at CD20
A. Most common autoimmune blistering disease and most expressing cells may be very effective
often presents in patients 20–40 years of age
B. Can present as a vesicular, bullous, or urticarial
eruption
C. Patients have few if any clinical symptoms of their skin
eruption
D. Characterized by linear immunoglobulin G (IgG) and/or
C3 at the basement membrane of stratified squamous
epithelium by direct immunofluorescence testing of
patient’s skin
E. Associated with gluten sensitive enteropathy