Current concepts in the treatment of epidermolysis bullosa acquisita.

INTRODUCTION: Long-term remission in EBA patients is difficult to achieve. Patients who are resistant or develop side effects to conventional immunosuppressive therapy (CIST) have been treated with several other agents. AREAS COVERED: This review focuses on the clinical outcome in patients treated with a single drug or combination, and determines if long-term remission can be induced. Data on 71 patients was analyzed. There are no controlled trials. The regimens used included dapsone, colchicine, mesalazine, cyclosporine, mycophenolic acid, intravenous immunoglobulin, rituximab, daclizumab, extracorporeal photochemotherapy, and plasmapheresis. An algorithm on treating a patient has been presented. EXPERT OPINION: The use of CIST, especially in wide spread and recalcitrant patients, usually does not produce a prolonged clinical remission and can have hazardous side effects. Intravenous immunoglobulin, rituximab and immunoadsorption have been successfully used in some, but the benefits from their use may require additional studies. The immediate future holds much promise for the development of a specific ELISA which may facilitate the early diagnosis of EBA. As the population ages, it is likely that the number of patients will increase and newer biological agents may emerge that may have a better clinical outcome. One of the challenges is to produce "targeted therapies".

Association between cancer and immunosuppressive therapy--analysis of selected studies in pemphigus and pemphigoid.

OBJECTIVE: To determine whether there is an association between the use of immunosuppressive agents (ISAs) and cancer in patients with pemphigus and pemphigoid-rare, potentially fatal diseases of the skin and mucous membranes, often requiring long-term use of ISAs. DATA SOURCE: Literature was accessed through PubMed (all years available), using the search terms cancer, immunosuppressive agents, pemphigoid, and pemphigus. STUDY SELECTION AND DATA EXTRACTION: A retrospective review of the literature was conducted. Inclusion criteria for studies were: (1) English language, (2) diagnosis of pemphigus and/or pemphigoid based on histology and immunopathology, (3) more than 10 patients evaluated, (4) investigators had a high index of suspicion of cancer and patients were monitored for it, (5) follow-up information was provided for at least 1 year after initiation of therapy, and (6) absence of diagnosis of cancer before initiation of an ISA. Case reports were not included in the analysis. DATA SYNTHESIS: A total of 929 patients diagnosed with either pemphigus or pemphigoid in 17 studies were identified. Patients were divided into 2 groups. Group A comprised patients treated with azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil in combination with prednisone. In Group A, 22 cases of cancer were reported in 21 of the 218 patients (9.6%). Group B comprised patients treated with systemic corticosteroids only. In this group, cancer was reported in 11 of the 711 patients (1.5%). In this study there was no control group (untreated patients) and the sample sizes were small. CONCLUSIONS: Preliminary data suggest a possible association between the use of azathioprine, cyclophosphamide, and cyclosporine and increased susceptibility to cancer in patients with pemphigus and pemphigoid.

Intravenous immunoglobulin therapy in autoimmune mucocutaneous blistering diseases: a review of the evidence for its efficacy and safety.

Intravenous immunoglobulin (IVIg) is a biologic agent that is being increasingly used in the treatment of autoimmune and chronic inflammatory disorders. It is approved by the US FDA for the treatment of primary immunodeficiencies, immune thrombocytopenic purpura, Kawasaki disease, bone marrow transplantation in patients aged over 20 years, chronic B-cell lymphocytic leukemia, and pediatric AIDS. IVIg has been used off-label for several diseases, clinical symptoms and syndromes. Our aim was to determine if there is evidence to support the efficacy of IVIg therapy in autoimmune mucocutaneous blistering diseases (AMBDs). We searched the PubMed database for studies on pemphigus and pemphigoid using the following criteria: (i) English language; (ii) minimum of five patients; (iii) diagnosis based on histology and immunopathology; and (iv) statistical analysis of data for comparison of efficacy provided. We evaluated the data and present information on the number of participants in each study, pre-IVIg therapy, indications for the use of IVIg, IVIg protocol (dose and interval) used, concomitant therapies, clinical outcome, follow-up period, and serologic studies. The quality of the evidence presented in this review is at Level A according to the UK National Health Service criteria. Twenty-three studies that were published between May 1999 and April 2010 were identified. One randomized controlled trial was found and all other studies were case series. Data on 260 patients treated with IVIg were analyzed: 191 patients with pemphigus and 69 patients with pemphigoid. Overall, 245 patients showed improvement with IVIg therapy. IVIg demonstrated a corticosteroid-sparing effect. In the studies presented, the incidence of serious adverse effects was not significant. The best available evidence in the literature indicates that IVIg is efficacious and has a good safety profile in the treatment of AMBDs.

Information for healthcare providers on general features of IGIV with emphasis on differences between commercially available products.

OBJECTIVE: Intravenous immunoglobulin (IGIV) has provided an essential replacement therapy for primary and secondary immunodeficiencies patients and prophylaxis of infectious diseases in them. It is also used in several autoimmune and chronic inflammatory disorders. An overview of IGIV with information on several commercially available IGIV products is discussed. DATA SOURCES: Medline databases and literature provided by the manufacturer for each product presented in the manuscript. STUDY SELECTION: From the vast body of information on IGIV, only those studies were selected that were pertinent to general features of IGIV (as presented below) or information provided by the manufacturer that facilitated comparing one product to the other. DATA EXTRACTION: Data was extracted on production, and purification procedures, removal of infectious agents, physical and biochemical properties and issues of safety. Data was extracted only for products available in the US. DATA SYNTHESIS: IGIV is prepared using pooled plasma. The purification of IGIV is a complex and multi-step process. There is a reciprocal relationship between the purity of IgG in the product and the recovery rate from the total plasma. It is quite possible that some of the biological mediators of the inflammatory and immune systems may be present in trace amounts. Screening and removal of blood borne pathogens is necessary and there are several different techniques available. The specifics of the administration are often variable and no consistent pattern or protocol has been used. When limited dosages are required IGIV may be administered subcutaneously. The side effects associated with IGIV are usually mild and self-limiting. CONCLUSION: There are differences in products produced by different manufacturers. The current data does not provide sufficient detail or information to be able to make specific recommendations for the use of a given commercial preparation in a specific disease state. The use of IGIV is associated with certain common and uncommon side effects. The identification of risk factors that might predispose a patient to developing them have been studied and reported. In choosing a IGIV preparation the user may avoid features that may predispose to certain side effects. Equally important is monitoring of patients during and after the IGIV therapy.

Serological studies in bullous pemphigoid: a literature review of antibody titers at presentation and in clinical remission.

Bullous pemphigoid is associated with antibodies to a 230 kDa and a 180 kDa protein. In a literature review we investigated the role of auto-antibodies as detected by different serological assays. Nine reports containing data on 143 patients were analyzed. Pre-treatment data showed that indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoblotting offer an 82.2% or greater probability of being positive. At the end of the study period, all patients had clinically improved, whether or not they were on therapy. Auto-antibodies were present in 29% of patients evaluated by monkey esophagus immunofluorescence and 75% of those evaluated by human skin immunofluorescence. Positive titers were also reported in 67.6% of patients evaluated by ELISA. In 100% of patients in whom immunoblotting was performed the titers became negative. In 3 patients (5.3%) using human skin immunofluorescence and in one patient (1.4%) using ELISA the titers were increased at the end of the study period. The correlation between anti-basement membrane zone antibodies and the clinical course of bullous pemphigoid requires further and long-term studies.

A current review of juvenile pemphigus vulgaris: analysis of data on clinical outcomes.

Forty-seven cases of juvenile pemphigus vulgaris have been reported in the English literature. Histology of lesional skin and direct immunofluorescence of perilesional skin are both necessary for a complete diagnosis. The autoimmune bullous condition can affect the skin and mucous membranes individually, but typically affects both concurrently. Disease characteristics in juvenile patients are similar to those in adults; however, a disruption of biologic and social development is of particular concern during adolescence. Although systemic corticosteroids have been used to successfully treat the disease in most cases, long-term use is often necessary for adequate control. Adverse effects from therapy can have devastating effects during this critical period of hormonal changes, physical and mental growth, and social and cultural development that occurs during adolescence. Newer therapies must be designed to adequately treat juvenile patients while also limiting serious adverse effects.

Efficacy of dapsone in the treatment of pemphigus and pemphigoid: analysis of current data.

Dapsone is a chemotherapeutic agent primarily used in treating leprosy, Pneumocystis jiroveci (previously carinii) pneumonia, and malaria. It is also used as an adjuvant in the treatment of pemphigus and pemphigoid. To assess the role of dapsone in the treatment of pemphigus and pemphigoid, a retrospective review of reports in the English-language literature was conducted. Information on the number of patients treated, their average age, prior therapies, indications for use, protocol (dose and interval) used, concomitant therapies, reported adverse effects, and clinical outcomes were analyzed. There were 35 case reports/series published describing the use of dapsone in a total of 427 patients. Data on 55 pemphigus patients were obtained from several case reports and some case series and one randomized controlled trial. Of these, 32 patients with pemphigus vulgaris and 14 patients with pemphigus foliaceus responded to dapsone. Data from 13 case series, each including at least five patients, accounted for 372 patients with pemphigoid. The overall response rates to dapsone, when given either alone or in combination with corticosteroids or immunosuppressive agents, were 84% in mucous membrane pemphigoid, and 81% in bullous pemphigoid. Hemolysis was the most common adverse effect observed. Dapsone is a promising and useful agent in patients with autoimmune mucocutaneous blistering diseases, especially in mucous membrane pemphigoid. It can be used as a corticosteroid-sparing agent. Therefore, its combined use with oral corticosteroids may be useful in pemphigus vulgaris and bullous pemphigoid. Adverse effects of dapsone are dose dependent and usually reversible. Hemolysis and concomitant anemia secondary to hemolysis are expected in most patients. In the opinion of the authors, dapsone is underutilized in the treatment of autoimmune mucocutaneous blistering diseases.

Pemphigus vulgaris in pregnancy: analysis of current data on the management and outcomes.

OBJECTIVES: The occurrence of pemphigus vulgaris (PV) during pregnancy is rare. The purpose of this review was to describe management of PV in the mother, and report maternal and perinatal outcomes associated with the disease. DATA SOURCES: A search of PubMed was conducted using the phrases "pemphigus and pregnancy" and "neonatal pemphigus." The bibliographies of retrieved articles were also searched for relevant reports. Only articles in English and in which the diagnosis of pemphigus had been made on the basis of histology or immunopathology were included. TABULATION, INTEGRATION, AND RESULTS: In 38 reports, pregnancies from 49 women with PV were described. Among the 40 patients in whom clinical profiles were provided, 33 had active disease and 7 were disease free. Prednisone was used in 37 of 49 (75%) patients with doses ranging from 5 to 300 mg/day (mean 152.5 mg). Concomitant therapies included plasmapheresis, plasma exchange, and dapsone in 1 patient each, and azathioprine in 5. Of the 44 live births, 20 (45%) neonates had PV lesions at birth and 24 (55%) were lesion-free. Five stillbirths were reported. In all neonates, PV lesions resolved within 1 to 4 weeks, either spontaneously or with mild topical corticosteroids treatment. Of the 5 intrauterine deaths, 1 was due to umbilical cord prolapse, 1 attributed to placental dysfunction, and 1 to cytomegalovirus pneumonitis. In the remaining 2, the cause was unknown. One neonate died 2 days after delivery due to meconium aspiration syndrome. Thus the aggregate perinatal mortality rate was 12% (6/49). CONCLUSIONS: The outcome of pregnancies complicated by pemphigus is generally good, but achieving good outcomes likely depends on the collaborative efforts of the dermatologist and obstetrician. The available data suggest that the rate of perinatal mortality is increased, but these data may be subject to publication bias. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to describe appropriate medical therapies for pemphigus vulgaris complicating pregnancy, and plan the management of pregnancies complicated by pemphigus vulgaris.

A review of the current use of rituximab in autoimmune diseases.

Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently it has also been used in the treatment of several autoimmune diseases. A literature review was conducted to determine the efficacy of rituximab in the treatment of some of these autoimmune diseases. Multiple mechanisms proposed for the rituximab mediated B cell depletion are also discussed. The efficacy of rituximab is well-established and it is FDA approved for treatment of Rheumatoid arthritis. In this review, data on the use of rituximab is presented from 92 studies involving 1197 patients with the following diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, Grave's disease, autoimmune hemolytic anemia, pemphigus vulgaris, hemophilia A, cold agglutinin disease, Sjogren's syndrome, graft vs. host disease, thrombotic thrombocytopenic purpura, cryoglobulinemia, IgM mediated neuropathy, multiple sclerosis, neuromyelitis optica, idiopathic membranous nephropathy, dermatomyositis, and opsoclonus myoclonus. The efficacy varies among different autoimmune diseases. The cumulative data would suggest that in the vast majority of studies in this review, RTX has a beneficial role in their treatment. While rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance. The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death.

Frequency of adverse events associated with intravenous immunoglobulin therapy in patients with pemphigus or pemphigoid.

BACKGROUND: Intravenous immunoglobulin (IVIG) therapy is widely used in immune-mediated diseases as an immunomodulatory agent and is considered to be a safe biologic agent. OBJECTIVE: To determine the frequency of adverse events associated with IVIG therapy in patients with pemphigus and pemphigoid. METHODS: We retrospectively reviewed data on patients treated with IVIG for pemphigus and pemphigoid over a 10 year period. Patients had pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigoid, or bullous pemphigoid. IVIG was given according to a published protocol at a dose of 2 g/kg administered over 3-5 days at prescribed intervals. Patient records were reviewed for information on sex, age, duration of treatment, number of cycles given, number of days each patient received IVIG, weight of each patient, IVIG dose each patient received per infusion, and early or delayed adverse effects reported by patients or observed by healthcare providers. RESULTS: We identified 9892 infusions given to 174 patients. Headaches were the most common adverse effects; they were observed during 886 (8.9%) infusions and involved 123 (70.6%) patients. The incidence of other minor adverse effects, including fatigue, nausea, vomiting, chills, urticaria, swollen glands, hoarseness, thoracic discomfort, and palpitations, was 0.57-3.4% per infusion and 0.04-1.3% per patient. Hoarseness of voice and swelling of cervical lymph nodes have not been previously reported. Acute renal failure occurred in one patient and was the only major adverse effect observed. None of the patients required hospitalization, and there were no deaths. CONCLUSIONS: Adverse events associated with IVIG therapy are usually mild and self-limiting. The incidence of serious adverse events is low. Identification of risk factors and close monitoring of high-risk patients throughout the therapy are likely to decrease the occurrence of rare serious and less likely fatal adverse effects.

Efficacy of various intravenous immunoglobulin therapy protocols in autoimmune and chronic inflammatory disorders.

OBJECTIVE: To determine the efficacy of various intravenous immunoglobulin (IVIG) protocols used in the treatment of autoimmune and chronic inflammatory disorders. DATA SOURCES: Literature retrieval was accessed through MEDLINE (November 1984-March 2007) and a search was conducted using the term intravenous immunoglobulin. References cited in the selected articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria for studies were (1) English language, (2) randomized controlled trials, (3) defined protocols, (4) a minimum of 15 patients, and (5) objective criteria provided to assess clinical outcomes and course. DATA SYNTHESIS: The therapeutic efficacy of IVIG therapy is well established, and defined protocols exist for treatment of Kawasaki disease, immune thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and autoimmune mucocutaneous blistering diseases. In the absence of a defined protocol, studies have demonstrated that IVIG therapy is effective in the treatment of myasthenia gravis, dermatomyositis, stiff person syndrome, antineutrophil cytoplasmic antibody positive systemic vasculitides, Graves' ophthalmopathy, and certain forms of systemic lupus erythematosus. It might also be of benefit in some patients with relapsing-remitting multiple sclerosis. The outcomes are variable in these studies. In toxic epidermal necrolysis and Stevens-Johnson syndrome, use of IVIG has dramatically influenced clinical response and reduced mortality. CONCLUSIONS: The cumulative evidence suggests that the clinical outcomes observed are significantly influenced by the use of a defined protocol. There is a need for multicenter trials approved by the Food and Drug Administration to better define the role of IVIG in many disease states. Such studies would be able to establish the indications for use, optimal dose, frequency of infusions, duration of therapy, and need for gradual withdrawal versus sudden cessation. Defined protocols resulting from the study of a large cohort of patients often convince insurance companies to create policies that provide access to IVIG therapy.

Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin.

BACKGROUND: Mucous membrane pemphigoid is an autoimmune mucocutaneous blistering disease. A subset, known as anti-epiligrin cicatricial pemphigoid is associated with a high risk for malignancy. Oral pemphigoid (OP) is limited to the oral cavity. The purpose of this study was to determine the association between malignancy and patients with OP with antibodies to alpha6-integrin subunit. METHODS: We determined the incidence of cancer in 72 patients with OP and compared it to the expected incidence using age and sex-specific rates of malignancy in the National Cancer Institute's Surveillance, Epidemiology, and End Results (NCI SEER) Registry. RESULTS: During a mean observation period of 9.1 years (range: 2.8-40), for 70, three OP patients developed malignancies. The expected number of cancers based on the NCI SEER Registry was 8.83. The relative risk for cancer in OP patients, with autoantibodies to alpha6-integrin, was 0.34 (95% CI, 0.07-0.99, P < 0.05). CONCLUSION: It appears that patients with OP, with antibodies to alpha6, may have a possible reduced relative risk for developing cancer.

Antigen specificity in subsets of mucous membrane pemphigoid.

Mucous membrane pemphigoid (MMP) has several subsets based on target antigens recognized by their sera. MMP and ocular cicatricial pemphigoid (OCP) sera recognize beta4 integrin subunit, oral pemphigoid sera recognize alpha6 integrin subunit, and anti-epiligrin cicatricial pemphigoid sera recognize laminin 5. Our aim is to determine if autoantibodies in the sera of patients with MMP, OCP, and oral pemphigoid (OP) recognize only their target antigens, and to see if this specificity is maintained throughout the clinical course. An immunoblot assay using bovine gingival lysate was used as substrate. Fifteen MMP patients, eight with OCP, and 15 OP patients were studied before therapy and at multiple intervals during the clinical course. Absorption and blocking studies were performed to determine binding specificity. Sera of patients with MMP and OCP recognize only beta4 integrin subunit, and sera of OP patients recognize alpha6 integrin throughout the clinical course. The sera of patients in the subsets of MMP described in this report show adherence and selectivity to target antigen during the entire clinical course, without crossover, interaction, or change. Hence, these subsets of MMP provide an excellent model to study clinical correlation with antigen and antibody specificity, in autoimmunity.