Autoimmune progesterone dermatitis: Update and insights.

UNLABELLED: Autoimmune progesterone dermatitis (APD) is rare autoimmune hypersensitivity reaction to the fluctuations of endogenous progesterone during a woman's menstrual cycle. It has a wide spectrum of clinical presentations including urticaria, eczema and vesiculobullous eruptions. The disease course depends on treatment modality. The pathogenic mechanisms of APD remain to be elucidated. OBJECTIVE: We aim to review the literature on APD and evaluate the different theories of pathogenesis and treatments for this condition. METHODS: A review of the English literature on APD was performed using PubMed, EMBASE and MEDLINE. RESULTS: 89 patients are included in this review. Initial symptom development in association with the menstrual cycle was reported in 65 (73%) patients. In some patients, it occurred shortly after hormone therapy (8.9%) or in relation to a pregnancy (14.6%). Associated factors were not defined in three patients (3.4%). Nearly 45% had a history of exposure to exogenous progesterone. Diagnosis of APD was usually confirmed with an intradermal progesterone sensitivity test. The goal of treatment was to suppress progesterone secretion through anovulation. Some cases were controlled with oral contraceptives or conjugated estrogen, while some patients had complete resolution post-hysterectomy. CONCLUSION: The wide spectrum of clinical presentations, histology, and response to therapy would suggest that there are multiple subsets in APD. The increase in the levels of progesterone may also influence the clinical profile and the corresponding immunological response. Further research on the pathogenesis of APD is required to provide a satisfactory treatment modality.

Positive clinical outcome with IVIg as monotherapy in recurrent pemphigoid gestationis.

Pemphigoid gestationis (PG) is an autoimmune blistering disease associated with pregnancy. It is characterized by the presence of autoantibodies against bullous pemphigoid antigens in the basement membrane zone. A 32 year old female developed PG in the first pregnancy and had a stillbirth. PG recurred during the second trimester of her second pregnancy. Systemic corticosteroid therapy was cause for concern since patient developed gestational diabetes. Patient was unwilling to use insulin. Intravenous immunoglobulin (IVIg) was used as a treatment of last resort. The dose was 2g/kg/cycle. It was given every two weeks antepartum and every three weeks for three months postpartum. PG improved within four weeks of IVIg therapy. Serum and tissue immunopathological studies were negative prior to delivery. A healthy neonate was born. No adverse events to IVIg were observed. No disease was observed ten months postpartum.

Management of pemphigus in pediatric patients.

The management of pemphigus in pediatric patients is divided into childhood (patient ≤12 years) pemphigus and juvenile (patients 13-18 years) pemphigus. In both groups the majority of patients have mucocutaneous disease. The mucose involved are oral, nasal, ocular, and anal. In both groups there is a high prevalence of genital involvement. Autoantibody titers can be detected in the sera of the majority of patients. The mainstay of therapy is oral corticosteroids. About half to two thirds of the patients develop systemic side effects. The most concerning is growth retardation present in 50% of the patients. Others include infection, obesity, psychological, and social distress. Immunosuppressive agents are used in many patients for their steroid-sparing effects. Surprisingly, Dapsone or sulphapyridine has not been used in more patients. The treatment lasts between two to three years. The prognosis in most cases reported was good. Intravenous immunoglobulin (IVIg) shows promise in early studies. Rituximab was effective in recalcitrant cases. There is no evidence in the literature suggesting that disease can continue into adult life or recur during adult life after a prolonged remission after childhood or juvenile disease. Even though it is quite rare, pemphigus should be considered in a pediatric patient presenting with blisters or erosions and excluded by a routine biopsy and direct immunofluorescence studies.

Response in patients with pemphigus vulgaris to rituximab therapy. Basis of the biology of B cells.

Rituximab (RTX) is a chimeric monoclonal antibody against CD20, which is present on B lymphocytes on the cell surfaces. Originally used for the treatment of B cell malignancies, recent studies show that RTX induced depletion of B cells resulted in a significant improvement on patients with pemphigus vulgaris (PV). This study enrolled 88 patients treated by the lymphoma protocol. A total of 80.7% had a complete response, 11.8% had a partial response, 5.7% did not respond and 2.3% died. The infection rate was 14.7%. Seventeen percent of patients had recurrence. Only 20.4% of the patients could discontinue concomitant therapies after RTX. The remaining had a reduction in the dosages but continued it. In 11% patients during a six-month period a total of 10 infusions of RTX and intravenous immunoglobulins (IVIg) were given. All patients had a complete response. Partial responders and non-responders were not reported. In two patients (18.2%) a recurrence, which responded to RTX and IVIg, was reported. No mortality or infections were observed. At a follow-up of 32 months post-RTX patients were still in a remission. Though the number of patients treated is limited, clinical outcomes appear to be better and lasting in the protocol using RTX and IVIg compare to RTX alone. One of the explanations for these differences in clinical outcomes may lie in the fact that the biological behavior of B cells in lymphoma patients is different from that in patients with autoimmune diseases.

Treatment of juvenile pemphigus vulgaris with intravenous immunoglobulin therapy.

We report the clinical response and follow-up on eight patients with juvenile pemphigus vulgaris treated with intravenous immunoglobulin. Six Caucasian females and two Caucasian males ages 15 to 18 (mean 15.5) were treated with intravenous immunoglobulin based on a published protocol. The indications were lack of response and development of serious side-effects to conventional therapy in four, lack of response to dapsone in two, and parental choice in two patients. In seven patients, a prolonged clinical remission was achieved. They received a mean of 28.5 cycles of intravenous immunoglobulin in a mean of 43.4 months and were followed for a mean of 29.8 months after discontinuing treatment. The remaining patient responded, but was lost to follow-up. Mean follow-up was 71.7 months. Six patients experienced mild headache, but no serious side-effects were observed in any patient. Intravenous immunoglobulin is a safe biological agent to use in the treatment of juvenile pemphigus vulgaris. It can be used as monotherapy and has the potential to induce and sustain long-term clinical remissions. In these eight patients, it appears that intravenous immunoglobulin is a safe biological agent without serious, immediate, or long-term side effects. Intravenous immunoglobulin is a valuable agent in the treatment of certain cases of juvenile pemphigus vulgaris.

Cytokine profiles in pemphigus vulgaris patients treated with intravenous immunoglobulins as compared to conventional immunosuppressive therapy.

Pemphigus vulgaris (PV) is a potentially fatal blistering disease of the skin and mucous membranes, characterized by the presence of autoantibodies against adhesion molecules (desmoglein, Dsg3) present on the surface of keratinocytes, which lead to the loss of cellular adhesion or acantholysis. The mainstay of treatment is conventional immunosuppressive therapy (CIST), i.e. high dose, long-term systemic corticosteroids with or without immunosuppressive drugs. Intravenous immunoglobulin (IVIg) has been used in patients refractory to CIST, and its use has resulted in long-term clinical remission. Since cytokines play an important role in the immunopathogenesis of PV, it would be useful to compare how both IVIg and CIST therapies affect cytokine levels in the serum of PV patients. Thus, the goal of this study was to conduct a comparative analysis of levels of various cytokines, during an 18 month consecutive period, after the initiation of CIST or IVIg treatment in PV patients, with similar extent and severity of disease in the two study groups, with 11 patients in each group. The cytokines measured were IL-1beta, IL-6, IL-8, IFN-gamma, IL-4 and IL-10. The levels of most of these cytokines were higher in the sera of untreated patients in both groups, compared to normal controls. The cumulative data collected over an 18 month period of treatment demonstrates that there is a gradual reduction in the levels of these cytokines, until they are at levels observed in normal individuals. The conclusions from this limited number of patients, prospectively studied, would suggest that both CIST and IVIg therapies are similar in their ability to influence a panel of cytokines in patients with pemphigus vulgaris.

Blistering disorders: diagnosis and treatment.

Blistering diseases are a heterogeneous group of disorders that can affect either skin and mucous membrane, or both, varying in presentation, clinical course, pathohistology, immunopathology and treatment. Not infrequently the diagnosis is delayed. This can result in severe, and sometimes fatal consequences. Although these diseases are rare, it is very important to make an accurate diagnosis based on a combination of clinical profile and laboratory observations. A brief review is presented of the following bullous diseases: pemphigus, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, linear IgA bullous disease, porphyria cutanea tarda, and subcorneal pustular dermatitis. Their clinical, pathohistologic and immunopathologic features and recommendations for therapy are discussed.

Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane pemphigoid.

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid (CP), is an autoimmune mucocutaneous, blistering disease which can lead to blindness and/or death from sudden asphyxiation, secondary to a scarring process. Conventional therapy for the treatment of MMP consists of high-dose systemic corticosteroids and/or immunosuppressive agents. Some patients do not respond to these treatments and develop multiple serious side effects, which can be potentially fatal. In such patients, alternative treatment modalities are needed. This study presents the use of intravenous immunoglobulin (IVIg) therapy in 15 patients with severe MMP whose disease was nonresponsive to the prolonged use of high-dose systemic corticosteroids and immunosuppressive agents and who developed multiple side effects to them. All 15 patients received an IVIg dose of 1-2 g/kg/cycle. The following objective parameters were used to assess the clinical outcome pre- and post-IVIg therapy: number of side effects, frequencies of recurrences and relapses, duration and total dosage of prednisone therapy, and the quality of life. The differences in these variables between the pre- and post-IVIg data were statistically analyzed using the SAS UNIVARIATE software running the two-sided Wilcoxon signed-rank and sign tests. A statistically significant difference was observed between pre- and post-IVIg therapy data when comparing the aforementioned variables. All 15 patients had an effective clinical response, were able to discontinue previous systemic therapies, and eventually achieved a prolonged clinical remission. IVIg improved the quality of life in all 15 patients and demonstrated a steroid-sparing effect. No serious side effects were observed. IVIg therapy is a safe and effective alternative modality in the treatment of patients with nonresponsive and progressive MMP and can induce a sustained clinical remission.

Identification of ocular cicatricial pemphigoid antibody binding site(s) in human beta4 integrin.

PURPOSE: To identify specific site(s) on human ss4 molecule to which sera from ocular cicatricial pemphigoid (OCP) patients bind and to determine its role in the process of blister formation. METHODS: Clone the fragments representing the extracellular and intracellular domain of ss4 molecule from normal human conjunctival mRNA into an expression vector; map the region to which sera from OCP patients bind by Western blot analysis. Determine the role of the immunodominant region in pathogenesis by demonstrating the ability of the rabbit antibody to the immunodominant region to produce separation of basement membrane zone (BMZ) from the basal epithelial layer when incubated with normal human conjunctiva in an in vitro organ culture model. RESULTS: Majority of the OCP sera tested bound to the C-terminal end of the intracellular domain (IC3.0) of the human ss4 integrin. Further subcloning of IC3.0 demonstrated that a smaller fragment extending from 1489 aa to 1572 aa (IC3.4) was responsible for this binding. This region may have multiple antibody binding sites. Antibody to human IC3.0 and IC3.4 produced in rabbit, resulted in BMZ separation, histologically identical with that observed when normal human conjunctiva was cultured with OCP sera in an human conjunctival organ culture model. CONCLUSIONS: These observations identify IC3.4 as the antibody binding site for sera of OCP patients and suggest a possible role for it in blister formation. Indirectly it highlights certain important aspects of the structural and functional dynamics of the biology of the hemidesmosomes and basement membranes.

Multiple sclerosis and bullous pemphigoid.

3 patients with multiple sclerosis (MS) who developed severe widespread bullous pemphigoid (BP) are presented. MS preceded the presentation of BP by 13-23 years (mean 18 years). BP was confirmed histologically and immunopathologically. Upon successful therapy with steroids, no recurrence of BP was observed over a 3-5 year (mean 3.7 years) follow-up. Several abnormalities of the immune system have been reported in both diseases. It is interesting to speculate that amidst existing immunologic abnormalities in all 3 patients with MS, a specific event, immunologic or viral or both may have triggered the development of BP.

Diagnosis of bullous disease and studies in the pathogenesis of blister formation using immunopathological techniques.

Several skin diseases may present as vesicles or bullae. Immunofluorescent studies are very helpful in differentiating the various disease entities. Familiarity with the procedure and the various kinds of patterns that are specific and non-specific is essential for the practicing dermatologist. Immunofluorescent patterns are particularly helpful in differentiating pemphigus, bullous pemphigoid, cicatrical pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA dermatosis and porphyria. Immunofluorescent studies of the skin and sera of these patients were vital to an understanding their pathogenesis. Immunoelectron microscopy has further helped in delineating the exact sites of immunoglobulin deposition, and, thus, identifying the location of the antigens. In pemphigus, studies at the molecular level reveal that the basic pathological process is mediated by an anti-cellular cement substance antibody. The binding of this antibody at the cell surface level results in a process that is seen at the light microscopy level in the form of acantholysis. In bullous pemphigoid cells may play an important role. It appears that the mast cell, eosinophil, and the lymphocyte in harmony with the polymorphonuclear leucocyte work together to bring about an enzymatic degradation of the basement membrane. The specific role of the anti-basement membrane zone antibody is also under current study. With advances in molecular immunology, especially monoclonal antibodies and gene technology, it is hoped that these cellular and molecular interactions will be better understood and further defined.