To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody ...(ANCA)-associated vasculitides (AAVs).
Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.
Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations.
AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions.
NCT01731561; Results.
Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis ...(AAV).
To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.
Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).
39 clinical centers in France.
68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.
Rituximab or placebo infusion every 6 months for 18 months (4 infusions).
The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.
From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (
= 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (
= 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients 12%) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients 9%). No deaths occurred in either group.
Potential selection bias based on previous rituximab response and tolerance.
Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.
French Ministry of Health and Hoffmann-La Roche.
To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).
Randomised, placebo-controlled study in patients with SSc to ...assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).
Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).
The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.
NCT01295736.
Giant cell arteritis (GCA) is one of the most common large vessel (LVV) vasculitis and is associated with a high risk of relapse and cardiovascular complications. Improving risk stratification ...remains a significant issue in this patient population. We aimed to perform a cluster analysis among GCA to identify clusters and evaluate their prognostic value.
In a multicenter cohort study, we performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with 283 GCA patients' characteristics to generate clusters and assess incidence of relapse, cardiovascular events and death.
Three clusters were identified: "Vascular relapsing profile" (23.0%), "Typical GCA profile" (47.7%), and "Ophthalmologic elderly profile" (29.3%). The "Vascular relapsing profile" cluster included younger patients with more frequent relapses and cardiovascular events, particularly thoracic aortic aneurysms. The "Typical GCA profile" was the largest, with classic cranial manifestations and frequently associated polymyalgia rheumatica. The "Ophthalmologic elderly profile" had the oldest patients with more visual loss and the highest mortality rate.
Our findings underline the varied prognostic landscape within GCA, emphasizing the poor cardiovascular prognosis of younger patients with LV involvement and the higher mortality among elderly patients. This reinforces the need for further research regarding the screening of aortic abnormalities and whether those patients might benefit from intensive treatment with biotherapy and cardiovascular risk factors management.
Myelodysplastic syndromes (MDS) can be associated with auto-immune disorders, possibly due to the proinflammatory environment in the bone marrow niche. Noticeably, TET2 mutations has been reported to ...be associated with an increased risk of auto-immune disease. On the other hand, auto-immune myopathies are associated with solid and hematologic neoplasia but associations between MDS and inflammatory myopathies are rare and only few cases have been reported so far. We report here the case of a 66-year-old patient suffering from a necrotizing myopathy diagnosed 7 years after the onset of a MDS with multilineage dysplasia (MDS-DML) and TET2 mutations.
Background Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancers. The risk factors and pathophysiological mechanisms of venous thromboembolic events (VTEs) of this new ...therapeutic class are still to be specified.
Methods The included patients had to have cancer and should be treated with ICI. Data analyzed included demographic data, biological data, and immune-related adverse events (IRAEs). We studied the prevalence of VTEs and the factors associated with VTEs.
Results Of 374 patients on ICI, over a median follow-up period of 15.2 months, the number of VTE was 50 (13.4%). The majority of patients were treated for metastatic melanoma or nonsmall cell lung cancer. There was no difference in prevalence or survival between cancer types. Patients with combined therapy composed of nivolumab and ipilimumab had higher 1-year cumulative VTE occurrence (29.3% 95% confidence interval CI: 9.7; 44.6) than patients with pembrolizumab (14.9%, 95%CI: 2.5; 25.8, p = 0.03) or nivolumab (9.1%, 95% CI: 5.0; 12.9, p < 0.01). The presence of IRAE was associated with a higher risk of VTE occurrence compared with patients without any IRAE (1-year VTE cumulative incidence: 17.42% 95% CI: 9.5; 24.65 vs. 9.46% 95% CI: 5.18; 13.55, p = 0.04). There was a higher risk of VTE in patients treated with the combination of nivolumab and ipilimumab (adjusted subdistribution hazard ratio SHR: 3.71 95% CI: 1.74; 7.90, p < 0.001) and in patients with IRAE (adjusted SHR: 2.14 95% CI: 1.22; 3.75, p < 0.01).
Conclusion The prevalence of VTE was 14.2% under ICIs. IRAE and combine treatment of nivolumab and ipilimumab were associated with VTE. The pathophysiological mechanisms are multiple and complex with a possible link to aberrant activation of the immune system.
In most patients with nonsevere systemic necrotizing vasculitides (SNVs), remission is achieved with glucocorticoids alone, but one-third experience a relapse within 2 years. This study was ...undertaken to determine whether the addition of azathioprine (AZA) to glucocorticoids could achieve a higher sustained remission rate of newly diagnosed nonsevere eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), microscopic polyangiitis (MPA), or polyarteritis nodosa (PAN).
All patients included in this double-blind trial received glucocorticoids, gradually tapered over 12 months, and were randomized to receive AZA or placebo for 12 months, with stratification according to SNV (EGPA or MPA/PAN). The primary end point was the combined rate of remission induction failures and minor or major relapses at month 24.
Ninety-five patients (51 with EGPA, 25 with MPA, and 19 with PAN) met the inclusion criteria, were randomized, and received at least 1 dose of AZA (n = 46) or placebo (n = 49). At month 24, 47.8% of the patients receiving AZA versus 49% of the patients receiving placebo had remission induction failures or relapses (P = 0.86). Secondary end points were comparable between the AZA and placebo arms. These included initial remission rate (95.7% versus 87.8%), total relapse rate (44.2% versus 40.5%), and glucocorticoid use. Two patients in the placebo arm died; 22 patients in the AZA arm (47.8%) and 23 patients in the placebo arm (46.9%) experienced ≥1 severe adverse event. For EGPA patients, the primary end point (48% in the AZA arm versus 46.2% in the placebo arm) and the percent of patients who experienced asthma/rhinosinusitis exacerbations (24% in the AZA arm versus 19.2% in the placebo arm) were comparable between treatment arms.
Addition of AZA to glucocorticoids for the induction of remission of nonsevere SNVs does not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.
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