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.

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.

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.

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.

Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial.

Non-blinded trials of pemphigus vulgaris suggest that mycophenolate mofetil (MMF) may be beneficial. In a prospective, multicenter trial, outpatients with mild or moderate pemphigus vulgaris were randomized to MMF (2 or 3 g day(-1)) plus oral corticosteroids or placebo plus oral corticosteroids for 52 weeks. The primary end point was the proportion of patients in the placebo and combined MMF groups responding to treatment (absence of new, persistent oral or cutaneous lesions, and prednisone dose < or = 10 mg day(-1) from weeks 48 to 52). Of 96 randomized patients, 94 were given treatment and 75 completed the study. Treatment responses occurred in 40 of 58 patients (69.0%) in the combined MMF group and 23 of 36 (63.9%) in the placebo group (P=0.6558, 95% confidence interval -17.4 to 27.6). MMF-treated patients showed faster and more durable responses. In post hoc analyses, more patients taking MMF showed sustained responses for 3 or 6 months than did placebo patients. MMF was well tolerated. Although MMF did not show an advantage on the primary end point, there seemed to be a beneficial treatment effect on several secondary end points, including time to response and duration of response. Thus, MMF may be a potentially useful agent in patients with mild or moderate pemphigus vulgaris.

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.

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.

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.

Adalimumab therapy for recalcitrant pyoderma gangrenosum.

OBJECTIVE: To describe a patient with treatment-refractory pyoderma gangrenosum and the outcome of a novel therapeutic approach. METHODS: Case report and review of the literature. RESULTS: A patient with inflammatory bowel disease developed severe pyoderma gangrenosum while receiving treatment with the chimeric anti-TNF-alpha antibody infliximab. Despite subsequent trials of numerous immunosuppressive and immunomodulatory medications, the dermatologic disease progressed. The patient's ulcers finally resolved when treatment with adalimumab, a fully humanized monoclonal antibody specific for TNF-alpha, was initiated. CONCLUSIONS: We report a novel application of the TNF-alpha inhibitor, adalimumab, in the treatment of pyoderma gangrenosum.

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 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.

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.

Mucous membrane pemphigoid and pseudopemphigoid.

PURPOSE: To describe the clinical characteristics of patients with mucous membrane pemphigoid (MMP) and pseudopemphigoid. DESIGN: Retrospective cohort study. PARTICIPANTS: Two hundred eighty consecutive patients referred for the evaluation of possible ocular MMP from January 1, 1985, to December 31, 2001. METHODS: Information on patients presenting for evaluation of possible MMP was entered prospectively into a database, which was supplemented by a retrospective chart review. Mucous membrane pemphigoid was diagnosed in patients with a compatible clinical picture by the linear deposition of antibodies to the basement membrane zone (BMZ) on direct immunofluorescent analysis of a mucous membrane biopsy specimen or by the presence of circulating autoantibodies to epithelial BMZ. MAIN OUTCOME MEASURES: Demographic and clinical characteristics of MMP and pseudopemphigoid; risk of ocular MMP among patients presenting with extraocular MMP without ocular disease. RESULTS: Among patients with ocular MMP, extraocular disease was common (82.4% of patients). The risk of ocular involvement among patients with MMP seen without ocular disease was approximately 5% per year over the first 5 years of follow-up (cumulative risk at 5 years, 22%). Although immunohistologic confirmation of the diagnosis was obtained in all patients, the initial conjunctival biopsy was positive for MMP in 80% of the patients diagnosed with ocular MMP. The most frequent presumed causes of pseudopemphigoid were topical glaucoma medications (28.3%), rosacea blepharoconjunctivitis (20.0%), atopic keratoconjunctivitis (8.3%), and conjunctival lichen planus (8.3%). CONCLUSIONS: Patients with ocular MMP typically have other systemic manifestations of MMP. Patients who are initially seen with extraocular MMP without ocular involvement are at risk for ocular disease developing. The clinical characteristics of ocular MMP and pseudopemphigoid are similar; therefore, immunohistologic evaluation of biopsied tissue is needed to confirm the diagnosis of MMP.

Differences and similarities among expert opinions on the diagnosis and treatment of pemphigus vulgaris.

BACKGROUND: As a result of a lack of large-scale controlled studies, the diagnosis and management of pemphigus vulgaris (PV) has been solely on the basis of expert opinion, rather than on empirical evidence. We have completed a survey of worldwide experts on the diagnostic and therapeutic approaches to PV. METHODS: We conducted a telephone-based survey of 24 physicians from academic, tertiary care centers worldwide with an average of 20 years experience treating pemphigus. Survey questions included referral patterns, diagnostic techniques, and therapeutic regimens. RESULTS: Of those surveyed, 50% receive referrals within 6 months after onset of symptoms, 17% within 1 year, and 8% within 3 years. Diagnosis is secured by 96% using skin biopsy specimen with direct immunofluorescence, and by indirect immunofluorescence alone for 4%. None of the participating physicians make the diagnosis of PV solely on clinical and histologic evidence. Of the physicians, 75% initially treat with prednisone and 25% use other agents or attempt to eliminate potential triggers. The physicians who initially used noncorticosteroid drugs did so with no relation to the nature or extent of the disease. Of those surveyed, 50% use prednisone doses of 1 mg/kg/d, 31% use 1 to 1.5 mg/kg/d, and 19% use 1.5 to 3 mg/kg/d. Azathioprine is used as an adjuvant by 44%, mycophenolate mofetil by 20%, cyclophosphamide by 16%, and methotrexate by 8%. Complete discontinuation of prednisone was the goal for 37% whereas others were satisfied with doses from 2.5 to 10 mg/d. CONCLUSION: Wide variation exists in diagnostic techniques and treatment of PV, even among the world's experts. The lag time from symptom onset to referral emphasizes the need for heightened awareness. There is clearly a need for consensus standards with regard to patient stratification and randomized controlled trials.