Systemic therapy of skin diseases Gabriella Emri
Therapy of skin diseases Systemic therapy + topical therapy Aim of systemic therapy: therapy of skin diseases considering the pathogenetic factors diminishing the subjective complaints accompanying the skin symptoms (e.g. pruritus, pain, fever) therapy of the cause of the skin symptoms (e.g in the case of an infection) therapy of the internal disease influencing the skin symptoms (e.g. cardial decompensation, diabetes mellitus, arteriosclerosis, chronic venous insufficiency)
Antibiotics Severe impetigo, pyoderma, superinfected atopic dermatitis: beta-lactames or clindamycine, makrolides, microbiological examination if necessary
Antibiotics Erysipelas: beta-lactames or clindamycine, makrolides, in combination if necessary: metronidazole, aminoglikozide
Antibiotics Acne: tetracyclines, erythromycine, clindamycine, sulfonamide+trimethoprim, microbiological examination if necessary Rosacea: metronidazole, tetracyclines, erythromycine, clindamycine, sulfonamide+trimethoprim, microbiological examination if necessary
Antibiotics Lyme-disease: doxycycline, benzylpenicilline, ceftriaxone Syphilis: benzylpenicilline, benzathine benzylpenicilline
Antiviral drugs Acyclovir guanozine-analogue, arrests the viral DNA-polymerase HSV-1, -2, VZV, CMV (prophylaxis) 5x200-800 mg/day p. o. or 3x5-10 mg/kg/day i. v. dose reduction in CRF herpes simplex prophylaxis: 2-3x200 mg careful application in pregnancy Famcyclovir 3x250 mg p. o. (zoster), 2x125 mg (recurrent herpes genitalis) Inosiplex 50 mg/kg alone not enough
Antifungal drugs Itraconazole effective against Dermatophytones, moulds, several yeasts (C. albicans, C. crusei) (inhibits the synthesis of ergosterole) contraindicated: in pregnancy several drug interaction is possible skin mycosis: 100-200 mg/d for 2-4 ws, onychomycosis: 2x200 mg/day for 7 ds, repeat at the 4 th and the 7 th ws, genital: 2x200 mg for 1 day
Antifungal drugs Terbinafine effective against Dermatophytones contraindicated: in renal or hepatic disease skin mycosis: 250 mg/d for 2-4 ws, onychomycosis: 250 mg/day for 6-12 ws
Antifungal drugs Fluconazole effective against Dermatophytones and yeasts (less efficient against: T. mentagrophytes, C. glabrata, C. guilliermondii) contraindicated: in severe hepatic disease, in pregnancy, by manifestation of any skin symptoms (TEN!) listen to drug interactions genital: 1x150 mg, invasive: 200-800 mg/d (for children 3-6 mg/kg/d), dermatophytones: 50 mg/d (1-2 mg/kg/d), onychomycosis: 150 mg/w for 3-6 or 6-12 ms
Invazive mycosis: Amphotericin B Antifungal drugs renal toxicity, fever, arthralgia, myalgia, nausea, headache are possible Voriconazole Caspofungin
Antihistamines Urticaria, anaphylaxia, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, pruritus, prurigo sedatives: hydroxyzine, promethazine, chloropyramine nonsedatives: (levo)cetirizine, fexofenadine, (des)loratadine after the age of 1 month: dimetindene contraindicated: in pregnancy, glaucoma, urinary retention
Corticosteroids Dose-dependent anti-inflammatorical effect (0.3-1 mg/kg prednisolone), immunosuppressive effect (>1 mg/kg) Inhibits the synthesis of cytokines and lipoid mediators of macrophages, the adhesion of neutrophils to the endothel, the synthesis and release of eosinophil and mastocyte mediators (anti-inflammatorical) Inhibits the cytokine-production of T-lymphocytes, the Ig-synthesis of B- cells, the cytokine-production and MHCII-expression of macrophages (immunosuppressive) 5 mg prednisolone = 4 mg methylprednisolone = 0.75 mg dexamethasone
Corticosteroids Short-term, intermediate dose therapy (32-48 mg methylprednisolone/d, reduced in 1-2 ws): severe allergic contact dermatitis, drug reactions, erythema nodosum, erythema multiforme, lichen planus, leukocytoclastic vasculitis, Sweet-sy., granulomatous inflammations
Corticosteroids High dose therapy (64-96 mg methylprednisolone): angioedema, Jarisch- Herxheimer reaction, lupus erythematosus, pyoderma gangrenosum
Corticosteroids Long-term therapy (starting with high dose, maintainance at the minimum effective dose, completing with other immunosuppressive drugs): autoimmune bullous diseases, connective tissue diseases, Sezary-sy., vasculitis
Corticosteroids contraindicated: in severe infection, osteoporosis, GI ulcer, myopathies, psychosis, glaucoma, recurrent thrombosis, in the first trimester of pregnancy listen to drug interactions IMPORTANT avoid systemic steroids in the following cases: Atopic dermatitis: fast response, but fast recurrence after stopping the steroid therapy Cutaneous lupus erythematosus: better to keep it for therapy of systemic symptoms Psoriasis: limited effect, after stopping rebound, even psoriasis pustulosa can be developed
Corticosteroids Side effects: osteoporosis (after 6 months 50%), hypertension, diabetes mellitus, infections, Cushing-sy. (skin symptoms: acne, folliculitis, furunculus, candida infection, hypertrichosis, effluvium, atrophy, teleangiectasia, purpura, striae, impaired wound healing)
Immunosuppressive agents Azathioprine purine-antagonist, decreases the activity of NK, T-, B-cells Bullous autoimmune diseases, LE, DM, vasculitis, Behcet-sy., pyoderma gangrenosum, CAD Contraindicated: in pregnancy, in hepatic disease, in myelosuppression, in the case of an active infection in TPMT-deficiency increased immunosuppression 1-3 mg/kg/d Side effects: leukopenia, thrombocytopenia, pancytopenia, pancreatitis, nausea, vomit, fever, hepatitis, arthralgia, stomatitis, increased skin cancer risk, alopecia, teratogenicity
Immunosuppressive agents Cyclophosphamide Alkilating agents Pemphigus vulgaris, LE, vasculitis, Wegener granulomatosis, pyoderma gangrenosum, Behcetsy. contraindicated: in pregnancy, in myelosuppression 1-3 mg/kg/d p. o. or 15 mg/kg p. o. 1x/m or 500 mg-1 g/m 2 i. v. 1x/m with strong hydration or mesna Side effects: cardiotoxicity, hepatotoxicity, myelosuppression, thrombocytopenia, leukopenia, pancytopenia, nausea, vomit, diarrhoea, haemorrhagic cystitis, sterility, azoospermia, amenorrhoea, alopecia
Dapsone (diaminodiphenylsulfone) Inhibits the folic acid synthesis, it has anti-neutrophil activity contraindicated: in severe cardiovascular disease, renal failure, pregnancy, sulfonamide allergy side effect: methb-induction, hemolysis (severe in G6PDdeficiency!), agranulocytosis, aplastic anaemia, nephrosis sy., renal papillar necrosis, peripheral motor neuropathy, sulfone sy. Lepra, Mo. Duhring, Pneumocystis carinii prophylaxis, pyoderma gangraenosum, autoimmune bullous diseases, bullous LE, granuloma faciale, erythema elevatum et diutinum, leukocytoclastic vasculitis 50-100 mg/d max. 200 mg, t 1/2 : 2-4 ds (renal elimination 90%) Alternative: sulfapyridine 1.5-2g/d
Immunosuppressive agents Cyclosporine inhibits the T h -cell function severe therapy-resistant psoriasis, atopic dermatitis, pyoderma gangrenosum, autoimmune diseases contraindicated: in cancer, hypertension, renal disease, pregnancy, active infection drug interactions! 2.5-5 mg/kg/d, with control of creatinine, potassium, bilirubine, liver enzyme level, uric acid, lipid level, blood pressure side effects: renal failure, leukopenia, hypertension, headache, tremor, gingiva hyperplasia, oral candidiasis, hirsutism Cave: UV-light!
Immunosuppressive agents Methotrexate Folic acid-antagonist Severe psoriasis, arthropathia psoriatica, bullous pemphigoid contraindicated: in pregnancy, GI ulcer, liver cirrhosis, renal, hepatic dysfunction, hepatitis, alcoholism, anemia, leukopenia, thrombocytopenia, severe infection Nota bene: avoid alcohol, salicylates, other NSAID, sulfonamide, increase fluid intake, serum procollagene II aminopeptid can be monitored (hepatic fibrosis) 7.5-25 mg p. o. 1x/w (3x2.5-7.5 mg q12 hs) side effects: myelosuppression (leukovorine 12 mg i. m. q6 hs 4-6 doses), hepatotoxicity (after >3 ys therapy and >1.5-2 g total dose liver biopsy may be necessary), pulmonary fibrosis, GI bleeding, anorexia, nausea, vomit, stomatitis, renal failure, seizures, defective spermatogenesis, alopecia, phototoxic dermatitis, skin ulceration
Biological therapy cellular immune response (signalisation, activation, citokine production) modifying molecules Nomenclature: mab: monoclonal antibody cept: fusion protein with receptor effect mu: human antibody xi: chimera (mouse-human) antibody zu: humanized mouse antibody li: anti-inflammatorical Examples: infliximab (TNF- inhibitor, Remicade), etanercept (TNFRII+IgG1 Fc domain, Enbrel), efalizumab (anti-cd11a, Raptiva), alefacept (anti-cd2)
Retinoids Influence on the keratinocyte differentiation, fibroblast activity, T- cell response Isotretionin acne, rosacea, Gram-negative folliculitis, severe sebaceus hyperplasia, XP, Gorlin-Goltz sy. 0.2-0.5 mg/kg/d for 4-10 ms or until 120 mg/kg total dose
Retinoids Acitretin psoriasis, Darier, pityriasis rubra pilaris, lichen planus, keratinisation diseases, Reiter, pustular diseases, CLE, epidermodysplasia verruciformis, multiplex keratoacanthoma 0.3-1 mg/kg/d for 2-4 ms, in genodermatoses 0.2-0.4 mg/kg
Retinoids Bexaroten (Targretin) CTCL 300 mg/m 2 /d, then 200 mg/m 2, then 100 mg/m 2
Retinoids Nota bene: draw women s attention to teratogenicity (informed consent), apply it in severe disease forms only, with control of liver enzyme levels and lipid levels Drug interactions: vitamin A (hypervitaminosis), tetracycline (pseudotumor cerebri), methotrexate (hepatotoxicity), alcohol (hepatotoxicity, TG-level increase) Side effects: teratogenicity (AC >6 ms after isotretionin, >2 ys after acitretin), mucous membrane dryness, skin dryness, alopecia, nail deformity, depression, hepatopathia, increased lipid levels, arthralgia, myalgia, hyperostosis, calcification, pseudotumor cerebri, visual dysfunction, hypothyreosis (bexaroten)
Cytostatics Alkilating agents: cyclophosphamide, lomustine, fotemustine Antimetabolites: methotrexate Antibiotics: bleomycine Vinca alkaloids: vincristine Other: dacarbazine, cisplatin Side effects: myelosuppression, haemorrhagic cystitis, sterility, teratogenicity, reversible alopecia, pulmonary fibrosis, acutely nausea, vomit, fever
Interferon-alfa Melanoma malignum, Kaposi sarcoma, Kaposiform haemangioendothelioma, mycosis fungoides weekly 3x3-10 million NE s. c. acutely fever, headache, arthralgia, myalgia at long-term use leukopenia, thrombocytopenia, hepatopathia, hypertrigliceridemia, weakness, depression, autoimmune disease (thyreoiditis) contraindicated: in autoimmune diseases (thyreoiditis), cardial arrythmias, hepatopathia, depression Immunotherapy
Colchicine Inhibits neutrophil functions by inhibiting microtubule function, inhibits collagen-synthesis, inhibits amiloid deposition gout, Behcet-sy., vasculitis, amiloid deposition (familiary mediterranean fever) contraindicated: in pregnancy 0.5-1 mg/d Side effects: thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, nausea, vomit, diarrhoea, azoospermia, myopathia, alopecia Other
Antimalarial drugs Stabilises the membrane of lysosome, decreases the MHC-expression, inhibits the neutrophil and eosinophil migration and function, inhibits the complement system, inhibits the PG-synthesis, etc. LE, RA, PFE, sarcoidosis, PCT contraindicated: in pregnancy, G6PD-deficiency, myasthenia gravis, hematopoietic diseases, hepatotoxic drugs Ophthalmological control q6-12 ms Chloroquine Side effects: agranulocytosis, hemolytic anemia, irreversible retinal damage, ECG-alterations, GI complaints, pigment abnormalities, psoriasis worsening
Other Thalidomide Anti-neutrophil activity, anti-tnf, anti-angiogenic Behcet-sy., severe aphtosis, pyoderma gangrenosum, LE (hyperkeratotic cases), prurigo nodularis Side effects: teratogenicity, peripheral neuropathia, nausea, vomit, thrombosis
Other Cyproterone Anti-androgenic Acne, hirsutism, androgenic alopecia
Medication during pregnancy and nursing contraindicated: azathioprine, colchicine, cyclophosphamide, NSAID, potassium-iodide, tetracyclines Antibiotics first choice: penicilline, cephalosporine, erythromycine alternative: clindamycine, sulfonamides contraindicated: tetracyclines, aminoglikozides Antimycotics best to avoid life-threatening infection: amphotericin B Antihistamines avoid Acyclovir in the case of possible fetal varicella or neonatal herpes, but fetal damage can not be excluded