Recommendations

1. Recommendations

2. In which conditions should acitretin be used? Acitretinmonotherapy is recommended in the treatment of: 1) Severe psoriasis, or psoriasis with severe effects on quality of life, meriting systemic therapy, which is resistant to topical therapy, phototherapy or is unsuitable for these treatments (A,1+). 1.1) Acitretin is recommended as a combination with PUVA therapy or narrowband phototherapy (A, 1+). 1.2) Acitretin is recommended with hydroxycarbamide (D, 3) 1.3) Acitretin is recommended in combination with calcipotriol ointment (A, 1+). 1.4)The following combinations are not recommended: Acitretin with ciclosporin: no evidence of additive efficacy (D, 3). Acitretin with methotrexate: potential for severe hepatic toxicity (except in exceptional cases) (D, 3). 2 )Palmoplantarpustular psoriasis (A, 1+). 3) Hyperkeratotic hand eczema (A, 1+).

3. 4) Severe Darier disease (keratosisfollicularis) (A,1+). 5) Severe congenital ichthyosis (D, 3). 6) Keratoderma (D, 3). There is evidence that the following conditions benefit from acitretin’s antimitotic and keratolytic actions: 1) Lichen planus (A, 1+) 2) Lichen sclerosus (A, 1+) 3) Discoid lupus erythematosus (A, 1+) 4) Prevention of cutaneous malignancies in organ transplant patients (A, 1+).

8. What special precautions should be taken when prescribing acitretin? Patients should not donate blood either during or for at least 1 year following discontinuation of therapy. Acitretin is not recommended in children, as there have been occasional reports of bone changes, the child should be carefully monitored for any abnormalities of growth parameters and bone development including plotting growth charts. The effects of UV radiation are enhanced by retinoid therapy, therefore patients should avoid excessive exposure to sunlight and use of sun lamps. Women (and men) should refrain from waxing as a method for hair removal as retinoids cause skin fragility. Retinoids are associated with greater insulin sensitivity and could therefore induce hypoglycaemia in patients on antidiabetic medications. In this subset of patients, serum glucose levels should be checked more frequently than usual in the early stages of treatment. People with diabetes, alcoholism and obesity need to be monitored more frequently as they have an increased risk of hyper TG Advice against exceeding recommended daily intake of vitamin A (2400–3000 IU daily, i.e. 0.8–1 mg daily) should be given.

10. What are the preliminary investigations prior to starting acitretin? • Teratogenicity: In women of childbearing age pregnancy must be excluded by negative pregnancy test within 2 weeks prior to therapy. Acitretin should be started only on the second or third day of the next menstrual cycle. Effective contraception must be practised for at least 4 weeks before and during therapy with acitretin, and for 3 years after treatment with acitretin has ceased. • Liver disease: Enquire regarding past or current history of liver disease, excess alcohol intake, and hepatotoxic drugs. Checkalanineaminotransferase, aspartateaminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin. • Renal disease: Enquire regarding past or current history of renal disease, nephrotoxic drugs. Checkurea, electrolytes and creatinine. • Hyperlipidaemia: Enquire regarding past or current history of disturbances of lipid metabolism, DM, obesity, alcoholism.Check fasting cholesterol, TG. • Abnormal glucose tolerance: Enquire regarding history of diabetes mellitus, antidiabetic drugs. Check fasting glucose.

11. How should acitretin be prescribed? Therapy should be initiated only under the responsibility of a supervising dermatologist The capsules should be taken once daily with meals or with milk. Effective doses of acitretin as a single agent appear to be in the range of 25–50 mg daily. Gradual dose escalation has been shown to be the most effective approach and allows gradual onset of ‘tolerance’ to side-effects. The initial daily dose, 25 mg or 30 mg for 2–4 Ws, may give satisfactory therapeutic results. The maintenance dose must be based on clinical efficacy and tolerability. In general, a daily dose of 25–50 mg taken for a further 6–8 Ws achieves optimal therapeutic results. It may be necessary in some cases to increase the dose up to a maximum of 75 mg daily.

12. Response is gradual and typically requires 3–6 Ms to reach a peak . Therapy can be discontinued in patients with psoriasis whose lesions have improved sufficiently. Relapses should be treated as described above. In patients with Darier disease a starting dose of 10 mg/d may be appropriate. Patients with severe congenital ichthyosis and Darier disease are likely to require long-term treatment with acitretin, as are some patients with psoriasis.

13. How should acitretin therapy be monitored? • Liver enzymes every 2–4 weeks for the first 2 Ms of therapy and then every 3 months. If abnormal results are obtained, weekly checks should be instituted and acitretin dose adjusted accordingly. Acitretin should be discontinued if transaminases are elevated to 3 times . • Fasting serum cholesterol and TG every 2–4 Ws for the first 2 Ms and then every 3 Ms. In the presence of a good therapeutic response to acitretin but persistently elevated lipid levels, dietary measures should be introduced before considering a lipid-lowering drug. Patients with TG > 400mg/dl should be referred to a lipidologist and investigated for other causes of hyperTG (e.g. alcohol, SLE, DM, hypothyroidism, renal and hepatic problems, hormonal dysfunction etc). HyperTG>800mg/dl warrants discontinuation of acitretin and urgent referral to a lipidologist, as it is a risk factor for acute pancreatitis. • BS levels in diabetic patients on insulin or antiglycaemic agents should also be monitored at similar intervals. These patients should check their capillary glucose more frequently than usual during the first few weeks of treatment. • Radiological investigation for skeletal changes need not be done routinely as there is a risk from exposure to radiation.

16. The cutaneous and systemic manifestations ofazathioprinehypersensitivity syndrome

17. INTRODUCTION: Azathioprine (AZA) (Imuran, Azasan), the nitroimidazole of 6-mercaptopurine (6-MP), was first used in 1961 as an immunosuppressant for kidney transplantation. Since then it has become an effective corticosteroid-sparing agent in a variety of autoimmune inflammatory diseases to include RA, SLE, vasculitis, IBD, BP, pemphigus, and others. Dose-dependent toxic side effects (myelosuppression, gastrointestinal side effects, hepatotoxicity) have been well recognized. Less well-characterized is AZA hypersensitivity syndrome and its cutaneous manifestations.

18. Case 1: A 39-year-old Caucasian woman with CD presented with vomiting, diarrhea, fever, and arthralgias 4 Ws after starting AZA therapy. Before she started AZA, her thiopurinemethyltransferase (TPMT) levels were in the normal range. Her AZA dose at presentation was 100 mg/d. She was also taking prednisone, 30 mg/d. Her AZA was discontinued, and shewas admitted to the hospital for work-up and treatment of sepsis and exacerbation of CD. Her WBC count on admission was elevated at 14,000 with84% NEUT .3 days later a mildly pruritic, generalized papulopustular eruption developed, which was most prominent on her lower legs and flexor forearms (at sites of shaving and venipuncture). Individual lesions were 5to 10mm firm, indurated, erythematous papules and nodules with a centralpustuleor vesicle . The patient had several painless oral mucosal and conjunctival erosions but no genital involvement.

19. A shave biopsy specimen showed a dermal and perivascular diffuse infiltrate of NEUT, Lym, and histiocytes with focal leukocytoclasis.Her systemic symptoms and eruption resolved 5 days after the AZA had been discontinued. Her work-up for sepsis yielded negative findings and other Lab findings were unremarkable. There was no evidence of eosinophilia or liver dysfunction. Several weeks later the patient underwent rechallenge with a 25mg dose of AZA. Within 24 hours, she developed arthralgias, malaise, and cutaneous lesions. The skin lesions again erupted on the forearms and distal legs with an appearance similar to that of the initial lesions. The AZA was discontinued, and the patient was diagnosed with AZA hypersensitivity syndrome.

20. Patient 1. Firm, indurated, erythematous papules and nodules, 5 to 10mm,with central pustules and vesicles.

21. Case 2: A 33-year-old obese Caucasian man with SLE complicated by a recurrence of proliferative glomerulonephritis was admitted to the hospital for fever, arthralgias, diarrhea, and dark urine 2 Ws after starting AZA. His TPMT level was in the normal range. On admission, he was taking AZA, 300 mg/d, and prednisone,35 mg/d. The AZA was discontinued and a work-up for sepsis was initiated. His serum Cr was elevated from a baseline of 1.4 to 2.7 mg/dL. He also had elevated alanineaminotransferase and aspartateaminotransferase at 89 U/L and 113 U/L,respectively. Although he had neutrophilia (83%), his WBC and eosinophils were within normal range. On his second day of hospitalization, he developed an induratedpapulopustular eruption on his face, neck, elbows, and hands .

22. Patient 2. Erythematous pustules on right side of face.

23. Patient 2. Indurated papules on palm of left hand.

24. A biopsy specimen showed marked papillary dermal edema with a dense infiltrate of neutrophils but no evidence of vasculitis. 4 days after admission, the patient’s systemic symptoms improved and his rash resolved. His work-up for sepsis was negative. Other laboratory findings, including complement levels and dsDNA, were unchanged compared with baseline. On hospital discharge, his serum Cr remained elevated at 2.1 mg/dL. He was not re-challenged with AZA as the initial presentation was consistent with AZA hypersensitivity syndrome.

25. Review of the literature: Including the present case series of two, 67 cases of AZA hypersensitivity from 1986 through 2009 were reviewed . Of these cases, 49%(33) had cutaneous manifestations. Of those presenting with cutaneous findings, 76% (25) had biopsy or clinical features consistent with a neutdermatosis, whereas the other 24% (8) were reported as a non-specific cutaneous eruption. Several earlier case reports had more detailed descriptions of skin findings suggestive of neutdermatoses, but were not biopsy confirmed. Of the patients with a biopsy-proven neutdermatosis, 64% (16/25) had IBD (CD,UC). Many of these cases met the diagnostic criteria for drug-induced Sweet’s syndrome, as described by Walker and Cohen. .

26. Other features of AZA hypersensitivity with respect to onset, systemic symptoms, TPMT activity, Lab findings, and concurrent steroid use were similar to those described in other case reports and reviews The age and sex of patients did not affect the presentation or risk for AZA hypersensitivity. The majority of patients developed AZA hyper sensitivity within the first 4 Ws of therapy. There were only 3 patients (4%) in our series who had dermatologic diagnoses (psoriasis,BP, and pemphigus). Concurrent use of corticosteroids at presentation was common, occurring in 39% of patients (26/67).

27. DISCUSSION: AZA is an effective and well-tolerated immunosuppressive agent. While approved by FDA for severe RA and prevention of rejection in renal transplantation. AZA continues to be a useful steroid-sparing medication in the treatment of many systemic autoimmune conditions such as IBD, SLE, MG, and others. The most common dermatologic conditions treated with AZA are BP and pemphigus and, less commonly, AD, psoriasis, and CAD. AZA is a purine analog that inhibits both RNA and DNA synthesis. It was originally synthesized from 6-MP by the addition of an imidazole ring. This imidazole ring improved efficacy and reduced the rapid catabolism of 6-MP. The initial metabolism of AZA results in two products: 6-MP and the imidazole derivative (methylnitroimidazole moiety). The metabolism of 6-MP by hypoxanthine phosphoribosyltransferase results in 6-thioguanine nucleotides, which are responsible for drug action and dose-dependent side effects. Further metabolism of 6-MP by TPMT and xanthineoxidase yields inactive metabolites.

28. The overall incidence of side effects from use of AZA necessitating drug withdrawal ranges from 10%-15%. Cases of a true hypersensitivity syndrome to AZA have been reported in approximately 2% of patients taking the drug. Dose-dependent side effects of AZA, such as myelosuppression, infection, nausea, vomiting, and hepatotoxicity, are well characterized and can occur at any time during drug-therapy. The incidence of dose-dependent side effects ranges from 4% -27%. These side effects are not allergic in nature, but are the result of direct toxicity from 6-thioguanine nucleotides and can be related to low TPMT activity or inhibition of xanthineoxidase.

29. AZA hypersensitivity reactions may be more common than is generally accepted. In 2001, Craner and Zajicek reported AZA hypersensitivity in 14 of 21 patients with MS. This evidence suggests that Patients with IBD or MS may be at higher risk for AZA hypersensitivity. The reasons for this are unclear but possibly involve a genetic polymorphism that predisposes persons to AZA hypersensitivity. This may also be due to the fact that more IBD and MS patients are treated with AZA, under-recognition of the disease, or reporting bias by certain specialties. Hypersensitivity reactions to AZA are dose independent and tend to occur during the first 4 Ws of therapy. Unlike dose-dependent side effects, these reactions occur regardless of TPMT levels.

30. The systemic symptoms of AZA hypersensitivity most commonly include fever, malaise, arthralgias, myalgias, nausea, vomiting, diarrhea, and rash. Occasionally, liver or kidney dysfunction, hypotension, and shock may be present. Skin manifestations have historically been described as macular-papular, vesicular, or pustular. In addition, there are reports of purpura, urticaria, and erythemanodosum.

31. More recently, there are several reports of Sweet’s syndrome (SS) associated with AZA hypersensitivity. Our first patient similarly displayed SS-like lesions, while our second patient met the diagnostic criteria for drug-induced SS. Despite the wide use of AZA in dermatology, there are very few case reports of hypersensitivity in patients treated for dermatologic conditions (eg, immunobullous disease, atopic dermatitis, psoriasis, photodermatoses).

32. More than 50% of the time, hypersensitivity reactions to AZA occur with systemic symptoms identical to those of SS (fever, leukocytosis, malaise, arthralgias), but no cutaneous manifestations or cutaneousfindings other than SS are described. There are cases of cutaneous eruptions that may resemble SS, as in our case, but are not characteristic or do not meet the diagnostic criteria outlined by Walker and Cohen. Similar to our findings (Table I), Fields et al found that 39% of patients (19/49) who were diagnosed with AZA hypersensitivity were taking C.S at presentation. This is atypical for SS since C.S are the treatment of choice. Other atypical features include the location of lesions and preponderance of gastrointestinal symptoms. In our study, 58% (7/12) of patients presented with gastrointestinal symptoms (nausea,vomiting, diarrhea), which is uncommon for SS.

33. On initial presentation, most cases of AZA h.s are confused with infection or exacerbation of an underlying condition, as was the case in our patients. The concern for infection is a priority, especially with fever and leukocytosis in a patient receiving immunosuppressive therapy. However, work-up for infection generally yields negative findings and screening serologies for disease activity, such as complement levels or dsDNAab, in SLE tend to be normal. Under these circumstances, the diagnosis of AZA h.s is implicated rather than a flare of the underlying disease. AZA h.s is often recognized upon resuming or re-challenge with AZA where symptoms recur within hours of the first dose. The presence of new skin findings in the absence of infection or disease flare should alert the clinician to the possibility of AZA hypersensitivity. Most cases of AZA h.s resolve within 2-3 days after withdrawal of the medication and may not necessitate an increase in corticosteroid dose.

34. we report two cases of AZA hypersensitivity with cutaneous manifestations of neutdermatoses. Our review of the literature indicated that the most common cutaneous manifestation of AZA hypersensitivity is a neutdermatosis. Biopsy findings were consistent with SS, EN, SVV, and AGEP. AZA hypersensitivity syndrome tends to occur within 4 Ws after initiation of therapy and is unrelated to the gender or age of the patient or TMPT levels.

36. Treatment of refractory chronic urticaria withtumor necrosis factor-alfa inhibitors

37. Chronic urticaria is a physically and emotionally debilitating condition that often fails to respond adequately to antihistamines. Systemic therapy with glucocorticoids,sulfasalazine, colchicine, intravenous immunoglobulin,dapsone, or other immunosuppressants including cyclosporine,cyclophosphamide, and methotrexate are used in many patients with the associated risks of renal and hepatic toxicity and anemia. Unfortunately, some patients have disease recalcitrant to these treatments.

38. The pathogenic mechanisms of chronic urticaria are not well understood, but the primary effector cell is likely the mast cell. Activated mast cells release mediators, including Tumor necrosis factorealfa(TNF-a), that recruit other immune cells and play a role in perpetuating an urticarial response. Several preclinical investigations have shown an upregulation of TNF-a in patients with chronic urticaria. Magerl et al described a patient with severe psoriasis and delayed pressure urticaria who became free of urticarial lesions after 4 days of treatment with etanercept.

39. Based on these preclinical investigations and the case report, we treated six of our most refractory chronic urticaria patients with TNF-a inhibitors. we used doses tested for other systemic inflammatory conditions, such as psoriasis. In our series of six patients who were recalcitrant to all other immunosuppressive therapies, we observed dramatic improvement with TNF-a inhibitors. In most cases, the improvement was durable,lasting for several years. These results suggest that targeted TNF-a therapy may be useful for disease refractory to conventional or immunosuppressive therapy. Larger, controlled studies with longer followeup periods are needed to further confirm the efficacy and safety of TNF-a inhibitors in the management of patients with chronic urticaria.

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