Ongoing randomized trials seek to validate the efficacy of rituximab as an induction agent for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, no studies directly ...address the role of rituximab as maintenance therapy.
This retrospective study reports the authors' experience with continuous rituximab administration in 39 patients in complete or partial remission at the time of rituximab initiation. All 39 patients had at least 1 year of follow-up, and 20 had 2 years of follow-up.
Disease activity, as measured by a modified Birmingham Vasculitis Activity Score, decreased from a median of 1 at baseline to 0 at 12 (P < 0.001) and 24 months (P = 0.02). Three patients experienced nonorgan-threatening flares during 708 patient-months of follow-up. Each flare occurred after at least 20 months of follow-up. The percentage of patients on cytotoxic immunosuppression decreased from 87% at baseline to 41% at 12 months (P < 0.001) and 30% at 24 months (P = 0.002). The percentage of patients on prednisone decreased from 92% at baseline to 59% at 12 months (P < 0.001) and 55% at 24 months (P = 0.02). Two patients developed late-onset neutropenia; both responded to treatment with recombinant granulocyte colony-stimulating factor.
The successful use of continuous anti-B cell therapy in patients with AAV in complete or partial remission is reported. This extends the potential role of rituximab beyond induction to include maintenance therapy. However, more data are required regarding the delayed adverse effects of rituximab.
Approximately 70% of illicit cocaine consumed in the United States is contaminated with levamisole. Most commonly used as a veterinary antihelminthic agent, levamisole is a known immunomodulating ...agent. Prolonged use in humans has been associated with cutaneous vasculitis and agranulocytosis. We describe the development of a systemic autoimmune disease associated with antineutrophil cytoplasmic antibodies (ANCA) in cocaine users. This complication appears to be linked to combined cocaine and levamisole exposure.
Cases were identified between March 2009 and November 2010 at Massachusetts General Hospital's ANCA laboratory. Cocaine exposure was identified from patient history in all cases. Medical records were reviewed for clinical presentation and for laboratory and diagnostic evaluation.
Thirty cases of ANCA positivity associated with cocaine ingestion were identified. All had antimyeloperoxidase antibodies and 50% also had antiproteinase 3 antibodies. Complete clinical and laboratory data were available for 18 patients. Arthralgia (83%) and skin lesions (61%) were the most frequent complaints at presentation. Seventy-two percent of patients reported constitutional symptoms, including fever, night sweats, weight loss, or malaise. Four patients had biopsy-proven vasculitis. Two cases of acute kidney injury and three cases of pulmonary hemorrhage occurred. From the entire cohort of 30, two cases were identified during the first 3 months of our study period and nine cases presented during the last 3 months.
We describe an association between the ingestion of levamisole-contaminated cocaine and ANCA-associated systemic autoimmune disease. Our data suggest that this is a potentially life-threatening complication of cocaine use.
Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. ...Left ventricular hypertrophy and coronary artery calcification are potent risk factors for mortality in CKD, and FGFs have been implicated in the pathogenesis of both myocardial hypertrophy and atherosclerosis. We conducted a cross-sectional study to test the hypothesis that elevated FGF-23 concentrations are associated with left ventricular hypertrophy and coronary artery calcification in patients with CKD.
In this study, 162 subjects with CKD underwent echocardiograms and computed tomography scans to assess left ventricular mass index and coronary artery calcification; echocardiograms also were obtained in 58 subjects without CKD. In multivariable-adjusted regression analyses in the overall sample, increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (5% increase per 1-SD increase in log FGF-23; P=0.01) and risk of left ventricular hypertrophy (odds ratio per 1-SD increase in log FGF-23, 2.1; 95% confidence interval, 1.03 to 4.2). These associations strengthened in analyses restricted to the CKD subjects (11% increase in left ventricular mass index per 1-SD increase in log FGF-23; P=0.01; odds ratio of left ventricular hypertrophy per 1-SD increase in log FGF-23, 2.3; 95% confidence interval, 1.2 to 4.2). Although the highest tertile of FGF-23 was associated with a 2.4-fold increased risk of coronary artery calcification > or =100 versus <100 U compared with the lowest tertile (95% confidence interval, 1.1 to 5.5), the association was no longer significant after multivariable adjustment.
FGF-23 is independently associated with left ventricular mass index and left ventricular hypertrophy in patients with CKD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy in CKD requires further study.
To compare two long-term remission maintenance strategies for antineutrophil cytoplasmic antibody (ANCA) vasculitis.
We conducted a prospective, single-centre, open-label, randomised controlled trial ...of patients with ANCA vasculitis in remission after completing at least 2 years of fixed-schedule rituximab. In the B cell arm, rituximab was reinfused upon B cell repopulation; in the ANCA arm, rituximab was reinfused upon significant rise in ANCA level. Evaluations were conducted every 3 months. The primary endpoint was clinical relapse, defined as a modified BVAS/WG >0 by 36 months. Secondary endpoints included serious adverse events (SAEs) and rituximab exposure.
115 patients were enrolled. Median follow-up time was 4.1 years (IQR 2.5-5.0). By Kaplan-Meier analysis, 4.1% (95% CI 1.0 to 15.6) of patients had a clinical relapse in the B cell arm, compared with 20.5% (95% CI 11.9 to 34.1) in the ANCA arm, at 3 years after study entry (log-rank p=0.045). Total SAEs, including infectious SAEs, and deaths did not differ. The number of SAEs due to COVID-19 was higher in the B cell arm (p=0.049). In the B cell arm, patients received a mean of 3.6 (SD 2.4) infusions (3.6 g) per person over the median study follow-up time of 4.1 years, compared with 0.5 (SD 1.4) infusions (0.5 g) per patient in the ANCA arm (p<0.001).
Rituximab dosed for B cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level in maintenance of remission for ANCA vasculitis. Overall safety was equivalent; SAEs due to COVID-19 and rituximab exposure were higher with the B cell strategy.
NCT02749292.
Objective
Late‐onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and ...recurrence.
Methods
We conducted a single‐center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of <1,000 cells/µl during B cell depletion. Secondary outcome measures included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox proportional hazards regression models. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.
Results
We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year of B cell depletion therapy was 6.6% (95% CI 5.0–8.7). The incidence rate during the first year was higher compared to thereafter (7.2 cases per 100 person‐years 95% CI 5.4–9.6 versus 1.5 cases per 100 person‐years 95% CI 1.0–2.3). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted HR 2.96 95% CI 1.10–8.01 and 1.98 95% CI 1.06–3.71, respectively). LON was not observed in minimal change disease or focal segmental glomerulosclerosis. The majority of episodes (59.4%) were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON.
Conclusion
LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, LON can be associated with serious infections and thus warrants vigilant monitoring.
Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable ...remission.
A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined.
In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score BVAS = 0) was achieved in all patients. Major relapse (BVAS ≥ 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population.
This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.
Remission induction in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis may be complicated by slow response to treatment and toxicity from glucocorticoids. We describe outcomes with a novel ...remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper.
Patients were included in this retrospective study if they had newly diagnosed or relapsing ANCA vasculitis with a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS-WG) ≥3 and received a standardized remission induction regimen. The primary outcome was complete remission, defined as a BVAS-WG of 0 and a prednisone dose of ≤7.5 mg/d.
We identified 129 patients who met the inclusion criteria, 31% of whom also received plasma exchange (PLEX) for rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage. Seventy percent of patients had myeloperoxidase (MPO)-ANCA and 9% had relapsing disease. Median time to complete remission was 4 months (interquartile range IQR 3.9–4.4), and by 5 months 84% of patients were in complete remission. Prednisone was tapered to discontinuation as tolerated, such that the median prednisone dose at 8 months was 0 mg/d (IQR 0–2.5). In patients with RPGN, proteinase 3–ANCA was associated with a greater increase in eGFR at 6 months compared with MPO-ANCA (16 vs. 5.6 ml/min per 1.73m2; P = 0.028). During the year following remission, 1 major relapse occurred over 122 patient-years. Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Four deaths occurred, 3 of which were associated with serious infections.
Combination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.
Abstract
Background
Consequences of long-term B cell depletion with rituximab are not well understood. We describe inflammatory vaginitis as a potential side effect of long-term rituximab treatment, ...distinct from previously described vulvovaginal pyoderma gangrenosum.
Methods
We performed a retrospective analysis of women treated with rituximab for more than 1 year to determine the prevalence and clinical characteristics of vaginitis cases. We conducted a case–control analysis with up to 3 controls for each vaginitis case.
Results
We identified sixteen inflammatory vaginitis cases. Women with vaginitis were age 23–68 (median 42), primarily being treated for ANCA-associated vasculitis (11/16; 69%). Most reported copious vaginal discharge (100%) and pain with sex (75%). All women with return of circulating B-cells to > 10 cells/mL had complete (5/9) or significant (4/9) improvement in symptoms. In case–control analysis there was no significant difference in length of B-cell depletion, immune parameters, creatinine levels, and history of neutropenia.
Conclusion
Inflammatory vaginitis is a potential side effect of prolonged continuous B cell depletion with rituximab. More studies are needed to characterize the incidence and etiology of vaginitis among women on long term rituximab therapy and establish a causal relationship.
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