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Drug-Induced Pemphigus w. Rahimi Pharm D. انوع نادر بيماريهاي تاولي در زمان تولد وجود دارند و در نتيجه به ارث رسيدن يك ژن غيرطبيعي از هر دو والد به صورت اتوزوم مغلوب به وجود ميآيند. بيماري باعث ميشوند كه پوست كل بدن خيلي شكننده شده و در صورت لمس ،تاول ايجاد شود .که ممكن است كشنده باشند. به طورمعمول بيماريهاي تاولي در بزرگسالي شايعترند. جزء بيماريهاي خود ايمني هستند ،پادتنهايي توليدی در بدن باعث آسيب پوست ميشوند. پمفيگوئيد شايعترين نوع بيماري تاولي پمفيگوس (اثر سيستم ايمنی بدن بر دزموگلين و ازبين رفتن پيوند بين سلولی دزموزوم زخم اپيدرم و نفوذ مايع ميان بافتی به زير پوست نفوذ کرده و ايجاد تاول ) اپيدرموليسيس بولوسا (فقدان کالژن بين اپيدرم و درم) درماتيت هرپتي فرم (آلرژي به گلوتن كه يك پروتئين موجود در گندم) پمفيگوس نسبت به پمفيگوئيد شيوع كمتري دارد. معموالً افراد با سن باالي 60سال را مبتال ميكند. تاولها ممكن است درهر قسمتي از بدن ظاهر شوند، اما اغلب در اطراف چشمها و داخل دهان به وجود ميايند. تاولها شكننده بوده و ممكن است به طور خود بخودي پاره شوند و تكههايي از پوست لخت را برجا گذارند. Vesicles and bullae are raised lesions that contain fluid. A vesicle is less than 0.5 cm in diameter. A bulla is larger than 0.5 cm in diameter. بسته به عمق پيوندهای گسسته شده و نوع نقص ايمنی ،انواع پمفيگوس بوجود دارد. يادآوری :در تمام موارد نقش ايمنوگلوبين جی IgGمشهود است. پمفيگوس وولگاريس ) ( Pemphigus Vulgarisکه ۷۰ درصد موارد اين بيماری را در بر ميگيرد. پمفيگوس فوليکوس ( )Pemphigus foliaceusکه نوع خوشخيم اين بيماری است و در اليه سطحی پوست ايجاد ميشود. پمفيگوس نئوپالست )(paraneoplastic pemphigus کمترين آمار موجود ولی نوع بدخيم بيماری. Drug-induced pemphigus is a wellestablished variant of pemphigus. Since the 1950s, evidence has grown that drugs may cause or exacerbate pemphigus. A drug origin should be considered in every new patient with pemphigus. The most common variant of pemphigus associated with drug exposure is pemphigus foliaceus, although pemphigus vulgaris has also been described. In penicillamine-treated patients, pemphigus foliaceus is more common than pemphigus vulgaris, with an approximate ratio of 4:1. Most patients develop the eruption a few weeks after starting therapy with the offending agent. In penicillamine use, the eruption may not develop until 6 months after the onset of therapy. Some patients may give a history of a nonspecific eruption prior to the development of pemphigus type lesions. Clinical manifestations of drug-induced pemphigus depend on the pathomechanism involved. Disease caused by thiol drugs tends to present with the clinical findings of pemphigus foliaceus. Erythematous, scaly, crusted plaques occur primarily on the trunk. Occasional superficial vesicles and bullae may be seen, but usually, they are ruptured. Oral lesions do not occur. Nonthiol drug-induced pemphigus presents predominantly as pemphigus vulgaris. Flaccid bullae and erosions occur on normal-appearing skin and, also, on the oral mucosa Speculation exists that genetic predisposition may be important in non-thiol– triggered pemphigus. Human leukocyte antigen DR4 (HLA-DR4) is associated with idiopathic pemphigus; however, few studies have provided data concerning HLA typing in cases of drug-induced pemphigus. Thiols implicated in drug-induced pemphigus are as follows: Penicillamine , Captopril, Lisinopril , Gold sodium thiomalat , Piroxicam, Bucillamine , Thiamazole, 5-Thiopyridoxine, Pyritinol, Thiopronine, Antibiotics implicated in drug-induced pemphigus are as follows: Penicillin and derivatives, Cephalosporins, Quinolones, Rifampicin Pyrazolone derivatives implicated in drug-induced pemphigus are as follows: Phenylbutazone , Aminopyrine, Azapropazone , Oxyphenylbutazone Propanolol Levodopa Progesterone Carbamazepine Phenobarbital Glibenclamide Heroin Lysine acetylsalicylate Imiquimod Cilazapril It is not possible to distinguish between idiopathic and drug-induced pemphigus based on histologic features. Withdrawal of the offending agent is the first step in treatment. Most, but not all, patients go into remission once the offending agent is stopped. Some patients may follow a chronic course identical to that of idiopathic pemphigus vulgaris. These patients require systemic corticosteroids and/or immunosuppressive therapy. For patients who have erosions involving a significant portion of the body surface area, the burn unit is helpful in providing wound care (cleansing, application of topical antibiotics, and bandaging). For patients in whom the disease does not resolve upon withdrawal of the offending agent, medical therapy is necessary. Generally, systemic corticosteroids or other immunosuppressants are required. Anecdotal reports support the use of alternate immunomodulating agents (eg, antimalarial drugs, rituximab, intravenous immunoglobulin, mycophenolate mofetil). Recent reports suggest targeting cholinergic drugs as antiacantholytic therapy for idiopathic pemphigus. Prednisone is the initial drug of choice for severe or recalcitrant cases of drug-induced pemphigus Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity. Azathioprine is useful in steroidresistant patients. It is less toxic than some other immunosuppressants. Generally, it is used in conjunction with low doses of systemic corticosteroids. Prior measurement of thiopurine methyltransferase (TPMT) levels can be useful in guiding the initial dose. Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Cyclophosphamide is effective in treating pemphigus; however, this drug also is very toxic. Secondary infections may occur in druginduced pemphigus because of the disruption of the skin barrier. Extensive erosions may promote entrance of bacteria, resulting in cutaneous infections, bacteremia, or sepsis. Systemic application of steroids is the first-line treatment (0.5-1.0mg/kg/d). Taper off to a maintenance dose or until it can be discontinued. Immunosuppressants (mycophenolate mofetil, CTX, AZT, MTX, cyclosporine) may be used. In intractable cases, plasma exchange therapy and IVIG can be performed. Antibiotics, fluid transfusion, nutrition management are conducted supplementarily. بيماريهاي تاولي كه افراد بالغ را مبتال ميسازند اغلب با درمان قابل كنترل هستند ،اما موارد خيلي كمي ،به طور دائمي عالج مييابند. هر چند پمفيگوئيد ممكن است خودبخود در عرض 5-2سال ناپديد شود ،اما پمفيگوس اغلب به درمان دارويي دراز مدت نياز دارد. به علت ماهيت آلرژيك درماتيت هرپتي فرم ،در صورت اضافه كردن مجدد گلوتن به رژيم غذايي ،اين بيماري ممكن است عود نمايد. Diseases with intraepidermal blistering (pemphigus-group) Pemphigus vulgaris Pemphigus foliaceus Pemphigus vegetans Pemphigus erythematosus Paraneoplastic pemphigus Drug-induced pemphigus Neonatal pemphigus Intercellular IgA dermatosis Brazilian pemphigus پس از تشخيص ،پر کاربردترين داروها شامل سيتوکينها(انواع اينترفرون و اينترلوکين) ،انواع داروهای ضد التهاب غير استروئيدی ،آنتی بيوتيک (پنيسيلين و مشتقات) ،انواع بتا بالکر ،مهارکننده های آنژيوتانسين()،ACE inhibitor هورمون پروژسترون و آنتاگونيست های کلسيم ميباشد. Diseases with subepidermal blistering (pemphigoid group) Bullous pemphigoid (BP) Herpes gestationis Cicatricial pemphigoid Epidermolysis bullosa acquisita Dermatitis herpetiformis (Duhring) Linear IgA bullous dermatosis (LAD) Bullous SLE Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Middle-aged and elderly people are most commonly affected Flaccid blisters Two main groups: vulgaris & foliaceus Nikolsky’s sign and Tzanck test are positive Autoimmune diseases Acantholytic intraepidermal blistering is produced by autoantibodies against desmoglein Anti-desmoglein antibodies are detected by ELISA In vivo IgG deposition and IgG antibodies are observed by immunofluorescence Oral steroids & immunosuppressants are mainly administered. Keratinocytes are firmly adhered by desmosomes. Transmembrane adhesion molecules in the cadherin superfamily, such as desmoglein 1 (Dsg 1), Dsg3, and desmocolin cadherin (DC), are important to intercellular adhesion. In pemphigus, autoantibodies are produced against Dsg1 and Dsg3, some of whose molecular functions are disturbed. This causes acantholysis. Clinical features Pathology Immunofluorescence ELISA DDx: bullous pemphigoid, impetigo, bullous drug eruption, dermatitis herpetiformis, erythema multiforme, Stevens-Johnson syndrome, etc. Vesicles and erosions Areas of friction, exposure Proliferate and elevate Suprabasal cell acantholysis DDx: chronic pyoderma and fungal granuloma, Hailey-Hailey disease, condyloma acuminatum, etc. The same as for pemphigus vulgaris Treat local infections Consider topical and systemic antibiotics Consider antifungal agents for candida Surgical excision of large vegetative growths Better prognosis than pemphigus vulgaris Clinical features Pathology Immunofluorescence ELISA DDx: pemphigus vulgaris, pemphigus erythematosus, drug-induced bullous disease, paraneoplastic pemphigus, etc. The same as for pemphigus vulgaris Oral steroid dosage may be less than that for pemphigus vulgaris In limited involvement cases, topical steroid are sufficient Clinical features Pathology Immunofluorescence DDx: paraneoplastic pemphigus, seborrheic dermatitis, lupus erythematosus, pemphigus foliaceus, etc. The same as for pemphigus foliaceus Diseases with subepidermal blstering (pemphigoid group) Bullous pemphigoid (BP) Dermatitis herpetiformis (Duhring) Subepidermal blistering occurs as a result of autoantibody action against epidermal basement membrane structural proteins Blisters are tense and do not rupture easily Divided into pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, dermatitis herpetiformis, herpes gestations, etc. Immunofluorescence is useful for diagnosis Steroids and dapsone are applied the area corresponding to the dermoepidermal junction stains with periodic acid-Schiff consists of the basal cell plasma membrane the lamina lucida the basal lamina the sub-basal lamina fibrous components acts as a mechanical barrier and penetration of substance between dermis and epidermis Autoantibodies are produced against hemidesmosome, type XVII collagen (BP180) and BP230 in the epidermal basement membranes, which leads to blistering. Autoantibodies against BP180 play a major role. Autoantibodies against hemidesmosomes The major pathogenic antigen is type XVII collagen (BP180). The roof of the blister has the full thickness of the epidermis Elderly people account for the majority of cases Characterized by subepidermal blisters Blisters do not rupture easily Oral steroids are effective The elderly are more commonly affected Multiple relatively large and severe tense blisters form immediately Often accompanied by edematous erythema Much less invasively to the mucous membranes (20% involved) The general condition is favourable May be complicated by malignant tumors Pathology: subepidermal blistering, accompanied by eosinophilic infiltration Immunofluorescence: linear IgG and C3 deposition in the basement membranes ELISA: autoantibodies against type XVII collagen (BP180) proteins High IgE values and elevated levels of eosinophils in peripheral blood Clinical features Pathology Immunofluorescence ELISA DDx: drug-induced bullous disorders, epidermolysis bullosa, epidermolysis bullosa acquisita, erythema multiforme, dermatitis herpetifomis, linear IgA dermatosis, etc. Oral steroids (0.5mg/kg/d) Gradually reduced Combination therapy of Immunosuppressants (CTX), DDS, tetracyclines and nicotinic-acid amide are also useful Avoid secondary infections Nutrition management is important for elderly Topical steroid application may be sufficient in mild cases Plasma exchange therapy and IVIG may also be used in severe cases Characterized by extremely intense itching and irritation, chronically recurrent erythema and vesicles Vesicles tend to form circular patterns Common in Caucasians, rare in Asians Granular IgA deposition in the dermal papillary Gluten-induced enteropathy develops as a complication Oral dapsone is effective composed of the sticky, storage proteins found in wheat exist conjoined with starch in the same grass-related grains, notably wheat, rye and barley IgA antibodies against tissue transglutaminase The granular IgA deposition in the skin is an immuno-complex Extremely intense itching Erythema and urticarial lesions Vesicles in a ring-shaped pattern Scratch and resulted crusts Heal with abnormal pigmentation or depigmentation Appear symmetrically on the entire body, esp. on the elbows, knees and buttocks Gluten-induce enteropathy is found in more than 90% of cases Pathology: subepidermal blistering, microabscesses of neutrophils in dermal papillary Immunofluorescence: granular IgA deposition in the dermal papillary Clinical features Pathology Immunofluorescence DDx: linear IgA bullous dermatosis, bullous pemphigoid, herpes gestationis, erythema multiforme, ect. Dapsone is effective Gluten-free diet antihistamines Clinical features Pathology Immunofluorescence ELISA DDx: bullous pemphigoid, impetigo, bullous drug eruption, dermatitis herpetiformis, erythema multiforme, Stevens-Johnson syndrome, etc. Systemic application of steroids is the first-line treatment (0.5-1.0mg/kg/d). Taper off to a maintenance dose or until it can be discontinued. Immunosuppressants (mycophenolate mofetil, CTX, AZT, MTX, cyclosporine) may be used. In intractable cases, plasma exchange therapy and IVIG can be performed. Antibiotics, fluid transfusion, nutrition management are conducted supplementarily. Vesicles and erosions Areas of friction, exposure Proliferate and elevate Suprabasal cell acantholysis DDx: chronic pyoderma and fungal granuloma, Hailey-Hailey disease, condyloma acuminatum, etc. The same as for pemphigus vulgaris Treat local infections Consider topical and systemic antibiotics Consider antifungal agents for candida Surgical excision of large vegetative growths Better prognosis than pemphigus vulgaris Most commonly affects the middle-aged and elderly Extremely fragile flaccid vesicles Some of the blisters dry to become leafy and to exfoliate successively The face, head, back and chest are most commonly affected When spreads over the whole body, it resembles exfoliative erythroderma Mucosa is not or occasionally involved Nikolsky’s sign is positive Clinical features Pathology Immunofluorescence ELISA DDx: pemphigus vulgaris, pemphigus erythematosus, drug-induced bullous disease, paraneoplastic pemphigus, etc. The same as for pemphigus vulgaris Oral steroid dosage may be less than that for pemphigus vulgaris In limited involvement cases, topical steroid are sufficient A subtype of pemphigus foliaceus Occurs most commonly in the middle-aged and elderly Frequently affects the seborrheic zones (head, face, chest and back) The mucosa is not involved Involvement of SLE is seen in some cases Clinical features Pathology Immunofluorescence DDx: paraneoplastic pemphigus, seborrheic dermatitis, lupus erythematosus, pemphigus foliaceus, etc. The same as for pemphigus foliaceus نام های ديگر در فارسی :اپيدرموليسيس بولوسا ،اپيدرموليز بولوزا، اپيدرموليسيس بولوسا ،اپيدرموليزيس بولوزا) يک بيماری ارثی در بافتهای پوستی میباشد که در پوست و غشای مخاطی ايجاد تاول میکند. شيوع اين بيماری ۱در ۵۰۰۰۰است .شدت بيماری از ماليم تا کشنده تغيير میکند. اين بيماری از يک جهش ژنتيکی در کراتين يا کالژن ايجاد میشود . در تمامی گروه های قومی و نژادی رخ می دهد و به طور مساوی بر مردان و زنان اثر می کند. پوست به شدت شکننده و کوچکترين اصطکاک يا آسيبی الیهای پوستی را جدا کرده و ايجاد تاول میکند .افراد دچارشده به اين بيماری در معرض ريسک سرطان پوست میباشند. پوست شامل دو اليه میباشد :اليه خارجی که روپوست (اپيدرميس) خوانده میشود و اليه داخلی، پوست (درميس). در افراد سالم ،قالبهای پروتئينی که از کالژن ساخته شدهاند بين دو اليه وجود دارند که مانع حرکت مستقل (اصطکاکی) اين دو اليه میشوند .در افراد مبتال بهای بی ،اين دو اليه پوستی فاقد اين پروتئين بوده و کوچکترين عملی که باعث ايجاد اصطکاک بين دو اليه میشود (مثل ماليدن يا فشار) ايجاد تاول و زخمهای دردناک میکند .مبتاليان بهای بی درد خود را با سوختگی درجه سه قابل مقايسه میدانند. درماتيت هرپتي فرم اين بيماري در همراهي با آلرژي به گلوتن كه يك پروتئين موجود در گندم ميباشد ،شكل ميگيرد .اين وضعيت منجر به ايجاد تاولهاي خارشدار ،معموالً بر روي آرنجها ،باسن و زانوها ميشود. كارهايي كه بايد انجام شوند در همه انواع بيماريهاي تاولي ،تشخيص معموالً براساس بيوپسي پوست صورت ميگيرد .اين روش عبارتست از برداشتن يك نمونه از پوست جهت بررسي .هيچ درمان موثري براي بيماريهاي تاولي ارثي وجود ندارد. والدين نوزاداني كه مبتال به اين بيماريها هستند ممكن است به دنبال مشاوره ژنتيك رفته ،تا از احتمال ابتالي بچههاي بعدي خود آگاهي يابند .اگر شما دچار پمفيگوئيد يا پمفيگوس هستيد ،پزشكتان كورتيكواستروئيد خوراكي تجويز خواهد كرد .بعضي افراد نيز ،نيازمند داروهاي تضعيف كننده سيستم ايمني براي چندين هفته يا ماه خواهند برد .اگر مبتال به پمفيگوئيد شديد هستيد ،ممكن است نياز به درمان فوري با داروهاي تضعيف كننده سيستم ايمني در بيمارستان داشته باشيد .در اكثر موارد درماتيت هرپتي فرم به محض اينكه فرد مبتال ،به رژيم فاقد گلوتن عادت كند ،ناپديد ميشود ،اما ممكن است داروي داپسون نيز براي پاك كردن تاولها الزم شود.