A. Razzaque Ahmed

Death in pemphigus

Pemphigus is frequently a fatal skin disease. The cause of death and the events leading to it were investigated by examining patient records and autopsy data of thirteen patients who died as a result of this disease at the UCLA Hospital between 1965 and 1980. The diagnosis was confirmed histologically and/or by immunofluorescent studies of the skin and serum. Infection was the most frequent cause of death, and septicemia was found in nine of thirteen cases. The most commonly found organism was Staphylococcus aureus. The skin was usually the source of infection. Nine patients had pneumonia on chest x-ray and autopsy examination. Most patients had low levels of serum proteins and serum albumin. Since the patients were on long-term high doses of corticosteroids, the signs and symptoms of inflammation were often masked. This study demonstrated that for this reason, long-term corticosteroid therapy is one of the significant factors contributing to the death of these patients. A cautious and judicious use of steroids is suggested.

Coexistence of lichen planus and systemic lupus erythematosus

Three cases of the simultaneous occurrence of lichen planus (LP) and systemic lupus erythematosus (SLE) are presented. Each patient had clinical, histologic, and immunopathologic LP. Additionally, each patient had clinical SLE that fulfilled the American Rheumatism Association criteria for the diagnosis of SLE. The clinical manifestations of SLE were predominantly cutaneous. The three patients had positive lupus band test and high titers of antinuclear antibodies. One patient had vitiligo in addition to SLE and LP. LP and SLE have common clinical, histologic, and immunopathologic features. It is possible that a common agent (or agents) may cause either disease or the overlap syndrome, depending on the immunogenetic predisposition of the patient.

Clinical features of pemphigus

Abstract Pemphigus is an autoimmune, blistering disease that affects the skin and mucous membranes. 1 It affects all ages. Pemphigus has been reported in children and young adults. The mean age of onset is the sixth decade in most large series, the range being 12–88 years. 2–4 The majority of patients are often in their fourth, fifth, and sixth decades. Thus it appears that pemphigus attacks individuals at the peak of their adult lives. This often has a deleterious effect on the psychology of the patient and the patients family. Age of anset is important because the prognosis in older patients is not as good as that in younger patients. 5 Pemphigus affects men and women equally. The incidence is slightly higher in Jewish women than men. 6 When large series are compared, and patients below the age of 20 are studied, it appears that there is a predilection for women in that group. 7 The exact incidence of pemphigus is unknown. Since it is not a reportable disease it is difficult to establish the incidence. This reproblem is further compounded by the fact that several drugs are now believed to induce pemphigus (Chapter 4). The establishment of a registry would greatly facilitate the study not only of incidence but other epidemiological features and clinical perspectives as well. In 1941, less than 1% of all cases seen in a large New York City hospital dermatology clinic accounted for pemphigus 6 ; however, at that time, pemphigus was not differentiated from other blistering diseases. 8 In 1976 in southern Arizona, the incidence was reported to be 0.5 cases per 100,000 population per year. 9 In 1977 in a study from Hartford County in Connecticut, the annual incidence was 0.42 cases per 100,000 people in general. 10 In the same area, the incidence was 3.2 per 100,000 in the Jewish population. It is generally believed that the incidence is significantly higher in patients of Jewish descent or origin. In a study from Jerusalem, the incidence was reported to be 1.62 cases per 100,000 population. 11 Pemphigus has been reported worldwide, and it affects all races. It is important to emphasize that pemphigus is a rare disease. It is nonetheless one of the few potentially fatal skin diseases. Early diagnosis is often associated with good response to therapy and a better prognosis. Direct and indirect immunofluorescent studies have greatly facilitated the diagnostic armamentarium of the clinician. The availability of these tests by mail has increased their practical utilization. There are four described variants of pemphigus: (1) pemphigus vulgaris, (2) pemphigus vegetans, (3) pemphigus foliaceus, and (4) pemphigus erythematosus. The four variants have different clinical presentations. The clinical presentation is dissimilar insofar as that each variant can be clinically differentiated. If the right kind of lesion is biopsied, they can frequently be differentiated histologically. The four variants can also be differentiated in most cases on direct immunofluorescence. On indirect immunofluorescence, the staining pattern is quite similar. It is universally agreed that pemphigus vegetans is a variant of pemphigus vulgaris. 12 Similarly, pemphigus erythematosus is considered a variant of pemphigus foliaceus. 12

Bullous Pemphigoid and Ulcerative Colitis

ABSTRACT: A 21‐year‐old white woman, who had ulcerative colitis for 14 years, developed generalized severe bullous pemphigoid. Following the resection of her colon, her skin showed marked clinical improvement, but this was only temporary. Direct immunofluorescence was performed on the surgical specimen and no antibodies (BMZ) to colonic mucosal cells were evident. Anti‐basement membrane zone antibodies were found on direct and indirect immunofluorescent studies and have persisted. Sera from 15 patients with ulcerative colitis and 11 patients with Crohns disease, evaluated for the presence of an anti‐basement membrane zone antibody did not contain any demonstrable levels of anti‐BMZ antibodies. The co‐existence of ulcerative colitis and bullous pemphigoid is more likely incidental rather than etiopathologic.

Acantholysis producedin vitro with pemphigus serum: Hydrocortisone inhibits acantholysis, while dapsone and 6-mercaptopurine do not inhibit acantholysis

Many studies have shown that human skin in organ cultures containing pemphigus antibody undergoes acantholysis, the histologic hallmark of pemphigus vulgaris. Thisin vitro organ culture system provides a good model to determine if drugs used to treat pemphigus inhibit the effect of pemphigus antibody after it is produced. In this study we determined if hydrocortisone, dapsone, and 6-mercaptopurine (6-MP) could inhibit acantholysis observed in human skin organ cultures containing high constant levels of pemphigus plasma. In six experiments we demonstrated that hydrocortisone (10−3 and 5×10−4M) present at the start of organ culture inhibited acantholysis induced by pemphigus sera. Thus, this study raises the possibility that the large doses of steroids used to treat acute pemphigus could act directly on the skin, inhibiting acantholysis in the presence of high titers of pemphigus antibody. Other effective immunosuppressive drugs, such as dapsone and 6-MP, probably do not act directly on the skin.

Interleukin-2 production in bullous pemphigoid.

Bullous pemphigoid (BP) is a chronic, autoimmune, blistering skin disease, characterized by the deposition of immunoglobulins and/or complement at the basement membrane zone (BMZ) [1]. The sera of the majority of the patients has an antibody of the IgG class against the BMZ of the skin [2]. Several studies have demonstrated that titer of this antibody does not correlate with disease activity or severity [3]. In vitro studies utilizing skin sections incubated in BP serum have demonstrated that leukocytes adhere to the BMZ, are activated, and cause BMZ damage histologically identical to that observed in clinical lesions [4, 5]. Lesions of BP often demonstrate degranulated mast cells and eosinophiles [6, 7]. A mastcell-derived eosinophile chemotactic factor has been demonstrated in BP blister fluid [8]. It now appears that the earliest cell to enter the dermis is a lymphocyte. Lymphokines with lymphocyte chemotractant activity [9] and lymphotoxin-like activity [10] have been found in BP blister fluid. The peripheral blood leukocytes (PBL) of BP patients with active disease contain a normal distribution of T cells, B cells, and Fc-receptor-bearing cells [11]. Using monoclonal antibodies, no loss or gain of a specific subset of T cells has been observed [12]. A functional assay, using pokeweed-mitogen-drived IgG synthesis by PBL of BP patients with active disease, did not demonstrate the lack of suppressor cell or increased helper-cell activity [12]. A similar observation has been made using the Con-A suppressor cell assay [13].

Partial purification and characterization of pemphigus-like antigens in urine.

SummaryThe inhibition of indirect immunofluorescence was used to detect the presence of pemphigus-like antigens in urinary proteins. Antigenic material was present in 12 of 40 urine samples obtained from 16 patients with bullous pemphigoid, cicatricial pemphigoid, or pemphigus vulgaris. Antigen could not be detected in the urine of patients with carcinoma of the bladder. Partial purification was accomplished by ion-exchange chromatography and column gel filtration. Antigenic activity was detectable in all fractions eluted from Sephadex G-200 in the broad range of molecular weight of 90,000–180,000 daltons. Pemphigus-like antigens were glycoproteins with an apparent molecular weight of 75,000 daltons by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). The antigens were immunogenic in mice, but were not detectable by double diffusion in agarose gels.

Bullous Pemphigoid Family of Autoimmune Diseases

Bullous pemphigoid (BP) was distinguished from other blistering disease by Lever* in 1953. This presentation is intended to highlight diseases associated with BP, and the importance of such an association, if any. In the review of the literature, we have included, as far as possible, only those cases in which there was direct or indirect immunofluorescence studies to document the diagnosis of BP.

ANA-negative systemic lupus erythematosus.

A subset of patients who often satisfy the ARA criteria for SLE but whose sera lack antinuclear antibodies when tested against various standard substrates is reviewed. Such a subset of patients forms a distinct clinical and serological group. The majority of these patients present with cutaneous lesions frequently seen in discoid or systemic lupus erythematosus. Involvement of other organ systems is less frequent in this group compared to ANA‐positive SLE. The sera of these patients usually contain anti‐Re and anti‐La antibodies detectable by double immunodiffusion. While most patients deposit immunoglobulins in the lesional skin, direct immunofluorescence of uninvolved skin is positive only in approximately ten per cent of patients. The clinical course is marked by relapses and remissions and is favourable compared to ANA‐positive SLE patients. Ten percent of SLE patients who are initially ANA‐negative become ANA‐positive on follow‐up of approximately 4 years. Topical therapy alone may be helpful when only cutaneous manifestations are present. Systemic steroids and antimalarials are the mainstay of therapy in most cases.

Therapy of pemphigus

Abstract Pemphigus is a serious autoimmune skin disease associated with a high morbidity and a significant mortality rate. Prior to the advent of steroid therapy, mortality rates of 70–100% were reported. 1 With the use of corticosteroids and antibiotics, the mortality associated with pemphigus has dropped to 15–44%. 2,3 Currently, where corticosteroids are used in conjunction with immunosuppressives, the mortality rate is approximately 10–20%. 4 Therapy of a pemphigus patient should include a thorough systematic evaluation. Accurate diagnosis, using clinical, histologic and immunofluorescent parameters, is important because the chemotherapy used can cause severe side effects, and untreated, active pemphigus can be fatal. Exogenous causes of pemphigus, especially drugs, 5 like penicillamine 6 and captopril, 7 should be ruled out. Diseases associated with pemphigus should be considered in the evaluation of the patient. The exact chemotherapy that should be used to treat each patient optimally is unclear. It is well recognized that corticosteroids are the most helpful agents in many patients, and the drugs of choice in severe or active disease. 8–10 However, severe and often life-threatening side effects are also associated with the prolonged administration of the high doses of corticosteroids used to treat pemphigus. 11,12 Alternative or adjuvant therapies are being used more frequently. This is an attempt to gain control of severe disease not controlled with corticosteroids, 13,14 to reduce maintenance steroid dose, 12,16 or to eliminate steroid therapy in mild disease in order to prevent the long-term side effects of corticosteroids. 9,16 At present at least eight therapeutic modalities have been reported as being effective in therapy of pemphigus: systemic corticosteroids; the immunosuppressive drugs, methotrexate, azathioprine, clyclophosphamide; gold; dapsone; sulfapyridine; and plasmapheresis. Emperic use of these therapies has yielded useful information. Since no prospective or retrospective controlled studies have been done to evaluate the effectiveness of one type of therapy versus another, the optimal combination of these therapies is currently not known.