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Disorders of keratinocytes- Psoriasis

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Disorders of keratinocytes- Psoriasis Powered By Docstoc
					Section 5: Disorders of skin components

Chapter 20: Disorders of keratinocytes: Psoriasis
Definition                                        (autosomal dominant) and at the opposite end
     A common, chronic, disfiguring,              is the more common form in which an obvious
inflammatory and proliferative skin disease, in   family history may be lacking and it is likely
which both genetic and environmental factors      that changes in multiple genes interacting both
have a critical role. The most characteristic     with each other and the environment, are
lesions are plaques (red, scaly, sharply          required for disease expression. The major
demarcated, indurated) present particularly       psoriasis genetic determinant is PSORS1,
over extensor surfaces and scalp. The disease     which probably accounts for 35-50% of the
is enormously variable in duration, periodicity   heritability of the disease and is located within
of flares and extent. Morphological variants      the MHC on chromosome 6p. Guttate
are common.                                       psoriasis is strongly associated whereas
                                                  palmoplanter pustulosis and late-onset (> 50
Epidemiology
                                                  years of age) psoriasis are not associated with
Incidence and prevalence: Prevalence is 1.5-
                                                  PSORS1.
3% of population of Western Europe and
                                                  Environmental factors: These are implicated
USA, 0.3% in China, and psoriasis is absent in
                                                  in the initiation and/or the exacerbation of
Latin American Indians. The incidence is 60
                                                  disease.
individuals per 100.000 per year (new cases).
There is a seasonal variation with 68% of         • Trauma: Psoriasis at the site of an injury is
cases first diagnosed in winter. Psoriasis        well known (Koebner phenomenon).
vulgaris (chronic plaque psoriasis) makes 90%     • Infection: Acute guttate psoriasis is strongly
of the cases while the variants account for       associated with preceding or concurrent
approximately 10%.                                streptococcal infection, particularly of the
Age of onset: Any age. There are 2 peaks: a       throat. Also, streptococcal infection may be
larger early peak (16-22 years) and a later one   important in chronic plaque psoriasis and
(57-60 years). The bimodal peak in disease        treatment with rifampicin and penicillin may
onset could be taken as evidence for the          lead to clearance of skin lesions. Acute guttate
existence of 2 pathogenetically different forms   psoriasis is much more common in individuals
similar to diabetes mellitus. Type 1 with early   with a family history of plaque psoriasis. One-
onset and more severe course and type 2 of        third of cases of guttate psoriasis progress to
late onset and mild course.                       the chronic plaque form.
Sex: Males and females are equally affected.      • Drugs: Some drugs may be responsible for
Aetiology                                         the onset or exacerbation of psoriasis e.g.
      Unknown. Psoriasis results from             lithium salts, antimalarials, β-blockers,
interplay of genetic and environmental factors.   NSAIDs, ACE inhibitors, and the withdrawal
Genetic factor: Evidences are that the            of corticosteroids.
incidence of psoriasis is much greater amongst    • Sunlight: Although sunlight is beneficial in a
first-and second-degree relatives of patients     minority of patients, psoriasis may be
than unaffected control subjects and, that the    provoked by strong sunlight which can also
incidence in monozygotic (identical) twins is 4   cause exacerbations in exposed skin during
times higher than in dizygotic twins.             summer. PUVA can be helpful in these
      The risk for a child to develop psoriasis   patients.
is 14% if one parent was affected, 41% if both    • Pregnancy: Approximately 50% improve
parents affected and 2% when no parent is         during pregnancy and 50% worsen during
affected.                                         postpartum period.
      The mode of inheritance in psoriasis        • Psychogenic factors: Stress has a role in
represents a spectrum: at one end are the rare    onset and exacerbation of psoriasis. Psoriasis
families in which changes in a single gene        has a detrimental effect on the psychological
may be sufficient to cause the disease            quality of life of patients.


                                              -227-
• Alcohol and cigarettes: Have a detrimental       capillaries contribute to the inflammatory
effect on psoriasis. Alcohol may exacerbate        process actively through surface expression of
the disease.                                       molecules involved in leukocyte homing. E-
• AIDS: Psoriasis flares severely if the patient   selectin is induced and intercellular adhesion
develop AIDS and if patients with AIDS             molecule-1 (ICAM-1) up-regulated on dermal
develop psoriasis de novo it is explosive in       vessels in lesional tissue, thus providing a
form. The prognosis of AIDS in patients with       mechanism for skin homing T lymphocytes to
psoriasis is poor.                                 accumulate within lesional dermis and
                                                   epidermis.
Pathogenesis                                       Immunopathogenesis: It is thought that
      This involves 3 cardinal features:           immunological factors play an important role
epidermal proliferation, dilatation and            in the pathogenesis of psoriasis and evidences
proliferation of dermal blood vessels
                                                   include:
(angiogenesis),      and     accumulation    of
                                                   1. Early influx of T lymphocytes into
inflammatory cells, particularly neutrophils
                                                   expanding lesions.
and T lymphocytes.
                                                   2. Strong association with MHC, particularly
Epidermal proliferation: There is increased
                                                   HLA-Cw6.
keratinocyte proliferation which is a
                                                   3. Ablative effect (albeit temporary) of anti-T
consequence of an increase in the proliferating
cell compartment in the basal and suprabasal       cell therapy e.g. ciclosporin.
levels of the epidermis, and not because of        4. Increased number and function of APCs,
shortened cell cycle time. The number of           (Langerhans’ cells and dermal dendrocytes) in
cycling cells is increased approximately 7         psoriatic plaques.
fold. These changes are not specific for           5. Development of psoriasis after bone
psoriasis as, for example, increased numbers       marrow transplant from psoriatic donor.
of proliferating keratinocytes are also seen in    6. The innate immune cytokine TNF is
wound healing and atopic dermatitis. Multiple      unregulated in psoriasis.
growth factors which mediate keratinocyte          7. Anti-TNF treatment is effective in psoriasis.
proliferation are present in lesional skin         8. Abundance of IL-23 in psoriatic tissue.
especially transforming growth factor-α            9. Circulating levels of IL-22 correlate with
(TGF-α).                                           disease activity.
Angiogenesis: Vertical dermal capillary loops      10. Response of psoriasis to ustekinumab,
in lesional skin are dilated, elongated and        which is a human monoclonal antibody
twisted. This is due to angiogenesis (vascular     against IL-23.
growth) by proliferation of endothelium of               Historically, evidence has suggested a
micro-vasculature of upper dermis which            primary role for Th1-type response in
increases to 4 fold. Epidermal keratinocytes       psoriasis pathogenesis. However, it has
are the primary source of angiogenic activity      recently been established that a more recently
by secreting mediators with angiogenic             described subset of T cells, thought to play a
activity e.g. interlukin-8 (IL-8), TGF-α, tumor    key role in autoimmunity, termed Th17, is the
necrosis factor-α (TNF-α), and vascular            primary pathogenic subset. IL-23 is a key
endothelial growth factor (VEGF). VEGF is          cytokine in generation of Th17, and is
over-expressed in psoriatic epidermis as are its   abundant in psoriatic tissue. Other cytokines
receptors on lesional psoriatic micro-             downstream of IL-23 in Th17 pathways,
vasculature.                                       include IL-17 and IL-22, have similar
Accumulation of inflammatory cells: T              functional effects.
lymphocytes have an important role in the                A pathogenic model has been suggested
development of plaques of psoriasis. There is      in which aberrations in the stratum corneum
early influx of T cells in expanding lesions.      trigger activation of innate immune
There is increased antigen presentation in         mechanisms, which in turn lead to recruitment
psoriatic plaques. Also, anti-T-cell therapy is    and activation of Th17 cells, which produce
ablative (though temporary) in psoriasis.          effector cytokines leading to epidermal
      Leukocyte homing into skin is induced        proliferation and a pro-inflammatory state.
by inflammatory mediators such as histamine,       Such mechanisms are the basis for the use of
neuropeptides, IL-1 and TNF-α. Dermal              biological therapies.


                                               -228-
Koebner and reverse Koebner phenomena:              Age
Trauma may elicit psoriasis in previously           • Children: Onset is most commonly with acute
uninvolved skin. The Koebner reaction usually       guttate psoriasis and less commonly with scalp
occurs 7-14 days after injury. Clearing of          psoriasis. Face affection is more common in
existing psoriasis following injury is termed       children than adults. Serious forms are rare in
the reverse Koebner reaction. One study found       children (erythrodermic, generalized pustular,
that 25% of patients gave a Koebner reaction        arthropathic). Congenital psoriasis is very rare.
and 67% a reverse Koebner reaction. These           Uncommon types include napkin psoriasis,
reactions suggest the presence of a circulating     pustular acrodermatitis, flexural and nail
element controlling the expression of the           psoriasis. Atypical forms include follicular
disease throughout the skin.                        psoriasis, one side plaque of eyelid and
                                                    unilateral perléche.
Histopathology                                      • Adults: Onset is commonest with scalp or
     Dermal changes (vasodilatation, papillary      elbows and knees. Sometimes flexural, nails
oedema and leukocyte infiltrates) precede           only, penis only, or acute guttate.
epidermal changes.                                  Symptoms
Epidermal changes                                   • Burning sensation: In erythrodermic and
                                                    generalized pustular psoriasis.
• Stratum corneum: Greatly thickened, mainly
                                                    • Itching: Very variable. It occurs in scalp
by parakeratotic cells (with slight hyper-
                                                    psoriasis, guttate psoriasis, unstable psoriasis
keratosis) arranged in lamellae with air spaces
                                                    and secondary infected flexural psoriasis. If in
in-between, causing the silvery appearance of       ordinary psoriasis it is psychogenic.
the scales. Parakeratosis is prominent.               General features
• Stratum granulosum: Absent or reduced.            • Primary lesion: Papules: Pinhead or larger
• Stratum Malpighii: Epidermal proliferation        (2-10mm), round, flat, well-defined, non-
(acanthosis) mainly the cells of the rete ridges.   itchy, dry, red (salmon-pink) and scaly.
Mitotic activity increased 10 times.                • Secondary lesions: Plaques: Same features
• Rete ridges: Greatly elongated and branched       as papules but larger than 1cm. they are
or club-shaped. Supra-papillary epithelium is       hypohidrotic due to obstruction of sweat ducts
much thinned (only 2-3 layers).                     in the stratum corneum by psoriasis cells. The
• Munro microabscesses: Intra-corneal, small,       psoriatic plaque may be enriched by a clear
collections of polymorphs which enter the           peripheral zone, the halo or ring of woronoff.
epidermis through the thinned suprapapillary        • Scales:
epithelium.                                         - Ordinary plaque psoriasis: Scales are silvery
• Spongiform pustule of Kogoj: Large,               white, dry, large and adherent.
multilocular, within the Malpighian layer, also     - Rupioid psoriasis :Waxy-yellow.
made of polymorphs.                                 - Guttate psoriasis: Single waxy scale
                                                    (differential    diagnosis    from     pityriasis
Dermal changes                                      lichenoides chronica).
     Occur in the papillae. There is oedema,        - Flexural psoriasis: Scales minimal and loss
vasodilatation, and the capillaries are             of silvery character.
increased, elongated and tortuous. Papillae are     - Auspitz sign (3 stages): Scratching produces
elongated and club-shaped (papillomatosis).         scales. More scratching displays the Buckley’s
Mixed mononuclear and neutrophil infiltrate.        (suprapapillary) membrane. More scratching
                                                    leads to bleeding points (over the suprapapillary
Auspitz sign                                        epithelium).
      The bleeding points are due to thinned
supra-papillary epidermis and the dilated           Morphological types of psoriasis
capillaries in the upper part of papillae.          Typical types
                                                    Guttate psoriasis: It is the shower of small
Clinical features                                   lesions (papules 2-10mm) over the body, in
Onset: Psoriasis may occur at any age. Its          children and young adults, and after acute
duration may vary from a few weeks to a             streptococcal infection. In the early stages the
whole lifetime. The course is unpredictable,        colour is not specific and there may be little
and the variations are numerous.                    scaling but later single waxy scale. There is



                                                -229-
itching and the number of lesions may be            Types according to site
numerous or few.                                    Scalp psoriasis: May be diffuse or occur as
Chronic plaque psoriasis: Commonest type,           discrete plaques. Scales may be thin or thick
plaques of variable sizes and shape, single or      and firm (rupioid). Pityriasis amiantacea,
multiple, on limbs, trunk, scalp.                   which occurs in children and young adults,
Pustular psoriasis: See later.                      may be an early manifestation of psoriasis.
Rupioid and elephantine psoriasis: These            Hair loss, sometimes cicatricial, is seen is this
terms describe plaques associated with gross        condition which consists of plaques of
hyperkeratosis. Rupioid psoriasis refers to         asbestos-like scaling, firmly adherent to the
cone-shaped lesions with scales which are           scalp and hair. Alopecia is unknown in scalp
firm and waxy yellow and occurring on the           psoriasis but psoriatic erythroderma is
soles or scalp. Elephantine psoriasis refers to     associated with severe hair loss.
large plaques with thick scaling that               Penis psoriasis: A single plaque without
sometimes occur on the back, hips or limbs.         scales but diagnosed by colour and well-
Erythrodermic psoriasis                             defined edge. To be differentiated from
• Two forms exist: In the first form, chronic       erythroplasia and Zoon’s balanitis.
lesions evolve gradually into extensive             Flexural (inverse) psoriasis: May occur de
plaques involving almost all the skin.              novo or as a Koebner phenomenon on top of
However, there are islands of uninvolved skin,      seborrhoeic or infective dermatitis. Scaling is
the psoriatic characteristics are retained, mild    minimal and not silvery but diagnosed by the
                                                    salmon pink colour of psoriasis, well-defined
treatment is well-tolerated and the prognosis is
                                                    edge, and failure of antibacterial or antifungal
good. The second form evolves from unstable
                                                    treatment. The surface has a glazed hue and
psoriasis either suddenly or after a period of
                                                    fissuring at the depth of the fold in common.
intolerance to treatment. It can be precipitated
                                                    Palms and soles psoriasis: It may present as
by infections, hypocalcaemia, antimalarials,
                                                    typical scaly patches in which fine silvery
tar, and classically by withdrawal of
                                                    scales can be evoked by scratching, as less
corticosteroids. The characteristics of psoriasis   well-defined plaques resembling lichen
are lost, the whole skin is involved, the           simplex or hyperkeratotic eczema, or as an
patients may be febrile and ill, the course is      acropustulosis. It may often be difficult to
often prolonged, relapses are frequent and          distinguish psoriasis from chronic eczema,
there is an appreciable mortality. In contrast to   with which it may sometimes alternate.
the table form, itching is severe.                  Nail psoriasis: Occurs in 25-50% patients and
• Metabolic complications of erythroderma           with all types of psoriasis. Pitting is the most
•• Disturbed body heat regulation: Danger of        frequent change. Pits, ridges and grooves
hypothermia under normal environmental              result from psoriasis of the nail matrix,
temperatures because of excessive heat loss         whereas onycholysis, subungual hyper-
from the body surface (partially compensated        keratosis and splinter hemorrhages are due to
by heat production from catabolism of               disease of the nail bed. Circular areas of
muscles i.e. wasting). Danger of hyperthermia       yellows brown discoloration of the nail bed
under high environmental conditions because         may resemble an ‘oil drop’ below the nail.
of hypohidrosis resulting from occlusion of         Seborrhoeic psoriasis: This is seborrhoeic
sweat ducts.                                        dermatitis on top of psoriasis or vice versa.
•• Hemodynamics: Skin blood flow, blood             They may alternate. Scales are soft and greasy
volume and cardiac output may be increased          rather than dry and shiny.
and together with anaemia may lead to heart         Mucosal psoriasis: Rare; 3 types: lips (silvery
failure in cardiac patients                         scaling), tongue (geographical tongue, benign
•• Malabsorption: Dermatogenic enteropathy.         migratory glossitis), and buccal (plaques or
•• Hypoalbuminaemia: Leading to oedema. It          annular lesions, yellowish-grey, diagnosed only
is caused by malabsorption and also protein         by presence of psoriasis elsewhere and biopsy).
(keratin) loss in excessively exfoliated scales.    Ocular psoriasis: Recorded are blepharitis,
•• Barrier skin efficiency: It is impaired          conjunctivitis and keratitis. Uveitis in patients
leading to increased transepidermal water loss.     with psoriatic arthritis or generalized pustular
•• Urine output: Tends to drop.                     psoriasis.


                                                -230-
Atypical types
• Digital and interdigital psoriasis.                Differential diagnosis
• Verrucous psoriasis (on the legs).                 Diseases with psoriasiform appearance
• Follicular psoriasis (in children, confused        • Psoriasiform seborrhoeic dermatitis: Lighter
with PRP).                                           colour, less well-defined, scales greasy and
• Linear psoriasis (Koebner to injury).              yellow, both may alternate or co-exist.
• Zonal psoriasis (Koebner after herpes              • Psoriasiform syphilide: Coppery red,
zoster).                                             infiltrated, condyloma lata, serological tests.
• Gyrate, geographical, annular and circinate        • Psoriasiform eczema: Sometimes eczema of
psoriasis.                                           the legs has a psoriasiform appearance but
                                                     there is itching, ill-defined edge and history of
Unstable psoriasis                                   oozing.
      It is not a type of psoriasis but a phase of   • Psoriasiform eczema in adults with
the disease in which activity is marked and          malabsorption         syndrome:        Lichenified,
the course and immediate outcome is                  pigmented, itching, response to gluten-free
unpredictable. It occurs when a previously           diet.
stable and chronic form is exacerbated by            • Psoriasiform carcinoma: A name given to
inappropriate treatment and threatens to             patches of Bowen’s disease, Paget’s disease,
become erythrodermic or pustular. Patients           and erythroplasia of penis having a
may develop such unstable phases repeatedly,         psoriasiform appearance. However there is
setting back again into the classical forms of       crusting, raw oozing base, and biopsy is
the disease. The condition is caused by              diagnostic.
withdrawal of intensive systemic or topical          • Psoriasiform patches of PRP: Follicular
corticosteroid therapy, hypocalcaemia, acute         keratosis, scaly scalp, etc.
infection, overtreatment with tar, dithranol or      • Psoriasiform lesions in mycosis fungoides.
UVR, or stress.                                      • Psoriasiform lesions in sarcoidosis
Reactive arthritis (formerly Reiter’s disease)       • Psoriasiform lupus vulgaris on legs.
      This is a syndrome of urethritis (caused       • Psoriasiform drug eruptions.
mainly by chlamydia trachomatis), arthritis            Psoriasis with atypical morphology
(polyarthritis and sacroiliitis), ocular changes     • Annular and circinate psoriasis: Erythema
(conjunctivitis, iritis), and oral ulcers in         annulare centrifugum, necrolytic migratory
addition to skin lesions. These occur in 5%          erythema, subcorneal pustular dermatosis.
of the patients with predilection for the soles,     • Erythrodermic        psoriasis:     Causes      of
legs, penis, hands, fingers, nails and scalp.        erythroderma.
The lesions of soles usually have thick              • Follicular psoriasis: PRP.
yellow scale and are often pustular                  • Verrucous psoriasis of legs: lichen planus.
(keratoderma       blenorrhagica).      Psoriatic    Psoriasis of special sites
plaques on the penis are referred to as              • Palms: Hyperkeratotic eczema, PRP, lichen
balanitis circinata. The course of the disease       planus, porokeratosis, and trichophyton
is often self-limited, lasting weeks or months,      rubrum infection.
but some patients may have chronic and               • Soles: PRP, porokeratosis, tinea pedis.
disabling disease.
                                                     • Flexural psoriasis: Seborrhoeic dermatitis,
Disease associations                                 tinea cruris, candidiasis.
     Psoriasis may coexist or alternate with         • Penis: Lichen planus, erythroplasia, Zoon’s
lichen planus, seborrhoeic dermatitis and            balanitis.
lichen simplex. There is a negative association      • Scalp: Lichen simplex, scaly scalp.
with atopic dermatitis. There is a positive          • Forearm near elbow: Lichen simplex
association with heart disease, hypertension,        (itching, elbow not affected).
and diabetes mellitus.                               • Acute       guttate      psoriasis:     Pityriasis
Laboratory findings                                  lichenoides chronica.
     There is no consistently present                Course and prognosis
laboratory abnormality in uncomplicated                   The course is unpredictable. It is usually
psoriasis.                                           chronic with remissions and relapses.

                                                 -231-
Remissions may occur for months or years,            then once or twice weekly for maintenance
with or without treatment. However, relapses         therapy. The use of anthralin is declining,
are the rule. Even severe cases can be               giving more way to topical corticosteroids and
maintained in prolonged remission by the use         calcipotriol.
of methotrexate, PUVA, ciclosporin or oral           • Topical corticosteroids: They are the
retinoids. Guttate psoriasis has the best            mainstay of topical therapy. In appropriate
prognosis. Pregnancy is beneficial in 50%.           concentrations, they are the treatment of
There is a high morbidity in arthropathic            choice on the face and neck, flexures, and
psoriasis and high mortality in erythrodermic        genitalia, where neither dithranol nor tar are
and pustular psoriasis. Only 3% of cases of          tolerated. Diluted topical corticosteroids are
napkin psoriasis develop later to true psoriasis.    also used in unstable, erythrodermic and
                                                     generalized pustular psoriasis, in preference to
Treatment of psoriasis                               tar or dithranol, although blend emollients
Topical therapy                                      may be more suitable. On the scalp and other
• Tar: It is assumed to have an antimitotic          parts of the body, they can be tried if tar has
effect (inhibition of DNA). The Goeckerman           failed and dithranol is inappropriate or
regimen has been a mainstay in in-patient            unsuccessful. Enhancement of corticosteroid
treatment. It is daily application of 2-5% crude     effect by polythene occlusion will magnify the
coal tar, combined with a tar bath and UV            side effects. Apart from side effects on the
light. It can clear stable discoid psoriasis in 3-   skin, plasma cortisol levels may be suppressed
6 weeks in 80% of patients. Concentrations of        by the most potent preparations (e.g.
coal-tar solution up to 10% can be                   clobetasol       propionate,      betamethasone
incorporated in various vehicles and many            dipropionate) or high doses.
commercial creams, ointments, lotions, gels                Presence of unwanted effects and the
and shampoos are available.                          occurrence of tolerance induced by intensive
      Tar is safe. Irritant contact dermatitis is    therapy, have stimulated the use of less
uncommon expect in unstable psoriasis, and on        frequent applications. These proved to be
the face, genitals and in the flexures. Allergic     effective in inducing and maintaining
contact dermatitis is rare. Folliculitis is the      remission for up to several months. Examples
most common side effect. Coal tar is                 are the use of 0.05% clobetasol propionate on
contraindicated       in    erythrodermic     and    alternate days, betamethasone dipropionate 3
generalized pustular psoriasis and with pre-         times over a 24h period each week (weekend
existing folliculitis or severe acne. Oil of cade    therapy), and fluticasone propionate once
is the form of tar used for psoriasis of the scalp   daily for 2 consecutive days per week.
or face in ointments of 1-10% concentration.               Intensive treatment of discoid psoriasis
• Anthralin (dithranol): It is effective for         with potent preparations can induce
chronic plaque psoriasis but is not suitable for     generalized pustular psoriasis. With less
head and neck, flexures or genitalia because it      potent or diluted preparations, the volume can
is too irritant. It also stains bed line and         be increased. Potent preparations are likely to
clothing irreversibly. This drug inhibits            be needed on the scalp and the knuckles
Keratinocyte proliferation.                          particularly. Conversely, the flexures and
      The original Ingram regimen (in-patient,       inner thighs need much weaker products, if
tar bath followed by suberythema UVB,                striae formation is to be avoided.
followed by dithranol paste application for                Triamcinolone acetonide (10 mg/ml) can
18h daily) is replaced by more simple                be infiltrated intradermally in localized
regimen. Anthralin paste or cream can be used        lesions. It is valuable in troublesome resistant
on an outpatient or in-patient basis and will        lesions on the back of hands and knuckles and
clear up the lesions in most patients within 3       intensely pruritic plaques. The effect is long-
weeks. In short contact therapy, start with          lasting and repetition of the injection may be
0.1% anthralin applied for 30 minutes and            unnecessary for several months. In treatment
then washed off. Check for irritation at 48          of psoriasis of fingernails, the nail fold can be
hours. According to tolerance the potency can        injected, but results are disappointing and the
be increased (to 0.3%, 0.5%, or 1%) and the          procedure is painful.
contact time shortened or, for resistant             • Vitamin D analogues: Calcitriol, the naturally
plaques, increased. Used daily for clearing and      occurring active metabolite of vitamin D3 and

                                                 -232-
its synthetic analogues e.g. calcipotriol, are       but may be helpful in intertriginous and facial
effective in psoriasis. The mechanism of action      psoriasis where there is better absorption.
is via binding to vitamin D 3 receptors on           • Treatment of the scalp: Psoriasis of the scalp
keratinocytes and inhibition of keratinocyte         can be intractable and resistant to therapy.
proliferation and differentiation and also           Tar-containing shampoos should be the first
inhibition of T-cell activation. Calcipotriol        approach, carried out daily if necessary. Tar
(50µg/g) ointment is as effective as 0.1%            lotions or gels, may be added, rubbed in at
betamethasone valerate ointment and more             night and shampooed out the following
effective than tar or dithranol therapy in plaque    morning. An ointment containing tar (oil of
psoriasis. Calcipotriol cream is slightly less       cade 15%) and salicylic aid (2%) applied at
effective than the ointment but more                 bed time and shampooed off in the morning is
cosmetically       appealing.     An     ointment    commonly used. Calcipotriol scalp lotion may
combining         calcipotriol    50µg/g      and    also be of value.
betamethasone dipropionate 0.5mg/g and                       If these measures fail, corticosteroid
applied once daily is more effective than either     scalp lotions should be tried, but even the most
component applied twice daily alone.                 potent (e.g. clobetasol propionate 0.05%
Calcipotriol 50µg/g ointment (Daivonex) used         alcoholic solution) is useless if painted on the
in combination with methotrexate enables             surface of thickly heaped up psoriasis. The use
lower cumulative doses of methotrexate to be         of tar-salicylic aid ointment twice daily for
used. The maximal amount of calcipotriol             few days can bring about marked
50µg/g ointment used should be 100g/ week in         improvement, allowing corticosteroids or
adults and 45g/week in children to avoid             calcipotriol solution to be used.
systemic absorption leading to hypercalcaemia,
hypercalcuria and renal stones. Calcipotriol         UV phototherapy
may irritate skin of the face leading to the need    UVB
for its withdrawal. Intertriginous and genital             Goeckerman first described the ability of
psoriasis can be effectively treated with            crude coal-tar applications followed by
surprisingly minimal irritation.                     exposure to UV radiation to clear psoriasis.
• Vitamin A analogues: Tazarotene is a               Later, it became clear that broad-band (290-
synthetic retinoid effective in treatment of         320nm) UV radiation (BBUVB) alone, if
psoriasis. 0.1% gel or cream are more                given in mildly erythemogenic dosage, is
effective than 0.05% gel or cream but are            capable of clearing psoriasis and can be as
more irritant and less well tolerated.               effective as PUVA.
Tazarotene modulates abnormal epidermal                    Philips TL-01 fluorescent lamps emit a
proliferation and differentiation. Like most         narrow-band UVB (NBUVB) at 311+2nm.
retinoids, it can be inherently irritating.          Irradiation with this source has been found to
Methods that are helpful in minimizing this          be superior to conventional BBUVB in
irritation are either to apply tazarotene at night   psoriasis, producing longer remissions, a
and a strong topical corticosteroid in the           lower incidence of burning and possibly a
morning or to start with a low concentration         lower risk of UV carcinogenesis. The
(0.05%) and to increase as tolerated.                effectiveness of NBUVB appears to be similar
Tazarotene is best reserved for thick,               to that of PUVA, but it is more convenient and
recalcitrant plaques of psoriasis.                   also probably les carcinogenic. The use of
• Topical cytotoxic therapy: Topical nitrogen        higher intensity (100W) TL-01 lamps has
mustard is effective but has 80% incidence of        confirmed the superiority of NBUVB over
allergic contact dermatitis. Fluorouracil 5%         conventional broad-band therapy, and has
cream can also clear psoriasis but causes            allowed shorter, more convenient exposure
painful erosive necrolysis of the epidermis.         times.
• Salicylic acid: 2% to 10% formulation                    Three times weekly appears to be
(lotion, cream, ointment) may be used along          optimum regimen for efficacy as 2 weekly
with corticosteroid, tar or anthralin therapy to     sessions took 50% longer (88 days versus 58
remove scales.                                       days, respectively) to clear psoriasis than 3
• Topical tacrolimus and pimecrolimus: Do            times weekly. Many patients prefer home
not appear effective in typical plaque psoriasis     NBUVB treatment than at hospital. NBUVB


                                                 -233-
radiation many emerge as the therapy of           Results: Therapeutic results are good to
choice in psoriasis.                              excellent in psoriasis vulgaris with clearance
        In general, UVB therapy is valuable       rates of up to 90% which are reached by 15-25
for discoid psoriasis and may be especially       treatments to a total of 100-200J/cm2. PUVA
valuable in guttate ad seborrhoeic forms. It is   is also of value in generalized pustular
of no value in erythrodermic and generalized      psoriasis, erythrodermic psoriasis, palmo-
pustular psoriasis and may aggravate them.        planter pustulosis and nail psoriasis, but
                                                  success rates are much lower in the atypical
Psoralen photochemotherapy (PUVA)
                                                  patterns of the disease. The value of
      Multiple studies confirmed the efficacy
                                                  maintenance therapy is controversial. A useful
of oral and topical PUVA therapy in various
                                                  compromise is to give maintenance treatment
types of psoriasis. However, with the
                                                  for 2 months and if psoriasis remains clear,
introduction       of      narrow-band     UVB
                                                  PUVA is stopped.
phototherapy a great reduction in the number
                                                  Patient monitoring: Regular blood counts,
of patients receiving PUVA resulted.
                                                  renal and liver function tests are not necessary.
Methodology: Standard oral dose using 8-
                                                  Eye examination by ophthalmologist should
MOP tablets is 0.6mg/kg, given 2h before
                                                  be done before therapy and at 6 months
irradiation. Absorption is delayed and reduced    intervals during maintenance therapy.
by a fat-rich meal. Other photoactive drugs       Combined therapy: The simultaneous use of
should be avoided. High-intensity fluorescent     acitretin and PUVA has been shown to be
UVA tubes are used, and initial UVA dosage        therapeutically superior to PUVA alone. In
is based on skin type. Type I (always burn,       severe erythrodermic or generalized pustular
never tan) receives 0.5J/cm2 as initial dose      psoriasis, a cytotoxic drug may be given
while skin type VI (deeply pigmented)             concurrently. Methotrexate with PUVA is
receives 3.0J/cm2. Treatment is given 2-4         effective. Calcipotriol combined with PUVA
times weekly. UVA dosage is increased by          is more effective than PUVA alone. Topical
increments of 0.5 to 1.5J/cm2 according to        corticosteroids may be used concurrently,
response. Persistent erythema or tenderness of    especially in areas inaccessible to UVA.
uninvolved skin may call for temporary            Side effects: Erythema and frank sunburn are
reduction of UVA dosage, or cessation of          the most common effects and are seen at some
treatment for a few days. Once substantial        stage in at least 30%. Nausea affects
clearance has been achieved, the frequency of     approximately 12% of patients and pruritus
treatment can be reduced, so that maintenance     approximately 25%. A mild facial dermatitis
treatment (the last UVA dose in the clearance     resembling seborrhoeic dermatitis occurs in
phase) is given once every 1-4 weeks.             5% of patients. Pigmentation is the most
Alternatively, the treatment may be stopped in    common skin change observed, and is dose
many cases, if the psoriasis remains clear.       related. It may be diffuse, poikiloderma-like or
Eye protection: During irradiation, UVA-          in a nevus spilus-like pattern, producing gross
opaque goggles must be worn. For the              freckling (PUVA lentigines). Other rarely
remainder of that day, UVA-blocking               reported side effects include nail pigmentation
sunglasses should be worn outdoors and            or onycholysis, bullae, hypertrichosis in
indoors during the daylight hours or under        females, lichenoid eruptions and actinic
fluorescent artificial lighting.                  keratosis. Worsening or new eruptive
Patient selection: Contraindications to the       psoriasis, resulting from a Koebner
use of PUVA are renal, hepatic or severe          phenomenon, occurs in 2% of patients.
cardiovascular disease, cataract formation, or          Severe cutaneous pain is a rare but well-
pre-exiting light-aggravated disease such as      recognized side effect. The pain starts 4-8
systemic LE, porphyria, and multiple              weeks after onset of PUVA therapy. Attacks
melanocytic naevi, particularly in the presence   may last from 15 min to several hours,
of a family history of malignant melanoma.        occurring especially at night. The pain is not
The treatment should not be given in              associated with itching. It settles over a few
pregnancy or to children under 18 years.          weeks.
PUVA is of no value for psoriasis in areas              Cataracts have been reported. Liver
where UVA access is impossible, such as the       function tests only rarely become abnormal
scalp or certain body flexures.                   and no changes were found in liver biopsies.

                                              -234-
Carcinogenicity: There is conclusive evidence       abandoned. For a 70-kg adult, an initial test-
for the carcinogenicity of PUVA. Non-               dose of 5-10mg is given to avoid early
melanoma skin cancer (squamous and basal            toxicity. Maintenance doses should be
cell carcinomas) may occur with cumulative          achieved by gradual increases of 2.5-5mg/
doses especially with approximately 100             week, and usually range between 7.5 and
treatments. Fair skinned persons (skin types I      30mg/week. Most patients are adequately
or II) are at higher risk for SCC than those        controlled on doses of 7.5-15mg weekly and
with skin types III or IV. Also, the male           few patients require more than 20mg.
genitalia appear particularly to be at this risk.   Methotrexate may be given as a single weekly
Shielding of the genitalia during PUVA              oral dose, or the dose is divided into 3 parts
therapy reduces the risk. The risk of malignant     given 12h apart over 24h. Parenteral therapy is
melanoma is increased. PUVA is best avoided         equally safe, similar doses being given
in those predisposed to malignant melanoma          intramuscularly or intravenously every week.
i.e. those with numerous melanocytic nevi and       The dosage, of methotrexate required to
a family history of melanoma.                       maintain adequate control of psoriasis will
PUVA using other psoralens: 5-MOP is as             vary from time to time and should be adjusted
effective as 8-MOP when given in the same           accordingly.
dose (0.6mg/kg). The main advantages of 5-          • Contraindications: Anaemia, leukopenia,
MOP are its better gastro-intestinal tolerance,     thrombocytopenia, active infection, (e.g. viral
nausea occurring only rarely and, it is             hepatitis, tuberculosis), peptic ulcer, ulcerative
associated with a lower incidence of                colitis,     alcoholism,     immunodeficiency,
phototoxic reactions and is therefore preferred     pregnancy, lactation and an unreliable patient.
in light-sensitive patients.                        • Risk factors: Pre-existing liver disease,
PUVA therapy with topical psoralens: A              impaired renal function, diabetes, obesity and
lotion of 8-MOP is effectively used on limited      increasing age.
areas of psoriasis. Use on extensive areas can      • Precautions before treatment: Renal, hepatic
cause systemic absorption. Treatment is given       and marrow function must be shown to be
2-5 times weekly, the dose of UVA being             normal. If renal function is impaired, a
slowly increased according to response. Bath        reduced dosage may be given with extreme
PUVA with 8-MOP at a concentration of 2.6-          care and regular monitoring.
3.7 mg/L, has been successful as oral PUVA          • Precautions during treatment
but with 50% less UVA. 37oC is an optimal           ο Function tests (monitoring)
bath temperature with a bath time of 15min,         ² Every 2 weeks: White and platelet count.
followed immediately by UVA; local head and
                                                    ² Every 2 months: Urine albumin and serum
foot treatment may require up to 40min before
                                                    SGOT and SGPT (liver function).
UVA. Psoriasis of the finger nails has been
                                                    ²   Every 4 months: Serum creatinine,
successfully treated with topical 1% 8-MOP
                                                    hemoglobin, serum albumin.
solution and UVA 2-3 times weakly.
                                                    ² Every year: Liver biopsy. It can also be done

Systemic therapy                                    every cumulative dose of 1.5g dosage (1-2
Methotrexate (folic acid antagonist)                years).
• Mechanism of effect in psoriasis                  ο Avoid:
  ο Inhibits DNA synthesis by competitive            ² Conception during treatment and 3 months

inhibition of dehydrofolate reductase and thus       after stop of treatment. Methotrexate inhibits
exerts an antimitotic effect on the epidermis.       spermatogenesis leading to oligospermia (use
  ο Inhibits the proliferation of lymphoid cells     condom) and in female it is abortifacient and
which are an important cellular target in            teratogenic.
psoriasis.                                          ² Drugs that may displace methotrexate from

 ο Inhibits polymorphonuclear leukocyte             plasma albumin thus raising its serum level.
chemotaxix.                                         Diuretics (especially furosemide) interfere
• Routes       of      administration:     Oral,    with tubular secretion of methotrexate and
intramuscular and intravenous.                      diuretic therapy should be avoided. Special
• Excretion: Via kidneys (mainly) and liver.        caution is needed with oral corticosteroids due
• Dosage: Oral therapy is given once weekly.        to additive effect on gastric mucosa and
Daily regimens are dangerous and have been          resistance to infection.


                                                -235-
• Indications: Erythrodermic psoriasis,                  Fatal complications of therapy include
generalized pustular psoriasis (life-saving),      renal failure, septicemia and bone marrow or
and intractable non-pustular psoriasis of hands    hepatic failure. Deaths are attributable to
and feet (skin or arthropathic).                   absolute or relative overdosage.
• Clinical response: Usually evident in 7-14       • Use in children: Although methotrexate
days, but maximal response may take 4-8            should rarely be used in the first half of life,
weeks. Generalized acute pustular psoriasis        this is sometimes inevitable, and the drug is
may respond within 48h. As soon as complete        used in children with severe psoriasis (0.2-
control is achieved lower the dosage or extend     0.4mg/kg/week).
the interval between doses. Quite small doses      • Accidental overdosage: Folinic acid
(e.g. 7.5-10mg/week) may give adequate             10mg/m2 given intramuscularly and repeated
control. Subsequent minor fluctuation in           every 6h as tolerated by the patient.
activity can be treated by other means e.g.        • Drug combinations: Methotrexate has been
topical therapy. Diuretics should be resisted      combined successfully with various other
and as the psoriatic inflammation is controlled,   therapies such as PUVA, acitretin and
spontaneous diuresis will follow.                  ciclosporin, in the hope of reducing dosage
• Side effects                                     and therefore toxicity of each drug, while
○ Cutaneous: Anagen alopecia, erosions,            maintaining efficacy.
ulceration and bleeding are rare with weekly
                                                   Acitretin
dose regimens. Other uncommon side effects
                                                   • Introduction: This is the main active
include epidermal necrolysis, candidiasis,
                                                   metabolite of etretinate which is a synthetic
folliculitis. A cumulative dose of more than 3g
                                                   derivative of vitamin A (retinoid). Both
over 4 years or more increases the risk of
                                                   acitretin and etretinate have a similar efficacy
developing squamous cell carcinoma.
                                                   and side effect profile. However acitretin is
ο Extra-cutaneous: In one study, 73% of            less lipophilic than etretinate with a significant
patients had side effects, most frequently
                                                   difference in half-life (60 hours vs 120 days).
abnormal liver function tests, and upper
                                                   However, in an unpredictable number of
gastrointestinal-symptoms. Oral regimens
                                                   patients reversed metabolism of acitretin to
commonly provoke transient anorexia, nausea,
                                                   etretinate occurs thus necessitating women to
and dyspeptic pain. Many patients feel unwell
                                                   avoid both drugs during pregnancy
for 24h or so after each dose. Bursting
                                                   (teratogenic) and avoid pregnancy for 2 years
headaches, lasting a day or so, may follow
                                                   after stop of the drugs. Acitretin has replaced
large parenteral doses. Burning sensation in
                                                   etretinate in many countries.
the psoriatic plaques, lasting several days, are
not uncommon after full doses, and herald
                                                   • Uses: In generalized pustular psoriasis of
                                                   Zumbusch (treatment of choice) and
rapid resolution of lesions. Toxic effects on
                                                   erythrodermic psoriasis. Efficacy is less
bone        marrow      include     leukopenia,
                                                   dramatic in chronic plaque psoriasis which is
thrombocytopenia and, rarely folate-deficient
                                                   best treated by its combination with another
megaloblastic anemia. Folic acid given with
                                                   modality e.g. corticosteroid cream, tar,
methotrexate (5 mg daily) prevents nausea and
                                                   dithranol, NBUVB, PUVA, methotrexate or
reduces the chances of bone marrow
                                                   cyclosporine. Care should be taken to decrease
supersession.
                                                   the dose of UVA and UVB by 50% when
      Methotrexate is hepatotoxic, causing
                                                   combined with acitretin. Some patients with
fibrosis and cirrhosis whose incidence is low
                                                   palmoplanter pustulosis improve with acitretin
with total dosage of less than 1.5g. It is best
                                                   alone or after its combination with PUVA.
diagnosed with liver biopsy. PIIINP is a
                                                         Acitretin is successful in children with
serological marker of fibrosis and its level is
                                                   generalized        pustular      psoriasis      or
normal with normal liver. It can be done every
                                                   erythrodermic psoriasis. However, retinoids
3 months and liver biopsy is restricted to cases
                                                   should not be given to children except in
in whom PIIINP levels are repeatedly
                                                   compelling circumstances because of their
elevated. Other side effects include
                                                   potential of skeletal toxicity i.e. premature
oligospermia, abortion, teratogenic effect,
                                                   closure of epiphyses, growth retardation and
ataxia,      keratoconjunctivitis,  depression,
                                                   hyperostosis during prolonged high-dose
activation of tuberculosis, and gastrointestinal
                                                   treatment.
bleeding.

                                               -236-
• Contraindications: Active liver disease,          ο Rare side effects: Lethargy, headache, loss
preexisting hyperlipidaemia, pregnancy and          of taste and smell, failure of dark adaptation
lactation. All oral retinoids are teratogenic and   leading to night blindness, nail plate thinning,
are therefore contraindicated during pregnancy      increased sweating and generalized oedema.
and lactation. Acitretin requires contraception
                                                    Cyclosporine
for 2 years after cessation of therapy,
whereas isotretinoin and bexarotene require
                                                    • Introduction: Cyclosporine is derived from a
                                                    fungus. It clears the skin lesions of psoriasis. It
contraception for only 1 month after
                                                    has anti-lymphocytic effect and selectively
cessation of therapy.
                                                    inhibits T-helper cell production of IL-2 while
• Dose: The starting daily dose in adults is
                                                    allowing increase of suppressor T-cell
usually 25mg, the optimum being 50mg
                                                    populations. It has no direct effect on
(0.66mg/kg/day) depending on therapeutic
                                                    keratinocytes and is not a mitotic inhibitor.
response and side effects.
                                                    Cyclosporine is metabolized in the liver by the
• Drug combinations: The combination of             cytochrome P-450 system. The side effects of
methotrexate and acitretin is useful in difficult   cyclosporine demand that it should be given
cases. However, extreme caution should be           only to patients with sufficiently severe
exercised in view of the potential for toxic        disease, in whom less toxic forms of treatment
hepatitis and increased blood levels of             have been unsuccessful (topical therapy,
methotrexate.         During     switch     from    PUVA, retinoids).
methotrexate to acitretin, combination
                                                    • Risk factors: Abnormal liver function,
treatment may be justified for up to 8 weeks
                                                    malabsorption, drug or alcohol abuse,
while the therapeutic effects of acitretin
                                                    concomitant use of drugs that affect
become established. Combination of acitretin
                                                    cyclosporine metabolism e.g. NSAIDs (used
with PUVA is therapeutically superior to
                                                    in      psoriatic      arthropathy,      enhance
PUVA alone and leads to reduction of the
                                                    nephrotoxicity      of     cyclosporine)      and
number of PUVA treatments required for
                                                    anticonvulsants (enhance metabolism of
clearance and the cumulative dosage of UVA.
                                                    cyclosporine by hepatic cytochrome P-450 and
• Side effects                                      thus cyclosporine may never reach therapeutic
ο Hypertriglyceridemia and hypercholesterolemia.    blood levels).
ο Liver: Minor elevations in serum enzymes          • Contraindications: Unreliable patient, renal
reflecting liver function occur in few patients     dysfunction,      un-controlled     hypertension,
and return to normal with drug withdrawal.          history of epilepsy, past or present
Hepatitis and cirrhosis occur in 1%.                malignancy, acute infections, other immuno-
ο Musculoskeletal: Radiological changes of          suppressive therapy, concomitant therapy with
spine (osteophytes, disc abnormalities) may         nephrotoxins.
occur and they may be asymptomatic or               • Dosage: The dosage used in psoriasis is
associated with back or neck stiffness. Other       lower than the dosages used to inhibit organ
musculoskeletal changes include arthralgia,         transplant rejection. The initial daily dose is
arthritis, stiffness and myalgia.                   2.5mg/kg given orally in 2 doses. If no
ο Dryness: Dryness of the lips, nose, eyes,         improvement occurs within 2 weeks, the
mouth, throat or vagina is common. Painful          dosage is increased gradually to a maximum
exfoliative cheilitis, urethritis, balanitis,       of 5 mg/kg/day. Maintenance dosage should
gingivitis, peeling of fingertips and corneal       be reduced to the minimum. Withdrawal of
ulceration may occur.                               cyclosporine is associated with relapse within
ο Other side effects: Rhagades, palmoplanter        weeks and this is less severe that the rebound
desquamation, burning sensation in the skin,        following withdrawal of systemic steroids.
especially of the face, pruritus, skin atrophy,     Ideally, cyclosporine should be used for short
increased hair loss, epistaxis, increased           courses of 3-4 months, maximum duration.
bruising,       widespread     erythema,      and   The accepted modern regimen (intermittent
paronychia. The term retinoid dermatitis            short courses of cyclosporine) is effective for
describes skin changes that include erythema,       at least 2 years, most patients require less than
peeling, dryness, burning, pruritus and             4 courses over this time with good control of
photosensitivity.                                   the disease and no significant side effects.



                                                -237-
• Side effects: The most important side-effects     role of T cells, pro-inflammatory cytokines
are     dose-related       hypertension       and   and Th1 cytokines in psoriasis.
nephrotoxicity. There is increased risk for skin          In general, these treatments are highly
SCCs. Other side effects include elevated           effective. Hey are indicated in severe or
serum potassium and uric acid levels,               extensive psoriasis and in patients not
anaemia, gum hyperplasia, hypertrichosis,           responding, or have a contraindication, to
acral paraesthesia, tremor, altered liver           other lines of therapy. However, the recent
function tests, and gastrointestinal intolerance.   withdrawal of one agent, efalizumab, on safety
• Monitoring during therapy: Regular                grounds, coupled with their high cost
monitoring is essential during cyclosporine         illustrates the need for careful patient
therapy. Serum creatinine is measured every 2       selection. When using these agents it is
weeks for the first 6 weeks, then monthly for       essential that appropriate safety screening and
the duration of cyclosporine treatment. The         monitoring measures are implemented.
drug should be stopped if serum creatinine                At present, there are 5 biological agents
                                                    licensed for the treatment of psoriasis:
rises more than 30% above the base line.
                                                    etanercept, infliximab, adalimumab, ustekinumab
Hypertension is an indication for dose
                                                    and alefacept. Infliximab is administered by
reduction or treatment with a calcium-channel
                                                    intravenous infusion while the others are
blocker such as nifedipine. Diltiazem and
                                                    administrated by subcutaneous injection.
verapamil are not recommended as they
                                                          Etanercept or adalimumab are first choice
inhibit the metabolism of cyclosporine.
                                                    for stable disease, particularly if not too
Potassium-sparing diuretics are best avoided
                                                    severe. Infliximab is first choice for unstable
as cyclosporine may raise serum potassium           or generalized pustular psoriasis. It is also the
levels.                                             most active agent for severe nail disease,
Systemic corticosteroids                            including acropustulosis of Hallopeau.
      Triamcinolone and Betamethasone have          Cytokines
more effect on psoriasis than prednisolone.              Plaques of psoriasis contain a
Corticosteroids are double edged weapons.           predominance of Th1 cytokines such as IL-2,
They produce rapid cure followed, if                IL-12 and IFN-γ. Systemic administration of
withdrawn, by either relapse of same lesions        Th2 cytokines such as IL-4 or IL-10 appears
after cure, or rebound i.e. occurrence of new       to neutralize the Th1 excess and improve
small eruptive lesions on the face and back of      psoriasis.   Subcutaneous     injections   of
hands, or the occurrence of generalized             recombinant IL-10 given either daily or 3
erythrodermic or Zumbusch pustular psoriasis.       times weekly produce a mean reduction in
When triamcinolone is given for the first time      psoriasis severity of 50%. Systemic
(12-20mg/day), clearance of the psoriasis is        administration of IL-4 has demonstrated very
rapid but the disease usually eventually breaks     significant reduction in clinical severity of
through, necessitating progressive increases in     psoriasis.
dosage and incidence of side effect.
         Corticosteroids are not indicated in       Pustular forms of psoriasis
ordinary psoriasis. Triamcinolone is indicated      A convenient classification is as follows:
if methotrexate is ineffective or contraindicated   1. Localized pustular psoriasis:
in cases with severe erythrodermic or                       a. Palmoplanter pustulosis.
generalized pustular psoriasis. Prednisolone is             b. Acrodermatitis continua.
given only in severe psoriatic arthropathy          2. Generalized pustular psoriasis:
(severe damage to joints) and start with high               a. Acute.
doses (40mg/day). Psoriasis may remain labile               b. Of pregnancy.
and resistant to treatment for many months                  c. Infantile and Juvenile.
after     the    withdrawal      of     systemic            d. Circinate.
corticosteroids.                                            e. Localized (not hands and feet).
Biological therapies                                Localized pustular psoriasis
     Biological therapies directed at selected      Palmoplanter pustulosis
target integral to the pathogenesis of psoriasis    • Definition: A common condition in which
arised from a more detailed knowledge of the        erythematous and scaly plaques studded with


                                                -238-
sterile pustules persist on the palms and soles.   leading to nail dystrophy or destruction.
The disease is chronic and very resistant to       Removal of scale may leave a bright red,
treatment.                                         glazed, very sore and painful digit. Slow
• Etiology: The relationship of palmoplanter       proximal extension may occur over years.
pustulosis (PPP) to psoriasis vulgaris is          Eventually, other digits may be involved.
controversial. PPP is an immunogenetically         Acrodermatitis continue may evolve into
distinct disease from psoriasis vulgaris.          generalized pustular psoriasis.
• Histopathology: The changes are essentially      • Differential diagnosis: Staphylococcal
of psoriasis, but the central feature is a fully   infection, pulp infection, herpetic whitlow,
developed large pustule within the epidermis,      tinea or contact dermatitis.
unilocular and full of neutrophils.                • Treatment:
• Clinical features: PPP is a disease of adults    ο Topical: Superpotent topical corticosteroids,
and is rare in children. It occurs on the thenar   tar-impregnated occlusive bandages.
and hypothenar eminences and/or heels and          ο Systemic: Oral tetracycline and topical
instep. Usually bilateral and symmetrical. The     betamethasone valerate, and a combination of
affected area is dusky red, glazed, scaly,         propylthiouracil and methotrexate, have been
studded with numerous small (2-5mm)                advocated for treatment, as has low-dose
pustules and itchy or burning. Pustules            cyclosporine.
approach the surface and dry giving large          • Histopathology: As PPP.
brown adherent scales.
                                                   Generalized pustular psoriasis (GPP)
• Course: Very chronic. As pustules dry to
                                                   Definition: GPP is an uncommon variant of
form scales new pustules erupt in the area.
                                                   psoriasis which may be acute, subacute or
• Associations: There is a significant             chronic with sterile pustulosis as the main
incidence of hyper- and hypothyroidism,
                                                   feature.
diabetes and various arthropathies.
                                                   Relationship      to     psoriasis    vulgaris:
• Differential diagnosis: Pompholyx,               Histopathology is similar though accentuated
dermatophytide, tinea, eczema, contact             in GPP. Relationship to psoriasis is clear,
dermatitis.                                        because patients may have phases of ordinary
• Treatment:                                       psoriasis before or after the GPP. Also,
ο Topical: 8-MP soaks, superpotent topical         methotrexate,      acitretin,    PUVA       and
corticosteroids.                                   cyclosporine are effective in both. Family data
ο Systemic: Acitretin alone or with oral           are similar.
PUVA are the best. Oral PUVA is effective          Provocative factors: Injudicious topical
and effect is enhanced by combination with         therapy (tar or dithranol), infection,
acitretin (Re-PUVA). Tetracycline 250mg            pregnancy, hypocalcaemia, drugs (salicylates,
twice daily may be effective. Cyclosporine         iodide, lithium, phenylbutazone, terbinafine).
2.5mg/kg/day give significant improvement          The most important drug provocation is by
and dosage as low as 1mg/kg/day may be             corticosteroids (withdrawal of systemic or
effective. Methotrexate is not effective.          intensive local therapy). Also withdrawal of
Triamcinolone 6mg/day initially and 2-4mg          cyclosporine therapy.
as maintenance may be effective but should         Histopathology: The earliest infiltrate is
be used with extreme caution.                      lymphocytic. Intense papillary and epidermal
Acrodermatitis continua (acropustulosis)           oedema cause spongiosis. The arrival of
• Definition: A chronic, sterile, pustular         masses of neutrophils leads to spongiform
eruption affecting initially the tips of fingers   pustule formation (Kogoj) and abscesses that
or toes that tends slowly to extend locally but    quickly become macroscopic. There is
which, in adults may evolve into generalized       acanthosis with elongation of rete ridges. The
pustular psoriasis.                                stratum corneum soon becomes parakeratotic
• Clinical features: Affects adults but may        and the subcorneal pustule is shed as
occur in children. Onset is on one finger more     epidermal turnover is accelerated.
often than a toe, after a minor trauma or          Acute generalized pustular psoriasis (von
infection. The skin over the distal phalanx        Zumbusch)
becomes red and scaly, and pustules develop.       • Etiology: Either de novo or on top of chronic
The nail folds an nail bed may be involved,        ordinary psoriasis present for years.


                                               -239-
• Clinical features: The onset is abrupt with       placental insufficiency leading to stillbirth,
high fever and severe malaise. Pre-existing         neonatal death or fetal abnormalities.
lesions become fiery and develop pinpoint           • Prognosis: Characteristically the disease
pustules. Sheets of erythema and pustulation        recurs in subsequent pregnancies and on
spread to involve unaffected skin particularly      subsequent use of oral contraceptives.
the flexures and genital regions. Any               • Laboratory findings: Hypocalcaemia.
configuration of pustular eruptions may occur:      Infantile and Juvenile pustular psoriasis: All
isolated pustules, lakes of pus, circinate          forms of pustular psoriasis are rare in
lesions, plaques of erythema with pustular          childhood. Infantile cases are usually benign.
collarettes or a generalized erythroderma.          Systemic symptoms are often absent and
Waves of pustulation may succeed each other,        spontaneous remissions occur. The majority of
subsiding into exfoliation of the dried             children are aged 2-10 years at onset. The
pustules. The nails become thickened or             disease may be of Zumbusch pattern, but
separated by subungual lakes of pus. The            annular and circinate forms are the most
buccal mucosa and tongue may be involved.           common. Attacks often settle within a few
• Course: If the patient does not die of            days, but repeated waves of inflammation may
exhaustion, toxicity or infection, a remission      follow. The prognosis is generally good.
may occur within days, or weeks, the psoriasis      Circinate, annular and linear pustular
returning to its normal state, or erythroderma      psoriasis: Circinate and annular forms of
develops. Relapses are common.                      pustular psoriasis with advanced pustular edge
                                                    and clearing centre, may occur in acute,
• Complications: In the absence of effective
                                                    subacute or chronic GPP. First described by
treatment death can occur in the acute stage
                                                    Lapière. Also linear forms may occur.
resulting from fatal renal tubular necrosis
                                                    Localized forms of GPP: One or more plaques
(Hypoalbuminaemia,              hypocalcaemia,
                                                    of psoriasis vulgaris develop pustules (e.g.
oligemia), liver damage (general toxicity,
                                                    after excessively irritant topical therapy). It is
drugs) or fatal pulmonary embolism. Other
                                                    not PPP or acropustulosis.
complications        include       polyarthritis,
malabsorption and gross hair loss.                  Differential diagnosis
• Laboratory findings: Lymphopenia at the                 Subcorneal pustular dermatosis, acute
onset followed quickly by polymorphonuclear         generalized exanthematous pustulosis (a
leukocytosis. Low plasma albumin, zinc and          spontaneously healing drug reaction to
calcium. Raised ESR.                                antibiotics), infantile acropustulosis (localized,
Generalized pustular psoriasis of pregnancy         no fever), Reiter’s disease, pemphigus
(impetigo herpetiformis)                            foliaceus, migratory necrolytic erythema of
• Definition: GPP occurring in pregnancy with       glucagonoma (wasting, glossitis, anaemia),
lesions symmetrical and grouped, starting in        pustular drug eruption to halides.
flexures and associated with severe                 Management
constitutional symptoms.                                 Admission to hospital, removal of
• Clinical features: Onset is usually in the last   possible    provocative      factors,   general
trimester and the disease tends to persist until    supportive measures and topical and systemic
the child is born. Onset is acute with severe       therapy.
symptoms (high fever, delirium, diarrhoea,          Withdrawal of provocative factors: e.g. tar or
vomiting, tetany). The eruption starts with         dithranol. Treatment of infection if present
pustules (minute, surrounded by red inflamed        (erythromycin). If GPP threatens maternal life,
areola, in groups, in flexures). The grouped        termination or early delivery.
pustules dry in the centre and extend               General measures: Bed rest in hospital, mild
centrifugally forming circinate patterns, or        sedation, ambient temperature, bland local
form patches in which eroded pustules become        applications, fluid and protein replacement.
fetid, crusted or vegetating. Condyloma-like        Topical therapy: Tar and dithranol are
lesions may form in the flexures. Healing           contraindicated. Only bland creams or lotions.
leaves a reddish brown pigmentation. Tongue         Weak corticosteroid cream may be helpful.
and buccal mucosa may be involved.                  Systemic therapy: Acitretin is the drug of
• Course: The more severe and long-standing         choice with rapid response to high dose
the disease, the greater are the results of         (1mg/kg/day) and lower doses for maintenance

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(0.5-0.75mg/kg/day). Combination with PUVA        Clinical features: Three subgroups are known,
is beneficial. Methotrexate is probably as        any of which may include the classical
effective as acitretin. In fulminating GPP        features of psoriatic arthritis i.e. distal
small (7.5-10mg) intravenous or intramuscular     interphalangeal joint involvement of fingers
doses, repeated every week, are safest. The       and toes, dactylitis or spondylitis.
dose should rarely exceed 0.3mg/kg/week. As       • Asymmetrical arthritis: Usually involving a
the GPP subsides, oral dosage is given, 0.2-      small number of joints with few erosions,
0.4mg/kg/week. Methotrexate has been used         infrequent deformity and good preservation of
with success in children with GPP.                function. There is sausage-like swelling of one
      Control of GPP has been achieved with       or more digits. Commonest type.
very high doses of cyclosporine (9-12mg/kg/day)   • Symmetrical polyarthritis: Frequently
but toxicity prevented prolonged treatment at     erosive, deforming and functionally disabling
these dose levels. With lower dosage, the         (arthritis mutilans). Distinguished from
addition of topical steroids allowed adequate     rheumatoid arthritis by association with distal
control.                                          interphalangeal joint involvement, spondylitis
      In the subacute and chronic forms of        and negative rheumatoid factor.
GPP, the use of dapsone (50-200mg/day) can        • Predominant spondylitis: Similar to
be considered, and may be particularly            ankylosing spondylitis, possibly accompanied
valuable in atypical variants and children.       by peripheral arthritis.
Systemic corticosteroids give an excellent              Involvement        of   cervical     joint,
short-term response with relapses occurring       temporomandibular joint and sternal joint is
with dosage reduction unless combined with        well recognized in psoriatic arthritis. Nail
another form of therapy as methotrexate or        involvement is much more common and more
acitretin.                                        severe in arthropathic psoriasis than psoriasis
      Biological agents give excellent effects    vulgaris. Eye lesions are common e.g
especially the TNF antagonist infliximab, and     conjunctivitis and uveitis.
rapidly control acute GPP. Prednisolone is the    Laboratory findings: The most important is
drug of choice in GPP of pregnancy because it     the negative test for rheumatoid factor in
carries the least hazard to the fetus.            mutilating arthritis.
Cyclosporine is also effective. Methotrexate,     Histopathology: Similar to that of rheumatoid
acitretin and PUVA cannot be used in              arthritis except absence of its characteristic
pregnancy unless termination has become           rheumatoid granulomas and presence of more
inevitable.                                       fibrosis and vascular changes in psoriatic
                                                  arthritis.
Prognosis                                         Radiological changes: There are changes
     GPP developing from acrodermatitis           indistinguishable from rheumatoid arthritis
continua had the worst prognosis. Patients        and include local demineralization, narrowing
with preceding ordinary psoriasis had a better    of joint spaces, articular erosion of varying
prognosis. The better prognosis of GPP of         degree and soft-tissue swellings. Features of
pregnancy reflects the abrupt removal of the      psoriasis arthropathy include destructive
main provocative factor by childbirth or by       changes in the distal interphalangeal joints, a
termination of pregnancy. GPP of children         tendency to hypertrophic changes and absence
also carries a more benign prognosis provided     of generalized demineralization. In arthritis
that oral corticosteroids and methotrexate can    mutilans there is the ‘opera-glass hand’ in
be avoided.                                       which the fingers can be pulled in and out
                                                  resulting from gross destruction and
Psoriatic arthritis                               absorption of the bones. The heads of the
Etiology: Arthritis prevalence among psoriasis    metacarpals and metatarsals may completely
patients is approximately 5%. The more severe     disappear, leaving a tapered bone looking like
the skin disease, the greater the prevalence of   a sharpened pencil.
arthritis. Psoriatic arthritis appears more       Differential diagnosis: Rheumatoid arthritis,
common in individuals with type 1 early-onset     gout, ankylosing spondylitis, osteoarthritis and
psoriasis vulgaris. As for skin psoriasis, T      Reiter’s disease.
cells probably have a key role in arthritis       Treatment: This is best supervised by a
pathogenesis.                                     rheumatologist

                                              -241-
• Symptomatic treatment: Avoid NSAIDs,              intramuscularly) is less effective than
systemic corticosteroids and antimalarials          methotrexate. Occasional exacerbation of skin
which may provocate skin psoriasis. Intra-          lesions may occur. Acitretin and PUVA give a
articular injection of corticosteroids is used to   modest effect.
treat monoarthritis.                                • Biological agents: Their introduction has
• Antirheumatoid drugs: The most commonly           revolutionized the treatment of psoriasis. They
used are methotrexate, cyclosporine and gold        improve psoriatic arthritis, especially cytokine
salts. Methotrexate is the most widely used,        blockers (TNF antagonists e.g. infliximab and
particularly as it is effective for the skin        adalimumab).
lesions, in a dose of 7.5-15mg/week.                • Surgery: e.g. Joint prosthesis, bone grafting
Cyclosporine        3-5mg/kg/day        produces      etc.
significant improvement of arthritis but less       Prognosis: There is less pain and disability
marked improvement for the skin lesions.            than rheumatoid arthritis. It is a mild disease,
Gold salts (e.g. Sodium thiomalate                  except arthritis mutilans (5%).




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