MIMs - Handbook of General Medicine 2019

TREATMENT APPROACHES 193

Diagnostic issues matrix metalloproteinases (MMP) occurs. An increase in Treatment approaches
MMP and decreased laminin shows increase in retinal
Glaucoma is often described as the thief of sight. Prima- ganglion cell death. The increased MMPs upregulate
ry open-angle glaucoma is seen most commonly in the glutamate receptors. A decrease in growth factors,
South African population and is asymptomatic. Using such as neurotrophin, including brain-derived neuro-
tools, such as the glaucoma quality of life questionnaire; tropin and TGF b2, causes increased apoptosis. Tumour
taking a detailed family history; and screening for glau- necrosis factor A (TNF A) in astrocytes leads to increases
coma, while examining other conditions, such as diabetes in cell death if its levels increase by direct destruction, as
and hypertension, should be the mainstay of detection well as by an increase in nitric oxide synthase-2.
and appropriate referral and treatment of glaucoma.
Factor 4: Vascular insufficiency and glaucoma. Cir-
Appropriate parameters for which to screen are:2,7 cumstantial evidence suggests a link as people with
• Testing the pupillary reaction to direct light, the con- migraine and peripheral vascular abnormalities have
a higher rate of glaucoma. The mechanisms are not
sensual response to light and the pupil constriction to clearly understood.
accommodation.
• Testing for decreased visual acuity, using a near and Factor 5: Glutamate-mediated toxicity has been im-
distant reading card, and to confirm that the visual plicated in apoptosis. To maintain the physiological
loss is not due to a refractive error, by using a pinhole concentrations and to protect retinal ganglion cells,
to identify this. The visual acuity must be tested with appropriate removal of synaptic glutamate is required.
the correct refraction in place. Muller cells and astrocytes move glutamate intracellu-
• Measuring raised intra-ocular pressure (IOP) by us- larly where it is converted to non-toxic glutamine.
ing a hand-held applanation tonometer, i care to-
nometer or a Schiotz tonometer. The normal range of Factor 6: Increased nitric oxide has been linked to an
IOP is 8-22 mmHg, although women have a naturally increased incidence of glaucoma. The nitric oxide dif-
higher intra-ocular pressure. fuses intracellularly where it produces highly reactive
• Testing for confrontation visual fields will also show a free radicals that cause massive cell destruction.
constricted visual field in advanced glaucoma. For-
mal visual field-testing is done, using manual or auto- Factor 7: Oxidative stress and free radicals have been
mated perimetry. shown to play an aetio-pathogenic role in retinal gan-
• Doing a disc assessment with a direct ophthalmo- glion cell death.
scope, fundus camera or smartphone. Indirect oph-
thalmoscopy is also an important aspect of assess- Genetics of Glaucoma9
ment in glaucoma. The disc assessment must include
- Cup-disc ratio (more than 0,6) Several genes have been implicated in glaucoma with
- Notching a monogenic, autosomal dominant trait. This, however,
- Loss of retinal nerve-fibre layer accounts for only 10% of all glaucoma. The first reported
- Optic disc haemorrhage locus for primary open-angle glaucoma was located on
- Bayonetting of blood vessels chromosome 1 (GLC1A). The gene encoding for myocilin
- Laminar dot sign of exposed cribriform plate (MYOC ) is located at that locus. Myocilin mutations are
- Nasalisation of blood vessels found in juvenile and early adult POAG with very high in-
- Peripapillary atrophy tra-ocular pressures. Individuals with the optineurin gene
- ISNT rule not followed on the disc (the order of the (OPTN, GLC1E) variations have normal intra-ocular pres-
sure. Optineurin may have a neuroprotective effect.
thickest to the thinnest part of the optic disc)
The disc assessment can also be done using an optic The CAV1/CAV2 (HGNC:1527/HGNC: 1528) locus on
nerve head OCT (optical coherence tomography) in 7q34 may be associated with POAG in European popu-
conjunction with colour fundus photographs and nor- lations. The CDKN2BAS (HGNC:34341) locus on 9p21 has
mative data for analysis. also been shown to be associated with glaucoma in
multiple cohorts.
Pathophysiology
Treatment options
Glaucoma is multifactorial, acting on cell bodies and
their axons and resulting in retinal ganglion cell death.8 Medical

Factor 1: Apoptosis causing neuronal loss mediated There are five classes of drugs available to lower intra-
by caspases (these are part of the cysteine aspartyl- ocular pressure. Medical management is usually the first
specific proteases). The caspases interact with TNF al- line of treatment (see Table 1). Unfortunately, the medi-
pha (extrinsic) and mitochondrion (intrinsic). cation alters the conjunctiva and can have detrimental
effects on doing glaucoma surgery. Some medications
Factor 2: Increased intra-ocular pressure results from need to be refrigerated, which can be difficult for pa-
changes in the trabecular meshwork (changes in cel- tients who do not have access to refrigeration or to sol-
lularity and the extracellular matrix.) The increased pres- diers who have been deployed. All medications have
sure triggers apoptosis and a second, slower phase due side effects to a degree, and the benefits of the medi-
to toxic effects of the already degenerating neurons. cation versus the side-effect profile should be discussed
and monitored for each patient, and treatment modi-
Factor 3: Molecular mechanisms of retinal ganglion fied accordingly. Access to medicine is also a problem
cell apoptosis occur with remodelling of type i and iv in certain settings, and one of the appropriate surgical
collagen, transforming growth factor b2 (TGF b2) and
HANDBOOK OF GENERAL MEDICINE VOL 1

194 TREATMENT APPROACHES

Table 1. Glaucoma drug options10

Class Generic name Mechanism of action Ocular effects Systemic effects
Beta-blocker - Decreases aqueous - Conjunctival allergy - Decreased blood
- Timolol - Hyperaemia
- Levobunolol production - Corneal epithelial pressure and pulse
- Carteolol - Bradycardia
- Betaxolol - Decreases aqueous disorders - Worsening asthma/
- Metipranolol production - Reduced corneal
COPD
Carbonic anhydrase - Dorzolamide - Increase in uveoscleral sensitivity - Depression
inhibitor - Brinzolamide outflow - Blurry vision - Impotence
- Acetazolamide (oral) - Lethargy
- Methazolamide ------------- - Same as beta blockers Topical:
- Increase in uveoscleral and - Bitter taste
Prostaglandin analogue - Latanoprost - Fatigue
- Travoprost and trabecular - Ocular irritation - Diuresis
- Unoprostone isopropyl meshwork outflow - Foreign body sensation - GIT upset
- Tafluprost Oral:
---------------- - Decreases aqueous - Same as beta blockers - Nausea
- Bimatoprost production and - Unpleasant taste
- Dysesthesia of fingers/
Alpha 2- adrenergic - Brimonidine - Increases uveoscleral - Eyelash growth
agonist - Iopidine outflow - Iris/eyelid lips
- Metabolic acidosis
Parasympathomimetic/ - Pilocarpine - Increases trabecular pigmentation - Rarely, upper
cholinergic agonist meshwork outflow - Deepening of upper
respiratory infection
eyelid sulcus - Rarely, myalgia
- Recurrence of herpes
- Macular oedema post - Affects BP/pulse
- Drowsiness
cataract surgery - Dizziness
- Allergic conjunctivitis - Dry mouth
- Hyperaemia - Dysarthria
- Mydriasis Direct-acting:
- Dry eye - Rare systemic reactions
Indirect-acting:
- Miosis - Sweating
- Visual field constriction - Tearing
- Night vision loss - Nausea/vomiting
- Myopia - Diarrhoea
- Red eye - Bradycardia
- Brow ache - Stomach ache
- Retinal detachment
- Cataract

options may be considered as first-line treatment, with • Alpha agonists are contra-indicated in children un-
decreased visits to the treating facility. der two years of age, but are often not prescribed
in children under four years due to the systemic side
The medication is given as a single drug or a combina- effects.
tion of therapies to reach optimal intra-ocular pressure.
• Beta-blockers are generally safe to use in children, but
Treatment algorithm for medical management10 systemic effects have been reported in premature ba-
• Prostaglandins are the first-line treatment of choice bies, and they should be used with caution. Beta-block-
ers can also have systemic side effects with regard to
for open-angle glaucoma and ocular hypertension. libido and can decrease compliance as a result.
Monotherapy is enough in some instances, but often
a second-line agent must be added. Beta-blockers • Beta blockers are most effective in the mornings and
are usually the next line added with certain fixed- prostaglandins are most effective in the evenings.
drug combinations.
• Prostaglandins cause changes in iris colour, length- • Oral carbonic anhydrase inhibitors have marked system-
ening of eyelashes, conjunctival hyperaemia and ic side effects and cannot be used in the long term.
orbitopathy and as such should not be given to one
side only. • A target pressure decrease of 20-50% is desirable, but
the endpoint needs to be monitored and adjusted
HANDBOOK OF GENERAL MEDICINE VOL 1 throughout the treatment of the patient.

Spersatan ®

Latanoprost 50 µg/ml *

• A first-line option for Glaucoma 1

• Lower incidence of hyperaemia than

bimatoprost and travaprost 2

• On the WHO essential drug list

for Glaucoma 3

* Requires refrigeration

References: 1. South African Glaucoma Society. Glaucoma algorithm and guidelines for glaucoma. c2016. Accessed 29 Nov 2018. Available from URL: http://docs.wixstatic.
com/ugd/280453_6b7e555101fe49c2ab599bbdf300993d.pdf 2. Denis P, Baudouin C, Bron A, et al. First-line latanoprost therapy in ocular hypertension or open-angle glaucoma
patients: a 3-month efficacy analysis stratified by initial intraocular pressure. BMC Ophthalmology 2010;10:4. 3. WHO Model List of Essential Medicines (March 2017). 20th
edition. Cited 2018 Nov 30. Available from URL: http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017.pdf

S4 Spersatan Eye Drop Solution. Each 1 ml contains: Latanoprost 50 μg. Reg. No. 46/15.4/0918. Under license from Novartis Pharma AG, Hettlingen, Switzerland. For full
prescribing information refer to the package insert approved by the medicines regulatory authority. Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston,
2021, South Africa. Telephone + 27 11 635 0000. www.adcock.com. 2018121310113824

196 TREATMENT APPROACHES

• The side effects during pregnancy and breastfeed- Surgical
ing are mostly category C. The risk to the foetus and
newborn needs to be weighed up against the risk of Surgically, there are many possibilities from which to
vision loss in the mother. choose. The options are divided into laser surgery and
incisional surgery. Incisional surgery is further divided into
• Generic medication is currently available, and the minimally invasive glaucoma surgery, non-penetrating
response to treatment of each must be monitored glaucoma surgery and penetrating glaucoma surgery.
for each patient. A raised episcleral venous pressure is a relative contrain-
dication to all trabecular procedures.
• The paradigm for treatment has shifted to neuropro-
tection, with treatment algorithms designed to add Laser surgery
agents that lower not only intra-ocular pressure, but
also offer a measure of neuroprotection. Table 2 describes the different types of laser surgery op-
tions available and when they are used. The indications
• Preservative-free medication is also more popular as for each type of surgery are listed as is the treatment
the traditional preservative benzalkonium chloride endpoint. All of these options aim to decrease intra-oc-
causes conjunctival scarring and exacerbates ocu- ular pressure, which is the only modifiable variant in the
lar surface disease. treatment of glaucoma.12

Table 2. Laser treatment options11,12

Laser Type Indications Site of action Effect

Argon laser - Argon - Second-line treatment - At the junction of - Blanching or tiny
trabeculoplasty - (or diode) bubble
(ALT) - Open-angle glaucoma non-pigmented and
50 micron spot, 0,1 sec - Sustained IOP
duration, power 300- - Not repeatable pigmented trabecular reduction
1000 mw
meshwork

Selective laser Frequency doubled Nd: - First line - Beam straddles entire - Small cavitation
trabeculoplasty YAG bubbles adjacent
(SLT) - Open-angle glaucoma trabecular meshwork to the trabecular
400 micron spot, 0,3 sec meshwork
duration, energy - Repeatable
0,8-1,0 mJ - Sustained IOP
reduction

Endoscopic Fibre optic cable Refractory glaucoma Pulsed continuous wave Gas-bubble formation
Can be combined with diode directly to ciliary Pigment dispersion
cyclophotocoagulation delivery of diode laser – phaco processes under direct Audible pop
visualisation (intra- 30% reduction in IOP
(ECP) 20-gauge probe ocular) Decreased medical
treatment
Power 0,2 W, continuous

wave mode, move the

probe closer or further

away to titrate effect.

Transscleral G-probe used to deliver Refractory paediatric Diode transscleral to Audible pop as end-
cyclophotocoagulation diode laser glaucoma ciliary processes point – can titrate the
(TCP) Adult glaucoma power by 150 mW up
Power 1250 mW, 4 sec or down – maximum
duration power used is 2 250 mW,
usually six spots per
quadrant

Laser iridotomy (LPI) Nd: YAG laser – can Narrow or closed angle, Aim beam at iris crypt or Iris patency of >0,1 mm
2-8 mJ increasing until
opening >0,1 mm have pre-treatment with usually with pupil block superiorly. superiorly
(ARGON settings-0,1
sec, 50 micron spot, Argon laser in thick iris
800-1000 mW)

Laser iridoplasty(LPIP) Argon laser Narrow or closed angle Beam aimed at
Size 300-500 micron, or
power 200-400 mW, Diode laser Pigment dispersion peripheral iris – 20-30
duration 400-500 ms
Plateau iris spots

Laser goniopuncture Nd: YAG - Used to augment Aimed at the anterior Puncture site
2-6 mJ and 1-20 shots deep sclerectomy edge of the trabeculo-
descemet membrane
- Exfoliative glaucoma to avoid a prolapse of
- POAG the iris

Excimer laser Xenon chloride laser - Open-angle glaucoma Aim at the outer wall of Endpoint is blood reflux
trabeculotomy (ELT) 308 nM wavelength, Schlemm’s canal 4-10 with decreased IOP and
1,2 mJ, 80 ns duration ab interno fibre optic channels observation of patent
delivery channels

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TREATMENT APPROACHES 197

Table 3. MIGS treatment options available13,14 Treatment approaches

Site of action Device Application Effects Complications

Increased trabecular Trabectome -Ab interno removal of a strip -Aqueous has direct -Increased IOP
outflow Electrocautery, irrigation of the trabecular meshwork access to collector -Blood reflux
and aspiration 550 kHz, -60-120 degrees nasal angle channels -Late hyphema
allows adjustment 0,1-watt -Decreased IOP
increments

iStent/iStent inject -Implanted into Schlemm’s -Decreased IOP -Blood reflux
Heparin-coated, non canal -Decreased -Stent malposition
ferromagnetic titanium -1 or 2 devices resistance in -Pigmentary
stent -iStent easier to insert the trabecular glaucoma- increase
meshwork in IOP

Hydrus stent - Inserted into Schlemm’s -Dilation of -Peripheral anterior
Crescent-shaped open canal via a corneal incision Schlemm’s canal synechiae
structure curved to match (3 clock hours) (4-5x)
the shape of Schlemm’s - Does not block collector -Lowers IOP
canal, made from nitinol channel ostia

Gonioscopy- -Ab interno trabeculectomy -The large area -Blood in the
associated transluminal -Catheter inserted through treated as opposed anterior chamber
trabeculectomy (GATT) goniotomy site to other devices -Choroidal folds
Illuminated microcatheter -Once 1 800, catheter -Lowers IOP -Shallow anterior
externalised. Repeat for chamber
second 1 800.

Excimer laser -Photo-ablation that vaporises -Decreased IOP -Microbleeding
trabeculectomy trabecular meshwork
Xenon laser 308 nm -Punctures small holes in the
anterior trabecular meshwork

Suprachoriodal shunts Cypass microstent -Inserted between the -Conduit between -Endothelial cell loss
the anterior -Early hypotony
(temporarily discontinued) ciliary body and the sclera chamber and the -Peripheral anterior
suprachoroidal synechiae
Polyamide implant, ab interno space -IOP spikes
-Prolonged
microholes along the length inflammation
-Stent obstruction
of the stent

iStent supra15 -Ab interno placement -Conduit between
polyethersulfone and between the ciliary body the anterior
titanium with heparin and the sclera chamber and the
coating suprachoroidal
space

SOLX gold microshunt16 -Ab externo conjunctival -Conduit between -Shunt fibrosis
24-carat gold implant scleral dissection – ab interno the anterior
not really a MIGS device chamber and the
-Useful in a patient with suprachoroidal
corneal opacities space
-Used in refractory glaucoma

Increased Xen implant17 -Non-physiological route for -Into the -Aqueous
subconjunctival shunts Porcine gelatine crosslinked aqueous outflow iridocorneal angle, misdirection
with glutaraldehyde - Ab interno placement through the sclera Endophthalmitis
- In an eye with no prior -tissue adhesions
conjunctival scarring -hypotony
-hyphema

Decreased aqueous Endocyclophoto- -Under direct visualisation -Causes ciliary -Anterior chamber
production coagulation(ECP) through a corneal wound processes to be haemorrhage
Diode laser 810 nM at 200- directly to the ciliary processes shrunk to produce -Retinal
400 mW continuous to treat -Endpoint is blanching or less aqueous detachment (rarely)
2 700-3 600 pops as tissue explodes

Treatment algorithm for laser management of glaucoma • After ALT, topical steroids are given 4-6 times per day
for four to seven days. SLT patients receive nonsteroi-
• Before the procedure, a drop of brimonidine or dal anti-inflammatory drug (NSAID) drops only. Can
apraclonidine must be instilled to prevent an IOP treat 180 or 360 degrees in ALT and SLT.
spike. One hour after laser intervention, IOP must be
checked for an elevation. • ECP and TCP patients receive topical cycloplegia,

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198 TREATMENT APPROACHES

antibiotics as well as topical steroids. Usually, 270-360 Non-penetrating glaucoma surgery11
degrees are treated. This avoids anterior segment is-
chaemia. The pressure-lowering from non-penetrating glaucoma
• TCP can cause macular oedema and anterior uveitis. surgery is not as effective as in penetrating surgery, and
• Advise patients to use their regular hypotensive drops often adjunctive methods are needed, such as gonio-
after laser intervention. puncture in deep sclerectomy to augment the effect.
• Prophylactic laser peripheral iridotomy has shown no The surgery is complicated, with a steep learning curve
benefit. with variable anatomy. There is no post-operative bleb
• With LPI and LPIP, instil 2% pilocarpine before the in- management, less hypotony and decreased incidence
tervention. of intra-operative complications.
• ELT treats one quadrant.
Deep sclerectomy takes place when a deep lamella
Minimally invasive glaucoma surgery of corneoscleral tissue is removed underneath the scle-
ral flap, and thus the outer wall of Schlemm’s canal is
Minimally invasive glaucoma surgery (MIGS) was de- removed. A scleral lake is created when the scleral flap
veloped because of patient non-response to medica- is repositioned. Implants are used to keep the lake open
tion, ocular toxicity and patient non-compliance. The and often a filtration bleb forms.
increasing cost of medication also makes this an attrac-
tive treatment option. Traditional surgical approaches, Viscocanulostomy uses the injection of hyaluronic
while still a good treatment option, have a higher risk acid into Schlemm’s canal, as well as dissecting and
profile with more follow-up visits and longer recovery excising a deep lamella. It widens Schlemm’s canal,
times. Table 3 gives a broad outline of the treatment as well as the collector channels and uses the diffusion
options available, the site of action and possible com- lake of the excised portion.
plications.13,14
Canaloplasty is indicated in primary open-angle glau-
Initially, the express implant was designed to drain into coma, pseudo-exfoliative glaucoma and pigmentary
the subconjunctival space, but due to erosion, it is now glaucoma. The canaloplasty uses a two-flap dissection
being placed with a scleral flap and as such moves into to the trabeculo-Descemet’s membrane (as in visco-
the penetrating glaucoma surgery category. canulostomy), but uses circumferential catheterisation
and visco dissection. A 10/0 polypropylene suture is left
Endocyclophotocoagulation is also mentioned with in place and pulled under tension to keep the canal
the laser surgeries, but has been grouped with MIGS as open and restore normal anatomy. Contra-indications to
well. canaloplasty are closed-angle glaucoma and neovas-
cular glaucoma (has a membrane covering the angle).
GATT has been described in the treatment of prima-
ry congenital glaucoma and juvenile glaucoma, but Penetrating glaucoma surgery11
has more recently been used in the treatment of adult
open-angle glaucoma.13 Absolute contra-indication to Penetrating glaucoma surgery offers long-term lower post-
GATT is the inability to stop anticoagulation, bleeding operative IOP than non-penetrating surgery, and fewer
diathesis and closed angles, with no view of the trabec- medications are needed to augment the effect of sur-
ular meshwork. gery. There is, however, a higher rate of hypotony, bleb
complications and a higher rate of cataract formation.
ELT is also best with normal episcleral venous pressure.
Suprachoroidal drainage can be as much as 50% of Trabeculectomy is performed most often with open-
all aqueous outflow. The precipitous drop in IOP with a angle glaucoma producing a guarded fistula. Modifi-
cyclodialysis cleft bears testimony to this fact. The use cation of techniques has made this a safer and more
of controlled devices to drain into the suprachoroidal predictable surgery. Long-term trabeculectomy survival
space resulted from this. The suprachoroidal space also can be as high as 90%. Indications for trabeculectomy
has a negative gradient of 3-4 mmHg that aids drain- are failure of medical therapy, difficulty to access medi-
age. cal therapy, failure of laser surgery or advanced glau-
The subconjunctival drainage methods use anti-me- coma. There is always the risk of snuff-out with surgery
tabolites to prevent scarring and also rely on unscarred in advanced disease due to the pressure variations
conjunctiva to work. intra-operatively. Risks associated with trabeculectomy
ECP is conjunctival sparing, bleb-less and can be are earlier cataract development and early or late
combined with cataract extraction. This method has endophthalmitis (usually bleb-related with thin-walled
traditionally been used for refractory glaucoma, but is cystic blebs in small treatment areas). Anti-metabolites
increasingly being used for mild to moderate glauco- are used during surgery to prevent bleb-scarring and
ma. ECP is discussed in laser treatment as well. failure.
Goniotomy can be performed with a Kahook dual
blade or a curved needle that crosses the anterior Trabeculotomy is performed alone or in combina-
chamber. The procedure is similar to the trabectome tion with trabeculectomy. Trabeculotomy is usually per-
where the trabecular meshwork is manually incised formed in congenital or paediatric glaucoma. The suc-
and/or removed. Traditionally, goniotomy is performed cess rate is lower in adults. This is the treatment of choice
in primary congenital glaucoma. The complications are if there is a hazy cornea. The enlarged globe will have a
the same. distorted Schlemm’s canal and locating this during sur-
gery may be difficult.
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TREATMENT APPROACHES 199

Glaucoma-drainage devices18,19 related to glaucoma or associated with the treatment Treatment approaches
of their glaucoma.
Glaucoma-drainage devices are usually used as sal-
vage- and end-stage procedures in refractory glauco- The section on diagnostic issues mentions the para-
ma. The first attempt at drainage surgery was in 1907, meters that are measured.
but it was revolutionised in the late 1960s and early 1970s
by Molteno who developed the first foot plate with the Summary
drainage device and explained the pathophysiology
around bleb resistance. The mainstay of treatment is to decrease intra-ocular
pressure as it is the only modifiable variant. Traditionally,
There are two types of implants, one with a unidirec- medical therapy is the starting point, but clinicians have
tional restrictive flow/valve and those without that rely been tailoring a patient-specific approach and modify-
on pressure gradients for flow. ing the treatment according to the type of glaucoma,
the resources available, patients’ access to medication
Many implants have been developed, but have not and follow-up, patient ethnicity in terms of prognostic
remained in use today. Currently, there are four non- factors, as well as the degree of advancement of the
valved implants and two valved implants. They differ in glaucoma.
their type and features, including whether they are for
paediatric use, whether the tube can be placed in the REFERENCES
anterior chamber or the pars plana and in their foot-
plate size and design 1. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and
classification of glaucoma in prevalence surveys. Br J Ophthalmol.
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• Non-valved implants
2. Labuschagne MJ. Glaucoma: What should the general practitioner
- Molteno (polypropylene) know? SA Fam Pract. 2010; 52(6):493-497.
- Baerfeldt (silicone)
- Schocket (silicone tube and encircling band) 3. Bordeianu C. Critical analysis of the classification of glaucomas is-
- Express (titanium implant) sued by the European Glaucoma Society in 2008. Clinical Ophthal-
• Valved implants mology. 2014;8:271-282.
- Krupin (silicone)
- Ahmed (polypropylene and silicone) 4. Kyari F, Abdull MM, Bastawrous A, Gilbert C, Faal H. Epidemiology
After the implant, there is an initial hypotensive phase, of glaucoma in sub-Saharan Africa: Prevalence, incidence and risk
then a hypertensive phase where the bleb becomes factors. Middle East Afr J Ophthalmol. 2013 Apr-Jun; 20(2):111-125.
encapsulated and, lastly, the stable phase. The attrition
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early hypotony and choroidal detachment, tube ob- 20(2):92-98.
struction, overhanging bleb, exposed tube and en-
dophthalmitis. 6. Nelson P, Aspinall P, Papasouliotis O, Worton B, O’Brien C. Quality of
life in glaucoma and its relationship with visual function. Journal of
Who to refer Glaucoma. 2003; 12:139-150.

Neonates or infants, if there is a larger-than-normal eye, 7. International Council of Ophthalmology: Guidelines for Glaucoma
epiphora, photophobia and a cloudy cornea. The chil- Eye Care. 2015
dren will likely need an examination under anaesthetic
and will have follow-on surgery at the time of the exami- 8. Agarwal R, Gupta SK, Agarwal P, Saxena R, Agrawal SS. Current
nation. concepts in the pathophysiology of glaucoma. Indian J Ophthal-
mol. 2009 Jul-Aug; 57(4):257-266.
Children with anterior segment abnormalities, such as
polycoria, pseudopolycoria and pseudogerontoxon, 9. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treat-
are at risk of glaucoma. ment of glaucoma: A review. JAMA 2014. May; 311(18):1901-1911.

Children with Sturge Weber syndrome will need 10. Yee S. Glaucoma therapy: Finding the right combination. Review of
screening as they have a raised episcleral venous pres- Optometry. 2017;46-52.
sure.
11. European Glaucoma Society Terminology and Guidelines for Glau-
Black patients with a family history of glaucoma will coma, 4th Edition - Chapter 3: Treatment principles and options sup-
need to be screened earlier to assess if any parameters ported by the EGS Foundation. Br J Ophthalmol. 2017 June;101(6)
exceed the normal range, such as increased cup-disc supplementary:129-195.
ratio and raised intra-ocular pressure.
12. Meyer JJ, Lawrence SD. What is new in laser treatment for glau-
Patients who complain of intermittent eye pain when coma? Current Opinion Ophthalmol. 2012; 23(2):111-117.
watching television in the dark, or when they see a
movie, will need to be screened for intermittent angle 13 Richter GM, Coleman AL. Minimally invasive glaucoma surgery:
closure and should be referred if any of the parameters current status and future prospects. Clinical Ophthalmology 2016;
are not within normal limits. 10:189-206.

Known glaucoma patients who have not been seen 14 Pillunat LE, Erb C, Junemann AGM, Kimmich F. Micro-invasive glau-
or received medication within the past 12 months. coma surgery (MIGS): A review of surgical procedures using stents.
Clinical Ophthalmology. 2017; 11:1583-1600
Known glaucoma patients who have new complaints
15 Myers J, Masood I, Hornbeak DM, et al. Prospective evaluation of
two iSHtent trabecular stents, one istent supra suprachoroidal stent,
and postoperative prostaglandin in refractory glaucoma: 4-year
outcomes. Adv. Ther. 2019;35:395-407

16 Le R, Gupta N. Gold shunt for refractory advanced low- tension
glaucoma with spared central acuity. International Medical Case
Reports Journal. 2016;9:69-72

17 Heidinger A, Schwab C, Lindner E, et al. A retrospective study
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2019;28(1):75-79

18 Singh P, Kuldeep K, Tyagi M, et al. Glaucoma drainage devices.
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1(1):77-82.

19 Lim KS, Allan BDS, Lloyd AW, et al. Glaucoma drainage devices:
past, present, and future. Br J Ophthalmol. 1998; 82:1083-1089

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200 TREATMENT APPROACHES

Acne vulgaris: prevention and treatment

R Lehloenya1 classification in the 2016 European S3 Acne Guidelines is
more descriptive and aligned to lesion morphology. The
BSc, MBChB, FCDerm(SA) guidelines classify acne as 1) comedonal, 2) mild-mod-
erate papulopustula, 3) severe papulopustular, mode-
T Isaacs1,2 rate nodular and 4) severe nodular or conglobate.
Severity and lesion morphology are important as they
MBChB, MFamMed, FCDerm(SA), MMed influence response to different therapies.6 For these rea-
sons, we use the latter classification in this review article.
RM Ngwanya2
Prevention of acne
MBChB, FCDerm (SA)
There are limited data on non-pharmacological strate-
1. Division of Dermatology, Department of Medicine, gies to prevent the development of acne lesions. It is
University of Cape Town and Groote Schuur Hospital, Cape Town not clear if the frequency of face-washing, the choice
2. Division of Dermatology, Department of Medicine, and use of soaps, antiseptic cleansers, alpha/beta-hy-
University of Cape Town and Red Cross War droxy acid cleansers or make-up have a role in prevent-
Memorial Children’s Hospital, Cape Town ing acne.7 The role of diet in acne is controversial. Re-
cent studies suggest that a high glycaemic index and
Acne vulgaris is a clinically diagnosed chronic inflam- consumption of low-fat or fat-free milk may predispose
matory disease of the pilosebaceous unit, character- to acne. However, the strength of this evidence is insuffi-
ised by a varying spectrum of non-inflammatory lesions cient to make conclusive recommendations on the role
(open and closed comedones), inflammatory lesions of diet in acne.8
(papules, pustules, nodules and cysts), post-inflamma-
tory hyperpigmentation and scarring. Current treatment modalities

Epidemiology Topicals5,6

Acne has a life-time prevalence of approximately 85%, Topical retinoids (tretinoin, tazarotene, adapalene and
peaking during adolescence.1 Acne can develop or alitretinoin) are vitamin A derivatives that regulate dif-
persist into adulthood, with >50% and >25% of women ferentiation and proliferation of follicular keratinocytes,
in their 20s and 40s having acne respectively.2 The face ultimately promoting normal desquamation. The differ-
is almost always affected, while the back and chest ent retinoids show comparable efficacy, but the newer
are affected by approximately 60% and 40% of cases ones, such as adapalene, are not as irritating to the
respectively.3 Neonates, infants and small children can skin. Their major side effects are irritant dermatitis and
also develop acne. Acne neonatorum occurs in up to photosensitisation. Irritation, which improves with time,
20% of newborns.4 is mitigated by using gentle, non-abrasive, non-soap
cleansers; avoidance of abrasive materials to wash and
Societal impact dry the skin; gradual increase of contact time with each
application; reducing the frequency of application;
The major impact of acne is psychological, being asso- using emollients; and if severe, short-term application of
ciated with impaired self-image, depression and anxi- low-potency topical corticosteroids. Nocturnal applica-
ety, negatively impacting the patient’s quality of life.5 tion minimises photosensitivity.

Pathogenesis Benzoyl peroxide is bactericidal on P. acnes without
inducing antibiotic resistance. This makes it an impor-
Pathogenesis of acne is multifactorial, involving abnor- tant component of antibacterial treatments targeting
malities of keratinisation of hair follicles, resulting in come- P. acnes. It also has comedolytic properties. Similarly to
done formation; altered and excessive sebum production retinoids, benzoyl peroxide can cause irritant dermatitis,
under the influence of androgens; colonisation of the hair which is similarly managed. It bleaches garments and
follicle by Propionibacterium acnes (P. acnes); complex hair if not allowed to dry.
pro-inflammatory pathways involving both the innate and
acquired immune systems; genetic predisposition; envi- Azelaic acid is a dicarboxylic acid that is bactericidal
ronmental exposures; and grooming practices.5 to P. acnes. It also has mild anti-inflammatory and kera-
tolytic properties. It is a mild tyrosinase inhibitor and im-
Classification and severity grading proves post-inflammatory hyperpigmentation.

An all-encompassing severity grading of acne does not Clindamycin and erythromycin are topical antibiotics
exist. The disease is most commonly graded as mild, with activity against P. acnes. They are used with ben-
moderate or severe, based largely on subjective clinical zoyl peroxide to minimise drug resistance and improve
assessment. For research purposes, lesion count is used. efficacy.
However, lesion count still fails to consider factors such
as lesion size and visibility that influence therapeutic re-
sponse and psychosocial impact respectively.5 A recent

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 201

Dapsone gel at concentrations of 5% and 7.5% has lymecycline), macrolides (erythromycin and azithromy- Treatment approaches
some efficacy in treating acne. Methemoglobinemia is cin), trimethoprim-sulfamethoxazole and clindamycin
a rare complication of the gel in susceptible individu- are the oral antibiotics most commonly used. Apart
als. When used concomitantly with benzoyl peroxide, it from their activity against P. acnes, tetracyclines have
results in transient yellow to orange discolouration of the an added anti-inflammatory effect, making them oral
hair and skin. antibiotics of choice for treatment of acne.

Salicylic acid is weakly keratolytic and has found use Hormonal therapy
in over-the-counter preparations to treat acne. It is use- Anti-androgens, such as oral contraceptives, cyproter-
ful in patients with intolerable irritant dermatitis due to one acetate, and spironolactone, are effective for re-
retinoids and benzoyl peroxide. ducing seborrhoea and are often used as adjunctive
therapy for female patients with acne.
Zinc, both as topical and oral formulations, has shown
some efficacy in some trials as a treatment for acne. Light therapies
Despite multiple clinical trials, its efficacy as adjuvant Laser- or light-based therapies disperse energy that
therapy in acne is still not established.9 excites endogenous (porphyrins) or exogenous photo-
sensitisers to create radical oxygen species targeted
Systemic retinoids either at P. acnes or the sebaceous glands to reduce
the bacterial load, inflammation and sebum produc-
Isotretinoin is the first-line treatment for severe, recalci- tion. There is currently uncertainty about the efficacy of
trant nodulocystic acne. It can also be used for milder these therapies.
acne that is resistant to treatment or associated with sig-
nificant scarring. The recommended dose is 0.5-1.0 mg/ Procedural therapies
kg over four to six months to reach a cumulative dose Chemical peels have been used to treat comedonal
of 120-150 mg/kg. The original studies showed that this acne, but the evidence supporting their efficacy is weak,
dosing regime reduced relapse and improved remission and the reported improvement is mild and short-lived.
rates. More recent studies, however, suggest that con-
tinuing isotretinoin beyond these doses for at least two Microdermabrasion, using abrasive crystals on the skin
months after complete resolution reduces relapse rates. has also been used. There is limited data supporting the
Initiation at a daily dose of 0.2-0.5 mg/kg reduces the efficacy of the procedure as the primary treatment.
risk of acute flares that are seen in 15% of those starting
isotretinoin.5 The role of low-dose isotretinoin has still not Comedone extraction is indicated for large come-
been clarified. dones that are resistant to treatment. Pre-treatment
with topical retinoids for a few weeks improves the out-
Isotretinoin is teratogenic, thus exclusion of pregnancy come. The procedure carries a significant risk of scarring
and use of appropriate contraception before initiating and post-inflammatory hyperpigmentation (PIHP).
the drug is mandatory for women of child-bearing age.
Dryness, photosensitivity, nose bleeds, delayed healing, Intralesional corticosteroids have been shown to
pyogenic granulomas, joint pains, as well as elevation speed up resolution of nodulocystic lesions as adjuvant
of transaminases and triglycerides are the other com- therapy. Repeated injections into the same site should
mon side effects. Recent literature suggests monitoring be avoided as this causes dermal atrophy.
of serum creatinine kinase is recommended, especially
in athletes who engage in strenuous physical activity TREATMENT OF ACNE TYPES
and those with abnormalities of the enzyme at base-
line.10 Although isotretinoin has historically been asso- Comedonal acne
ciated with depression and other psychiatric disorders, Although considered the mildest form, comedonal
this association is not supported by the most robust acne is often challenging to treat. There is a paucity
data.11 However, it is appropriate to screen all patients of good comparative studies of different therapies for
on isotretinoin for depressive symptoms. Individuals with comedonal acne. Topical retinoids are effective and
symptoms, and a personal or family history of a mental still considered first-line treatment. Although not clinical-
disorder may benefit from a referral to a mental health ly obvious, comedonal acne has an inflammatory com-
professional when isotretinoin is initiated.12 ponent. Addition of benzoyl peroxide, topical clinda-
mycin or topical dapsone to topical retinoids enhances
Oral antibiotics their efficacy.6 The combination of topical clindamycin
and benzoyl peroxide is also effective.13 Azelaic acid
Oral antibiotics are an effective treatment for inflam- also shows efficacy and has the added advantage of
matory acne. In treating acne, they are used for pro- being the least irritating.6
longed periods at sub-therapeutic doses for most other
indications. This exerts pressure on microbial selection, Mild-moderate papulopustular acne
enhancing the risk of drug resistance. Thus, both topical Topical retinoids in combination with benzoyl peroxide
and systemic antibiotics should not be used as mono- or the combination of topical clindamycin and ben-
therapy to treat acne. The combination with benzoyl zoyl peroxide have the strongest recommendation in
peroxide is the preferred method to limit resistance. the treatment of mild-moderate papulopustular acne.
Their benefit beyond four months of use is limited. Tet- Monotherapy with benzoyl peroxide, topical retinoids
racyclines (tetracycline, doxycycline, minocycline and
HANDBOOK OF GENERAL MEDICINE VOL 1

202 TREATMENT APPROACHES

or azelaic acid shows comparable efficacy that is less and antibiotics are amongst the topical treatments that
than combination therapy. Oral antibiotics with or with- can be used in pregnancy. Topical retinoids have a
out anti-androgens can be added to combination topi- questionable teratogenic potential and are best avoid-
cals for more severe or treatment-resistant cases.5,6 ed in pregnant women. Macrolides (erythromycin and
azithromycin) are considered the safest systemic anti-
Severe nodular and conglobate acne biotics for managing acne in pregnancy. Cephalexin,
Monotherapy with oral isotretinoin is the first-line treat- amoxicillin, and trimethoprim-sulfamethoxazole can
ment for severe nodulocystic or conglobate acne. Ad- be used when the benefits of treating acne outweigh
dition of oral corticosteroids, e.g. prednisone at doses the risks, as they are thought to be low-risk. Oral tetra-
ranging from 30-60 mg/day, at the initiation of isotretin- cyclines are contra-indicated in pregnancy, including
oin for four to six weeks reduces systemic symptoms, beyond the first trimester.14 Although their efficacy is
flares and speeds up clearance. Oral antibiotics togeth- questionable, light-based therapies, including photody-
er with a topical retinoid/benzoyl peroxide combination namic therapy with aminolevulinic acid, are considered
or azelaic acid is the other alternative, although they safe in pregnant women.15
are less effective than isotretinoin. In females, hormonal
therapy may be added to a combination of oral antibi- Acne in lactating women
otics and non-antibiotic topical treatment.5,6
The choice of treatment in lactating women is largely
Maintenance therapy post-treatment for acne similar to that in pregnancy. Amongst the topical retin-
The majority of patients treated for acne, regardless of oids, tretinoin and adapalene are the most compat-
severity and treatment modality, has some degree of ible with lactation because of the low levels of systemic
relapse. Topical retinoids, with or without benzoyl perox- absorption. Hormonal therapies should be avoided in
ide, are the agents of choice in preventing post-treat- breastfeeding because their high oestrogen content
ment relapse. Azelaic acid as monotherapy is the other decreases milk production. Oral tetracyclines, despite
alternative. their high affinity for calcium ions in breast milk and a
theoretical risk of systemic absorption, are generally
Acne in pregnancy considered safe for use in breastfeeding.15
Treatment of acne in pregnancy is challenging because
the most effective treatments are contra-indicated or Neonatal and infantile acne
not recommended. Ethical issues around clinical trials in
pregnancy means that most of the guidelines and rec- Acne in neonates is usually mild and self-limiting, resolv-
ommendations are based on data derived from obser- ing within three months. If treatment is necessary, azela-
vational and animal studies using cautious approaches. ic acid, topical retinoids, benzoyl peroxide or topical
As a general rule, topical agents are safer in pregnancy erythromycin may be used. Infantile acne usually starts
because of lower systemic absorption. Benzoyl perox- at six months and resolves by the age of five years. In ne-
ide, salicylic acid, azelaic acid, dapsone, zinc products onatal acne, inflammatory lesions are more common.
It is treated with topicals. Isotretinoin and tetracyclines
are contra-indicated. Infantile acne is associated with

Comedonal
Topical retinoids ± benzoyl peroxide;
topical antibiotics/benzoyl peroxide;
topical dapsone; benzoyl peroxide,
azelaic acid; azelaic acid/benzoyl

peroxide; topical clindamycin/
benzoyl peroxide

Pregnancy and lactation Acne Papulopustular
benzoyl peroxide; topical salicylic vulgaris topical retinoids/benzoyl peroxide ±
acid, azelaic acid; topical dapsone; oral antibiotics ± antiandrogens; topical
zinc products; topical antibiotics/ clindamycin/benzoyl peroxide ± oral
benzoyl peroxide; oral macrolides antibiotics ± antiandrogens; topical
antibiotics/benzoyl peroxide; topical

dapsone; azelaic acid

Neonatal and infantile Nodulocystic and conglobate
usually self-limiting isotretinoin;

azelaic acid, topical retinoids ± benzoyl oral antibiotics/topical retinoid/benzoyl
peroxide; benzoyl peroxide; topical peroxide ± antiandrogens; oral antibiotics/
erythromycin/benzoyl peroxide
azelaic acid ± antiandrogen

Figure 1. Summary of treatment approaches for different variants of acne and in special populations in order
of recommendation

HANDBOOK OF GENERAL MEDICINE VOL 1



204 TREATMENT APPROACHES

more severe disease in later years that is likely to scar. In increasing data include early and appropriately more
severe or recalcitrant cases of both neonatal and infan- aggressive treatment to prevent life-long scarring; ex-
tile acne, a work-up for congenital adrenal hyperplasia, tending treatment with isotretinoin for two months af-
a virilising tumour, or underlying endocrinopathy and ter resolution to reduce the risk of recurrence; and the
exclusion of infectious cause is warranted.4 use of higher cumulative doses of isotretinoin in severe
recalcitrant cases. The indications, dosing, duration, ef-
Treatment of acne vulgaris is summarised in Figure 1. ficacy and safety of using low-dose isotretinoin are yet
to be defined. Similarly, the efficacy of light therapies is
Acne-scarring yet to be proven.
Acne scars are for all intents and purposes permanent.
Effective, rapid and lasting treatment for acne-associat- REFERENCES
ed scars is not available. Prevention of scarring by iden-
tification and effective early treatment of individuals 1. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol.
and lesions prone to scarring is the most cost-effective 2013;168(3):474-85.
strategy. Risk factors for scarring include severity, dura-
tion and extent of inflammatory lesions, family history, 2. Collier CN, et al. The prevalence of acne in adults 20 years and old-
manipulation of lesions and trunk localisation. A com- er. J Am Acad Dermatol. 2008;58(1):56-9.
bination of treatment modalities based on the type of
scarring (atrophic, keloidal and hypertrophic), gives the 3. Del Rosso JQ, et al. A closer look at truncal acne vulgaris: Prevalence,
best results in the treatment of established scars. These severity, and clinical significance. J Drugs Dermatol. 2007;6(6):597-600.
include resurfacing and lifting procedures, intralesional
corticosteroids or bleomycin, cryotherapy, silicone gel 4. Serna-Tamayo C, et al. Neonatal and infantile acne vulgaris: An up-
sheeting, laser therapy and surgical excision with or date. Cutis. 2014;94(1):13-6.
without radiation. Treatment of acne-scarring is best left
to clinicians experienced in these procedures. 5. Thiboutot DM, et al. Practical management of acne for clinicians:
An international consensus from the Global Alliance to improve out-
Post-inflammatory hyperpigmentation comes in acne. J Am Acad Dermatol. 2018;78(2 Suppl 1):S1-S23 e1.
Strategies to prevent post-inflammatory hyperpigmen-
tation include early recognition of susceptible indi- 6. Nast A, et al. European evidence-based (S3) guideline for the treat-
viduals and treatment of underlying acne-associated ment of acne – update 2016 – short version. J Eur Acad Dermatol
inflammation, sun protection and avoidance of lesion Venereol. 2016;30(8):1261-8.
manipulation. Topical retinoids, hydroquinone, kojic
acid and azelaic acid individually or in combinations 7. Stringer T, et al. Clinical evidence for washing and cleansers in acne
that include mild topical corticosteroids and antioxi- vulgaris: A systematic review. J Dermatolog Treat. 2018;29(7):688-93.
dants, such as vitamin C, improve post-inflammatory hy-
perpigmentation. Long-term side effects of each treat- 8. Bronsnick T, Murzaku EC, Rao BK. Diet in dermatology: Part I. Atopic
ment have to be considered when selecting treatment. dermatitis, acne, and nonmelanoma skin cancer. J Am Acad Der-
Chemical peels, lasers and other light therapies can also matol. 2014;71(6):1039 e1-e12.
be used, but can themselves cause post-inflammatory
hyperpigmentation and should be used with caution. 9. Cervantes J, et al. The role of zinc in the treatment of acne: A review
The low cost-to-benefit ratio of procedural therapies un- of the literature. Dermatol Ther. 2018;31(1).
dermines their utility in treating post-inflammatory hyper-
pigmentation.5 10. Marson JW, Baldwin HE. New concepts, concerns, and creations in
acne. Dermatol Clin. 2019;37(1):1-9.
INDICATIONS FOR REFERRAL
11. Huang YC, Cheng YC. Isotretinoin treatment for acne and risk of de-
Most patients with acne can be managed in primary pression: A systematic review and meta-analysis. J Am Acad Derma-
care. However, referral to a specialist is advised if they: tol. 2017;76(6):1068-76 e9.
• fail to respond or tolerate standard therapy
• have severe forms, such as acne conglobata, acne 12. Oliveira JM, et al. Association of isotretinoin with depression and suicide:
A review of current literature. J Cutan Med Surg. 2018;22(1):58-64.
fulminans or cystic acne
• have a high risk of scarring 13. Gold MH, Baldwin H, Lin T. Management of comedonal acne vul-
• are at risk of severe psychosocial complications garis with fixed-combination topical therapy. J Cosmet Dermatol.
• have acne that is associated with an underlying en- 2018;17(2):227-31.

docrinological cause or another systemic disorder 14. Chien AL, et al. Treatment of acne in pregnancy. J Am Board Fam
• require management of complications such as post- Med. 2016;29(2):254-62.

inflammatory hyperpigmentation and scarring. 15. Kong YL, Tey HL. Treatment of acne vulgaris during pregnancy and
lactation. Drugs. 2013;73(8):779-87.
CONCLUSIONS

Although acne is common and non-life-threatening,
it has a major impact on the quality of life it affects.
Recent adjustments to management strategies with

HANDBOOK OF GENERAL MEDICINE VOL 1



206 TREATMENT APPROACHES

Atopic dermatitis: diagnosis and management

T Isaacs1,2 Diagnostic issues

MBChB, MFamMed, FCDerm(SA), MMed Atopic dermatitis is a clinical diagnosis as there are cur-
rently no reliable biomarkers. Numerous diagnostic cri-
RM Ngwanya2 teria, mainly for use in clinical trials, exist. The revised UK
Working Party criteria have been validated in hospital
MBChB, FCDerm (SA) and community settings (see Figure 1).

R Lehloenya2 • Must have:
• Pruritus/itching
BSc, MBChB, FCDerm(SA) Plus three or more of the following:
• Visible flexural dermatitis (front of elbows, back of
1. Division of Dermatology, Department of Medicine,
University of Cape Town and Red Cross War Memorial knees, front of neck, around eyes) or involvement
Children’s Hospital, Cape Town of cheeks and/or extensors in children up to 18
2. Division of Dermatology, Department of Medicine, months
University of Cape Town and Groote Schuur Hospital, Cape Town • History of flexural dermatitis
• Generalised dry skin
Atopic dermatitis (AD), also referred to as atopic ec- • Onset less than two years of age
zema, is a chronic, relapsing, pruritic, inflammatory skin • Personal history of asthma or allergic rhinitis (or
condition affecting children and adults, that is often family history of atopy in younger than four years)
associated with elevated serum immunoglobulin (IgE) Figure 1. Revised UK Working Party criteria for the diag-
levels and occurs in families with atopic diseases. The nosis of atopic dermatitis
allergic march refers to the development of atopic der-
matitis in infancy followed by allergic rhinitis, asthma or Acute atopic dermatitis is characterised by erythema,
food allergy at a later age. Although considered a nat- oedema, vesiculation, weeping and crusting. Chronic
ural progression of atopy, the march is not a universal disease is characterised by dry, scaly, thick, lichenified
phenomenon.1 and fissured skin. There is an age-dependent distribution
of atopic dermatitis. In children under two years of age,
Epidemiology atopic dermatitis is commonly distributed on the face
and extensor surfaces (see Figure 2).
Atopic dermatitis affects 10-20% of children in devel-
oped countries and 1-3% of adults.2 In South Africa, a Figure 2. Facial involvement with nasal-sparing
developing country, the one-year prevalence rate in the infantile phase
amongst 13-14-year olds in Cape Town was 8.3-13.3%,
with 2.3% being severe.2 In 3- to 11-year-old Xhosa chil- In individuals older than two years, it is distributed
dren, the one-year prevalence rate was 1-2.5%, with more on flexor surfaces, including the cubital and pop-
increased prevalence in urban environments.3 Atopic liteal fossae, anterior neck and gluteal creases. How-
dermatitis starts most commonly between three- to six ever, any bold fold may be affected (see Figure 3). In
months of age, with 60% of cases developing in the first adults, the face and hands are commonly involved.
year of life, and 90% before the age of five years. While
the majority resolve, 10-30% persist into adulthood.4

Impact on society

Atopic dermatitis is associated with significant morbidity
and can profoundly impact quality of life (QOL). The lack
of sleep from relentless pruritus affects both patient and
caregiver, as well as functioning at school and work.

Pathophysiology

Atopic dermatitis is a chronic multifactorial disease, result-
ing from a dysfunctional skin barrier and immune respons-
es that are influenced by genetic and environmental fac-
tors. A strong family history of atopy and loss of function
mutations in the filaggrin gene have been strongly asso-
ciated with atopic dermatitis development. Other asso-
ciated genes include claudin-1 (CLDN1) and serine pro-
tease inhibitor Kazal-Type (SPINK5). Immune responses in
atopic dermatitis are characterised by an increase in TH2
and TH17 responses.

HANDBOOK OF GENERAL MEDICINE VOL 1

LEPETTA 083 415 6431 11314T THEY DON’T STOP
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MAINTENANCE THERAPY
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WITH 4 YEARS SAFETY DATA, PROTOPIC IS A RESPONSIBLE CHOICE*2,3

Rapidly e ective, with clinical improvements within 3 days of starting therapy4
Progressive increase in e cacy that is sustained long-term*4
Proactive management with PROTOPIC® may overcome limitations associated
with long-term topical steroid use5
Protective against ares and topical corticosteroid-related adverse events5-9

Progressive.4 Proactive.1,10 Protective.2,5,6

*Protopic maintenance therapy should be applied once a day, twice per week. Continuation of treatment should be reviewed after 12 months1
References: 1. PROTOPIC® 0.03 % and 0.1 % ointment package insert. February 2017. 2. Hani n JM, Paller AS, Eichen eld L, et al, for the US Tacrolimus Ointment Study Group. E cacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad
Dermatol 2005;53:S186-94. 3. Wollenberg A, Oranje A, Deleuran M, et al, for the European Task Force on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad
Dermatol venereal 2016. DOI: 10.1111/jdv.13599. 4. Kapp A, Allen BR, Reitamo S. Atopic dermatitis management with tacrolimus ointment (Protopic®). J Dermatol Treatment 2003;14(Suppl 1):5-16. 5. Kirsner RS, He ernan MP, Antaya R. Safety and E cacy of Tacrolimus Ointment Versus
Pimecrolimus Cream in the Treatment of Patients with Atopic Dermatitis Previously Treated with Corticosteroids. Acta Derm Venereol 2010;90:58–64. 6. Danby SG, Chittock J, Brown K, et al, The e ect of tacrolimus compared with betamethasone valerate on the skin barrier in volunteers with
quiescent atopic dermatitis. Br J Dermat 2014;170:914–921. 7. Breneman D, Fleischer AB, Abramovits W,et al, for the Tacrolimus Ointment Study Group. Intermittent therapy for are prevention and long-term disease control in stabilized atopic dermatitis: A randomized comparison of 3-times-
weekly applications of tacrolimus ointment versus vehicle. J Am Acad Dermatol 2008;58:990-9. 8.Thaçi D, Reitamo S, Gonzalez Ensenat MA, et al, for the European Tacrolimus Ointment Study Group. Proactive disease management with 0.03 % tacrolimus ointment for children with atopic dermatitis:
results of a randomized, multicentre, comparative study. Br J Dermatol 2008;159:1348–1356. 9. Reitamo S, Rustin M, Harper J, et al, and the 0.1 % Tacrolimus Ointment Long-term Follow-up Study Group. A 4-year follow-up study of atopic dermatitis therapy with 0.1 % tacrolimus ointment in
children and adult patients. Br J Dermatol 2008;159:942–951. 10. Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis – an emerging concept. Allergy 2009: 64: 276–278.
S4 PROTOPIC® 0,03 % Ointment. Each 1 g contains 0,3 mg of tacrolimus as tacrolimus monohydrate (0.03%). Reg. No. A40/13.12/0219. S4 PROTOPIC® 0intment. Each 1 g contains 1,0 mg of tacrolimus as tacrolimus monohydrate (0.1%). Reg. No. A40/13.12/0231. Under licence from LEO
Pharmaceutical Products, Ballerup, Denmark. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. 2019013110120330.

Adcock Ingram Limited. Reg. No. 1949/034385/06, Private Bag X69, Bryanston, 2021, South Africa , Telephone + 27 11 635 0000,www.adcock.com

STRONG STEROID ACTION
WITH THE BALANCE BETWEEN EFFICACY AND SAFETY1-4

A MAINSTAY TREATMENT OPTION WITH STRONG TOPICAL MINIMAL
ANTI-INFLAMMATORY ACTION1,5-7
steroid related
High therapeutic index with a favourable benefit:risk ratio1 SIDE-EFFECTS1
Rapid onset of therapeutic effect8
Comparable potency and efficacy to mometasone furoate 0.1 %, betamethasone valerate 0.1 % and
betamethasone dipropionate 0.1 %2,-4,9,10
Low risk of local and systemic adverse events1
Available in a range of formulations for added treatment flexibility5,6

LEPETTA 083 415 6431 11314T References: 1. Fölster-Holst R, Abeck D, Torrelo A. Topical hydrocortisone 17-butyrate 21-propionate in the treatment of in ammatory skin diseases: pharmacological data, clinical e cacy, safety and calculation of the therapeutic index. Pharmazie 2016;71:115-121. 2. Demana PH. Topical
corticosteroid formulations: bioequivalence assessment and guidelines for appropriate use. S Afr Pharm J 2014;81(1):26-31. 3. Finzi AF. The clinical e cacy of hydrocortisone 17-butyrate (Locoid) ointment and betamethasone 17-valerate ointment in patients with psoriasis. Clin Trials J
1981;18(2):128-137. 4. Helander I. Treatment of exural eczema. A Double-Blind Study to Compare the E cacy of Hydroxortisone 17-Butyrate 0.1 % Cream (Locoid) with that of Betamethasone 17-Valerate 0.1% Cream. Clin Trials J 1982;19(5):269-274. 5. Locoid approved package insert, Nov 2011.
6. Locoid Crelo approved package insert, Jun 2001. 7. Eichen eld LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Part 2: Management and Treatment of Atopic Dermatitis with Topical Therapies. J Am Acad Dermatol. 2014;71(1):116–132. doi:10.1016/j.
jaad.2014.03.023. 8. Gip L, Lindberg L, Nordin P, et al. Clinical Study of Mometasone Furoate Cream 0.1 % Compared to Hydrocortisone Butyrate Cream 0.1 % in Treatment of Atopic and Seborrheic Dermatitis. Today’s Therapeutic Trends. 1990;8:21-34. 9. Fowler JF, Fransway AF, Jackson JM, et al.
Hydrocortisone Butyrate 0.1 % Cream in the Treatment of Chronic Dermatitis. Cutis. 2005;75:125-131. 10. Piérard-Franchimont C, Willemaers V, Fraiture A-L, et al. Pharmacology and therapeutics. Squamometry in seborrheic dermatitis. Intl J Dermatol 1999;38:712–715.
S4 LOCOID® Cream. Hydrocortisone 17-butyrate 1 mg per 1 g water soluble cream base. H/13.4.1/107. S4 LOCOID® Lipocream®. Hydrocortisone 17-butyrate 1 mg per 1 g oil-in-water cream base. W/13.4.1/355. S4 LOCOID® Ointment.
Hydrocortisone 17-butyrate 1 mg per 1 g anhydrous ointment base. H/13.4.1/109. S4 LOCOID® Lotion: Hydrocortisone 17-butyrate 1 mg per 1 ml aqueous solution. H/13.4.1/108. S4 LOCOID® Crelo topical emulsion. Hydrocortisone 17-butyrate 1
mg per 1g in a bu ered oil in water emulsion. 34/13.4.1/0221. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 2019050310136316.
Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Telephone + 27 11 635 0000.www.adcock.com

TREATMENT APPROACHES 209

atopic dermatitis by increasing hydration of the skin. Treatment approaches
They contain a base of occlusives (petrolatum, mineral
Figure 3. Flexural involvement of cubital, popliteal oil) that form an occlusive layer and decrease evapora-
fossae and the neck in childhood atopic dermatitis tion of water alone, or are combined with humectants
(glycerol, urea, lactic acid) which help attract water to
Differential diagnosis the stratum corneum. They may also contain emollients
(lanolin, glyceryl stearate) which lubricate and soften
When diagnosing atopic dermatitis, the possibility of the the skin. The ideal moisturiser for use in atopic dermatitis
following diseases must be taken into account. should aim to restore the skin barrier, soften skin effec-
• Seborrhoeic dermatitis tively, be devoid of fragrance and colourants, as well as
• Nummular eczema be pleasant to use.4
• Contact dermatitis, irritant and allergic
• Psoriasis Moisturisers exist in various formulations, including
• Drug reaction creams, ointments, gels and lotions. The choice of formu­
• Cutaneous T-cell lymphoma lation depends on patient preference and the severity of
• Scabies the disease. Examples of simple moisturisers include ce-
• Insect bites tamacrogol and emulsifying ointment. Aqueous cream is
• Onchocerciasis used as a wash, not a leave-on topical, and should not
be used as a moisturiser. Ointments generally lack pre-
Management servatives compared to creams, and consequently are
less likely to cause contact dermatitis or irritation. Most
Management of atopic dermatitis is individualised ac- moisturisers show benefit, producing better results when
cording to age, severity and extent (see Figure 4). used with active treatment, prolonging time to flare, and
reducing the number of flares and quantity of topical
Basic measures corticosteroids needed to treat atopic dermatitis. Pre-
scription emollient devices (PED) are newer agents with
Moisturisers ratios that supposedly mimic endogenous lipids. They are
Moisturisers form the cornerstone of non-pharmacolog- supposed to target specific skin-barrier defects in atopic
ical treatment. Moisturisers improve clinical features of dermatitis. There is no evidence that prescription emol-
lient devices are superior to other moisturisers.5

Most guidelines recommend liberal and frequent ap-
plication (at least twice a day) of emollients, preferably
immediately after bathing.4 For other basic measures in
managing atopic dermatitis, see Figure 4.

Pharmacological treatment

Topical corticosteroids

Topical corticosteroids have traditionally been the first-
line pharmacological treatment of atopic dermatitis.
They are indicated both for treating acute flares, as
well as preventing relapses. Topical corticosteroids are
grouped into seven classes, from very high potency (I)
to very low potency (VII) (see Table 1).4

Selection of appropriate topical corticosteroids

This depends on age, disease severity and distribution,
cost, accessibility and the patient’s vehicle preference.
• Reactive treatment: For control of acute flares, mild- to

higher-potency topical corticosteroids (short courses)
help gain rapid control of symptoms, even in children.
Follow this by a weaning regimen to weaker-potency
topical corticosteroids on resolution.
• Proactive therapy involves the scheduled application
of topical corticosteroids twice a week to previously
involved sites. This has been shown to reduce the re-
lapse rate and prolong time to flare.6
• For long-term management, the least potent topical
corticosteroid that controls the disease should be used.
• Use lower-potency steroids on sensitive sites, such as the
face, neck, periorbital and intertriginous sites, where in-
creased penetration and absorption may occur.

HANDBOOK OF GENERAL MEDICINE VOL 1

210 TREATMENT APPROACHES

Diagnosis of AD

Mild AD Moderate AD Severe AD
• Areas of dry skin • Areas of dry skin • Widespread areas
• Infrequent itching • Frequent itching
OR SCORAD <25 of dry skin
and redness • Incessant itching
OR SCORAD 25-50
and redness
OR SCORAD >50

Basic • Moisturise liberally and frequently
treatment • Use non-soap cleansers
• Avoid triggers, and common irritants, including soaps and wool, rough-

textured clothing
• Wash once a day. Avoid too hot/long baths or showers
• Education

Reactive • Topical corticosteroids • Reactive treatment • Reactive treatment
• TCI for mild AD+ for moderate AD+
• Antihistamines
• Wet wrap • Systemic treatment
• Infection control (CSA, AZA, MTX, MMF)

• Consider short-term
SCS

• Admission
• Photography
• Biologics

Proactive • Twice-weekly topical corticosteroids of TCI to previously involved areas
treatment

AD – atopic dermatitis; SCORAD – scoring atopic dermatitis; TCI – topical calcineurin inhibitors;
CSA – cyclosporine A; AZA – azathioprine; MTX – methotrexate; MMF – mycophenolate mofetil;
SCS – systemic corticosteroids

Figure 4. Algorithm for treatment of atopic dermatitis based on clinical assessment/objective SCORAD

Table 1. Classes of topical corticosteroids and examples4

Class Generic name Strength (%)
I. Very high potency
II. High potency Clobetasol propionate 0.05

III-IV. Medium potency Betamethasone diproprionate 0.05
Mometasone furoate 0.1
V. Lower medium potency Triamcinolone acetonide 0.5
VI. Low potency
VII. Lowest potency Betamethasone valerate 0.1
Fluocinolone acetonide 0.025
Fluticasone propionate 0.05; 0.005
Methylprednisolone aceponate 0.1

Hydrocortisone butyrate 0.1
Hydrocortisone valerate 0.2

Fluocinolone acetonide 0.01

Hydrocortisone acetate 0.5-1
Hydrocortisone 0.25; 0.5; 1

• There is no universal standard for the amount of appli- clinical practice. Recent evidence, however, suggests
cation of topical corticosteroids. Suggested methods that once-daily application is as effective.4
include the fingertip unit (from distal interphalangeal • Wet-wrap therapy consists of an application of topical
joint to end of the phalanx). One unit will treat the size corticosteroids, usually under two layers of cotton band-
of two adult palms. ages, consisting of a wet inner layer covered by a dry
outer layer for 8-24 hours per day. Wet-wrap therapy is
• Creams are suitable for wet lesions and intertriginous indicated for short-term control in severe or refractory
sites; lotions and gels for hair-baring sites. Ointments atopic dermatitis flares. Wet-wrap therapy improves
are best for dry, lichenified eczema. topical corticosteroid penetration, decreases trans-ep-
idermal water loss, reduces pruritus and acts as a bar-
• Most studies on topical corticosteroids involve twice-
daily application, which is currently the most common

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 211

rier to scratching. There is only low-quality evidence that Adverse effects Treatment approaches
wet-wrap therapy is more effective than standard ther- The most common adverse effect of topical calcineu-
apy in atopic dermatitis.7 Wet-wrap therapy use should rin inhibitors is localised stinging and burning.8 However,
not exceed 14 days as it increases the risk of localised in- symptoms are usually mild and transient, and decrease
fection, striae and skin atrophy, especially in vulnerable with time or if preceded by a short period of topical
sites, such as the intertriginous areas. corticosteroid use. High-dose systemic topical calcineurin
inhibitors have been associated with lymphoma. Howev-
Adverse effects of topical corticosteroids er, a systematic review of current data identified no cases
of lymphoma associated with topical calcineurin inhibitor
The chronic use of potent topical corticosteroids is limited use.8
by the adverse effects, including atrophy, telangiecta-
sia, striae, topical corticosteroid-induced acne and rosa- Crisaborole
cea, and perioral derma­titis. If used peri-orbitally, there is
a risk of glaucoma, cataracts and herpes keratitis. The risk Crisaborole ointment 2% is a novel anti-inflammatory
of hypothalamus-pituitary axis suppression is low, but in- phosphodiesterase inhibitor 4 (PDE4), not yet available
creases with prolonged, continuous use of high-potency in South Africa. It is an effective and well-tolerated new
classes in individuals receiving concurrent corticosteroids topical option for the management of mild- to mode-
in other forms (inhaled, intranasal or oral) and small chil- rate atopic dermatitis in patients older than two years.
dren. It has the potential to be used for chronic treatment of
atopic dermatitis without the adverse effects of topical
Topical calcineurin inhibitors corticosteroids.10

Topical calcineurin inhibitors (TCI) are immunomodula- Phototherapy
tors that work by inhibiting calcineurin in the skin, thus Phototherapy is an effective treatment option to im-
inhibiting T-cell proliferation and the production of pro- prove skin lesions and reduce itch with remission of at-
inflammatory cytokines involved in the pathogenesis of opic dermatitis of up to six months. It acts by suppressing
atopic dermatitis. the antigen-presenting function of Langerhans’ cells,
and induces apoptosis of T-cells and antimicrobial pep-
Two topical calcineurin inhibitors are available, i.e., tides. It is indicated as second-line treatment after fail-
pimecrolimus cream (1%) and tacrolimus ointment ure of basic measures and topical anti-inflammatories.11
(0.03% and 0.1%). Topical calcineurin inhibitors have The mode of light therapy depends on age, skin type,
been shown to decrease the physician’s global evalua­ availability and skin-cancer history. Narrowband UV-B is
tion scores, as well as the percentage of body-surface the most commonly recommended, considering its low
area involved and patient evaluation of symptoms and risk and efficacy. According to a recent systematic re-
signs.8 Tacrolimus is approved for moderate- to severe at- view, evidence exists for the use of narrow-band UV-B
opic dermatitis, while pimecrolimus is indicated for mild- and UV-A1 in moderate to severe atopic dermatitis, but
to moderate disease. While tacrolimus 0.03% is superior it is rarely used for PUVA.12
to low-potency corticosteroids, tacrolimus 0.1% is superior
to low-potency topical corticosteroids and equivalent Systemic therapy
to moderate- to potent topical corticosteroids.8 Hence, Systemic therapy is indicated for a small subset of patients
both are a suitable alternative to topical corticosteroids with atopic dermatitis, who are refractory to topical treat-
for recalcitrant periorbital or facial eczema. ment and/or phototherapy, or with significantly impaired
quality of life.11 There are few studies which compare sys-
The main role of topical calcineurin inhibitors is that temic therapies; hence it is difficult to compare the rela-
of steroid-sparing agents, particularly in sensitive skin tive efficacies of various agents. The most commonly used
areas, such as the face, neck and intertriginous sites. systemic agents are cyclosporine, azathioprine, metho-
They have also been demonstrated to be more effec- trexate and mycophenolate mofetil (MMF) and systemic
tive in reversing skin atrophy than the vehicle. corticosteroids (SCS). Besides systemic corticosteroids,
none of the systemic agents has been approved by the
Dosing FDA for the treatment of atopic dermatitis.

• Tacrolimus 0,03% and pimecrolimus 1% are indicated Cyclosporine A
for use in patients older than two years, while tacro-
limus 0.1% strength is approved in those older than Cyclosporine A (CSA) is an immunomodulator that sup-
15 years. However, both these agents have been presses T-cells and inhibits pro-inflammatory cytokines,
safely and effectively used in children younger than especially IL2. It constitutes effective atopic dermatitis
two years of age, in clinical trials,9 and off-label use of treatment for recalcitrant atopic dermatitis in adults and
tacrolimus 0.1% in children suggests that 0.1% is more children, significantly decreasing disease activity within
effective than 0.03%.4 two to six weeks of treatment initiation. Induction doses
are 3-5 mg/kg/day, divided into two daily doses. After
• Twice-daily application is more effective than once- six weeks, the dose can be tapered down to a main-
daily application. tenance dose of 2,5-3 mg/kg/day. Treatment duration

• Topical corticosteroids are more useful as mainte- HANDBOOK OF GENERAL MEDICINE VOL 1
nance after gaining control with topical cortico-
steroids during acute flares.

• Proactive therapy of twice-weekly application to pre-
viously involved sites has been shown to reduce re-
lapse rates and prolong time to flares.6

212 TREATMENT APPROACHES

usually varies between three months and one year Cy- combined with topical corticosteroids. Adverse events
closporine A is usually considered the first-line agent for include injection-site reactions, conjunctivitis, head-
those requiring systemic therapy.11 Its long-term use is ache, nasopharyngitis, erythrodermic psoriasis and alo-
limited by hypertension and renal toxicity. pecia areata.

Azathioprine Other potential biologics, but not approved for atop-
Azathioprine (AZA) is a purine analogue that inhibits ic dermatitis, include nemolizumab, tralokinumab, leb-
DNA production, and proliferation of B-cells and T-cells. rikizumab, fezakinumab, rituximab, omalizumab, janus-
It is effective in treating refractory atopic dermatitis in kinase inhibitors and tezepelumab.
adults and children. The onset of action is slow, with
maximal efficacy attained at 8-12 weeks. A starting Antimicrobials
dose of 50 mg/day is recommended. The dose may be
increased to the maintenance dose of 2-3 mg/kg/day. Due to impaired skin-barrier function, patients with atop-
Low thiopurine-methyl transferase (TPMT) activity is asso- ic dermatitis are predisposed to infections with, in par-
ciated with increased risk of myelotoxicity. Baseline TPMT ticular, Staphylococcus aureus and herpes simplex virus.
screening can identify those at risk. Adverse effects in- Ninety per cent of patients with atopic dermatitis are
clude gastro-intestinal (GIT) disturbances, elevated liver colonised with S. aureus. The use of systemic antibiotics
enzymes, hypersensitivity reactions and myelot­oxicity. is only recommended for overtly infected atopic der-
It has been associated with an increased risk of non- matitis.14 Although bleach baths have been shown to
melanoma skin cancer and lymphoma.11 reduce atopic dermatitis severity, they have not been
found to be more effective than water baths alone.15
Methotrexate
Methotrexate is a folate antagonist and blocks DNA, Oral antihistamines
RNA and purine synthesis. Methotrexate is equally effec-
tive to AZA in atopic dermatitis in adults and children.13 Antihistamine use in atopic dermatitis is limited. There is,
Its onset of action is slow and maximal clinical efficacy however, a role for intermittent use of sedating antihis-
is reached at 8-12 weeks. The recommended dose is tamines to improve sleep loss secondary to pruritus.15
7,5 mg-25 mg/week for adults and 10-20 mg/m2/week
for children. Methotrexate causes treatment-limiting Referral
nausea and vomiting, hepatotoxicity and myelotoxic-
ity. It is teratogenic and women of child-bearing age Indications for referral to a dermatologist include:
must be on effective contraception. Folate supplemen- • Uncertain diagnosis.
tation is essential to prevent myelosuppression. • Frequent flares despite appropriate treatment.
• Atopic dermatitis on the face that has not responded
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is an immunosuppressant to appropriate treatment.
that blocks the biosynthesis of purines and selectively • Atopic dermatitis causing significant psychosocial
affects B-cells and T-cells. It is an alternative systemic
agent for refractory cases of atopic dermatitis, with problems for a child or parent.
variable efficacy.11,14 The onset of action is slower than • Severe and recurrent infections.
cyclosporine A and the recommended dose is 2 g/day. • Suspected contact dermatitis.
Side effects include gastro-intestinal disturbances, hae- • Urgent referral if eczema herpeticum.
matological abnormalities and teratogenicity.
References
Systemic corticosteroids
Systemic corticosteroids are not recommended for the 1. Williams H, Flohr C. How epidemiology has challenged 3 prevail-
continuous or chronic intermittent treatment of atopic ing concepts about atopic dermatitis. J Allergy Clin Immunol.
dermatitis.14 Although rapidly effective, they have an 2006;118(1):209-13.
unfavourable risk/benefit profile and a high rate of re-
lapse or rebound on withdrawal. In acute cases, they 2. Williams H, Robertson C, Stewart A, et al. Worldwide variations in
may be used to gain rapid control, followed by rapid the prevalence of symptoms of atopic eczema in the International
tapering and replacement with topical, phototherapy Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol.
or systemic treatment.11,14 1999;103(1 Pt 1):125-38.

Biologics 3. Chalmers DA, Todd G, Saxe N, et al. Validation of the U.K. Working
Dipulimab is a human monoclonal antibody against the Party diagnostic criteria for atopic eczema in a Xhosa-speaking Afri-
alpha subunit of the IL-4 receptor. It is the only biologic can population. Br J Dermatol. 2007;156(1):111-6.
approved for moderate to severe atopic dermatitis that
has failed standard therapy. Efficacy is improved when 4. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the
management of atopic dermatitis: Section 2. Management and
HANDBOOK OF GENERAL MEDICINE VOL 1 treatment of atopic dermatitis with topical therapies. J Am Acad
Dermatol. 2014;71(1):116-32.

5. Van Zuuren EJ, Fedorowicz Z, Christensen R, et al. Emollients and mois-
turisers for eczema. Cochrane Database Syst Rev. 2017;2:CD012119.

6. Schmitt J, von Kobyletzki L, Svensson A, et al. Efficacy and tolerability
of proactive treatment with topical corticosteroids and calcineurin
inhibitors for atopic eczema: Systematic review and meta-analysis of
randomized controlled trials. Br J Dermatol. 2011;164(2):415-28.

7. Gonzalez-Lopez G, Ceballos-Rodriguez RM, Gonzalez-Lopez JJ, et
al. Efficacy and safety of wet wrap therapy for patients with atopic
dermatitis: A systematic review and meta-analysis. Br J Dermatol.
2017;177(3):688-95.

8. Cury Martins J, Martins C, Aoki V, et al. Topical tacrolimus for atopic
dermatitis. Cochrane Database Syst Rev. 2015(7):CD009864.

9. El-Batawy MM, Bosseila MA, Mashaly HM, et al. Topical calcineurin
inhibitors in atopic dermatitis: a systematic review and meta-analy-
sis. J Dermatol Sci. 2009;54(2):76-87.

TREATMENT APPROACHES 213

10. Hoy SM. Crisaborole Ointment 2 %: A review in mild to moderate Treatment approaches
atopic dermatitis. Am J Clin Dermatol. 2017;18(6):837-43.

11. Wollenberg A, Oranje A, Deleuran M, et al. ETFAD/EADV: Eczema
task force 2015 position paper on diagnosis and treatment of atopic
dermatitis in adult and paediatric patients. J Eur Acad Dermatol Ve-
nereol. 2016;30(5):729-47.

12. Perez-Ferriols A, Aranegui B, Pujol-Montcusi JA, et al. Phototherapy
in atopic dermatitis: A systematic review of the literature. Actas Der-
mosifiliogr. 2015;106(5):387-401.

13. Schram ME, Roekevisch E, Leeflang MM, et al. A randomized trial of
methotrexate versus azathioprine for severe atopic eczema. J Al-
lergy Clin Immunol. 2011;128(2):353-9.

14. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the man-
agement of atopic dermatitis: Section 3. Management and treat-
ment with phototherapy and systemic agents. J Am Acad Dermatol.
2014;71(2):327-49.

15. Chopra R, Vakharia PP, Sacotte R, et al. Efficacy of bleach baths in
reducing the severity of atopic dermatitis: A systematic review and
meta-analysis. Ann Allergy Asthma Immunol. 2017;119(5):435-40.

HANDBOOK OF GENERAL MEDICINE VOL 1

214 TREATMENT APPROACHES

Psoriasis: diagnosis and treatment

RM Ngwanya1 PATHOPHYSIOLOGY

MBChB, FCDerm (SA) The aetiology of psoriasis is multifactorial and involves
genetic, environmental and immunological factors. The
T Isaacs2 inflammatory pathway is mediated by aberrant activa-
tion of dermal dendritic cells producing tumour necrosis
MBChB, MFamMed, FCDerm (SA), MMed factor (TNF) and interleukin-23. These dendritic cells stim-
ulate auto-immune Th17 (T-helper cell 17) and Tc 17(T-
R Lehloenya1 cytotoxic cell 17) to migrate into the epidermis, where
they recognise epidermal auto-antigens and produce
BSc, MBChB, FCDerm (SA) Th17 cytokines interleukins 17 and 22. Th17 cytokines
trigger the epidermal phenotype of plaque psoriasis,
1Associate Professors, Division of Dermatology, which is characterised by an abnormal keratinocyte hy-
Department of Medicine, University of Cape Town perproliferation and the activation of keratinocytes to
and Groote Schuur Hospital, Cape Town produce antimicrobial peptides and chemokines.7 The
2Senior consultant, Division of Dermatology, TNF-IL-23-TH17 pathway is central in the pathogenesis of
Department of Medicine, University of Cape Town plaque psoriasis.8
Red Cross War Memorial Children’s Hospital and
Groote Schuur Hospital, Cape Town Environmental factors that are known triggers of pso-
riasis include mild trauma in the so-called Koebner phe-
Psoriasis is an immune-mediated, inflammatory disease nomenon, sunburn, chemical irritants and stress. Other
characterised by increased epidermal-cell turnover triggers are drugs such as the beta-blockers, antima-
rate mainly involving the skin and joints. The disease is larials and lithium, as well as infections such as Strepto-
genetically determined, strongly influenced by epige- coccus and HIV. In HIV-infected individuals, the disease
netic mechanisms, and is often triggered by environ- tends be more severe and is resistant to treatment.
mental factors.1 The World Health Organization (WHO)
characterises psoriasis as a chronic, non-communica- DIAGNOSTIC ISSUES
ble, painful, disfiguring and disabling disease for which
there is no cure. Psoriasis is a clinical diagnosis. The plaque-type psoriasis
shows a silvery scale when scratched using an orange
Prevalence stick. The Auspitz sign that refers to the appearance of
small bleeding points after successive layers of scale
The prevalence of psoriasis varies in different popula- have been removed from the surface of psoriatic pap-
tions and parts of the world. It is higher in people of Euro- ules or plaques can be useful in the diagnosis of psoria-
pean descent compared to Africans and it is less com- sis.9 Unfortunately, it is neither specific nor sensitive.
mon in the tropics. Approximately 2-3% of people are
affected by psoriasis globally. Psoriasis is more prevalent In difficult cases, dermoscopy and a skin biopsy may
in females, but males tend to have more severe dis- be helpful. Both reveal relatively distinctive patterns, de-
ease. The disease can develop in anyone at any age, pending on the morphology of the disease. Dermosco-
but shows a bimodal distribution, peaking between 20 py is an in-office, non-invasive method that aids in the
to 30 years and between 50 to 60 years. Approximately diagnosis of psoriasis. It has been shown to be a useful
10-15% of new cases occur before the age of 10 years. tool in difficult-to-diagnose cases of the scalp, nail and
the skin. The consistent features for cutaneous psoria-
Impact on society sis demonstrable on dermoscopy are the regularly dis-
tributed red dots, glomerular vessels and erythematous
Psoriasis has a major negative impact on the lives of indi- or pinkish background with white or yellowish scales.10
vidual patients and society. In a comparative study with The skin biopsy for plaque-type psoriasis shows marked
other chronic diseases, such as myocardial infarction, epidermal regular acanthosis, elongation of the rete
cancer and congestive cardiac failure, only depression ridges, mounds of parakeratosis, spongiform pustules,
and chronic lung diseases impaired psychological qual- micro-abscesses, dilated and tortuous blood vessels
ity of life (QOL) more than that of psoriasis.2 The disease that reach the tips of the dermal papillae, and thinning
impacts negatively on occupational functioning, inter- of supra-papillary plates.
personal relationships and sexual functioning.3 Psoriatics
as a group are more prone to depression and suicide, SEVERITY GRADING
and have a higher incidence of metabolic syndrome
and cardiovascular diseases.4 The cost of medical care The severity of psoriasis influences treatment decisions,
and loss of productivity place a major financial burden i.e. the number of topical treatments or change to sys-
on both the patient and society.5 In 2013, the Execu- temic therapies, as well as tracking response to treat-
tive Board of the WHO declared psoriasis a major health ment. Psoriasis Area Severity Index (PASI), the Body Sur-
problem.6

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 215

face Area (BSA) and the Physician Global Assessment • Pustular psoriasis has two variants; localised and Treatment approaches
(PGA) are some of the tools used to establish severity in generalised. The localised variant can either be re-
psoriasis. The disease is severe if PASI, BSA and the Der- stricted to the palms and soles or involve tips of both
matology Life Quality Index (DQLI) is equal or greater fingers and toes (see Figure 3). Generalised pustular
than 10. It is often referred to as the rule of tens.11 psoriasis, characterised by disseminated pustules,
can develop in the background of established pso-
Clinical types riasis or arise de novo. Pustular psoriasis, together
with erythrodermic psoriasis, represents the severest
Five morphological types of psoriasis are recognised, form of psoriasis and is regarded as a dermatological
namely plaque, guttate, pustular, inverse and erythro- emergency. Facial involvement denotes severity.
dermic.
• Plaque psoriasis, also called psoriasis vulgaris, is the

most common, accounting for approximately 90% of
cases. It is characterised by scaly, erythematous, well-
defined plaques (see Figure 1). Plaques may be few
or can involve wide areas of the skin. The typical areas
affected in plaque psoriasis are the extensor surfaces
of arms and legs (see Figure 2), lower back, scalp as
well as retro-auricular and periumbilical areas.

Figure 1. Plaque-type psoriasis Figure 3. Localised pustular psoriasis

Figure 2. Psoriasis involving the extensors and Nails and joints are involved with any of the types of
the knees psoriasis. Nail involvement occurs in about 50% of psoria-
sis patients. Both the finger and toenails may be affect-
Definitions ed. Clinically, the nail shows onycholysis (detachment
of the nail from the nail bed), sublingual hyperkeratosis,
• When more than 90% of the body surface area is oil spots and pitting. Ninety percent of patients who
affected by the erythematous scaly plaques, it is re- have psoriatic arthritis have nail involvement.
ferred to as erythrodermic psoriasis.
Management
• Guttate (droplet) psoriasis is characterised by a rapid
onset of scaly erythematous papules usually follow- Psoriasis requires life-long management and should be
ing a streptococcal infection. personalised according to disease type, severity and
patient needs. It includes both pharmacological and
• When psoriasis primarily affects the flexures or the in- non-pharmacological approaches. The conventional
tertriginous areas, it is called inverse psoriasis. In these treatment includes topical and systemic treatments,
areas, the typical scale is not obvious due to mac- phototherapy and biologics.
eration.
Non-pharmacological treatment
Non-pharmacological treatment includes lifestyle
adjustments, such as management of stress, a known
trigger; weight reduction, cessation of smoking and
avoidance of alcohol, all of which contribute to meta-
bolic syndrome and a higher risk of cardiovascular dis-
ease.

Topical pharmacological treatment
• Patients with mild to moderate psoriasis can be man-

aged with topical formulations. The challenge with
topicals is the effort of daily application, treatment
acceptability and topical side effects.
• Emollients and keratolytics: These reduce scales and
moisturise the skin. Keratolytics, such as salicylic acid,
promote shedding and decrease the cell-cell cohe-
sion in the stratum corneum. They are used to flat-
ten psoriatic plaques before initiating conventional
treatment.

HANDBOOK OF GENERAL MEDICINE VOL 1

216 TREATMENT APPROACHES

• Tar: Its mechanism of action is not fully understood. of nucleic acid synthesis in activated T-cell, keratino-
It is thought to reduce keratinocyte proliferation by cytes, adhesion molecules, angiogenesis and inflam-
suppressing DNA synthesis. Formulations include oint- matory cytokines. Its immunomodulatory and anti-
ment, creams, lotions, gel and shampoos that can inflammatory effects are mediated by regulatory
be used alone or in combination with other topicals T-cells through the adenosine pathway.13 It is effec-
for plaque, scalp and palmoplantar psoriasis. Tar can tive, cheap, has a relatively good safety profile and
cause irritation and is best avoided in body folds. is easily administered. It is used for both induction and
Other side effects include folliculitis and photosensi- long-term treatment of moderate to severe plaque,
tivity. Tar preparations can be applied twice daily. pustular and erythrodermic psoriasis that has not re-
sponded to topical therapies, as well as psoriatic ar-
• Corticosteroids act by reducing the expression and thritis. The starting dose is between 20-25 mg/week
production of inflammatory mediators. They are orally or subcutaneously. The dose may be reduced
available in different formulations and potency. The by 5 mg/week, depending on clinical response. Folic
formulations include creams, ointments, gels, lotions acid should be co-administered at a daily dose of
and aerosols. The choice depends on the patient’s 5 mg, except on the day of taking methotrexate. A
age, body-surface area and extent of the disease. test dose of 5 mg weekly is recommended for those
Intertriginous areas are best treated with low-poten- with impaired renal function.14 Methotrexate is con-
cy creams, whereas palms and soles would require tra-indicated in severe liver disease, renal failure, al-
the highest-potency formulations. Side effects of cohol abuse, immunodeficiency, acute peptic ulcers
topical corticosteroids include skin atrophy, telangi- and bone-marrow suppression. Side effects include
ectasia, tachyphylaxis, acne, rosacea and striae. Re- treatment-limiting nausea and vomiting, general
bound refers to the exacerbation of the psoriasis on malaise, hepatitis and pneumonitis. Before initiating
discontinuation of corticosteroid use. methotrexate, a baseline chest x-ray, liver-function
tests, full blood count, renal profile, pregnancy test
• Vitamin D analogues: Calcipotriol reduces levels of and exclusion of immunodeficiency are mandatory.
interleukins 1 and 6. This promotes the production These should be repeated weekly or monthly, de-
of anti-inflammatory T-helper cell cytokines (such pending on baseline findings. Signs of acute metho-
as interleukin-10), decreases infiltration of inflamma- trexate toxicity include myelosuppression, mucosal
tory T-cells in lesional skin and increases expression of ulceration and skin necrosis and ulceration. Leuco-
transforming growth factor, thereby inhibiting epithe- vorin, a methotrexate antidote, should be given in
lial cell growth.12 Calcipotriol has a favourable side- cases of acute toxicity. Methotrexate should be ini-
effect profile, compared to corticosteroids. It is avail- tiated and regularly followed up by a clinician with
able as an ointment or a gel that is applied once a an understanding of the short- and long-term side
day. The total weekly dose should not exceed 100 g effects of the drug.
to avoid the risk of excessive calcium absorption. The • Acitretin is a vitamin A derivative indicated for mode-
most notable side effect is a mild irritant dermatitis. rate to severe plaque, and localised or generalised
pustular and erythrodermic psoriasis. It has antiprolif-
• When combined with a corticosteroid (betametha- erative effects and is also useful as a chemopreven-
sone), the two have a synergistic effect on inhibitory tive therapy for certain skin tumours. It is recommend-
pathways and anti-proliferative effects. The fixed- ed for induction therapy up to 16 weeks followed by
dose combination is indicated for mild body and maintenance therapy at the lowest effective dose.
scalp psoriasis. The drug is initiated at a dose of 0.3-0.5 mg/day/
kg. This is increased to 0.5 mg-0.8 mg/kg after one
• Anthralin (dithranol): This is a plant extract that has month. Acitretin is fat-soluble and should be taken
anti-proliferative activity on keratinocytes and anti- with milk or a fatty meal. Acitretin is teratogenic and
inflammatory effects by suppressing IL-6, IL-8 and all women of childbearing age on the drug should
TNF-alpha. Anthralin, depending on the formulation, use contraceptives for at least two years after stop-
can be left in incremental contact with the skin for a ping treatment. Other side effects include xerosis,
few minutes (short contact) or up to 24 hours (long photosensitivity, hyperlipidaemia and bone pain.
contact). Its side effects include irritation and staining Monitoring includes doing fasting triglycerides, liver
of the skin, clothing, bedding, floors and baths. Due enzymes, pregnancy tests when indicated, and an
to its irritating potential, anthralin is best applied and annual x-ray of the spine to exclude diffuse idiopathic
washed off under the supervision of experienced skeletal hyperostosis. Acitretin can be combined with
clinical staff. other therapies, such as phototherapy, methotrexate
or cyclosporine.
Systemic pharmacological therapy • Cyclosporine-A is indicated for moderate to severe
psoriasis after the failure of conventional topical
Systemic therapy is indicated for moderate to severe therapy. It is also useful as rescue therapy in pustu-
psoriasis where the disease is unresponsive to topical lar and erythrodermic psoriasis during the induction
treatment and for psoriasis in special sites, such as the phase. It has a rapid onset of action and it forms
scalp, genitals, palmar-plantar regions and nails. Mode-
rate to severe psoriasis is defined as PASI >10 or BSA
>10% and/or DQLI >10.
• Methotrexate is a folic acid antagonist that has immu-

nosuppressive, immunomodulator and anti-inflam-
matory effects. It suppresses immunity via inhibition

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TREATMENT APPROACHES 217

a complex with cyclophilin, which inactivates cal- Biologics are divided into Treatment approaches
cineurin phosphorylase, preventing the phospho- • TNF inhibitors
rylation of nuclear factor of activated T-cells and, These include etanercept, the receptor-fusion protein
therefore, the transcription of interleukin-2. Inter- and the monoclonal antibodies infliximab and adali-
leukin-2 is required for full activation of the T-cells. mumab.
The starting dose of cyclosporine-A in psoriasis is 2.5- • IL-12/IL-23p40 inhibitor
3 mg/kg/day in two divided doses for 12-16 weeks. Ustekinumab is a monoclonal antibody that tar-
If there is no significant improvement in 4 weeks,
the dose should be increased by 0.5 mg/kg/day gets the common p40 subunit that is shared by IL-
until the disease is stable. The maximum dosage 12 and IL-23.
per day is 5 mg/kg. The dose may also be started • IL-17 targeted therapy
at the maximum dose and be reduced by 0.5 mg/ These are secukinumab, ixekizumab and brodalu-
kg/day. Its side effects include renal toxicity and mab
hypertension. Creatinine levels should be moni-
tored weekly in the first month of use, then monthly. TNF inhibitors
If creatinine increases by more than 30%, the dose
should be reduced. Etanercept
• Phototherapy is indicated for moderate to severe
psoriasis unresponsive to topical treatment. Photo- This is a soluble TNF receptor Fc fusion protein that binds
therapy is available as broadband ultraviolet light B soluble and membrane-bound TNF-alpha, as well as
(UVB), narrow-band (NB-UVB), and psoralen plus UVA lymphotoxin-beta. The dosage is 1 x 50 mg or 2 x 50 mg
(PUVA). NB-UVB can be given to all patients, includ- subcutaneously weekly during the induction phase of
ing children and pregnant women. It is safe and 12 weeks, followed by a maintenance dose of 1 x 50 mg
there is no evidence showing that it causes skin can- weekly. It is contra-indicated in active infections (such
cer. There are, however, difficulties associated with as tuberculosis and acute and chronic hepatitis), con-
its use, including treatment costs and the need for gestive cardiac failure and hypersensitivity to etaner-
frequent visits (three times a week for three months cept. The side effects include infections at the injection
initially). Carcinogenicity limits the use of PUVA. Both site,15 opportunistic and upper respiratory tract infec-
phototherapy and photochemotherapy are used for tions, fever, allergic reactions and hepatitis.
the short-term control of psoriasis. Sunburn is another
side effect of phototherapy. Infliximab

Biologics This is a chimeric monoclonal antibody binding soluble
and membrane-bound TNF-alpha. It is indicated for
These are indicated when traditional systemic therapies moderate to severe psoriasis patients who have failed
have failed to achieve an adequate response or are systemic treatment, psoriatic arthritis, phototherapy and
unsuitable due to comorbidities or not tolerated be- one of the TNF-alpha antagonist treatments. It is adminis-
cause of side effects. tered intravenously at 5 mg/kg body mass at weeks 0, 2
and 6 for induction, followed by infusions every 8 weeks.

Mild Psoriasis plaque type Moderate to severe
Body surface area <10% No arthritis Arthritis

Calcipotriol/betamethasone Phototherapy Refer to a
(Dovobet) Methotrexate rheumatologist
Topical corticosteroids Acitretin
Keratolytics Cyclosporine

Response Combination of topical therapy and systemic therapy

Yes No Response
Yes No
Continue treatment for
maintenance

Continue treatment for Biologics therapy
maintenance

Figure 4. Therapeutic algorithm for plaque-type psoriasis

HANDBOOK OF GENERAL MEDICINE VOL 1

218 TREATMENT APPROACHES

The infusion is given over two hours and the patient is • When the diagnosis is in doubt
observed for an hour. Infliximab is contra-indicated in • Patients with moderate to severe psoriasis
the presence of active infections, such as tuberculosis, • Erythrodermic psoriasis
chronic hepatitis B, heart failure, hypersensitivity to inflixi- • Pustular psoriasis
mab and pregnancy. The side effects include infusion- • Special patient population, such as children, preg-
site reactions, headache, fever, infections, allergic re-
actions and raised liver enzymes. nant women, elderly patients with comorbidities,
those with a history of malignancy, and those who
Adalimumab are to have surgical procedures.
This is a recombinant human immunoglobulin G 1 (IgG1) • Psoriatic arthritis
monoclonal antibody-binding, soluble and membrane-
bound TNF-alpha. The indication is for moderate to References
severe psoriasis, failure of conventional systemic treat-
ment, phototherapy and psoriatic arthritis. Dosage is 1. Deng Y, Chang C, Lu Q. The inflammatory response in psoriasis: A
80 mg subcutaneous on day 0 for induction, followed comprehensive review. Clin Rev Allergy Immunol. 2016;50(3):377-89.
by 40 mg every two weeks for maintenance. It is contra-
indicated in active infections, including tuberculosis, 2. Rapp SR, et al. Psoriasis causes as much disability as other major
congestive cardiac failure, pregnancy and allergy to medical diseases. J Am Acad Dermatol. 1999;41(3 Pt 1):401-7.
adalimumab. The side effects include injection-site re-
action, infections and headache. 3. Kolli SS, et al. Psychosocial impact of psoriasis: A review for derma-
tology residents. Cutis. 2018;102(5S):21-5.
IL-12/IL-23p40 inhibitor
4. Liang SE, Cohen JM, Ho RS. Psoriasis and suicidality: A review of the
Ustekinumab literature. Dermatol Ther. 2018:e12771.
This is a recombinant, human IgG1 antibody with high
specificity and affinity to the p40 subunit of IL-12 and 5. Hawro T, et al. Impact of psoriasis severity on family income and
IL-23. The indications are as for the other biologics, but quality of life. J Eur Acad Dermatol Venereol. 2015;29(3):438-43.
it is also used for psoriatic arthritis. Dosage is 45/90 mg
subcutaneously at weeks 0 and 4 for induction. The 6. Boehncke WH, Schon MP. Psoriasis. Lancet. 2015;386(9997):983-94.
45 mg is intended for patients weighing <100 kg and the 7. Hugh JM, Weinberg JM. Update on the pathophysiology of psoria-
90 mg for patients weighing 100 kg or more. The main-
tenance treatment is 45/90 mg s.c. every 12 weeks. It is sis. Cutis. 2018;102(5S):6-12.
contra-indicated in active infections, including tubercu- 8. Conrad C, Gilliet M. Psoriasis: From pathogenesis to targeted thera-
losis, pregnancy, hypersensitivity and malignancy. The
side effects include upper respiratory tract infections, pies. Clin Rev Allergy Immunol. 2018;54(1):102-13.
pain and reactions at the injection site, headache, sore 9. Bernhard JD. Clinical pearl: Auspitz signs in psoriasis scale. J Am
throat and allergic reactions.
Acad Dermatol. 1997;36(4):621.
IL-17 targeted therapy 10. Golinska J, Sar-Pomian M, Rudnicka L. Dermoscopic features of

Secukinumab psoriasis of the skin, scalp and nails – a systematic review. J Eur
This is a fully human monoclonal IgG1 antibody that Acad Dermatol Venereol. 2018.
binds and antagonises the cytokine IL-17A. Indications 11. Nast A, et al. European S3-Guidelines on the systemic treatment
are for moderate to severe psoriasis which has not re- of psoriasis vulgaris – Update 2015 – Short version – EDF in co-
sponded to conventional systemic therapy. Dosage is operation with EADV and IPC. J Eur Acad Dermatol Venereol.
300 mg subcutaneously at weeks 0, 1, 2, 3, for induction. 2015;29(12):2277-94.
This is followed by 300 mg s.c. every four weeks for main- 12. Lovato P, et al. Calcipotriol and betamethasone dipropionate
tenance, starting in week four. The contra-indications exert additive inhibitory effects on the cytokine expression of in-
are acute infections, including tuberculosis, pregnancy, flammatory dendritic cell-Th17 cell axis in psoriasis. J Dermatol Sci.
live attenuated viruses, hypersensitivity reactions and 2016;81(3):153-64.
cancer. The side effects are infections, diarrhoea, ele- 13. Chen Z. What’s new about the mechanism of methotrexate action
vated liver enzymes and allergic reactions. in psoriasis? Br J Dermatol. 2018;179(4):818-9.
14. Menting SP, et al. Methotrexate dosing regimen for plaque-type
Guideline psoriasis: A systematic review of the use of test-dose, start-dose,
dosing scheme, dose adjustments, maximum dose and folic acid
The treatment algorithm for psoriasis is contained in Fig- supplementation. Acta Derm Venereol. 2016;96(1):23-8.
ure 4. 15. Thomaidou E, Ramot Y. Injection site reactions with the use of bio-
logical agents. Dermatol Ther. 2019:e12817.
When to refer

It is advisable to refer the patient in the following condi-
tions:

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 219

Skin treatments for the patient who wants Treatment approaches
to look younger

M Smit and women. Awareness of the damage UV-radiation
can cause to facial appearance also reduces the risk
MBChB MSc Sports Medicine, Adv Dip Aesth Med of developing cutaneous lesions later in a patient’s life.

Aesthetic and Sports Physician in Private Practice, Pretoria Diagnostic features

The skin is a unique organ with both functional and psy- External characteristics of cutaneous facial ageing in-
chosocial purposes. Facial skin appearance plays a clude:
major role in social perceptions within various cultures • fine and coarse wrinkle formation
and societies. To ensure that skin ageing is treated ef- • pigmentary changes (hyper- and hypo-pigmented
fectively and safely, it remains important to understand
the anatomy, histology and also the pathology of skin lesions)
ageing. This chapter will give an overview of the pathol- • sallow colour
ogy of skin ageing. • dry texture
• loss of elasticity
Prevalence • loss of skin tone
• skin fragility
Cutaneous ageing signs become noticeable from as • telangiectasia
early as the twenties in fairer skin, especially with exces- • keratosis and other sun-induced lesions
sive sun or environmental exposure. The prevalence • sagging subcutaneous tissues
and severity of photo-ageing signs increase with age • underlying facial muscle hypertrophy
and with increased exposure to environmental fac- • volume loss in the face.
tors, in particular solar radiation, as expected. Between
the ages of 30 to 49 years, there is a sharp increase in The extent of photo-ageing is assessed according to
the prevalence of skin changes, both photo-ageing- the Glogau classification (see Table 1). This classification
related, as well as intrinsic, such as wrinkle formation. system is useful to grade a patient before treatment, and
Early facial wrinkles seem to be best ascribed to intrin- also helps guide a physician in terms of the degree and
sic ageing and largely consist of expression lines. These intensity of treatments needed to reverse the ageing signs
include furrows between the eyebrows (frown lines) on the skin.
and fine lines on the forehead, the two earliest signs of
ageing which affect many individuals before the age Histological changes seen in skin photo-ageing or so-
of 30 years. In contrast, signs most clearly ascribable to lar elastosis:
photo-ageing (pigmented spots, i.e. lentigines) affect • Epidermal atrophy or atypia
most patients one to two decades later, depending on • Stratum-corneum-thickening due to slow cell turnover
photo-exposure. Generally, women are more affected • Stratum basale atypia and impairment
psychologically by this situation than men, owing to the • Flattening of the dermo-epidermal junction
widespread social perception that female attractive- • Atypical keratinocytes
ness diminishes with cutaneous ageing. However, the • Irregular distribution of melanocytes
health impact of photo-ageing is similar in both men • Dermal elastosis
• Changes in collagen and elastic fibre network within

the dermis.

Figure 1. External signs of photo-ageing on facial skin

HANDBOOK OF GENERAL MEDICINE VOL 1

220 TREATMENT APPROACHES

Table 1. Photo-ageing: Glogau's classification

I MILD (typically age 28-35)
A. Little wrinkling or scarring
B. No keratosis
C. Requires little or no make-up

II MODERATE (age 35-50)
A. Early wrinkling; mild scarring
B. Sallow colour with early actinic keratosis
C. Little make-up

III ADVANCED (age 50-65)
A. Persistent wrinkling or moderate acne-scarring
B. Discolouration with telangiectasias and actinic keratoses
C. Wears make-up always

IV SEVERE (age 65-75)
A. Wrinkling: photo-ageing, gravitational and dynamic
B. Actinic keratoses with or without skin cancer or severe acne scars
C. Wears make-up with poor coverage

The next important classification – the Fitzpatrick clas- skeletal remodelling, muscular facial activity, and so-
sification (see Table 2) – is fundamental when planning lar changes. With skin ageing, there are two main pro-
treatment protocols. In order to make the correct deci- cesses involved: extrinsic and intrinsic. Extrinsic ageing is
sions and help fulfill the patient’s needs and expecta- caused by environmental factors, such as sun exposure,
tions, the physician has to understand the difference in air pollution, smoking, alcohol abuse, and poor nutrition.
skin type. Intrinsic ageing reflects the genetic background and
depends on time. Various expressions of intrinsic ageing
Wrinkle classification for facial wrinkles: include smooth, thinning skin with exaggerated expres-
• Dynamic wrinkles – only present with movement sion lines. Extrinsically aged skin is characterised by pho-
• Resting – present during rest and movement todamage, such as wrinkles, pigmented lesions, patchy
hypopigmentations and actinic keratoses.
Dynamic wrinkles can often be effectively treated
with muscle-relaxing injections (botulinum toxin type A) Excessive sun exposure (UV-irradiation) activates a
only. This treatment will temporarily prevent the progress complex sequence of specific molecular responses
of dynamic wrinkles to resting wrinkles. When wrinkles that damages the skin’s connective tissue (see Figure
are present during rest and movement, the patient may 1). Chromophores absorb UV and convert the energy
not be completely satisfied with only botulinum toxin into chemical reactions. Photo-ageing is mediated by
treatment. These wrinkles may also need skin-resurfac- direct UV-absorption and ROS-mediated photochemi-
ing, skin-rejuvenating or dermal-filling procedures, com- cal reactions. Skin collagen becomes degraded and
bined with botulinum toxin treatment. thus impairs the structural integrity of the dermis. UV-irra-
diation also impairs ongoing collagen synthesis, leading
Facial muscle action is further classified as: to acute loss of collagen in the skin.
• Hyperkinetic
• Hypokinetic Smoking causes premature ageing and wrinkling of
the face in white and Asian skins. Premature wrinkling
This provides the practitioner with guidance regard- and skin damage increase with increased pack-years
ing the dosage, the frequency of sessions and intensity of smoking. When smoking and excessive sun exposure
of the treatment protocol for wrinkle-relaxing injections. are combined, the effects of smoking on wrinkling are
multiplicative.
Pathophysiology of facial ageing
Genetic aspects and various skin types also affect the
The major forces responsible for facial ageing include ageing process.
gravity, soft-tissue maturation (decline and descent),

Table 2. Fitzpatrick skin types classification

Skin type Colour Reaction to sun
Always burns
I Very white or freckled Usually burns
Sometimes burns
II White Rarely burns
Very rarely burns
III White to olive Never burns

IV Brown

V Dark brown

VI Black

HANDBOOK OF GENERAL MEDICINE VOL 1

*

DYSPORT® OFFERS:

HIGH PATIENT FAST LONG LASTING
SATISFACTION 1 ONSET  2 RESULTS  3

* Natural elegance: In the APPEAL survey, subjects responded that after Dysport® injections, they experienced different feelings, CLOSTRIDIUM BOTULINUM TOXIN TYPE A
including more harmony, self-esteem, youth, beauty, and symmetrical appearance.4

References: 1. Molina B, et al. Patient satisfaction after the treatment of glabellar lines with Botulinum toxin type A (Speywood Unit): a multi-centre European
observational study. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1382-8. doi:10.1111/jdv.12881. Epub 2014 Dec 12. 2. Moy R. et al. Long-term Safety and
Efficacy of a New Botulinum Toxin Type A in Treating Glabellar Lines Arch Facial Plast Surg. 2009;11:77-83. 3.Brandt F, Swanson N, Baumann L, Huber B.
Randomized, placebo-controlled study of a new botulinum toxin type A for treatment of glabellar lines: efficacy and safety. Dermatol Surg. 2009;35(12):1893-901.

S4 Dysport Each vial contains 500 U of Clostridium botulinum type A toxin-haemagglutinin complex. Excipients: Human albumin solution, lactose.
Reg No.: 37/30.4/0683. Applicant: Litha Pharma (Pty) Ltd. Reg. no. 1994/008717/07. LP2761 05/2019.

222 TREATMENT APPROACHES

Overview of treatment options Table 3. Botulinum toxin adverse effects
for facial skin ageing
Adverse event BOTOX® Double- Placebo Double-
This section gives a brief overview of the treatments for blind study period blind study
skin ageing. Refer to further reading for more detailed
information. Performance of the treatments requires (n=405) period (n=130)
practical training.
Headache 13.3% 17.7%
Botulinum toxin for the cosmetic treatment
of facial wrinkles Respiratory 3.5% 3.8%
infection
Facial wrinkles treated with botulinum toxin include gla-
bellar wrinkles, crow’s feet or peri-orbital wrinkles, fore- *Blepharoptosis 3.2% 0.0%
head wrinkles, smoker’s lines or peri-oral wrinkles, mari-
onette lines or mouth-drooping, platysma bands and Nausea 3.0% 2.3%
necklines. Botulinum toxin is also used with advanced
techniques to improve the aesthetic appearance of fa- Flu syndrome 2.0% 1.5%
cial asymmetries.
*Blepharoptosis is consistent with the pharmacological action of
Glabellar lines are the dynamic wrinkles between botulinum toxin and may be technique-related.
the brows caused by the contraction of the corruga-
tor and/or procerus muscles. Movement of corrugator mine the correct dosing into hyperkinetic, hypokinetic,
and procerus muscles can cause the skin between the hypertonic and hypotonic movements.
brows to crease. Peri-orbital wrinkles are dynamic wrin-
kles caused by excessive contraction of the orbital part The most frequently occurring adverse events of botu-
of the orbicularis muscle in a sphincter manner. Peri- linum toxin injections are indicated in Table 3.
oral wrinkles are caused by excessive and repeated
contraction of the orbicularis oris muscle in a sphincter Less frequently occurring (<3%) adverse reactions in-
manner. clude pain in the face, erythema at the injection site,
and muscle weakness. These events are thought to be
As skin becomes less elastic over time, repeated con- associated with the injection and occur within the first
traction of these muscles may create visible lines and week.
wrinkles.
Botulinum toxin is indicated for the temporary im-
Botulinum toxin is injected directly into the muscles provement in the appearance of moderate- to severe
causing the wrinkles, i.e. corrugator and procerus mus- glabellar lines associated with corrugator and/or pro-
cles, where it will enter the nerve endings to block the cerus muscle activity in patients 18 to 65 years of age.
release of acetylcholine, the chemical that causes mus-
cles to contract. Once the muscles are at rest, the skin The most common adverse events following injection
becomes smoother and negative facial expressions are
reduced. Figure 2 illustrates the typical points of injec- include blepharoptosis and nausea. Localised pain, in-
tion of botulinum toxin.
Figure 2. Typical points of injection of botulinum toxin
The lower face is associated with more side effects,
especially in beginner injectors. Upper face injection
should be placed correctly to avoid side effects, such
as lid ptosis, brow ptosis or Mephisto side effect (where
the eyebrows become more arched).

Botulinum toxin is to be reconstituted only with 0.9%
sterile, non-preserved saline (100 units in 2.5 ml saline)
before intramuscular injection. Do not exceed the rec-
ommended dosage and frequency of administration of
botulinum toxin. Botulinum toxin is supplied in 100-unit
and 50-unit vials. Other diluents, including lidocaine,
should not be used for reconstitution. (Refer to the
package instructions of the product.)

Wrinkle classification for botulinum toxin treatment:
• Dynamic wrinkles are wrinkles only present with facial

expressions or movement and are ideal for botulinum
toxin therapy.
• Resting or static wrinkles are present with or without
movement and usually necessitate combination
therapy.
Facial muscle action is commonly classified to deter-

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TREATMENT APPROACHES 223

fection, inflammation, tenderness, swelling, erythema Most side effects are transient, especially with absorb- Treatment approaches
and/or bleeding/bruising may be associated with the able fillers, but may be long-term with permanent fillers.
injection. Patients with neuromuscular disorders, such Some may need medical or surgical intervention.
as ALS, myasthenia gravis or Lambert-Eaton syndrome,
may be at increased risk of serious adverse events. The most feared side effect is the intravascular place-
ment of fillers in certain facial arteries, causing emboli
Serious and/or immediate hypersensitivity reactions and resulting in skin necrosis, ulceration, scarring and
have been rarely reported. These reactions include ana- even blindness.
phylaxis, urticaria, soft-tissue oedema and dyspnoea. If
such a reaction occurs, further botulinum toxin injection Knowledge of facial anatomy, the product used and
should be discontinued, and appropriate medical ther- of the various techniques will limit side effects and pro-
apy instituted immediately. duce superior results.

Dermal fillers Indications for dermal fillers:
• Superficial-wrinkle-filling: peri-orbital lines, peri-oral
Soft-tissue augmentation using dermal filler injections is
a popular method of addressing contour defects that lines, forehead lines, glabellar lines, superficial acne
result from ageing, photo damage, trauma and/or scars
scarring or disease. Numerous filling agents exist; there- • Medium-wrinkle-filling: nasolabial folds, lip augmen-
fore the physician is responsible for knowing which sub- tation, marionette lines, tear-trough deformities
stance is best suited to address a particular defect in • Volumising filling: cheek enhancement, mid-face re-
the individual patient. juvenation, chin- and nose-remodelling, lipo-atrophy
correction
Consensus exists on the properties of the ideal dermal Injection techniques used with dermal-filling (see Fig-
filler; these properties include the following: safety, ef- ure 3):
fectiveness, reproducible technique and result, easy to • Multipuncture technique with needle for superficial
inject, high use potential, low abuse potential, non-car- injections
cinogenic, non-teratogenic, non-migratory, cost-effec- • Linear threading for medium lines or folds
tive, physiologic, semi-permanent, minimal side effects • Fanning or cross-hatching for volumising areas
and legally registered. • Cannula technique, which has become more popu-
lar due to the decreased risk of intravascular place-
Hyaluronic acid remains the international gold-stand- ment, reduced bruising and swelling.
ard dermal filler for cosmetic indications. Numerous
other fillers are also available worldwide, but may be A Serial puncture B Linear threading
restricted due to local legislation. These can include bo-
vine and porcine collagen, autologous collagen, cal- C Fanning D Cross-hatching
cium hydroxyl apatite, calcium triphosphate, poly lactic
acid, poly acrylamide, silicone and others. 1

Fillers are classified as either absorbable, semi-per- 23 9
manent or permanent. Permanent fillers are associated 8
with greater side effects and long-term complications. 5
Hyaluronic acid fillers can be reversed with an enzyme, 47
hyaluronidase, to correct incorrect placement, making
this a better product due to its reversibility. 6

Side effects and complications should always be Figure 3. Injection techniques used with dermal-filling
communicated to the patient before injection.
Often prior injection with botulinum toxin over an area
The general class side effects of fillers may include the with excessive movement will improve results and mini-
following: mise migration of the dermal filler.
• Swelling
• Bruising or haematomas Chemical peels
• Erythema
• Localised infections This is a chemical exfoliation using a chemical solution
• Allergic reactions to induce a healing process after a controlled depth of
• Nodule formation injury. It is used to improve and smooth the texture of the
• Migration of product
• Granuloma formation
• Local skin necrosis that can occur with occlusion of

superficial cutaneous vessels
• Rarely, anaphylactic reactions
• Cyst formation

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224 TREATMENT APPROACHES

facial skin by removing the indicated damaged outer Refer to Table 4 for peeling agents, actions and benefits.
layers. It removes selected layers of sun-damaged skin Chemical peels remain an affordable method of reju-
cells, stimulates cell-healing and produces skin that has venating ageing skin and treating other skin imperfec-
a more even surface and colour. It also focuses on stim- tions or pathological changes of the skin.
ulating fibroblasts, with resultant new collagen forma- Superficial peeling treatment is suitable for almost all
tion and increased glycol-amino glycans, and thereby skin types and has very few limitations. The treatment
improves skin texture and appearance. Peels may result procedure is very simple and does not have many risks
in superficial, moderate-depth or deep skin injury. if the procedure is followed according to instruction.
This treatment can be done two- to four-weekly and
Alpha hydroxy acids (AHAs) – such as glycolic acid, continued treatment results in a healthier skin barrier,
gluconolactone, lactic acid, salicylic acid, phytic acid, enhanced appearance and reduced photo-ageing
kojic acid and other agents – are used for superficial pathologies.
peeling of the skin. Agents used for medium-depth peel- Medium and deep peelings require more intensive
ing of the skin include a combination of trichloroacetic training of the physician to understand skin reactions,
acid (TCA) and other agents. Phenol and certain other wound-healing, post-care and other aspects that will
agents are used for selective, deep peeling of the skin. ensure safe and effective therapy.

The precise formulae used may be adjusted to meet Skin mesotherapy
the patient's needs. Chemical peels are indicated for
skin imperfections, wrinkles, uneven skin pigmentation, This treatment focuses on treating skin-ageing at vari-
photo damage and melasma. They may also remove ous levels of the skin, from epidermic through to dermal
pre-cancerous skin growths, soften facial acne scars level. The treatment originated in France; French physi-
and even control acne.

Table 4. Peeling agents: actions and benefits

Peeling agent Depth of peel Actions Benefits
Glycolic acid Superficial Reduces wrinkles, photoageing, acne
Keratinocyte discohesion and dull skin, skin renewal, depigmenting
Kojic acid Superficial Epidermolysis action
Azelaic acid Increases type 1 collagen and hyaluronic
Lactic acid Superficial acid in skin Reduces pigmentation and melasma
Superficial Comedolytic
Phytic acid Reduces pigmentation and melasma
Superficial Depigmenting action: reduces synthesis
Salicylic acid of melanin by inhibiting activity and Skin renewal, skin hydration
Retinoic acid Superficial synthesis of tyrosinase, regulates melanin and exfoliation
Superficial production
Trichloracetic acid Reduces pigmentation and inflammation
Phenol <15% Superficial Tyrosinase inhibition, regulates melanin
>20% Medium production, keratinisation normalisation, Improvement of acne and blocked pores
Deep anti-bacterial action, anti-oxidant action Wrinkles, active acne, pigmentation
and photo-ageing reduction
Keratolysis, metabolic stimulation by
interfering with enzymes to decrease Wrinkles and photo-ageing reduction,
corneocyte cohesion, renewal of improvement in acne scars and stretch
epidermal cells, skin hydration, collagen marks
deposition Photo-ageing reduction, depigmenting,
anti-wrinkle (medium- to deep wrinkles),
Anti-oxidant reduces acne-scarring, skin-tightening
Chelating action on iron, copper and
calcium
Lightening action by blocking the
entrance of iron and copper in the
formation of melanin

Keratolysis, comedolytic, antibacterial
action

Corneus cells desquamation,
keratoregulating, comedolytic,
keratinisation normalisation, protects
collagen fibres, regulates melanin
production

Protein precipitation, dissolves keratin,
coagulates skin proteins, augments
collagen production

Keratin protein coagulation, augments
collagen production, antiseptic,
antifungal, anaesthetic properties

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 225

Table 5. Summary of treatments Treatment approaches

Treatment Mechanism of action Indication for use Side effects
Muscle relaxants Dynamic wrinkles
Botulinum toxin type A Blocks the release of Temporary headaches, eyelid ptosis, poor
acetylcholine, reducing placement with incorrect muscle paralysis
Dermal fillers the activity of the
Cross-linked hyaluronic targeted muscles. Superficial, medium and Safest filler on the market, but nodule
acid deep wrinkles formation and granulomas are possible.
Volume replacement in Volume replacement Poor placement can be corrected with
Porcine collagen the dermis hyaluronidase
Medium and deep Nodule formation, granulomas (especially
Polyacralimide Volume replacement in wrinkles in other collagens), poor placement
Calcium hydroxyl apatite dermis Volume replacement
and calcium triphosphate Medium and deep Nodule formation, granulomas, poor
Chemical peels Volume replacement in depressions placement
Glycolic acid peels dermis Medium and deep Too-superficial placement can lead to
Volume replacement in depressions granulomas and nodules
Salicylic acid peels deep dermis or subdermis
Trichloracetic acid peels level Skin ageing, pigmentary Poor technique and formulation can cause
changes, superficial deeper skin damage with side effects
Phenol peels Keratolysis wrinkles and skin similar to TCA peels
Epidermal healing imperfections
Fibroblast stimulation
Acne and blocked pores Same as with glycolic acid.
Keratolysis Salicylism and salicylic acid toxicity

Protein denaturation of Medium-depth wrinkles, Post-treatment hyperpigmentation is
the epidermis and mid- pigmentation and skin common in Fitzpatrick skin types 3 and
dermal level imperfections above
Deep dermal
denaturation Medium and deep Poor formulation and aftercare has a high

wrinkles, severe cutaneous risk of permanent hypopigmentation and

ageing changes scar formation

cians have been using the technique to treat various When to refer
pathologies since the 1940s.
It is important to maintain good relationships with medi-
Mesotherapy is a safe and effective method to re- cal colleagues. Refer cancerous skin lesions to a der-
plenish ageing and dehydrated skin with the necessary matologist. Severe cutaneous and facial ageing that
vitamins, minerals and especially hyaluronic acid. The needs surgery should be referred to a plastic surgeon
technique used for skin rejuvenation consists of super- to avoid patient dissatisfaction with non-invasive proce-
ficial, multiple and fast injections over the skin surface dures.
to ensure complete skin cover. The injection techniques
require some training, and include “nappage” or epi- Further reading
dermal, multi-puncture methodology. Mesotherapy
techniques are often replaced with skin-needling de- 1. Redaell A, Braccini F. Facial ageing. Oeofirenze. 2012;44- 60.
vices. These consist of a roller with fine needles that cre- 2. Puizina Ivic N. Skin ageing. Acta Dermatovan APA. 2008;17:2:47-54
ate multiple punctures in the skin surface, allowing the 3. Glogau RG. Chemical peeling and ageing skin. J Geriatr Dema-
mesotherapy solution to penetrate the epidermis and
dermis. The skin-needling rollers or electronic devices tol.1994;2:30-35
require fewer skills than traditional mesotherapy tech- 4. Kokoska MS, Thomas JR. Anatomy and pathophysiology of facial
niques.
ageing. Facial Plast Surg Clin North Am. 2001;9:179-187
Other skin treatments used for facial skin ageing not 5. Carruthers A and J. Botulinum toxin. Elsevier Inc. 2005
discussed in this article include various light- and laser- 6. Sengelmann RD. Dermal fillers. eMedicine Specialities. Feb 2006
based techniques, such as IPL, fractional laser, radiofre- 7. Chemical peel patient education information. ASAPS information
quency, PDT and PDT-ALA, laser treatments and various
other evolving therapies. website. Updated 2007.

Summary of treatments HANDBOOK OF GENERAL MEDICINE VOL 1

Table 5 summarises the skin-ageing treatments.

Notes

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CIPLA MEDPRO (PTY) LTD. Co. Reg. No. 1995/004182/07. Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA. Website: www.cipla.co.za
Customer Care: 080 222 6662. 1121276a

Each actuation delivers Salmeterol 25 µg, Fluticasone propionate 50 µg; 125 µg; 250 µg. For further prescribing information, refer to the package insert.
A 21.5.4 S4 Reg. No. 42/21.5.4/0218, 0219, 0220

CIPLA MEDPRO (PTY) LTD. Co. Reg. No. 1995/004182/07. Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA. Website: www.cipla.co.za
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