The role of adjuvant therapy in pemphigus: A systematic review and meta-analysis.

BACKGROUND: The assumption that adjuvant modalities have added value to oral glucocorticoids in the treatment of pemphigus is intuitively sound but has not been conclusively proven. OBJECTIVE: We sought to compare the efficacy and safety of oral glucocorticoid treatment with or without adjuvants for pemphigus vulgaris and pemphigus foliaceus. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials. The primary outcome was remission. Secondary outcomes were disease control, time to disease control, relapse, time to relapse, cumulative glucocorticoid dose, withdrawal because of adverse events, and all-cause death. Trials were pooled irrespective of adjuvant type evaluated. RESULTS: Ten trials (559 participants) were included. Adjuvants evaluated were azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, intravenous immunoglobulin, plasma exchange, and infliximab; not all were included in every analysis. Although adjuvants were not beneficial for achieving remission, they were found to collectively decrease the risk of relapse by 29% (relative risk 0.71, 95% confidence interval 0.53-0.95). LIMITATIONS: Different adjuvants were pooled together. CONCLUSION: Adjuvants have a role in pemphigus treatment, at least in reducing the risk of relapse. Further randomized controlled trials of other promising modalities are warranted.

Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective study of 47 patients.

BACKGROUND: Rituximab is increasingly being appreciated as a remarkably effective treatment for pemphigus, mostly concomitantly with other immunosuppressive medications. The majority of studies have used a single cycle of rituximab with the same dosage as approved for the treatment of lymphomas, ie, 375 mg/m(2) weekly × 4 weeks. Rituximab is also approved for the treatment of rheumatoid arthritis, with a different dosing regimen: 1000 mg × 2, days 1 and 15. OBJECTIVE: We aimed to assess the clinical response of patients with pemphigus to a single cycle of rituximab at the dosage used in rheumatoid arthritis. We also evaluated the response to repeated cycles of rituximab. METHODS: A total of 47 patients with pemphigus who were treated with rituximab at a dosage of 1000 mg × 2, days 1 and 15, most with concurrent immunosuppressive medications, were retrospectively studied. RESULTS: Remission rates after the first treatment cycle reached 76%. Repeating the treatment further increased the remission rates to 91%. There was a 22% relapse rate at a median time of 8 months, but 75% of relapsing patients achieved remission again with additional cycles. The side-effect profile was similar to previous reports, except for an immediate postinfusion pemphigus exacerbation in 4 patients. LIMITATIONS: This was a retrospective study with a limited follow-up period. CONCLUSION: The rheumatoid arthritis dosage of rituximab was efficacious and well tolerated in patients with pemphigus. Patients who fail to achieve remission after 1 cycle or patients who relapse seem to benefit from repeated rituximab cycles.

Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy.

PURPOSE: To evaluate the effectiveness of immunosuppressive drug therapy in the treatment of ocular mucous membrane pemphigoid (MMP). DESIGN: Retrospective cohort study. PARTICIPANTS: Ninety-four patients with biopsy-proven ocular MMP seen at the Pemphigoid Clinic at Wilmer Eye Institute from July 1984 through November 2006. METHODS: Data recorded included demographics, use and doses of immunosuppressive drugs, response to therapy, and side effects associated with drug use. MAIN OUTCOME MEASURES: Outcome measures included: (1) ocular control, defined as resolution of inflammation and cessation of cicatrization of the conjunctiva; (2) ocular remission, defined as ocular control for 3 months or more after the cessation of immunosuppressive drug therapy; and (3) ocular relapse, defined as the recurrence of ocular disease in either eye after a remission. RESULTS: By 1 year of treatment, 82.9% of patients had complete control of the inflammation, and of these, 86.3% achieved a remission at some point during follow-up. The incidences of ocular control, remission, and relapse were 1.03 (95% confidence interval [CI], 0.78-1.33), 0.50 (95% CI, 0.37-0.67), and 0.04 (95% CI, 0.02-0.09) events per person-years (PY), respectively. Among patients initially treated with prednisone and cyclophosphamide (n = 44), 91% of patients achieved a remission within 2 years after the initiation of immunosuppressive drug therapy. Characteristics at presentation associated with failing to achieve remission in the univariate analysis were trichiasis (relative risk [RR], 0.28; 95% CI, 0.08-097), prior eyelid surgery (RR, 0.11; 95% CI, 0.02-0.78), and esophageal involvement (RR, 0.29; 95% CI, 0.10-0.83). After adjusting for confounding, an initial treatment regimen containing cyclophosphamide and prednisone was associated with a greater likelihood of achieving ocular remission (RR, 8.53; 95% CI, 2.53-28.86; P = 0.001) when compared with other initial treatment regimens. Infections, hematuria, and anemia were the most common side effects observed in patients receiving cyclophosphamide therapy. The rate of discontinuing cyclophosphamide resulting from side effects was 0.20/PY; however, 74% of these patients still achieved remission despite early discontinuation of cyclophosphamide. CONCLUSIONS: In patients with ocular MMP, most achieved ocular disease control with immunosuppressive drug therapy. Treatment with cyclophosphamide and prednisone was strongly associated with the development of ocular remission. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Transformation of cutaneous gamma/delta T-cell lymphoma following 15 years of indolent behavior.

Subcutaneous gamma/delta (gamma/delta) T-cell lymphoma is a rare lymphoma, characterized by its unique immunophenotype and clinical course. It has been shown to behave more aggressively than its counterpart bearing the alpha/beta receptor and has recently been removed from the subcutaneous panniculitis-like T-cell lymphoma category for this very reason. We present a case of a patient with a 15-year running diagnosis of panniculitis. Following these years of indolent behavior, the disease began an aggressive clinical course and she was diagnosed with gamma/delta T-cell lymphoma. Molecular analysis identified a T-cell clone, which through retrospective analysis, was also shown to be present in the patient's original biopsy material. We present this case as a rare example of initial indolent behavior in a lymphoma typically considered very aggressive.

Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies.

Paraneoplastic pemphigus (PNP) has been described as an antibody-mediated mucocutaneous disease occurring almost exclusively in patients with lymphocytic neoplasms. We describe 4 patients with the clinical features of the lichenoid variant of PNP in the absence of detectable autoantibodies. On the basis of these findings, we conclude that the spectrum of PNP likely includes patients with disease predominantly or exclusively mediated by cytotoxic T cells rather than autoantibodies. The pathophysiology and range of PNP disease are likely more complex than was initially believed.

Rituximab therapy in severe juvenile pemphigus vulgaris.

Juvenile pemphigus vulgaris (PV) is a rare and often misdiagnosed condition. Although PV frequently is severe in children, a substantial portion of the morbidity and mortality associated with juvenile PV has been attributed to treatment. This report demonstrates the efficacy of rituximab therapy in juvenile PV. We report 2 cases and review the literature. Rituximab treatment was effective in helping to control 2 recalcitrant cases of juvenile PV without inducing the adverse effects associated with other adjuvant therapies. Rituximab should be considered when treating resistant cases of PV in pediatric populations to avoid the long-term side effects of other immunosuppressive treatments.

Role of electron microscopy in the diagnosis of ocular mucous membrane pemphigoid.

PURPOSE: To evaluate the role of electron microscopy (EM) for the diagnosis of ocular mucous membrane pemphigoid (MMP) among patients with cicatrizing conjunctivitis. DESIGN: Retrospective case series. PARTICIPANTS: One hundred twenty-eight patients with cicatrizing conjunctivitis referred for the evaluation of possible ocular MMP between January 1985 and February 2002 who underwent conjunctival biopsy and evaluation with EM and direct immunofluorescent (DIF) techniques. METHODS: The diagnosis of each patient was based on DIF techniques. The reproducibility of EM readings was measured by assessing intraobserver and interobserver variability. The diagnosis from EM was compared to the DIF diagnosis from the same patient to evaluate the validity of the EM diagnosis. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, and negative predictive value of EM for diagnosing ocular MMP. RESULTS: One hundred twenty-six of 128 conjunctival biopsies were available for evaluation of EM findings. The percent agreement between 2 readings from the same observer was 92%, and the percent agreement between 2 independent observers was 78%. The sensitivity and specificity of EM for the diagnosis of ocular MMP were 51% and 72%, respectively. The positive predictive value of EM for the diagnosis of ocular MMP was 49%. CONCLUSIONS: The reproducibility of EM findings was good as indicated by high percent agreement for both intraobserver and interobserver measurements. However, the sensitivity, specificity, and positive predictive value of EM for the diagnosis of ocular MMP was low. It seems that EM has limited usefulness in the diagnosis of ocular MMP.

Mucous membrane pemphigoid of the vulva.

BACKGROUND: Mucous membrane pemphigoid is a rare autoimmune blistering disease primarily affecting mucosal surfaces. Blistering and scarring may occur in the eyes, mouth, esophagus, larynx, and on the vulva. Scarring can result in severe structural changes to the vulva that may mimic the findings of other inflammatory dermatologic disorders of the vulva, including lichen sclerosus and lichen planus. CASE: A 58-year-old woman presented with vulvar erosions, esophagitis, and laryngeal blisters. The clinical picture and the histopathology of a vulvar biopsy were suggestive of erosive lichen planus. Direct immunofluorescence, however, revealed findings diagnostic of mucous membrane pemphigoid. CONCLUSION: This case illustrates the importance of examining extragenital mucosal surfaces of any woman presenting with vulvar lesions. In addition, it demonstrates the importance of vulvar biopsy and the usefulness of direct immunofluorescence to differentiate between conditions with similar clinical and histopathologic changes.

Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice.

There are two major clinical subsets of pemphigus vulgaris (PV)-mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV IgG into wild-type (WT) mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic animal crossed to the mDsg3 knockout line. Expression of hDsg3 in the mucosa rescues the mDsg3 knockout phenotype. Well-characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice, as detected by indirect immunofluorescence (IF). The majority of mPV sera preferentially recognize hDsg3 compared with mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming the pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by IF. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.

Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus.

OBJECTIVE: To study the clinical and immunopathologic findings of drug-induced, Ro/SSA-positive cutaneous lupus erythematosus (CLE). DESIGN: Retrospective medical and laboratory record review. SETTING: Immunodermatology Division of Johns Hopkins Hospital (Baltimore, Md). PATIENTS: Of 120 patients found to have anti-Ro/SSA antibodies by hemagglutination and/or double immunodiffusion, 70 had clinical and immunopathologic confirmation of CLE. Fifteen of these 70 patients had a history of new drug exposure, defined as less than 6 months, associated with disease development. RESULTS: The disease-associated drugs included hydrochlorothiazide (5 patients), angiotensin-converting enzyme inhibitors (3 patients), calcium channel blockers (3 patients), interferons (2 patients), and statins (2 patients). The most common presentations were photodistributed diffuse erythema and subacute CLE-type lesions without evidence of significant systemic disease. All specimens revealed interface dermatitis and fine granular IgG deposition along the basement membrane zone and throughout the epidermis. Most patients experienced improvement or resolution of clinical lesions within 8 weeks and decrease of Ro/SSA titers within 8 months after discontinuation of drug treatment. CONCLUSIONS: Antihypertensive drugs are the most commonly associated with Ro-positive CLE. Clinical and immunopathologic features of this drug-induced variant do not seem to differ from the idiopathic disease. In most cases, the disease improves or resolves on discontinuation of the offending drug treatment. It is not known if these drugs precipitate disease in patients who have subclinical disease. Drug-induced Ro/SSA-positive CLE should be included on the differential diagnosis in patients presenting with photosensitive or subacute CLE-type eruptions.

Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil is increasingly being used as a corticosteroid-sparing agent in immunosuppressive regimens. OBJECTIVE: To elucidate the effectiveness of mycophenolate as adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. DESIGN: Historical prospective study. SETTING: University hospital. PATIENTS: The study included 42 consecutive patients with pemphigus (31 with pemphigus vulgaris and 11 with pemphigus foliaceus) who had relapses during prednisone taper or had clinically significant adverse effects from previous drug therapy. RESULTS: Remission was achieved in 22 (71%) and 5 (45%) of patients with pemphigus vulgaris and pemphigus foliaceus, respectively. Partial remission was achieved in 1 (3%) and 4 (36%), respectively. The median time to achieve complete remission was 9 months (range, 1-13 months). The treatment was administered for a median of 22 months, and the median follow-up period was 22 months. Seventy-seven percent of patients had no adverse effect. Two patients had side effects severe enough to necessitate discontinuation of treatment, one because of symptomatic but reversible neutropenia and the other because of nausea. CONCLUSION: Mycophenolate is an effective and safe adjuvant in the treatment of both pemphigus vulgaris and pemphigus foliaceus.

The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators.

OBJECTIVE: We aimed to develop consensus-based recommendations for streamlining medical communication among various health care professionals, to improve accuracy of diagnosis and treatment, and to facilitate future investigations for mucous membrane pemphigoid. PARTICIPANTS: Because of the highly specific nature of this group of diseases, the 26 invited participants included either international scholars in the field of mucous membrane pemphigoid or experts in cutaneous pharmacology representing the 3 medical disciplines ophthalmology, oral medicine, and dermatology. EVIDENCE: The first author (L.S.C.) conducted a literature search. Based on the information obtained, international experts who had contributed to the literature in the clinical care, diagnosis, and laboratory investigation for mucous membrane pemphigoid were invited to participate in a consensus meeting aimed at developing a consensus statement. CONSENSUS PROCESS: A consensus meeting was convened and conducted on May 10, 1999, in Chicago, Ill, to discuss the relevant issues. The first author drafted the statement based on the consensus developed at the meeting and the participants' written comments. The draft was submitted to all participants for 3 separate rounds of review, and disagreements were reconciled based on literature evidence. The third and final statement incorporated all relevant evidence obtained in the literature search and the consensus developed by the participants. The final statement was approved and endorsed by all 26 participants. CONCLUSIONS: Specific consensus-based recommendations were made regarding the definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators for mucous membrane pemphigoid. A system of standard reporting for these patients was proposed to facilitate a uniform data collection.

Lichen planus and cicatrizing conjunctivitis: characterization of five cases.

PURPOSE: To report the clinical and immunopathologic features and the response to therapy in a series of six patients with cicatrizing conjunctivitis due to lichen planus. DESIGN: Retrospective case series. METHODS: All six patients were seen in an ocular pemphigoid clinic. Clinical, immunopathologic, and serologic features were evaluated and therapeutic response in each patient was monitored. RESULTS: All six patients had evidence of conjunctival scarring. Five patients had lichen planus of the oral mucosa and gingiva; one patient had involvement of the skin. Histologic findings consisted of thickened epithelium and an interface lymphocytic infiltrate along the lamina propria. In three patients, electron microscopy of the conjunctiva revealed thickening, fragmentation, and duplication of the basement membrane zone. Direct immunofluorescence examination of the conjunctiva and oral mucosa demonstrated linear and shaggy fibrinogen deposition along the basement membrane zone, confirming the diagnosis of lichen planus. All six patients were placed on immunosuppressive therapy with control of the disease. However, only one patient was able to discontinue the anti-inflammatory medication and have the lichen planus remain in remission. CONCLUSIONS: Lichen planus should be included in the differential diagnosis of cicatrizing conjunctivitis. Performing appropriate investigations to distinguish conjunctival lichen planus from other autoimmune diseases such as mucous membrane pemphigoid is critical to managing the patient with cicatrizing conjunctivitis appropriately. Oral cyclosporine effectively controlled the conjunctival lichen planus in four of the six cases.

Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations.

The review included 163 cases of paraneoplastic pemphigus (PNP) reported between 1990 and 2003, including a new unique case of PNP associated with occult breast cancer and an ovarian cyst of borderline malignancy. Hematologic-related neoplasms or disorders were associated with 84% of the cases, with non-Hodgkin lymphoma (38.6%) as the most frequent, followed by chronic lymphocytic leukemia (18.4%) and Castleman's disease (18.4%). The non-hematologic neoplasms comprised 16% of all cases: epithelial origin-carcinoma (8.6%), mesenchymal origin-sarcoma (6.2%), and malignant melanoma (0.6%). Carcinoma cases comprised 58% of the non-hematologic neoplasms. Carcinoma cases (n = 14) consisted of adenocarcinoma (n = 7), squamous cell carcinoma (n = 2), multiple skin tumors probably basal cell carcinoma (n = 1), and bronchogenic carcinoma (n = 1). Of the 10 (6.2%) sarcoma cases, there was one case each of leiomyosarcoma, liposarcoma, malignant nerve sheath tumor, poorly differentiated sarcoma, reticulum cell sarcoma, dendritic cell sarcoma and inflammatory myofibroblastic tumor. The oral mucosa was involved in all of cases. Isolated oral ulcerations were the first sign in 45% of the cases. Diffuse and persistent oral ulcerations with a progressive course could be a sign of malignancy, either recognized or occult. In the absence of a clear diagnosis, malignancy should be suspected and extensive work-up performed. The full spectrum of signs of PNP may not be present initially. Repeated biopsies, direct and indirect immunofluorescence as well as screening indirect immunofluorescence on murine bladder are required for diagnosis. Clinicians should be highly suspicious when signs and symptoms suggestive of PNP are present in cancer patients, of hematologic and non-hematologic origin.

Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies.

BACKGROUND: Anti-desmoplakin (DP) antibodies are present in paraneoplastic pemphigus (PNP) as a component of a complex humoral autoimmune reaction characterized by antibodies against proteins of the plakin family, desmogleins, and an unidentified 170 kd protein. Anti-DP antibodies have also been rarely identified in other blistering diseases. The significance of anti-DP antibodies in the pathogenesis of bullous diseases is unclear. OBSERVATION: We studied 3 patients with severe and chronic mucosal dominant pemphigus vulgaris (PV). In addition to anti-desmoglein 3 antibodies, these patients had anti-DP autoantibodies, demonstrable by immunofluorescence (IF), immunoprecipitation (IP), and indirect immunoelectromicroscopy (IIEM). This finding suggested these patients may have had PNP and not PV. However, antibodies against periplakin, envoplakin, bullous pemphigoid antigen 1 (BPAG 1), plectin, and 170 kd PNP antigen could not be detected using IP and immunoblotting. Extensive and repeated investigations for an underlying neoplasm throughout the follow-up period were consistently negative for all patients. CONCLUSION: This study demonstrates that anti-DP antibodies without the presence of any other anti-plakin antibodies are not specific for PNP, and are present in some cases of PV. Cellular disadhesion induced by anti-desmoglein antibodies can trigger an epitope-spreading phenomenon with a secondary formation of autoantibodies against desmoplakins, intracellular desmosomal antigens. The role of anti-DP antibodies in the pathogenesis of these PV patients is still unclear. The presence of anti-DP antibodies will produce a false positive serologic interpretation for the diagnosis of PNP especially if one uses only indirect IF on murine bladder, the most commonly employed screening test to identify PNP. More specific immunologic tests are required in this subset of patients with PV.

Bullous diseases in the elderly.

The elderly are prone to several autoimmune bullous diseases that have significant morbidity, and an accurate diagnosis is essential for proper management. It is important to be aware of the potential adverse effects of the various systemic agents that can be used.

Using rituximab (anti-CD20 antibody) in a patient with paraneoplastic pemphigus.

Paraneoplastic pemphaigus (PNP) is a rare autoimmune mucocutaneous blistering disease that is commonly associated with underlying B-cell neoplasms. There is no standard therapy for PNP. Potent immunosuppression has been the only potentially effective treatment in the setting of malignancy because there is no correlation between tumor burden and activity of disease. Two recent case reports have noted the resolution of lesions of PNP after treatment of the underlying CD20+ B-cell lymphomas with rituximab. Rituximab is an anti-CD20 antibody that has had some success in treating proliferative B-cell disorders. We report a case of PNP in the setting of B-cell lymphoma that did not respond to this novel therapy, and discuss rituximab's putative mechanism of action along with the clinical settings in which this novel therapy may prove useful in the treatment of PNP.

Pemphigus vulgaris autoantibody profiling by proteomic technique.

Pemphigus vulgaris (PV) is a mucocutaneous blistering disease characterized by IgG autoantibodies against the stratified squamous epithelium. Current understanding of PV pathophysiology does not explain the mechanism of acantholysis in patients lacking desmoglein antibodies, which justifies a search for novel targets of pemphigus autoimmunity. We tested 264 pemphigus and 138 normal control sera on the multiplexed protein array platform containing 701 human genes encompassing many known keratinocyte cell-surface molecules and members of protein families targeted by organ-non-specific PV antibodies. The top 10 antigens recognized by the majority of test patients' sera were proteins encoded by the DSC1, DSC3, ATP2C1, PKP3, CHRM3, COL21A1, ANXA8L1, CD88 and CHRNE genes. The most common combinations of target antigens included at least one of the adhesion molecules DSC1, DSC3 or PKP3 and/or the acetylcholine receptor CHRM3 or CHRNE with or without the MHC class II antigen DRA. To identify the PV antibodies most specific to the disease process, we sorted the data based on the ratio of patient to control frequencies of antigen recognition. The frequency of antigen recognition by patients that exceeded that of control by 10 and more times were the molecules encoded by the CD33, GP1BA, CHRND, SLC36A4, CD1B, CD32, CDH8, CDH9, PMP22 and HLA-E genes as well as mitochondrial proteins encoded by the NDUFS1, CYB5B, SOD2, PDHA1 and FH genes. The highest specificity to PV showed combinations of autoantibodies to the calcium pump encoded by ATP2C1 with C5a receptor plus DSC1 or DSC3 or HLA-DRA. The results identified new targets of pemphigus autoimmunity. Novel autoantibody signatures may help explain individual variations in disease severity and treatment response, and serve as sensitive and specific biomarkers for new diagnostic assays in PV patients.