Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Rituximab vs Cyclophosphamide Induction Therapy for Patients With Granulomatosis With Polyangiitis.

Importance: Results of randomized clinical trials have demonstrated rituximab's noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3-positive AAV. Objective: To compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients. Design, Setting, and Participants: This comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022. Exposures: At least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018. Main Outcomes and Measures: The primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity. Results: Among 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3-ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA-positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]). Conclusions and Relevance: In this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

Long-term prophylaxis in hereditary angioedema management: Current practices in France and unmet needs.

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Comparative study of granulomatosis with polyangiitis subsets according to ANCA status: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To investigate whether antineutrophil cytoplasm antibody (ANCA)-negative and myeloperoxidase (MPO)-ANCA-positive granulomatosis with polyangiitis (GPA) differ from proteinase-3 (PR3)-ANCA-positive GPA. METHODS: Diagnostic characteristics and outcomes of newly diagnosed French Vasculitis Study Group Registry patients with ANCA-negative, MPO-ANCA-positive or PR3-ANCA-positive GPA satisfying American College of Rheumatology criteria and/or Chapel Hill Conference Consensus Nomenclature were compared. RESULTS: Among 727 GPA, 62 (8.5%) were ANCA-negative, 119 (16.4%) MPO-ANCA-positive and 546 (75.1%) PR3-ANCA-positive. ANCA-negative patients had significantly (p<0.05) more limited disease (17.7% vs 5.8%) and less kidney involvement (35.5% vs 58.9%) than those PR3-ANCA-positive or MPO-ANCA-positive, with comparable relapse-free (RFS) and overall survival (OS). MPO-ANCA-positive versus PR3-ANCA-positive and ANCA-negative patients were significantly more often female (52.9% vs 42.1%), older (59.8 vs 51.9 years), with more frequent kidney involvement (65.5% vs 55.2%) and less arthralgias (34.5% vs 55.1%), purpura (8.4% vs 17.1%) or eye involvement (18.5% vs 28.4%); RFS was similar but OS was lower before age adjustment. PR3-positive patients' RFS was significantly lower than for ANCA-negative and MPO-positive groups combined, with OS higher before age adjustment. PR3-ANCA-positivity independently predicted relapse for all GPA forms combined but not when comparing only PR3-ANCA-positive versus MPO-ANCA-positive patients. CONCLUSIONS: Based on this large cohort, ANCA-negative versus ANCA-positive patients more frequently had limited disease but similar RFS and OS. MPO-ANCA-positive patients had similar RFS but lower OS due to their older age. PR3-ANCA-positive GPA patients' RFS was lower than those of the two other subsets combined but that difference did not persist when comparing only PR3 versus MPO-ANCA-positive patients.

Localized versus systemic granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe the main features at diagnosis and evolution over time of patients with localized granulomatosis with polyangiitis (L-GPA) compared with those of systemic GPA (S-GPA). METHODS: EULAR definitions of L-GPA, i.e. upper and/or lower respiratory tract involvement, and S-GPA were applied to patients from the French Vasculitis Study Group Registry. L-GPA and S-GPA patients' characteristics at diagnosis and long-term outcomes were analysed and compared. RESULTS: Among the 795 Registry patients, 79 (10%) had L-GPA. Their main clinical manifestations were rhinitis, lung nodules, sinusitis and otitis. L-GPA vs S-GPA patients at diagnosis, respectively, were younger, more frequently had saddle nose deformity or subglottic stenosis and were less often PR3-ANCA-positive. L-GPA vs S-GPA induction therapy less frequently included CYC but more often a combination of MTX and glucocorticoids; 64% of MTX-treated patients experienced disease progression within 18 months post-diagnosis. L- and S-GPA patients' estimated relapse-free-survival probabilities, relapse rates and refractory disease rates at each time point were comparable, but L-GPA patients had more frequent ENT and lung relapses, and higher overall survival rates (P<0.02). Over a median follow-up of 3.5 years, 18 (22.8%) L-GPA progressed to S-GPA, either as a relapse after a period in remission or more frequently in the context of refractory disease. L-GPA patients experienced more ENT-related damage. CONCLUSIONS: The relapse risks of L-GPA and S-GPA were similar, but relapse patterns differed and L-GPA overall survival rate was higher. About one-quarter of L-GPA patients developed S-GPA over time, but without end-stage organ involvement.

Significance of eosinophilia in granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe disease presentation and long-term outcome of granulomatosis with polyangiitis (GPA) patients according to blood eosinophils count (Eos) at vasculitis diagnosis. METHODS: Data from newly diagnosed GPA patients registered in the French Vasculitis Study Group database with available eosinophil count at diagnosis were reviewed. Disease characteristics, rate and type of relapses, and overall survival were analysed according to Eos, categorized as normal (<500/mm3), mild-to-moderate hypereosinophilia (HE) (between 500 and 1500/mm3) and severe HE (>1500/mm3). RESULTS: Three hundred and fifty-four patients were included. At diagnosis, 90 (25.4%) patients had HE ≥500/mm3; they were more likely male (73% vs 56%, P = 0.006) and had more frequent cutaneous manifestations (49% vs 33%, P = 0.01), peripheral neuropathy (32% vs 17%, P = 0.004) and higher BVAS (21 vs 18, P = 0.01), compared with those with Eos <500/mm3. Patients with severe HE (n = 28; median Eos 2355, range 1500-9114) had more frequent renal function worsening at presentation (P = 0.008). After a median follow-up of 3.95 (interquartile range 1.95-6.76) years, no difference was found in overall relapse rates according to baseline Eos, but those with HE experienced more neurological (P = 0.013) and skin (P = 0.024) relapses and had more frequently peripheral neuropathy as damage at last follow-up (P = 0.02). Overall survival was not significantly different in patients with normal Eos or HE at diagnosis. (P = 0.08). CONCLUSIONS: Blood HE at diagnosis, observed in about one-quarter of GPA patients, identifies a subgroup of patients with a more severe disease and higher rate of skin and neurological involvement both at presentation and during follow-up.

Patients of 75 years and over with ANCA-associated vasculitis have a lower relapse risk than younger patients: A multicentre cohort study.

BACKGROUND: Little is known about antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years. METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively. RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65-75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause-specific hazards ratio [CSHR] 0.54, 95% CI [0.33-0.89], p = 0.016, Cox model; subdistribution hazard ratio [SHR] 0.46, 95% CI [0.29-0.74], p = 0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI [0.11-0.68], p = 0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95% [CI 0.24-0.67], p < 0.001). CONCLUSIONS: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen.

Granulomatosis with polyangiitis: Study of 795 patients from the French Vasculitis Study Group registry.

OBJECTIVE: To describe the characteristics and long-term outcomes of patients with granulomatosis with polyangiitis (GPA) from the French Vasculitis Study Group database. METHODS: Patients' clinical and laboratory characteristics, Birmingham Vasculitis Activity Score (BVAS)-assessed disease activity, malignancies, opportunistic infections, and vital status were collected at diagnosis and each visit. Estimated probabilities and predictors of overall (OS) and relapse-free survival (RFS) were analyzed by Cox regression. RESULTS: We enrolled 795 newly diagnosed patients, followed for a median of 3.5 years. Initial clinical manifestations involved ear, nose & throat (ENT; 80%), lungs (68%) and kidneys (56%). Among the 728 available ELISA results, 75.0% were PR3-ANCA-positive, 16.5% MPO-ANCA-positive and 62 (8.5%) ANCA-negative. Relapses occurred in 394 (50%) patients, involving ≥1 organ(s) affected at onset in 179 (46%), mainly ENT, lungs and kidneys, with mean BVAS 10.2 points below that at diagnosis (p<0.001). Five- and 10-year RFS rates were 37% and 17%, respectively. PR3-ANCA-positivity independently predicted relapse (p = 0.05) and prolonged survival (p = 0.038). OS-but not RFS-improved significantly over time (p<0.001); 10-year OS reached 88.2% (95% CI 83.9 to 92.7) for the 660 patients diagnosed after 2000. Infections were the main causes of death. Malignancy or opportunistic infection each occurred in ≤5% of the patients. CONCLUSION: Survival has improved dramatically over the last decades but the high relapse rate remains a major concern for GPA patients, once again stressing the need for therapeutic strategy optimization to lower it. PR3-ANCA-positivity was associated with increased probability of relapse and survival.

Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression.

Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown. Objective: To determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel. Methods: We collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology. Results: Spontaneous TNFα, IL-6, IL-1ß, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1ß serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04). Conclusion: Our data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1ß, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Orbital mass in ANCA-associated vasculitides: data on clinical, biological, radiological and histological presentation, therapeutic management, and outcome from 59 patients.

OBJECTIVE: Orbital mass is a rare and sight-threatening manifestation of ANCA-associated vasculitides, which remains a therapeutic challenge. We aimed to describe the presentation, therapeutic management and outcome of ANCA-associated vasculitides-related orbital mass. METHODS: We conducted a French nationwide retrospective study of patients with orbital mass in the setting of ANCA-associated vasculitides according to ACR criteria and/or Chapel Hill Consensus Conference definitions. RESULTS: Fifty-nine patients [33 women, median age 46 (range 7-90) years] were included. Fifty-six (95%) patients had granulomatosis with polyangiitis, two eosinophilic granulomatosis with polyangiitis and one microscopic polyangiitis. Orbital mass was unilateral in 47 (80%) cases, and seemed to develop from ENT involvement in most cases. Orbital mass biopsy was available in 32 (54%) patients, showing lymphoplasmacytic infiltration in 65%, fibrosis in 55%, granulomas in 48% and vasculitis in 36%. All patients but one received glucocorticoids as first-line therapy associated with immunosuppressive agents in 82%, mainly cyclophosphamide. Response to therapy was noted in 52% of patients treated with cyclophosphamide compared with 91% of those treated with rituximab. Twenty-seven (46%) patients required a second-line therapy because of relapse (59%) or refractory course (41%). Sequelae included visual impairment in 28%, with definitive blindness in 17%. Refractory course was associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis. CONCLUSION: Orbital mass is associated with refractory course and high frequency of sequelae, especially blindness. Refractory course is associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.

Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides.

OBJECTIVE: To compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides. METHODS: The 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary endpoint was the major-relapse rate at month 60. Relapse and serious adverse event-free survival were also assessed. RESULTS: Among the 115 enrolled patients, only one was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4% (95% CI 38.0% to 64.3%) and 71.9% (95% CI 61.2% to 84.6%) (p=0.003); minor and major relapse-free survival rates were 37.2% (95% CI 26.5% to 52.2%) and 57.9% (95% CI 46.4% to 72.2%) (p=0.012); overall survival rates were 93.0% (95% CI 86.7% to 99.9%) and 100% (p=0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p<0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse. HRs of positive ANCA to predict relapse increased over time. CONCLUSION: The rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival. TRIAL REGISTRATION NUMBER: NCT00748644.

Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert®) in a French cohort.

Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria. Berinert® (CSL Behring) is a plasma-derived human C1 inhibitor (C1-INH) concentrate, approved for the treatment of HAE with C1-INH deficiency (C1-INH-HAE), however, it is often used off-label in Europe to treat HAE with normal C1-INH. To report the clinical characteristics of patients with HAE with normal C1-INH (with F12 gene mutation; FXII-HAE) or of unknown origin (U-HAE), and their response to Berinert®. Data from 2007 to 2016 (obtained retrospectively from the French Cohort BeRinert Angiœdème [COBRA] registry of HAE patients with everyday use of Berinert®) were analysed; no control group was included. Diagnostic criteria for FXII-HAE and U-HAE included a normal C1-INH antigenic level and function and refractoriness to high-dose antihistamines. For FXII-HAE, diagnosis also included F12 gene mutation, and U-HAE a positive family history for the disease. To date, 28 patients with FXII-HAE or U-HAE were identified (mean age: 27 years; first angioedema attack at 19.8 years; 85.7% female) with 78 documented Berinert®-treated attacks, the majority occurring in the laryngeal and abdominal regions. Efficacy assessment of Berinert® was available for 38 of 78 documented Berinert®-treated attacks; 22 improved within 60 minutes of treatment initiation, nine within 60-180 minutes, four after 180 minutes, and three showed no improvement. No severe or serious adverse effects were reported. Data to date suggest that Berinert® may be a safe and efficacious treatment option for the majority of HAE patients.

Diagnosis and treatment of upper airway oedema caused by acute angio-oedema in the emergency department: a French consensus statement.

Angio-oedema is a transitory, localized, noninflammatory oedema of subcutaneous tissue or mucous. When the oedema affects the mouth, lips, tongue or larynx, it can result in fatal asphyxiation in the absence of specific treatment. Oedema secondary to plasma extravasation is usually mediated by either histamine or bradykinin. As laboratory tests are not available in an emergency setting, the implicated mediator cannot be readily determined. The challenge for the emergency physician is to determine the aetiological type, evaluate severity and initiate adapted treatment by means of a structured approach. A team of experts from the French Reference Centre for Angio-oedema reached a consensus for recommendations for the diagnostic and therapeutic strategy to be adopted by emergency departments faced with angio-oedema of the upper airways in adults. The experts defined 11 important questions. Responses were rated using a two-round Delphi methodology. The 11 recommendations were related to triage on admission, a step-by-step diagnostic protocol, definition of attack severity, discouragement of instrumental examination, prioritization of treatment for severe attacks according to clinical signs and anticipation of access to specific treatments by the hospital. Angio-oedema of the upper airways can be fatal and requires anticipation by the emergency department. A search for the aetiology, an evaluation of clinical symptoms and the availability of the treatments are challenges justifying these recommendations.

Rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy: impact on global disability and health-related quality of life.

OBJECTIVES: To investigate the effects on health-related quality of life (HRQOL) and functional capability of rituximab vs azathioprine for ANCA-associated vasculitis (AAV) maintenance therapy. METHODS: In a 24-month phase III randomised-controlled trial, 115 patients over time received rituximab or azathioprine for AAV maintenance therapy. Mean changes of 36-item Short-form Health Survey (SF-36) and Health Assessment Questionnaire (HAQ) scores from baseline were analysed. RESULTS: Mean improvements of HAQ scores, from baseline to month 24 were significantly better for the rituximab (0.16 points lower) than the azathioprine group (p=0.038). As demonstrated by SF-36, study patients' baseline HRQOL was significantly impaired compared with age- and sex-matched US norms. At month 24, mean changes from baseline of SF-36 physical component score tended to be better for the rituximab group (+3.95 points, p=0.067) whereas mean changes from baseline of the SF-36 mental component score were significantly better for the azathioprine group (+4.23 points, p=0.041). CONCLUSIONS: Azathioprine-treated patients' for AAV maintenance therapy showed a decline in physical abilities when compared to RTX at M24 in the MAINRITSAN trial. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00748644.

Intravenous Immunoglobulin as an Immunomodulating Agent in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A French Nationwide Study of Ninety-Two Patients.

OBJECTIVE: Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV. METHODS: We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV. RESULTS: A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1-156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%. CONCLUSION: This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease.

Hereditary angioedema and lupus: A French retrospective study and literature review.

Hereditary angioedema (HAE) is a rare genetic disorder that is primarily caused by a defect in the C1 inhibitor (C1-INH). The recurrent symptoms are subcutaneous edema and abdominal pain. Laryngeal edema, which can also occur, is life threatening if it goes untreated. HAE can be associated with some inflammatory and autoimmune disorders, particularly lupus. The aim of this study was to describe cases of lupus among HAE patients in France and to perform a literature review of lupus and HAE studies. Case detection and data collection (a standardized form) were performed, thanks to the French Reference Center for Kinin-related angioedema. Data were collected from 6 patients with type 1 HAE and lupus in France; no cases of systemic lupus erythematosus were reported. In the literature review, 32 cases of lupus combined with HAE were identified, including 26 female patients. The median patient age at the time of first reported HAE symptoms and at diagnosis were 17.5 years (range, 9-41 years) and 19 years (range, 9-64 years), respectively for our 6 patients and 14 years (range, 3-30 years) and 17 years (range, 7-48 years), respectively, for the literature review. The clinical manifestations of HAE were mainly abdominal pain (83% in our patients vs 47% in the literature) and edema of the limbs (83% vs 38%). The C4 levels were low (for 100% of our cases vs 93% in the literature). Eighteen patients in the literature demonstrated HAE symptoms prior to the lupus onset vs 5 for our patients. The mean patient age at lupus onset was 20 years (range, 13-76 years) for our patients and 19.5 years (range, 1-78 years) in the literature, respectively. In the literature, 81% of the patients had skin manifestations, 25% had renal involvement and 28% received systemic steroids to treat lupus. Treatment with danazol did not modify the clinical expression of lupus. The association between lupus and HAE is a rare but not unanticipated event. Patients are often symptomatic for HAE before developing lupus. Lupus cases associated with HAE share some characteristics of lupus cases related to other complement deficiencies, such as the absence of severity and the predominance of cutaneous symptoms.

Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.

BACKGROUND: The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission. METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both). RESULTS: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer). CONCLUSIONS: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).

Acquired C1-inhibitor deficiency: 7 patients treated with rituximab.

BACKGROUND: Acquired C1-inhibitor deficiency can occur secondary to excessive C1-inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported. METHODS: Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I. RESULTS: Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment. CONCLUSION: Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles.