Use of rituximab in the treatment of mucous membrane pemphigoid: An analytic review.

Mucous Membrane Pemphigoid (MMP) is a potentially fatal mucocutaneous autoimmune blistering disease. Autoantibodies are produced against various components of the dermo-epidermal or mucosal-submucosal junction are referred to as basement membrane zone (BMZ). The hallmark is deposition of of Ig and C3 on the perilesional tissues and in some patients detection of anti-BMZ autoantibodies. A unique characteristic of MMP is that as the blisters or erosions heal, they leave irreversible scarring. This scarring results in serious and catastrophic sequelae that affect the quality of life. Conventional therapy consists of anti-inflammatory and immunosuppressive agents (ISA). In patients who fail conventional therapy or develop significant side effects to them, rituximab (RTX) has been used off label. In this review, the clinical outcomes of patients with MMP treated with RTX were studied. 124 patients were identified, 47.58% being male. 72 patients were treated by the Lymphoma Protocol and 51 by Rheumatoid Arthritis (RA) protocol. Follow up for the entire cohort was 36 months (range 0.5-72). On follow-up 64 patients (51.61%) achieved complete clinical remission (CR) off therapy, 25 patients (20.16%) were in CR on therapy, 5 patients (4.03%) were non-responders, and 9 patients (7.25%) were failures. 52 patients (41.93%) experienced a relapse, after 36 months follow-up. Duration between last RTX infusion and relapse was 10.5 months (range 1-30). Most patients with relapses were treated with additional RTX. A statistically significant better outcome was observed in patients treated with RTX as monotherapy compared to those who received RTX with ISA. Clinical outcomes in patients treated with Lymphoma protocol were better than RA protocol at a statistically significant level. Data on CD20+ B cell depletion and repopulation was limited. Interestingly relapses were seen in patients with CD20+ B cell depletion and after repopulation. In the final analysis, 89 patients (71.77%) were in complete remission. Data in this review indicated that RTX was a useful agent to treat MMP. While a randomized control trial may not be practically possible, better and disease specific protocols need to be developed. When publishing, authors should attempt to provide complete and detailed information. In doing so, they will benefit their colleagues and the patients with MMP they treat with RTX.

Nodular Pachymeningitis Associated With Relapsing Polychondritis and Crohn Disease Responsive to Adalimumab and Prednisone.

OBJECTIVES: To review the previous literature on the associations of pachymeningitis with Crohn disease (CD) and relapsing polychondritis (RP) and to describe a new case occurring in association with both in addition to highlighting its positive response to steroid and adalimumab treatment. METHODS: We review the patient's clinical presentation, diagnostic workup (serum and CSF testing), and MRI findings in detail and chronicle the response of the pachymeningitis to intensive immunotherapy. We contrast this case against previous reports of pachymeningitis occurring in association with RP and inflammatory bowel disease that were found on PubMed. RESULTS: Only 2 cases of ulcerative colitis and 5 cases of RP were found in association with pachymeningitis; there were no cases in association with CD. Our patient presented with symptoms isolated to a steroid-responsive headache in the setting of normal neurologic and rheumatologic examinations. Her preceding history was notable for long-standing CD and increasingly active symptoms referable to RP. Focal nodular pachymeningitis was seen overlying the left hemisphere on brain MRI. An extensive serum and CSF workup and body fluorodeoxyglucose-PET scan failed to identify an alternative etiology beyond her underlying autoimmune inflammatory disorders. After adding prednisone and adalimumab to her preexisting treatment of methotrexate, she responded dramatically both clinically and radiographically. CONCLUSIONS: Although exceptionally rare, pachymeningitis may occur as a neuroinflammatory complication of CD and RP.

Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: A single center experience.

BACKGROUND: The use of immune checkpoint inhibition (ICI) has revolutionized cancer treatment. However, these medications are associated with significant and potentially debilitating immune-related adverse events (irAEs). While certain toxicities have been well studied, rheumatic complications have been less widely recognized and characterized. METHODS: We report our experience of patients who were evaluated by rheumatology after the development of a suspected rheumatic irAE following ICI treatment. Cases of rheumatic irAEs were included if active rheumatic signs or symptoms developed during or after ICI treatment and were confirmed by a treating rheumatologist. RESULTS: Twenty-nine patients were evaluated by rheumatology for suspected rheumatic irAEs. Eighteen patients had confirmed toxicity including inflammatory arthritis (n = 12) and PMR (n = 6). Twelve patients had de novo toxicity and six had a flare of a pre-existing rheumatic condition. The onset of de novo toxicity occurred late into treatment (median 38 weeks), while patients with pre-existing rheumatic disease flared soon after initiation of ICI treatment (median 4.6 weeks). Management often required systemic or intra-articular steroids, with initiation of disease modifying anti-rheumatic drug (DMARD) therapy in those unable to wean off steroids. CONCLUSION: De novo rheumatic irAEs are generally delayed in onset after ICI initiation, while flares of pre-existing rheumatic conditions occur shortly after ICI initiation. Effective management often requires systemic corticosteroids as well as DMARDs in a subset of patients. Future prospective studies are needed to accurately describe the incidence and spectrum of rheumatic irAEs and to identify the most effective management strategies.

Reducing glucocorticoid duration in ANCA-associated vasculitis: A pilot trial.

OBJECTIVE: Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. METHODS: Patients with active AAV received an 8-week prednisone taper and RTX 375mg/m2 weekly for 4 weeks. Patients with severe glomerulonephritis or diffuse alveolar hemorrhage requiring mechanical ventilation were excluded. In-person and telephone visits were scheduled for disease activity assessment. The primary endpoint was complete remission at 24 weeks (no disease activity while being off prednisone with no intercedent relapses). Secondary analysis included comparing study outcomes to historical controls from the Rituximab in AAV (RAVE) trial. RESULTS: Fourteen of 20 patients (70%) achieved the primary outcome. The patients in our trial achieved the primary outcome at a rate similar to that of controls from the RAVE trial (adjusted OR 1.31 [0.26-6.56]), had fewer median adverse events per patient (2 versus 8, p < 0.001) but were more likely to relapse (30% versus 7%, p = 0.03). Most relapses occurred in patients who had severe vasculitic manifestations at trial entry. Disease damage did not differ between the two trial populations. CONCLUSION: An 8-week course of prednisone with RTX resulted in a similar rate of complete remission at 6 months as in the RAVE trial, with fewer adverse events but more frequent relapses. Further study of this protocol is warranted in selected patient populations.

Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured regularly during the trial period. We performed mixed-effects regressions to examine the associations of time-dependent cumulative average glucocorticoid use and disease activity with changes in BMI over time, while adjusting for potential confounders. RESULTS: The mean ± SD baseline BMI of the 197 patients enrolled was 28.8 ± 6.3 kg/m2 . Patients with newly diagnosed AAV tended to have a lower mean ± SD BMI than those with relapsing disease (28.0 ± 5.7 kg/m2 versus 29.6 ± 6.8 kg/m2 ) and higher disease activity (mean ± SD Birmingham Vasculitis Activity Score for Wegener's Granulomatosis 8.7 ± 3.3 versus 7.4 ± 2.7). The most significant change in BMI occurred during the first 6 months of the trial (mean ± SD increase of 1.1 ± 2.2 kg/m2 ; P < 0.0001). Disease activity improvement, glucocorticoid exposure, and randomization to rituximab were each independently associated with an increase in BMI (P < 0.001 for all analyses). CONCLUSION: Our findings suggest that changes in BMI, as well as glucocorticoid exposure, are independently associated with improvements in disease activity in AAV. Rituximab may also have effects on BMI independent of its impact on disease activity.

Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis.

OBJECTIVES: To develop a Glucocorticoid Toxicity Index (GTI) to assess glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies. METHODS: Nineteen experts on GC use and outcome measures from 11 subspecialties participated. Ten experts were from the USA; nine from Canada, Europe or Australia. Group consensus methods and multicriteria decision analysis (MCDA) were used. A Composite GTI and Specific List comprise the overall GTI. The Composite GTI reflects toxicity likely to change during a clinical trial. The Composite GTI toxicities occur commonly, vary with GC exposure, and are weighted and scored. Relative weights for items in the Composite GTI were derived by group consensus and MCDA. The Specific List is designed to capture GC toxicity not included in the Composite GTI. The Composite GTI was evaluated by application to paper cases by the investigators and an external group of 17 subspecialists. RESULTS: Thirty-one toxicity items were included in the Composite GTI and 23 in the Specific List. Composite GTI evaluation showed high inter-rater agreement (investigators κ 0.88, external raters κ 0.90). To assess the degree to which the Composite GTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared with case ranking by the Composite GTI, yielding excellent agreement (investigators weighted κ 0.87, external raters weighted κ 0.77). CONCLUSIONS: We describe the development and initial evaluation of a comprehensive instrument for the assessment of GC toxicity.

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's): Distinct Patient Subsets.

OBJECTIVE: To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). RESULTS: Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement. CONCLUSION: We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.

OBJECTIVE: To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. METHODS: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. RESULTS: PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. CONCLUSIONS: Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. TRIAL REGISTRATION NUMBER: NCT00104299; post-results.

Corticosteroids in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Glucocorticoids (GCs) have been the cornerstone of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) therapy since their advent in the 1950s. There is considerable variation in their use, both with respect to dose and duration. Given considerable treatment-related morbidity and mortality, refining the role of GCs is becoming increasingly important. This article discusses the current role of GCs in various phases of AAV treatment, including remission induction, maintenance therapy, treatment of relapses, and the use of local GCs. It discusses current controversies relating to GC use as well as research efforts that seek to reduce GC toxicity in AAV.

Challenging mimickers of primary systemic vasculitis.

The need to distinguish true primary systemic vasculitis from its multiple potential mimickers is one of the most challenging diagnostic conundrums in clinical medicine. This article reviews 9 challenging vasculitis mimickers: fibromuscular dysplasia, calciphylaxis, segmental arterial mediolysis, antiphospholipid syndrome, hypereosinophilic syndrome, lymphomatoid granulomatosis, malignant atrophic papulosis, livedoid vasculopathy, and immunoglobulin G4-related disease.

A neurologist's guide to safe use of immunomodulatory therapies.

Increased understanding of the pathogenesis of immune-mediated neurologic conditions with concomitant development of new therapeutic agents modulating various aspects of the immune system has resulted in the use of innovative therapies in the treatment of these diseases. These novel immunomodulatory therapeutic regimens also augment the potential for complications, including severe adverse effects.In this review, the authors address practical issues regarding management of patients with neuroimmunological conditions treated with immunomodulatory therapies, including glucocorticoids, methotrexate, azathioprine, mycophenolate, cyclophosphamide, rituximab, tumor necrosis factor-α inhibitors, and intravenous immunoglobulins. Particular focus is placed on their infectious and noninfectious adverse effects, contraindications, safety monitoring, risk surveillance, and preventive strategies in clinical practice.