and their differential diagnosis and management STEVE KOSSARD, MB BS, PhD, FACD The type and pattern of cutaneous blisters may provide an essential clue to the diagnosis of specific dermatological disorders. Physical and chemical injury, insect bites, contact dermatitis, medications and infections are the most frequent causes of selflimited blisters in general practice. Individuals with persistent and puzzling forms of blistering disease may have a variety of autoimmune blistering skin disorders including bullous pemphigoid and pemphigus or have epidermolysis bullosa or porphyria. Drug-related blistering may mimic these dermatoses and should always be considered a potential cause. The development of blisters is a feature which is shared by a large number of skin disorders. The ultimate diagnosis often is readily apparent from the clinical history and presentation, but occasionally may require a range of investigations including skin biopsy, immunofluorescence or ultrastructural studies. Blisters are traditionally classified as vesicles if they measure less than 0,5 cm in diameter and bullae if they are larger. Superficially located blisters which are intraepidermal or subcorneal tend Dr Kossard is Consultant, Skin and Cancer Foundation, Darlinghurst; and Visiting Dermatologist, St Vincent's Hospital, Sydney, NSW, Australia. He wrote this article specially for MODERN MEDICINE. to be flaccid and transitory while subepidermal blisters are often tense and are more readily identified. A practical approach to the diagnosis of cutaneous vesiculobullous disorders is to consider common causes (Table 1) which may result in blisters prior to considering the bullous disorders as a special group. Common causes of skin blisters Chemical or physical injury This usually provides no difficulties in diagnosis and usually the blisters are painful, asymmetrical and correspond to the site of contact. Occasionally a chemical contactant may not be readily identified or suspected in the workplace. Contact dermatitis This is characterized by markedly pruritic vesiculobullous reactions which may have a Linear or streaked configuration (Figure 1) on the exposed sites due to plants such as the rhus tree (Figure 2). There is often a lag of 24 to 48 hours after contact with the allergen prior to the development of lesions, reflecting a delayed hypersensitivity reaction. Most cases can be managed with topical corticosteroids, but severe and extensive involvement may require a course of oral prednisone (Meticorten, et al) commencing at a dose of 40 mg in the morning, reducing by 10 mg weekly decrements for four weeks to avoid rebound of the rash. Insect bite reactions These often are scattered and appear as grouped excoriated pruritic papules on exposed TABLE 1 Common causes for skin blisters Physical or chemical injury Contact dermatitis Insect bites Herpes simplex Impetigo Drugs MODERN MEDICINE OF SOUTH AFRICA 9
continued Contact dermatitis may appear af t e r a [ a g 0f 24-48 hours after contact with the allergen: this is a delayed hypersensitivity reaction. Figure 3. Grouped blisters on lower limbs due to insect Figure 4. Clusters of vesicles bites. cipated by sun exposure. sites. They are more often bullous in young children, migrants or the elderly (Figure 3). Insect bites may benefit symptomatically from the use of topical antihistamine creams; insect repellants should be utilized to diminish subsequent episodes. Herpes simplex Herpes simplex is readily recognized as grouped vesicles recurring at a localized site with MODERN MEDICINE OF SOUTH AFRICA 99
Impetigo blisters are superficial and continued I ten(i f0 transitory, resulting in multiple, crusted, highly contagious lesions. a self-limited course (Figure 4). Herpes may pose difficulties in diagnosis when the lesions are extensive in a primary episode or in disseminated infections and also when the lesions are at an unusual site. A Tzanck smear of the blister floor on a glass slide reveals viral giant cells allowing for rapid diagnosis. Acyclovir (Zovirax) has proved to be a valuable agent in the treatment of frequent recurrent episodes of herpes simplex and in disseminated infections, particularly in immunocompromised patients. Impetigo Impetigo blisters are superficially located and tend to be transitory resulting in multiple, crusted lesions which are highly contagious and usually are associated with staphylococcal infection. Blistering also may occur overlying a cellulitis due to Staphylococcus (Figure 5). Topical mupirocin ointment (Bactroban) is a useful addition for the treatment of localized impetigo. Drugs Drugs may cause blisters through a variety of mechanisms and may mimic a range of dermatoses which will be detailed prior to summarizing the varied drug reactions which may be bullous. Allergic and autoimmune bullous disorders (Table 2) Erythema multiforme Erythema multiforme represents an allergic reaction which is characterized by symmetrical papular eruption localized particularly to the extensor surfaces of the limbs. The lesions often have a target-like appearance and may be bull- Figure 5. Cellulitis with blisters due to staphylococcal Figure 7. Burn-like blisters infections. necrolysis. Figure 6. Target lesions associated with erythema multi- Figure 8. Tense blisters on forme. with bullous pemphigoid. 1 MODERN MEDICINE OF SOUTH AFRICA / OCTOBER 1990
continued. Dermatitis herpetiformis is intensely I p r u rm c ; although few patients have bowel symptoms, gluten-sensitive enteropathy is almost universal. Figure S. Linear deposition of immunoglobulin Figure 11. along Excoriated papulovesicular lesions i basement membrane zone seen on immunofluorescence metrical distribution on the trunk and elbows typica in bullous pemphigoid. matitis herpetiformis. Figure 10. Flaccid blisters on chest wall Figure of a patient 12. Blisters with and scars on the dorsum of ha pemphigus vulgaris. patient with porphyria. ous (Figure 6). Generalized erythema multiforme with severe involvement of the mucous membranes has been designated as the Stevens- Johnson syndrome. Extensive involvement of the skin may result in burn-like blisters termed "toxic epidermal necrolysis" (TEN) (Figure 7). Herpes simplex and drugs are the most frequent triggering MODERN MEDICINE OF SOUTH AFRICA 10
continued Pemphigus vulgaris used to be a fatal disorder, but the use of high dose oral steroids controls it: immunosuppressive agents have changed the outlook. factors for this reaction pattern. Acyclovir has been used prophylactically with success to prevent recurrent erythema multiforme triggered by herpes simplex. The use of oral corticosteroids has not been shown to alter the ultimate course of severe erythema multiforme. Bullous pemphigoid This may occur at all ages but particularly affects the elderly. It is characterized by urticarial plaques followed by tense blisters (Figure 8). Blisters are often generalized and may be accentuated in the flexural areas. A similar disorder termed "herpes gestationis" may occur during pregnancy. A variant of bullous pemphigoid involving the mucous membranes and resulting in scarring and occasionally blindness is termed "cicatricial pemphigoid". This group of autoimmune disorders all have circulating antibodies which are directed against the basement membrane zone (Figure 9) resulting in subepidermal blisters. Any elderly individual who suddenly develops widespread pruritic blisters which are tense should be biopsied as bullous pemphigoid can readily be diagnosed. Oral prednisone, commencing usually at a dose of 60 mg, remains the mainstay of management of bullous pemphigoid and usually needs to be continued for several years at a low dose (5-10 mg prednisone) to prevent relapse. Pemphigus vulgaris This is characterized by flaccid blisters often arising on normal skin (Figure 10). The peak incidence occurs in patients aged between 40 and 60 years. In most patients the initial lesions are localized to the oral mucous membranes. A superficial form which is localized particularly to the upper trunk and face may resemble impetigo and is termed "pemphigus foliaceus". Pemphigus is associated with circulating antibodies directed against the intercellular substance between the keratinocytes of the epidermis resulting in loss of intercellular adhesion and a process of acantholysis. Any chronic blistering or erosive process affecting the mucous membranes should be biopsied to rule out potentially serious bullous dermatoses such as pemphigus or cicatricial pemphigoid. Pemphigus vulgaris was formerly a fatal disorder but the use of high dose, oral steroids often exceeding 100 mg prednisone to bring the clinical activity under control and subsequent addition of immunosuppressive agents, such as azathioprine (Imuran, et al) has radically changed the outlook. Dermatitis herpetiformis This is an intensely pruritic disorder characterized by excoriated papulovesicular lesions localized particularly over the extensor surface of the elbows and knees and extending over the back (Figure 11), buttocks, face and scalp. The lesions may become bullous. The disorder occurs at all ages, but particularly in middle life. Skin biopsy 1 MODERN MEDICINE OF SOUTH AFRICA/OCTOBER 1990 shows neutrophilic microabscesses in the dermal papillae associated with granular IgA deposition demonstrable by immunofluorescence. Although the majority of patients do not have bowel symptoms, glutensensitive enteropathy is found almost universally. The control of this with a gluten-free diet has had a positive effect on the cutaneous disease. Dapsone, at a dosage of 50-200 mg, remains the major form of treatment and often the rapidity of the clinical response is dramatic in dermatitis herpetiformis. Special bullous disorders Epidermolysis bullosa This is represented by a range of blistering disorders due to structural abnormalities in the skin affecting its capacity to resist injury. This group is characterized by mechanical fragility of the skin and ranges from fatal forms presenting in the neonatal period to mild forms confined to the palms and soles in adults. Ultrastructural studies have helped to separate subtypes and recently prenatal sampling has allowed early diagnosis to be established. The level of the blister in epidermolysis bullosa may occur intraepidermally (epidermolytic), through the basement membrane (junctional) or under the basement membrane (dermolytic). The dystrophic recessive form, which is dermolytic, leads to extensive scarring and may eventually be complicated by multiple skin cancers. Careful skin care and
1. SCHEDULING STATUS: S3 2. PROPRIETARY NAME (AND DOSAGE FORM): Lopid Capsules 3. COMPOSITION: Capsules containing 300mg gemfibrozil Special precautions: Diabetes Mellitus: As gemfibrozil may elevate the fasting blood sugarsduring treatment periodic blood sugar determinationsareadvisable in diabetics receiving LOPID toassureadequate control. Cholelithiasis: Because LOPID may increase cholesterol excretion into the bile leading to cholelithiasis, gallbladder studiesare indicated if cholelithiasis issuspected. LOPID therapy should be discontinued if gallstones are found. 4. PHARMACOLOGICAL CLASSIFICATION: Category A: 7.5 Serum-cholesterol reducers 5. PHARMACOLOGICAL ACTION: LOPID is a lipid-regulating agent which produces an increase in the cholesterol content of the high density lipoprotein (HDL) fraction and lowers elevated total serum cholesterol and triglycerideconcentrationsdue todecreases in thevery lowdensity lipoprotein (VLDL) and low density lipoprotein (LDL) fractions. The mechanism by which these actions occur has not been firmly established. In animalstudies LOPID has been shown to reduce the incorporation of long-chain fatty acids into rat liver triglycerides and to inhibit adipose tissue lipolysis. In humans LOPID inhibits peripheral lipolysis and decreasesthe hepatic uptake of plasma free fatty acids leading to reduced hepatic triglyceride production. It also inhibits the production and increases the turnover rate of the ^-apoprotein moiety of VLDL, the resulting decrease in VLDL providing the basis for the drug's ability to reduce total lipid levels. Lopid increases plasma HDL levels by stimulating the synthesis of the major apolipoproteins of HDL. 6. INDICATIONS: Lopid is indicated as adjunctive therapy to diet and weight loss in the treatment of the following hyperlipidaemias: 1. Fredrickson Type lla 2. Fredrickson Type lib 3. Fredrickson Type IV NOTE: LOPID should be prescribed only for patients with a potentially responsive lipid or lipoprotein abnormality where appropriate dietary therapy alone is insufficient to correct the condition. Excess body weight and excessive alcohol intake may be important factors in hypertriglyceridaemia and should be addressed prior to any drug therapy. Appropriate physical exercise may be a valuable ancillary measure. Contributory underlying pathology should be adequately treated e.g. hypothyroidism and diabetes mellitus. 7. CONTRA-INDICATIONS: (1) Hepatic and/or severe renal dysfunction, including primary biliary cirrhosis (2) Gall-stones (3) Hypersensitivity to gemfibrozil. Safe use in pregnancy has not yet been established. It is not known whether or not gemfibrozil is secreted in human milk. Gemfibrozil should be avoided during pregnancy and lactation. Safety and efficacy in children have not been established. 8. DOSAGE AND DIRECTIONS FOR USE: 1200mg in divided dosestwicedaily. 900mg in divided doses twice daily will prove sufficient in some patients and should be tried in cases of intolerance at normal dosage. When maximal triglyceride reduction is desired up to 1500mg daily in divided doses may be needed. 9. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Side-effects. The most frequently occurring side-effects are gastro-intestinal and include abdominal and epigastric pain, diarrhoea, dyspepsia and flatulence, nausea and vomiting. Other important side-effects include headache, fatigue, rash, dermatitis, pruritus, urticaria, vertigo, impotence, myositis manifesting as painful extremities and myalgia accompanied by an increase in creatine phosphokinase. Other possibly related side-effects to which the physician should be alerted include dry mouth, constipation, anorexia, blurred vision, paraesthesia and tinnitus, insomnia, malaiseand syncope, arthralgia, swollen jointsand musclecramps, back pain, hypokalemia, leucopenia and anaemia. Drug Interactions: As prothrombin time may be increased if coumarin-type anticoagulants are administered inconjunction with LOPID, caution should be exercised. The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized. General Because long-term administration of LOPID may be needed, all baseline values including lipid profile, blood count and liver function tests, should be reliably measured beforetreatmentand periodicdeterminationsof serum lipidsshould be obtained. The drug should be withdrawn after 3 months if the response is inadequate. A paradoxical elevation of serum lipids has occasionally been observed, usually in patients with alcoholic hepatic disease. Mild haemoglobin, haematocrit and white blood celldecreases have been observed in occasional patients following initiation of LOPID therapy. However, these levels stabilize during long-term administration. Therefore, periodic blood counts are recommended during the first 12 months of LOPID administration. Abnormal liver function tests have been observed occasionally during LOPID administration, including elevationsofsgot.sgpt, LDH, and alkaline phosphatase. These are usually reversible when LOPID is discontinued. Therefore periodic liver function studies are recommended and LOPID therapy should be terminated if abnormalities persist. 10. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Symptomatic and/or supportive treatment. 11. IDENTIFICATION: Capsule with white opaque body and maroon opaque cap, imprinted LOPID and LOPID 300 in grey ink. 12. PRESENTATION: 300mg capsules in packs of 120. 13. STORAGE INSTRUCTIONS: Store in a cool (15 C to 25 C), dry place out of the reach of children. 14. REGISTRATION NUMBER: S/7.5/295 Lopid reduces the risk by raising HDL and lowering LDL cholesterol 15. NAME AND BUSINESS ADDRESS OF THE APPLICANT: PARKE-DAVIS, Division of WARNER-LAMBERTS.A. (Pty) Ltd. 241 Main Road, RETREAT 7945 16. DATE OF PUBLICATION OF THIS PACKAGE INSERT: 7 February 1990
continued. Regular venesection to lower the serum iron levels has been the most important treatment of porphyria cutanea tarda. TABLE 2 Differential diagnosis of autoimmune bullous disorders Lesion Major sites Level of blister Immunofluorescence Bullous pemphigoid Tense blister Cicatricial pemphigoid Erosions, scars Herpes gestationis* Grouped blisters Pemphigus vulgaris Flaccid blister, erosions Pemphigus foliaceus Erosions, crusts Dermatitis herpetiformis Excoriated papulovesicles "During pregnancy and postpartum period Generalized skin Mucous membranes Trunk, limbs Mucous membrane Upper trunk, face Knees, elbows, buttocks (lamina lucida) (lamina lucida) (lamina lucida) Intraepidermal Subcorneal (under basal lamina) Linear; basement membrane zone Linear; basement membrane zone Linear; basement membrane zone Intercellular Intercellular Dermal papillae protection remains the mainstay of management in epidermolysis bullosa although occasionally phenytoin sodium (Epanutin) may benefit individual cases. Porphyria Porphyria presents characteristically in middle-aged individuals who have increased skin fragility and blisters over the dorsal aspect of their hands associated with scarring (Figure 12). Skin hyperpigmentation, hypertrichosis and facial suffusion may be additional signs. Oestrogens and alcohol may precipitate the disorder. Measurement of urinary porphyrins will establish the diagnosis. Regular venesection to lower the serum iron levels has been the most effective treat- TABLE 3 Bullous drug reactions Erythema muttiforme Fixed drug eaction Toxic epidermal necrolysis - Phototoxic Pseudoporphyria Pemphigus ment of porphyria cutanea tarda. Bullous drug reactions (Table 3) Erythema multiforme This may be precipitated by drugs such as sulphonamides, penicillin, phenytoin sodium and phenylbutazone. A fixed drug reaction This is characterized by localized erythematous plaques which may blister and typically heal with hyperpigmentation. The lesions may be on mucous surfaces, and recur at the same sites on readministration of the specific drug. Tetracyclines, sulphonamides and phenolphthalein are among the most common precipitants. Toxic epidermal necrolysis This is characterized by the sudden development of tender erythematous skin which is shed as loose sheets simulating a burn. It rapidly becomes generalized and is associated with mucous membrane involvement. Approximately 50% of patients follow a fatal course despite intensive treatment. Allopurinol, phenytoin sodium and sulphonamides are among the most common causes. Phototoxic drug reactions These mimic sunburn and may culminate with painful blisters on exposed sites. Thiazides, sulphonamides, tetracyclines and dithranol may result in phototoxic reactions. Pseudoporphyria This shows the same pattern of blistering as seen with porphyria, but urinary porphyrin studies give negative results. Nalidixic acid, tetracycline, frusemide and naproxen are the most frequently reported causes. Pemphigus This also may be precipitated by drugs and, in some cases, settle on discontinuing the medication. The most frequently reported drug associated with this is penicillamine, but other drugs including rifampicin and captopril may also induce this reaction. MODERN MEDICINE OF SOUTH AFRICA 10