? A 45 year old male presents with well-defined erythematous papules
and plaques, which are surmounted with large, silvery loose scales.
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There is also associated joint pain
? Provisional diagnosis
? Psoriasis with psoriatic arthritis
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? The treating physician plans an immunosuppressive (e.g.methotrexate) and with other routine investigations (e.g. CBCs, ESR,
BUN, creatinine etc.), orders serum virological markers (for HBV, HCV,
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HIV)
? In a tropical country like India, which other infection/ inv. is also
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routinely indicated before treatment? Tuberculosis
? CXR
Methotrexate (MTX)
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? An antimetabolite Used as a chemotherapeutic agent since the early
1950s
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? Immunosuppressive and antiinflammatory effects? Used therapeutically in a variety of rheumatological, gastrointestinal,
neurological and dermatological inflammatory disorders
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Uses? Severe psoriasis with/without arthritis
? Offlabel (often as a steroidsparing agent) in immunobul ous disorders (pemphigus,
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bul ous pemphigoid, cicatricial pemphigoid and epidermolysis bul osa acquisita),? Connective tissue diseases (dermatomyositis, lupus erythematosus and scleroderma),
? Vasculitides
? Neutrophilic dermatoses (pyoderma gangrenosum and Sweet syndrome)
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? Other inflammatory (such as atopic eczema, sarcoidosis, cutaneous Crohn disease andchronic idiopathic urticaria) and proliferative (mycosis fungoides, S?zary syndrome,
pityriasis lichenoides and pityriasis rubra pilaris) disorders
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Efficacy in psoriasis? In treatment of psoriasis and psoriatic arthritis - MTX is considered
the "gold standard"
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? Based on several studies - Approximately 45% of patients see a 75%
improvement in their Psoriasis Area and Severity Index (PASI) score
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? Takes - 4 to 8 weeks to see a response to changes in MTX dosageDoses
? In dermatological usage, MTX is usually taken orally in weekly (rather
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than daily) doses,
? Also - Intramuscular, intravenous, subcutaneous
? Usual weekly dose ? 7.5-20 mg
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Mechanisms of action
? A structural analogue of folic acid
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? MTX blocks the metabolism of folic acid through competitiveinhibition of dihydrofolate reductase (DHFR)
? DHFR catalyses the conversion of DHF to tetrahydrofolate (THF), a
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singlecarbon transfer source essential to the generation of purine &
pyrimidine nucleotides Therefore for nucleic acid and protein
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synthesisRisks, Precautions, Common ADRs
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Pretreatment screeningOngoing monitoring
Liver biopsy
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? The gold standard to assess MTX-induced liver fibrosis - Percutaneousneedle biopsy
? Patients without risk factors for liver injury - Current
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recommendations suggest consideration of liver biopsy after 3.5 to 4
g total cumulative dosage.
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? For patients with risk factors - For MTX-induced liver injury, a delayedbaseline liver biopsy should be considered (after 2-6 months of use,
when it is apparent the medication is efficacious, well tolerated, and
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likely to be continued) and again at a cumulative dose of 1.0 to 1.5 g
Folate Supplementation
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? Daily supplementation with 1 to 5 mg of folate - Reduced adverseeffects and toxicities without compromising the efficacy of MTX
? Nausea, vomiting, diarrhea, alopecia, stomatitis and oral ulceration,
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elevated transaminases, and mild myelosuppression ? May be
prevented
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? Pneumonitis & moderate to severe myelosuppression - Not mitigatedby folate supplementation
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Overdose? MTX overdose ? Must be treated promptly (within 24-36 hours after
overdose) with folinic acid (leucovorin)
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? Folinic acid is metabolized in vivo to tetrahydrofolate in the absence
of dihydrofolate reductase - Provides an alternative supply of DNA
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and RNA precursors? An oral dose of 10 mg/m2, or 15 to 25 mg every 6 hours for 6 to 10
doses should be given on first suspicion of MTX overdose without
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delay for a serum assay
? If serum assay is available, oral or parenteral doses may be continued
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every 6 hours until the serum concentration of MTX falls to less than10-8 M
Drug Interactions
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Azathioprine? A potent immunosuppressive, antiinflammatory and antiproliferative
drug
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? To prevent graft rejection and to treat haematological malignancies
and a variety of rheumatological, gastrointestinal, neurological and
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dermatological inflammatory disordersUses
? Pemphigus and pemphigoid
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? Often used as an adjunct to other immunosuppressive agents such asprednisolone and may exert a steroidsparing effect
? Systemic lupus erythematosus and dermatomyositis
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? Atopic eczema? Chronic actinic dermatitis
? Also for use in - Lichen planus, contact dermatitis, polymorphic light
eruption, leukocytoclastic vasculitis, pyoderma gangrenosum, Beh?et
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disease and chronic cutaneous lupus erythematosus
MoA
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? Azathioprine is a prodrug that is metabolized to 6-mercaptopurine (6-
MP) and acts as an immunosuppressant/ anti-inflammatory
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? Has better availability when given by mouth than 6-MP? 6-MP is further anabolized via hypoxanthineguanine phosphoribosyl
transferase (HGPRT) ultimately to a purine analog, 6-thioguanine
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(6-TG) which inhibits RNA and DNA synthesis and repairimmunosuppression
CIs & Common ADRS
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Doses? Usual dose: 1-2.5 mg/kg
? Azathioprine can be initiated as monotherapy
? Initially combined with prednisone is often used in steroid-responsive
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bullous disorders
Cyclophosphamide
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? Cyclophosphamide is an alkylating agent and acts primarily bycrosslinking DNA - A classic cell cycle-nonspecific cytotoxic drug
? In oncology - Used as an antineoplastic agent
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? In dermatology - Used as an immunosuppressive and steroid-sparingagent particularly for autoimmune blistering disorders and systemic
vasculitis
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Indications? In dermatology, used in only the most serious diseases
? In particular - Pemphigus vulgaris - In combination with steroids -
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Evidence supports its steroid-sparing benefits? Cyclophosphamide - Also used for the treatment of mucous
membrane pemphigoid
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? Other diseases that may respond - Pyoderma gangrenosum,
necrobiotic xanthogranuloma, cutaneous amyloidosis, lichen
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myxedematosus, giant cell reticulohistiocytoma, primary cutaneousdiffuse large B-cell lymphoma and mycosis fungoides
Doses
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? Oral doses - Typically 1 to 3 mg/kg/d either divided or as a single
morning dose
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ADRs
Mycophenolate mofetil
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? Mycophenolate mofetil (MMF) potent immunosuppressant? Prodrug of mycophenolic acid (MPA) Used primarily to prevent
solidorgan graft rejection
Dermatological uses
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? MMF has a predictably beneficial effect in the treatment of
immunobullous disorders (in particular pemphigus and pemphigoid)
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? A less consistent effect in psoriasis, atopic eczema, connective tissuedisorders and vasculitides
Dose
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? Twicedaily dosing
? Starting dose for dermatological indications 250 mg BD first week
? Until a maximum of 1.5 g twice daily is reached
? Dosage should be tailored to individual tolerance
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? The clinical response is slowCiclosporin
? Ciclosporin is a highly effective and rapidly acting potent inhibitor of
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Tcell function? Central importance in the management of severe inflammatory skin
disease, particularly psoriasis
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Indications
? Cicloporin psoriasis (plaque type) and atopic eczema
? Common offlabel uses include chronic urticaria, pyoderma
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gangrenosum, hand eczema and palmoplantar pustulosis
ADRs
? MC - Hypertension, nephrotoxicity, hyperlipidaemia, myalgia and headache
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? Others include gingival hyperplasia, fatigue, gastrointestinal disturbances,? tremor and paraesthesiae in the hands and feet
? A variety of metabolic abnormalities (hyperbilirubinaemia, hypercalcaemia,
? hypomagnesaemia, hyperuricaemia)
? Most are dose related and respond rapidly to dose reduction/ treatment
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cessation
? Longer term use carries significant, predictable risk, particularly of
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nephrotoxicity, and is general y not recommendedDoses
? Start - In the lower dose range (2.5 mg/kg/day), escalating to higher
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doses (up to 5 mg/kg/day) after a month of therapy in the event of a
poor response
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? If disease is acute, severe and/or unstable -5 mg/kg/day? The lowest possible therapeutic dose should be used
? Ciclosporin remains an extremely useful, predictably effective and
generally welltolerated drug for shortterm use
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? Longterm use is complicated by nephrotoxicity
? Potent immunosuppression.
Thalidomide
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? Hypnosedative, immunomodulatory, and neural/vascular tissue
effects
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? Initially removed from the market because of severe teratogeniceffects (phocomelia) in 1961
Indications
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? Thalidomide - Later found to be effective in treating erythemanodosum leprosum
? Off-label use treating dermatoses including AIDS-related Kaposi
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sarcoma, pyoderma gangrenosum, bullous pemphigoid, prurigo
nodularis, uremic pruritus
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Dose and regimens? The dose range for dermatological conditions is 50?300 mg/day,
taken as a single dose at bedtime to reduce the impact of sedation
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Systemic retinoids? The synthetic retinoids are a class of organic molecules derived from
and with similar biological activity to the naturally occurring vitamin A
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group of retinoids, which includes retinol, retinal and retinoic acid
Indications
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? Isotretinoin is licensed for the treatment of severe acne resistant toadequate courses of standard therapy, although offlabel it has been
used in rosacea, hidradenitis suppurativa and dissecting cellulitis of
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the scalp
? Alitretinoin has a product license to treat severe chronic hand eczema
? Also been approved by FDA for the topical treatment of the
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cutaneous lesions of Kaposi sarcoma
? Acitretin severe psoriasis, resistant to standard therapies,
palmoplantar pustulosis, inherited ichthyoses and Darier disease
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? Bexarotene is indicated for the treatment of the cutaneous
manifestations of advanced cutaneous Tcell lymphoma
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? Retinoids have also been used offlicense to treat pityriasis rubrapilaris, lupus erythematosus and lichen planus
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DosesADRs
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Pretreatment screening? Women of childbearing potential - explicit counsel ing on the teratogenicity
of retinoids
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? Either adopt birth control measures or abstain from coitus
? Pregnancy should be excluded prior to commencing retinoid therapy
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? Pregnancy should be avoided for the duration of therapy and for anappropriate time thereafter (1 month for isotretinoin, alitretinoin and
bexarotene, and 2 years for acitretin)
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? The recommendations regarding isotretinoin, which can be adapted of the
other retinoids, suggest that women deemed at risk of conceiving should
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be recruited into the isotretinoin pregnancy prevention plan (iPLEDGE inthe USA
Monitoring
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? Reasonable followup Monthly clinical evaluation? Blood tests (liver function tests and fasting lipid profile, with
occasional renal function tests and full blood count) for 3?6 months,
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then 3monthly reviews with blood tests? Thyroid function should be monitored in patients receiving
alitretinoin and bexarotene
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