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Long-term safety and efficacy of rituximab in 7 Japanese patients with ANCA-associated vasculitis
Abstract
Objectives:
The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.
Methods:
Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1.
Results:
The mean age of the 7 patients was 57 (range, 34-71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract infection, sepsis, and cytomegalovirus infection. Two patients died due to recurrent infections and airway obstruction, caused by an AAV lesion.
Conclusions:
Rituximab had a beneficial effect on refractory AAV in Japanese patients, but several adverse effects occurred during rituximab treatment.
... A clinical study on seven refractory AAV patients with a median age of 57 years old was conducted for the long-term assessment of the safety and efficacy of RTX. It was shown that RTX provided CR in six patents and the BVAS score was significantly decreased following 12 months of 4 × 375 mg/m 2 /w [32]. The BIOGEAS group in Spain studied 196 patients with systemic autoimmune diseases, including 19 cases of AAV. ...
... The emerging infections following RTX therapy can be divided into bacterial, viral, and fungal infections. In addition, to increase the risk of de novo life-threatening infections, such as sepsis [32,41,228] and viral hepatitis [32], several studies warn about the risk of the reactivation of chronic infections. The most common site of infection is the respiratory tract, especially the lower respiratory tract, and also pneumonia was the most common side effect [43,108,118,229]; however, the involvement of the ear and nose was probable [40]. ...
... The emerging infections following RTX therapy can be divided into bacterial, viral, and fungal infections. In addition, to increase the risk of de novo life-threatening infections, such as sepsis [32,41,228] and viral hepatitis [32], several studies warn about the risk of the reactivation of chronic infections. The most common site of infection is the respiratory tract, especially the lower respiratory tract, and also pneumonia was the most common side effect [43,108,118,229]; however, the involvement of the ear and nose was probable [40]. ...
Background and aim: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease developed by autoantibody production against human neutrophilic granulocytes, including proteinase-3 (PR3) and myeloperoxidase (MPO). The management of AAV patients is difficult due to the multiorgan involvement, high rate of relapse, and complications of immunosuppressive agents that make it challenging. This study aims to investigate the efficacy and safety of rituximab (RTX) therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) subtypes. Method: The PubMed/Medline database was searched for any studies related to RTX therapy in ANCA-associated vasculitis (GPA and MPA subtypes), from inception to 1 August 2022, and proceeded in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Our search resulted in 1082 initial records. After the elimination of review papers, irrelevant studies, and non-English records, 223 articles were included, and the data related to the efficacy and safety of RTX therapy were extracted. Several randomized and non-randomized studies showed that RTX is an effective treatment option for patients with AAV. Most of the studies showed the very effective effect of RTX in controlling disease in AAV patients, including pediatrics, adults, and elderlies, although RTX cannot completely prevent relapse. However, maintenance therapy helps delay the disease’s relapse and causes sustained remission. Not only the licensed dose (375 mg/m2 intravenous per week for 4 weeks) could induce disease remission, but studies also showed that a single infusion of RTX could be effective. Although RTX could resolve many rare manifestations in AAV patients, there are few reports showing treatment failure. Additionally, few sudies have reported the unexpeted worsening of the disease after RTX administration. Generally, RTX is relatively safe compared to conventional therapies, but some serious adverse effects, mainly infections, cytopenia, hypogammaglobinemia, malignancy, and hypersensitivity have been reported. Conclusions: RTX is an effective and relatively safe therapeutic option for AAV. Studies on the evaluation of the safety profiles of RTX and the prevention of severe RTX-related side effects in AAV patients are required.
... included individual information on response to therapy and disease recurrence, showing a positive therapeutic response for 100%, sustained disease remission in 63.5% (15/24) at mean follow up of 29.0 months (n = 9; range = 4 to 108 months; median = 13.5 months), and disease recurrence in 37.5% (9/24) at a mean of 26.2 months following initial RTX treatment (n = 5; range = 12 to 72 months; median = 16 months). Of the 15 cases with sustained [15], and 6 years (1/20, 5.0%) [24]. One patient (1/20, 5.0%) received additional RTX cycles at increasing intervals from 3 to 6 months [40]. ...
... A total of 83.3% (55/66) of patients who received RTX treatments for non-infectious/nonmalignant orbital inflammation reported no adverse events. Four cases (4/66, 6.1%) experienced orbital disease exacerbation [23,30,33], all prior to the routine use of systemic corticosteroids as pre-conditioning, and there was one case each (1/66, 1.5%) of interstitial pneumonitis [53], severe adenovirus pneumonitis leading to death [15], de novo hepatitis B [24], orbital discomfort with infusion [40], itching and breathlessness with infusion [50], nausea [18], and fatigue [40]. ...
... There was a 0.89 to 1 male to female ratio, and mean age at time of treatment was 42.7 years (range = 4 to 72 years; median = 42.0 years). The mean interval from diagnosis of GPA to initiation of RTX treatment was 59 [24], nausea [18], and adenovirus pneumonitis that resulted in death [15] was also described. ...
Purpose
To provide a comprehensive review of rituximab use for the treatment of non-infectious/non-malignant orbital inflammation.
Methods
Review of literature through January 2021.
Results
Individual data was available for 167 patients with refractory non-infectious/non-malignant orbital inflammation who received treatment with rituximab (RTX). Rituximab was generally utilized as third-line or later treatment (108/149, 72.5%) at a mean of 44.6 months following the diagnosis of orbital inflammation (range = 0 to 360 months; median = 13.7 months). Patients with non-infectious/non-malignant orbital inflammation either received prior treatment with corticosteroids only (27/122, 22.1%), or with one (31/122, 25.4%), two (25/122, 20.5%), or three or more (25/122, 20.5%) corticosteroid-sparing immunosuppressive agents with or without corticosteroids before initiation of RTX treatment. The rheumatologic protocol (two infusions of 1 gram of RTX separated by 14 days) was utilized most frequently (80/144, 55.6%), followed by the oncologic protocol (four weekly infusions of 375 mg/m² RTX; 51/144, 35.4%). Various other off-label regimens were used infrequently (13/144, 9.0%). Rituximab treatments resulted in a positive therapeutic response for the majority of patients with orbital inflammation (146/166, 88.0%). Commonly treated diagnoses included granulomatosis with polyangiitis (99/167, 59.3%), IgG-4 related disease (36/167, 21.6%), and orbital inflammation of indeterminate cause (25/167, 15.0%). No side effects were reported in 83.3% (55/66) of cases. The most common RTX-induced adverse event was an infusion-related temporary exacerbation of orbital disease (4/66, 6.1%), which occurred prior to the routine use of systemic corticosteroids as pre-conditioning.
Conclusions
Overall, RTX appears to be both efficacious and well-tolerated as second- or third-line therapy for patients with non-infectious/non-malignant orbital inflammation.
... Inhaled steroids alone are not typically used as a long-term maintenance therapy for granulomatosis but may be used in combination with other immunosuppressive drugs to control airway inflammation during flares. Recurrence rates for granulomatosis have been reported to be as high as 40% at five years, but long-term remission is achievable with aggressive treatment and close follow-up care [46]. ...
The efficacy of inhaled steroids in the treatment of airway laryngeal granuloma is an important topic of research, given the increasing prevalence of this condition. In this systematic review, we aimed to evaluate the existing evidence on the effectiveness of inhaled steroids in treating airway granuloma. The search was performed in several electronic databases including PubMed, Embase, and the Cochrane Library. We included all relevant studies that were published in the English language between 2005 and 2021. A total of nine studies were eligible for inclusion in our systematic review, including one randomized controlled trial, one case-control study, and seven retrospective studies. The results of our review suggest that inhaled steroids may be effective in treating airway granuloma, but more research is needed to confirm these findings. The limitations of the included studies, such as small sample sizes, inconsistent study designs, and a lack of long-term follow-up, suggest that additional research is needed to confirm the effectiveness of inhaled steroids in treating airway granuloma. Overall, this systematic review highlights the need for further studies to confirm the effectiveness of inhaled steroids in treating airway granuloma.
... In detail, we found 16 retrospective cohort studies [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] [41][42][43] that enrolled 6 cases, and 18 single case reports [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61], for a total of 368 EGPA patients. Supplementary Table S1, available at Rheumatology online shows characteristics and results of all studies. ...
Objective
to analyze the available evidence about the use of rituximab (RTX) and other biologic agents in Eosinophilic Granulomatosis with Polyangiitis (EGPA) patients and to provide useful findings to inform the design of future, reliable clinical trials.
Methods
A systematic review was performed. A systematic search was conducted in PubMed/MEDLINE, Scopus, Web of Science and the Cochrane library databases and an extensive literature search on other biologic agents.
Results
45 papers pertinent to our questions were found: 16 retrospective cohort studies, 8 case series, 3 prospective cohort studies and 18 single case reports, for a total of 368 EGPA patients. More than 80% of evaluable patients achieved complete or partial remission with a tendency towards a higher rate of complete response in pANCA positive subgroup.
Conclusion
Although the majority of the evaluable EGPA patients treated with RTX appears to achieve complete remission, we strongly believe that a number of sources of heterogeneity impairs a clear interpretation of results and limits their transferability in clinical practice. Differences in design, enrollment criteria, outcome definition and measurement make a comparison among data obtained from studies on RTX and other biologic agents unreliable.
... A report of seven Japanese patients with AAV refractory to treatment with CYC demonstrated the induction of remission using RTX in six, with one death. 26 These patients did not receive planned maintenance, with relapse being seen in five of the six surviving patients. Wendt et al 27 similarly reported good outcomes using RTX for treatment of patients with "difficult" refractory or relapsing disease, although one patient died in this series. ...
... The present study revealed that, in patients with excessive B cell differentiation, the concomitant use of RTX was more effective than that of conventional therapy and yielded improvements similar to that achieved by patients without excessive B cell differentiation. In addition to showing that RTX is effective in patients who are resistant to CY or experience relapse after treatment with CY [12][13][14][15], various clinical studies have demonstrated that RTX is as effective as CY against AAV accompanied by serious organ involvement [3,16]. However, it is still unknown which patients should be treated with RTX and which with CY. ...
Objectives:
B cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear.
Methods:
Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment.
Results:
There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The rate of Birmingham Vasculitis Activity Score (BVAS) improvement at 6 months tended to be higher in the RTX group than in the IV-CY group. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = - 0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgD-CD27- B cells among all B cells was > 2 SDs higher than the mean in the HCs. The rate of BVAS remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS-remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment.
Conclusions:
The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients.
... The present study revealed that, in patients with excessive B cell differentiation, the concomitant use of RTX was more effective than that of conventional therapy and yielded improvements similar to that achieved by patients without excessive B cell differentiation. In addition to showing that RTX is effective in patients who are resistant to CY or experience relapse after treatment with CY, [12][13][14][15] various clinical studies have demonstrated that RTX is as effective as CY against AAV accompanied by serious organ involvement. [3,16] However, it is still unknown which patients should be treated with RTX and which with CY. ...
Objectives: B-cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear.
Methods: Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment.
Results: There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = -0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgD⁻CD⁻ B cells among all B cells was >2 SDs higher than the mean in the HCs. The rate of Birmingham Vasculitis Activity Score (BVAS) remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment.
Conclusions: The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients.
... Результаты ретроспективного анализа пациентов с АНЦА-СВ, которые в течение 2 лет получали поддерживающую терапию РТМ через фиксированные промежутки времени, свидетельствуют об эффективности этого подхода к поддерживающей терапии [62]. В серии открытых клинических исследований продемонстрирована эффективность РТМ в отношении органных проявлений АНЦА-СВ, в том числе некротизирующего склерита [63], легочных гранулем [64], при ЭГПА [65][66][67][68], у пациентов, резистентных к терапии ЦФ и другими иммуносупрессивными препаратами [69][70][71][72][73][74][75][76], а также комбинированной индукционной терапии РТМ и ЦФ [77]. Важно, что на фоне терапии РТМ концентрация «патогенных» IgG АНЦА снижается в большей степени, чем уровень общего IgG [78]. ...
Impaired B-cell immunological tolerance plays a central role in the pathogenesis of immuno-inflammatory rheumatic diseases (IIRD). B-cells link innate and acquired immunity: they express Toll-like receptors that respond to danger signals; act as antigen-presenting cells; induce an antigen-specific immune response; determine the development of immunological memory; and synthesize a wide range of cytokines that regulate (stimulate or suppress) an immune response and inflammation. In IIRD, there are metabolic and B-cellular signaling disturbances that lead to defects in B-regulatory, T-regulatory, follicular T-helper, and dendritic cells. B-cells synthesize organ-nonspecific and organspecific autoantibodies that are biomarkers for autoimmune diseases and play an important role in their immunopathogenesis. Anti-B-cell therapy that causes B-cell depletion in blood and target organs is effective in a wide range of IIRD. Its efficiency is determined by various mechanisms, such as suppression of pathogenic autoantibody synthesis; modulation of the function of B-cells (antigen presentation, cytokine synthesis, and costimulation), T-lymphocytes and dendritic cells. Further study of a strategy for targeted anti-B-cell therapy, mechanisms of action, and new targets is important for the progress of modern rheumatology to improve the treatment strategy of IIRD.
... A report of seven Japanese patients with AAV refractory to treatment with CYC demonstrated the induction of remission using RTX in six, with one death. 26 These patients did not receive planned maintenance, with relapse being seen in five of the six surviving patients. Wendt et al 27 similarly reported good outcomes using RTX for treatment of patients with "difficult" refractory or relapsing disease, although one patient died in this series. ...
Rbab Taha,1 Hadeel El-Haddad,1 Abdulqader Almuallim,2 Fatma Alshaiki,3 Elaf Obaid,2 Hani Almoallim1,2,4 1Department of Medicine, Dr Soliman Fakeeh Hospital, Jeddah, 2Department of Medicine, Faculty of Medicine, Umm Al-Qura University, Mecca, 3Department of Medicine, East Jeddah Hospital, Jeddah, 4Rheumatic Diseases, Umm Al-Qura University, Mecca, Saudi Arabia Abstract: Rituximab (RTX) is established for the treatment of rheumatoid arthritis. This systematic review of the literature since 2006 summarizes evidence for the use of RTX in the treatment of additional rheumatological diseases: antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), hepatitis C virus-related cryoglobulinemic vasculitis, Henoch–Schönlein purpura, ankylosing spondylitis, and Raynaud’s phenomenon. Data from randomized controlled trials are available only for AAV, confirming efficacy for remission induction, including in disease resistant to conventional treatment, and maintenance of remission. Further studies are required to confirm optimal maintenance regimens in AAV, important questions needing to be addressed including protocol administration versus treatment in response to clinical relapse and the importance of maintaining B-cell depletion. Sufficient data are available in other diseases to suggest RTX to be useful and that randomized controlled trials should be conducted. Keywords: anti-CD20 monoclonal antibody, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, refractory ankylosing spondylitis, resistant cryoglobulinemic vasculitis, refractory rheumatological diseases
... Despite expectations, large randomized controlled clinical trials of rituximab for non-renal and renal SLE (EXPLORER and LUNAR, respectively) did not achieve the primary goal [4,5]. In addition, adverse reactions such as hepatitis B virus reactivation, opportunistic infections, malignancies, and inefficacy in AAV patients who were treated with rituximab have been reported in a Japanese cohort (RiCRAV) [6]. ...
B cells play a pivotal role in autoimmunity not only by producing pathogenic autoantibodies but also by modulating immune responses via the production of cytokines and chemokines. The B cell-activating factor/a proliferation-inducing ligand (BAFF/APRIL) system promotes B cell survival and differentiation and thus plays a prominent role in the pathogenesis of autoimmune diseases. Currently, BAFF and APRIL inhibitors are in clinical trials for systemic lupus erythematosus with significant efficacy. However, several studies have demonstrated the efficacy of the BAFF/APRIL blockade which showed considerable variability in the response to B cell-targeted therapy. This may indicate substantial heterogeneity in the pathogenesis of autoimmune diseases. Therefore, objective markers that can predict the effect of BAFF/APRIL-blocking agents could be valuable to the precision medicine linked clinically and to cost-effective therapy.
... However, approximately 36-60% of patients receiving RTX treatment develop infections (Stone et al. 2010;Geetha et al. 2015). Nagafuchi et al. (2015) reported that Japanese patients receiving RTX for the treatment of refractory AAV showed beneficial outcomes; however, these patients also developed various infections. We suggest that the incidence of infections in RTX-treated patients with AAV may be attributable to the dosage used, which is equivalent to that used to treat B-cell lymphoma (four consecutive weekly doses of 375 mg/m 2 ). ...
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is systemic vascular inflammation. Microscopic polyangiitis (MPA) is a major type of AAV in Japan. MPA often affects the kidneys and lungs, leading to death if untreated. Induction therapy (i.e., initial treatment) for MPA has not been optimized, although methylprednisolone and cyclophosphamide are commonly used. Recently, rituximab (RTX) (a monoclonal antibody against the protein CD20) has also been used to treat refractory AAV. RTX at 375 mg/m²/week for 4 weeks (i.e., the conventional lymphoma dosing schedule) is used, but the optimal dosing schedule is controversial. Indeed, a single-dose of RTX successfully controlled nephrotic syndrome. However, to date, the effectiveness of a single RTX dose in treating MPA has not been fully investigated in Japan. This was a retrospective observational study. Six newly diagnosed patients with MPA were initially treated with methylprednisolone and a single dose of RTX (375 mg/m²). We investigated the patients’ clinical features, as well as the efficacy and safety of RTX treatment. All patients attained remission on a tapered prednisolone dose of < 10 mg/day during the first 12 months. One patient relapsed after 12 months whereas another required hospitalization owing to infective spondyloarthritis. Adverse reactions to RTX infusion and late-onset neutropenia were not observed. Therefore, a single-dose treatment with RTX induced remission with few complications, and allowed tapering the prednisolone treatment. We conclude that a single dose of RTX is a promising induction therapy for MPA, reducing the cost associated with multiple doses.
... The main drugs used in the combination therapy are corticosteroids and cyclophosphamide. 14 Furthermore, in Japan, other than the aforementioned standardized drugs for remission induction therapy, various treatments (eg, intravenous immunoglobulin therapy for cases with peripheral nerve involvement caused by steroid-resistant EGPA 15 ; or treatment with the anti-CD20 antibody, rituximab, 16 in GPA or MPA that is resistant to the standard therapy with cyclophosphamide and corticosteroids) are permitted under the medical care insurance system. ...
In patients with connective tissue disease, vascular injury induced by primary or secondary vasculitis syndromes can lead to organ dysfunction due to the loss of nutrient supply from the blood. Such vasculitis syndromes can be refractory to treatment and fatal. The nomenclature and the definition of vasculitis syndromes have recently been revised, and clinical practice guidelines for diseases associated with vasculitis syndrome are evolving. The present review provides an overview of vasculitis syndromes from the viewpoint of diagnosis and treatment.
... Most of the current therapies trialed so far in patients have the potential for serious side effects and or reduce patients' overall immune competence (Nagafuchi et al 2015;Carson et al 2009;Salliot and van der Heijde 2009). This is increasingly leading the search for safer mechanisms of either central or peripheral tolerance induction, though this work has been confined to animal models. ...
In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.
Background
The risk of infectious complications among patients with pemphigus managed by rituximab is yet to be precisely elucidated.
Objective
To evaluate the risk of infections in patients with pemphigus managed by rituximab versus first-line corticosteroid-sparing agents (azathioprine and mycophenolate mofetil [MMF]).
Methods
A global population-based cohort study compared pemphigus patients initiating rituximab (n = 963) versus azathioprine or MMF (n = 963) regarding the risk of 26 different infections. Propensity score matching was conducted to optimize comparability.
Results
In the initial 12 months following treatment, patients under rituximab experienced elevated risk of COVID-19 (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.06-3.14; P = 0.028), parasitic diseases (HR, 3.22; 95% CI, 1.04-9.97; P = 0.032), and cytomegalovirus infection (HR, 1.63; 95% CI, 1.04-2.58; P = 0.033). When evaluating infections developing ≥12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR, 1.45; 95% CI, 1.00-2.10; P = 0.047), COVID-19 (HR, 1.87; 95% CI, 1.49-2.33; P < 0.001), osteomyelitis (HR, 2.42; 95% CI, 1.11-5.31; P = 0.023), herpes simplex (HR, 2.06; 95% CI, 1.03-4.11; P = 0.037), and cytomegalovirus (HR, 1.63; 95% CI, 1.07-2.49; P = 0.023) infections.
Conclusion
Within the first 12 months after treatment, patients under rituximab experience an elevated risk of COVID-19, parasitic and CMV infections. Rituximab is associated with pneumonia, osteomyelitis, and viral diseases even beyond the first year after therapy. Pneumococcal vaccine and suppressive antiviral therapy should be considered even one year following therapy. No signal for elevated risk of tuberculosis, hepatitis B virus reactivation, pneumocystis jiroveci pneumonia, and progressive multifocal leukoencephalopathy
Patients with antineutrophil cytoplasmic antibody‐associated vasculitis (AAV) are vulnerable to opportunistic infections, including cytomegalovirus (CMV) infection. This narrative review aims to identify factors associated with CMV infection in patients with AAV. The literature review was conducted on Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, PubMed, Scopus, and Web of Science. The start date of the literature search was unrestricted and the end date was February 2022. CMV infection was defined as (a) CMV pp65 antigenemia or positive CMV DNA viral load by polymerase chain reaction or CMV detection on histological specimens, with associated signs and symptoms compatible with CMV infection; (b) presence of CMV clinical syndrome (defined as presence of compatible symptoms and signs and documentation of CMV by biopsy by virus isolation, rapid culture, immunohistochemistry, or DNA in biopsy material as defined by the CMV Drug Development Forum); and (c) CMV infection as coded by the International Statistical Classification of Diseases and Related Health Problems, 10th revision with at least one prescription for CMV treatment. We identified 4505 articles, of which three (2327 patients with AAV) were included. All studies were retrospective and only one of the three studies included only patients with AAV. Low or decreasing lymphocyte counts and higher prednisolone usage were associated with CMV infection in patients with AAV. Patients with AAV with lymphopenia and on high doses of prednisolone should be monitored closely for signs and symptoms of CMV infection, and might benefit from CMV prophylaxis. Prospective studies are urgently needed to better identify causes of CMV infections in patients with AAV.
Objectives
Rituximab (RTX) efficacy for Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has been reported in large randomized studies; however, the efficacy of RTX in Japanese AAV patients, especially the elderly, is not well known. We aimed to determine the clinical efficacy of RTX in Japanese AAV patients including elderly patients.
Methods
This study included 78 AAV patients newly diagnosed with AAV and treated in Fukushima Medical University Hospital or Ohta-Nishinouchi Hospital from April 2004 to September 2019. Clinical records were retrospectively reviewed, and clinical efficacy and outcome (1-year survival) between the RTX treatment group (23 cases) and the conventional therapy group (immunosuppressive therapy other than RTX, 55 cases) were compared. We also analyzed the clinical efficacy and outcome in elderly-onset (>75 years) AAV patients (23 cases).
Results
The RTX group showed similar efficacy and 1-year survival compared to the conventional therapy group. Conversely, after 6 months of treatment, prednisolone doses significantly decreased in the RTX group compared to the conventional therapy group (p < 0.01). In the elderly-onset AAV patients, clinical efficacy and outcome were not significantly different in both groups.
Conclusions
RTX was effective in Japanese AAV patients and may be useful for prompt tapering of prednisolone doses, even in elderly-onset AAV patients.
Objectives We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.
Methods We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety.
Results We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = 0.122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group.
Conclusions RTX maintenance therapy could be effective and safe in Japanese GPA patients.
Introduction
The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known.
Objective
The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX.
Methods
PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I² > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression.
Results
The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I² = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I² = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I² = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I² = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I² = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03).
Conclusion
Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.
Aim
Anti‐neutrophil cytoplasmic antibody‐associated vasculitis (AAV) is commonly seen in older patients. The present study intended to clarify whether elderly‐onset AAV (at age ≥75 years) shows any specific clinical features and outcomes in Japanese patients.
Methods
This study was a retrospective cohort study. A total of 36 AAV patients who were initially treated at the Department of Rheumatology, Fukushima Medical University Hospital (Fukushima, Japan) between 2004 and 2016 were included. AAV patients were divided into an elderly group (≥75 years) and a younger group (<75 years), and their clinical records were reviewed.
Results
Elderly AAV patients showed similar clinical features to younger AAV patients, except that they were more often women, weighed less, had an increased frequency of kidney involvement and had lower serum ferritin levels. Kaplan–Meier analyses showed significantly lower 1‐year survival in elderly AAV (P =0.008) as well as AAV patients enrolled not receiving additional immunosuppressive treatment (P =0.023). The cause of death was disease progression itself or infection.
Conclusions
The clinical features of AAV are similar between elderly and younger patients, except for increased kidney involvement and lower serum ferritin levels. Proper monitoring of the disease and adverse events, and providing conventional immunosuppressive therapy is suggested to avoid a poor outcome, especially in elderly AAV patients. Geriatr Gerontol Int 2018; ••: ••–••.
Objective: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan.
Methods: The previous CPG was published in a classical review style in Japanese in 2012 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements.
Results: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy.
Conclusion: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.
Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.
Objectives. Rituximab has been shown to induce remission of ANCA-associated vasculitides (AAVs). Our study was undertaken to describe AAV clinical responses to rituximab used for remission-induction and/or maintenance therapy, assess rituximab’s safety profile and evaluate French clinical practices.
Methods. This retrospective study concerned AAV patients who had received one or more rituximab infusion between 2002 and January 2011 and had follow-up lasting ≥12 months.
Results. Eighty patients were included, most with refractory or relapsing AAV: 70 (88%) with granulomatosis with polyangiitis (GPA), 9 (11%) with microscopic polyangiitis and 1 (1%) with eosinophilic GPA. Rituximab was the first agent used to induce remission in 73 patients. The two most commonly administered regimens were an infusion of 375 mg/m2/week for 4 weeks (54 patients) and an infusion of 1 g every 2 weeks for a month (16 patients). Rituximab was first prescribed to maintain remission in seven patients. Respective 1-, 2-, and 3-year relapse-free survival rates after the first infusion were 80% (95% CI 72, 89), 63% (51, 77) and 52% (39, 70). Relapse-free survival was longer for patients receiving rituximab maintenance therapy (P = 0.002). Among 22 (28%) rituximab-treated patients experiencing severe adverse events, 12 (15%) had infectious complications leading to 4 (5%) deaths. Only 15 (19%) patients had received anti-pneumococcal vaccine before rituximab.
Conclusion. Rituximab was able to induce AAV remission and seemed to maintain remission better than other agents, but caution is needed concerning its safety, especially regarding bacterial infections, in this population.
Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear.
We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment.
All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded.
In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.
Objective:
Rituximab (RTX) is an anti-CD20 antibody used successfully in granulomatosis with polyangiitis (GPA) for induction and maintenance of remission. Our study aims to evaluate the long-term efficacy and safety of chronic pre-emptive RTX therapy in GPA.
Methods:
Retrospective study of 35 GPA patients treated with RTX between April 2004 and September 2011 for active disease and maintenance. RTX was initiated as two 1 g infusions 2 weeks apart and thereafter 2 g of RTX was readministered annually. Patients were followed for 47 (2-88) months. They received a median RTX dose of 8 g (2-13) over 5 (1-10) rounds.
Results:
All patients had a clinical response, but nine relapses were recorded (flare rate of 6.6/100 patient-years). At last visit, 13 patients (37%) had discontinued RTX mainly due to hypogammaglobulinaemia (57%). Nine patients (26%) had severe infections (infection rate of 6.6/100 patient-years) and 10 patients (29%) had chronic infections. Risks factors for severe infections are a high cumulative dose of CYC, low CD4 cell count and a significant drop in total immunoglobulins after the first RTX round. Risks factors for chronic infections are low IgG level during RTX maintenance and possibly the cumulative RTX dose.
Conclusion:
Long-term pre-emptive RTX maintenance was efficacious in reducing the risk for relapse but was discontinued in one-third of the patients. The patients' net state of immunodeficiency under RTX changes over time as low immunoglobulin serum levels increased the risk for infections.
Background and objectives:
B cell significance in ANCA disease pathogenesis is underscored by the finding that ANCA alone can cause disease in mouse models and by the effectiveness of rituximab as therapy in ANCA-small vessel vasculitis (ANCA-SVV). To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies after rituximab treatment.
Design, setting, participants, & measurements:
The B cell phenotype was investigated in patients with active ANCA-SVV and in remission. From 2003 to 2009, 54 patients were followed longitudinally for 4-99 months and compared with 68 healthy controls. In a subset of 19 patients, the B cell immunophenotype was examined in samples after rituximab therapy.
Results:
Patients with active ANCA-SVV had lower %CD5(+) B cells, whereas %CD5(+) B cells from patients in remission were indistinguishable from healthy controls. After rituximab, median time to relapse was 31 months in patients maintaining normalized %CD5(+) B cells, with or without maintenance immunosuppression. Among patients whose B cells repopulated with low %CD5(+) B cells or had a sharply declining %CD5(+) B cells, those who were on low or no maintenance immunosuppression relapsed sooner (median 17 months) than patients who were maintained on high levels of oral maintenance immunosuppression (29 months; P=0.002).
Conclusions:
The %CD5(+) B cells, as a component of the human B regulatory cell phenotype, is a useful indicator of disease activity, remission, and future relapse, and thus may guide remission maintenance therapy after rituximab treatment.
The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission.
We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point.
Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03).
In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.
Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)
Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.
We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.
The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14).
A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)
To evaluate the longterm safety of rituximab in clinical trials in patients with rheumatoid arthritis (RA).
Pooled analysis of safety data, including adverse events (AE) and infections, from patients treated with rituximab in combination with methotrexate in a global clinical trial program.
A total of 2578 patients with RA received at least 1 course of rituximab. Safety analyses were based on 5013 patient-years of rituximab exposure. The most frequent AE was infusion-related reactions (25% of patients during the first infusion of Course 1). Less than 1% of infusion-related reactions were considered serious. Rates of AE and serious AE (SAE; 17.85 events/100 patient-yrs, 95% CI 16.72, 19.06) were stable following each course. The overall serious infection rate was 4.31/100 patient-years (95% CI 3.77, 4.92). Infections and serious infections over time remained stable across 5 courses at 4-6 events/100 patient-years. Compared with other patients with RA and with the general US population, there was no increased risk of malignancy.
In this longterm safety update in RA clinical trial patients, rituximab remained well tolerated over multiple courses. SAE and infections remained stable over time and by treatment course.
Standard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up.
The authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo.
Nineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab.
Rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.
Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee.
To modify and validate version 3 of the BVAS in patients with systemic vasculitis.
The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis.
The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test).
BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.
B-cell depletion with rituximab, a chimeric anti-CD20 antibody, is a novel treatment for refractory and relapsing ANCA-associated small-vessel vasculitis. Data are limited and most reports describe single patients or small numbers of patients followed prospectively.
We report a single-centre experience with 15 patients who received rituximab for refractory or relapsing ANCA-associated vasculitis. All patients had been treated with corticosteroids and cyclophosphamide and a variety of other second-line immunosuppressive agents. None of the patients had evidence of infection and received four infusions of 375 mg/m(2) of rituximab. Disease activity was assessed in accordance with the Birmingham Vasculitis Activity Score (BVAS). BVAS, C-reactive protein and ANCA titres were recorded at baseline and during follow-up.
B-cell depletion was achieved in all patients. Partial or complete remission was seen in 14 of 15 patients with a significant decline in BVAS compared to baseline (P < 0.007). One patient with granulomatous ANCA-associated vasculitis did not respond to rituximab. There were no side effects during rituximab infusion. Transient leucopenia was observed in two patients. One patient with bronchial stenosis died of pneumonia 5.5 months after the initiation of rituximab treatment. One initially anti-HBc-positive/HBsAg-negative patient experienced a reactivation of hepatitis B, developed end-stage renal failure and died after refusal of dialysis.
We report the largest case series of rituximab use for ANCA-associated vasculitis so far. Our data support that the drug is capable of inducing partial or complete remission in refractory or relapsing patients. Leucopenia and infectious complications remain a matter of concern.
An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study.
We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses).
At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges.
In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
B cell-deficient mice are susceptible to infection by Pneumocystis carinii f. sp. muris (PC). To determine whether this susceptibility is due to a requirement for B cells to prime T cells, we compared CD4 T cell responses to PC in bone marrow chimeric mice that express MHC class II (MHCII) on all APCs (wild-type (WT) chimeras) and in bone marrow chimeric mice that express MHCII on all APCs except B cells (MHCII(-/-) chimeras). Although PC was rapidly cleared by WT chimeric mice, PC levels remained high in chimeric mice that lacked MHCII on B cells. In addition, although T cells were primed in the draining lymph nodes of MHCII(-/-) chimeric mice, the number of activated CD4 T cells infiltrating the lungs of these mice was reduced relative to the number in the lungs of WT chimeras. We also adoptively transferred purified CD4 T cells from the draining lymph nodes of PC-infected normal or B cell-deficient mice into SCID mice. Mice that received CD4 cells from normal mice were able to mount a response to infection in the lungs and clear PC. However, mice that received CD4 cells from B cell-deficient mice had a delayed T cell response in the lungs and failed to control the infection. These data indicate that B cells play a vital role in generation of CD4(+) memory T cells in response to PC infection in the lungs.
The first description of what is now known as antineutrophil cytoplasmic autoantibody-associated necrotizing vasculitis appeared more than 140 yr ago. Since then, many aspects of the pathogenic pathway have been elucidated, indicating the involvement of antineutrophil cytoplasmic autoantibodies, but why antineutrophil cytoplasmic autoantibodies are produced in the first place remains unknown. Over the years, many hypotheses have emerged addressing the etiology of antineutrophil cytoplasmic antibody production, but no exclusive factor or set of factors can so far be held responsible. Herein is reviewed the most influential hypotheses regarding the causes of antineutrophil cytoplasmic antibody-associated vasculitis with the aim of placing in an epidemiologic background the different hypotheses that are centered on environmental and genetic influences.
Objective
To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods
The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). ResultsAlthough remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)–ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion
Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.
Reports in haematology, transplantation medicine and rheumatology indicate that Rituximab, a B cell depleting therapy, increases the risk for Pneumocystis jiroveci pneumopathy. Patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis have an increased incidence of P. jiroveci pneumopathy compared to other autoimmune diseases and Rituximab is often used to induce and maintain remission. Herein, we present a case of a patient with granulomatosis with polyangiitis treated with Rituximab for relapse that developed P. jiroveci pneumopathy 3 months after and we review the relevant literature to assess P. jiroveci pneumopathy incidence and risks factors under Rituximab. We also discuss whether P. jiroveci screening before Rituximab and P. jiroveci pneumopathy prophylaxis under Rituximab are indicated. P. jiroveci colonisation is found in 25 % of patients with autoimmune diseases. However, the association between colonisation and P. jiroveci pneumopathy development is not very strong. P. jiroveci pneumopathy incidence in ANCA-associated vasculitis patients treated with Rituximab is found to be 1.2 %. Therefore, evidence and practice do not support the use of P. jiroveci pneumopathy chemoprophylaxis in all ANCA-associated vasculitis patients receiving Rituximab. CD4 cell count cut-off does not work well in patients treated with Rituximab as it does not reflect T cell impairment following B cell depletion. To help stratify the risk of both colonisation and P. jiroveci pneumopathy development, assessment of the patient's net state of immunodeficiency before administering Rituximab-including age, renal or lung involvement, previous infections due to T cell dysfunction, blood tests (lymphocytopenia, low CD4 cell count) and concomitant therapy-is warranted.
In this review, we summarise the current understanding of the potential link between cancer and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener's; GPA) and microscopic polyangiitis (MPA). As is true for many autoimmune or inflammatory rheumatic diseases, AAV diagnosis and therapy are associated with an increased risk of de novo cancer development, likely as a result of impaired immunosurveillance, direct oncogenicity of immunosuppressive agents and perhaps malignant degeneration of tissues undergoing chronic immune stimulation. Data from several studies suggest a standardised incidence ratio of cancer in AAV of 1.6-2.0 compared to the general population and a possibly higher risk in GPA than in MPA. The most prominent cancers observed in AAV include urinary tract cancer, leukaemia and non-melanoma skin cancer. The effect of individual therapeutic agents is difficult to dissect, but cyclophosphamide has emerged as a major contributor to cancer development because of its direct carcinogenic properties. Awareness of cancer risk in AAV calls for increased implementation of measures to prevent or screen for cancer and development of less carcinogenic therapies. Cancer has also been suggested as a potential trigger or cause of AAV. Although some studies found that prior or concomitant history of cancer increases the risk of AAV, available data are inconsistent and suggest that the fraction of AAV that might be attributable to cancer is at best small.
Granulomatosis with polyangiitis (GPA) is a type of vasculitis that affects the respiratory tract and kidneys. Without treatment, half of patients die within 6 months. Standard therapy (a daily combination of cyclophosphamide and glucocorticoids) can induce remission, but the duration is short and treatment is plagued by serious morbidity. Advances in understanding the potential target of cyclophosphamide-B cells, that indirectly give rise to antineutrophil cytoplasmic antibodies (ANCA)-led to a new B-cell-targeted strategy. We administered rituximab, an anti-B-cell agent, to patients with severe GPA and microscopic polyangiitis. Overall, rituximab matched the efficacy of cyclophosphamide in inducing remission and was superior in patients with relapsing disease. The timing of re-treatment can be individualized based on patients' B-cell counts and ANCA levels in patients with chronically relapsing GPA.
Objective:
To study safety and potential efficacy of a 2-treatment course (month 0/6) with rituximab (RTX) in early diffuse systemic sclerosis (dcSSc).
Methods:
Two years' followup (open-label study) was done of 8 patients with early dcSSc. Patients received an infusion of 1000 mg RTX 2 times at months 0 and 6, with 100 mg methylprednisolone. Clinical measurements, Disease Activity Score, functional status, and CD19+ peripheral blood count were performed at months 0, 3, 6, 12, 15, 18, and 24 and histopathological evaluation of the skin at months 0, 3, 12, and 24.
Results:
There was a clinically significant change in skin score, with a mean Modified Rodnan skin score of 24.8 at baseline (SD 3.4) and 13.6 at Month 24 [SD 5.6; mixed models analyses (MMA) p < 0.0001] and a significant decrease in Disease Activity Score (DAS), with a median of 4.5 at baseline (range 1.5-7.5) and 0.5 at Month 24 (range 0.0-5.5; MMA p < 0.0001). Indices of internal organ involvement remained stable throughout the study. RTX induced effective B cell depletion at baseline and Month 6 (< 5 CD19+ cells/μl blood). The blindly assessed hyalinized collagen score changed significantly over time (MMA p = 0.009), with a mean of 69.3 at baseline (SD 22.8) and 33.1 at 24 months (SD 27.0). Five serious adverse events were considered unrelated to the RTX treatment.
Conclusion:
A 2-treatment course (months 0/6) with RTX appears to be well tolerated and may have potential efficacy for skin disease and stabilization of internal organ status in early dcSSc. Clinical Trials Registration NCT00379431.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.
To evaluate the efficacy compared to the relapse risk and tolerance of systematic rituximab (RTX) infusions as maintenance therapy for patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), who entered remission taking conventional immunosuppressants or RTX.
A retrospective study of the main clinical characteristics, outcomes, and RTX tolerance of patients who had received ≥ 2 RTX maintenance infusions in our center, regardless of induction regimen, between 2003 and 2010.
We identified 28 patients [4 MPA and 24 GPA; median age 55.5 yrs (range 18-78); 17 (60%) males] who received a median of 4 (range 2-10) RTX maintenance infusions, with median followup of 38 months (range 21-97) since diagnosis or last flare. None experienced a RTX infusion-related adverse event; 15 patients (among the 21 with available data) had hypogammaglobulinemia (predominantly IgM) prior to their last RTX maintenance infusion; 3 had infectious events (1 cutaneous abscess, 1 otitis, 1 fatal H1N1 flu). Two patients suffered pulmonary relapses shortly before a planned RTX maintenance infusion (both had increased antineutrophil cytoplasmic antibody levels and 1 had CD19+ lymphocyte reconstitution).
Rituximab maintenance therapy was well tolerated but did not completely prevent relapses and persistent "grumbling" disease. These preliminary results remain to be confirmed by a randomized controlled trial currently in progress.
First, to investigate the overall efficacy and safety of rituximab (RTX) in refractory granulomatosis with polyangiitis (GPA) in a tertiary referral centre. Second, to compare the efficacy of RTX in granulomatous and vasculitic manifestations in GPA.
This study comprised a retrospective, standardised data collection from all patients who received RTX for refractory Wegener's granulomatosis from 2002 to 2010. Patients were assessed by a standardised interdisciplinary diagnostic procedure (including ear, nose and throat and ophthalmology assessment, MRI, immunodiagnostics, B-cell levels and Birmingham Vasculitis Activity Score) and were treated by standardised therapeutic regimens according to available evidence.
59 patients received 75 cycles of RTX. 9.3% achieved complete remission. A response was documented in 61.3% (improvement in 52%, unchanged disease activity in 9.3%), 26.7% had refractory disease. Birmingham Vasculitis Activity Score, disease extent index, erythrocyte sedimentation rate, C-reactive protein and prednisolone demand decreased significantly. All patients achieved B-cell depletion. Granulomatous manifestations such as orbital granuloma and pachymeningitis were more frequently refractory to RTX than vasculitis or other granulomatous manifestations. Thus, for example, complete remission/improvement was found in 89.2% of patients with renal disease and in only 44.4% of those with orbital masses (p=0.003). The relapse rate was 44.4% after a median period of 13.5 months. Adverse events occurred in 29%, pneumonia in 15% and death in 3%.
The overall response rate of refractory GPA to RTX was high (61.3% complete remission or improvement). Response rates of vasculitic manifestations were excellent; failure of response/progress was mostly due to granulomatous manifestations, especially orbital masses. Relapse rates were high (40%) despite maintenance treatment.
Refractory vasculitis occurs in 4-5% of patients with anti-neutrophil cytoplasmic antibody associated vasculitis (AAV). Differences between therapies used for refractory disease are mostly reflected in the percentages of complete and partial remissions, but also in the number of serious side effects. Rituximab is considered the most safe second line therapy and should be advocated as a first alternative choice for cyclophosphamide in disease induction in refractory AAV.
Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are both frequently associated with antineutrophil cytoplasmic autoantibodies (ANCA). Immunosuppressive treatment has dramatically improved outcome for these patients, but today we have to deal with the problems of relapses, cases refractory to treatment, and long-term side effects of therapy. This study comprises a consecutive series of 123 patients with WG (n=56) or MPA (n=67) with biopsy-confirmed renal involvement, followed up for a median of 55 mo (range, 0.1 to 273.2 mo). ANCA was detected by enzyme-linked immunosorbent assay in 97% of patients. Nearly half of the patients (46%) relapsed. There was no statistically significant difference in overall relapse rate according to type of ANCA. Renal survival was 78% in patients alive at the end of follow-up. Three variables seemed important for renal survival: serum creatinine, the titer of proteinase 3-ANCA measured by capture enzyme-linked immunosorbent assay, and B thrombocyte count, at time of referral. Cancer incidence data were obtained from the population-based South Swedish Regional Tumor Registry. Standardized morbidity ratio was calculated using expected values from the health care region. We found an 11-fold increase in risk for bladder cancer in patients treated with cyclophosphamide for at least 12 mo. Skin carcinoma had the strongest relationship with azathioprine use for at least 12 mo and with corticosteroid therapy for at least 48 mo. In addition, four patients developed myelodysplastic syndrome and five had carcinoma in situ of the skin. Because the therapeutic regimen used today is not efficient enough to prevent relapses and is associated with a host of side effects, of which the risk for cancer is by far the most important, improved therapy and medical care are needed for patients with WG and MPA.
To review the use of monoclonal antibodies (MAbs), specifically rituximab, in the treatment of non-Hodgkin's lymphoma (NHL) and to describe the nursing management of patients receiving rituximab.
Published articles, abstracts, book chapters, drug manufacturer, lectures, and personal experience with rituximab.
NHL ranks sixth among malignancies in incidence and mortality in the United States. The most common subtype, low-grade follicular lymphoma, is considered incurable. Lack of specificity may limit the usefulness of chemotherapy for low-grade follicular NHL. However, MAb therapy may deliver a cytotoxic effect specifically to the targeted cancer cell. Rituximab is the first MAb approved for cancer therapy. Clinical trials indicate that rituximab is efficacious and safe for recurrent or chemotherapy-resistant, B-cell, low-grade NHL. Infusion-related side effects are the most common and can be managed effectively by following the infusion rate recommendations.
Monoclonal antibody therapy is an effective and safe treatment modality for cancer. Infusion-related side effects are managed effectively by following infusion rate recommendations.
Nurses need to be knowledgeable about MAb therapy to educate patients and families regarding the mechanism of action and side-effect profiles of these agents, which often differ from those of chemotherapy or radiation therapy. Nurses should be familiar with the unique side effects of rituximab and also specific infusion-rate instructions, measures to reduce the incidence of side effects, and criteria for stopping the infusion when necessary.
As a group, antibody deficiencies represent the most common types of primary immune deficiencies in human subjects. Often symptoms do not appear until the latter part of the first year of life, as passively acquired IgG from the mother decreases to below protective levels. As with the T-cell immune deficiencies, the spectrum of antibody deficiencies is broad, ranging from the most severe type of antibody deficiency with totally absent B cells and serum Igs to patients who have a selective antibody deficiency with normal serum Ig. In addition to the increased susceptibility to infections, a number of other disease processes (eg, autoimmunity and malignancies) can be involved in the clinical presentation. Fortunately, the availability of intravenous immune serum globulin has made the management of these patients more complete. Recently, molecular immunology has led to identification of the gene or genes involved in many of these antibody deficiencies. As discussed in this review, this has led to a better elucidation of the B-cell development and differentiation pathways and a more complete understanding of the pathogenesis of many of these antibody deficiencies.
Wegener's granulomatosis is necrotizing granulomatous vasculitis of unknown origin, which untreated has a high mortality within the first year of onset. The introduction of corticosteroids and cyclophosphamide in the treatment has considerably improved survival rates, but past studies have indicated an increased cancer risk, including an increased risk for urinary bladder cancer. No large assessment of the general cancer occurrence in Wegener's granulomatosis has been reported. The aim of our study was to assess the general incidence of cancer in patients with Wegener's granulomatosis and to put this in relation to the risk for bladder cancer. We identified a population-based cohort of 1,065 patients with Wegener's granulomatosis in the Swedish In-patient Register. Through linkage with the Swedish Cancer Register, we followed the cohort for cancer occurrence for up to 26 years. Standardized incidence ratios (SIR) between observed and expected numbers of cancers were used as a measure of relative risk. There was a 2-fold overall increased risk for cancer in the cohort. The increase was most pronounced for bladder cancer (SIR = 4.8; 95% CI 2.6-8.1), squamous cell skin cancer (SIR = 7.3; 95% CI 4.4-12), leukemias (SIR = 5.7; 95% CI 2.3-12) and for malignant lymphomas (SIR = 4.2; 95% CI 4.2-8.3). The results confirm previous indications of an increased risk for cancer of the urinary bladder but also points to increased risks for cancer at other sites.
In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch-Schonlein purpura (HSP).
A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK.
Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69-1.05; P = 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14-0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95% confidence interval 3.72-9.74; HSP, relative risk 5.25, 95% confidence interval 2.4-11.5). The presence of ANCA was not predictive of malignancy.
In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy.
Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV.
Patients with newly diagnosed AASV, with serum creatinine levels <150 mumoles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing).
One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036).
MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.
To determine the safety and efficacy of additional courses of rituximab in patients with rheumatoid arthritis (RA).
An open-label extension analysis of RA patients previously treated with rituximab was conducted. Patients who had participated in any of 3 double-blind trials were eligible for additional courses (2 infusions of 1,000 mg given 2 weeks apart) if they exhibited a swollen joint count and tender joint count of > or =8 with > or =16 weeks elapsing after the previous course. Safety was assessed in patients receiving all or a portion of a rituximab course. Efficacy was assessed 24 weeks after each course, using the American College of Rheumatology 20% criteria for improvement (ACR20), ACR50, ACR70, European League Against Rheumatism (EULAR) response criteria, Disease Activity Score in 28 joints, the disability index of the Health Assessment Questionnaire, and Short Form 36 scores, stratified according to prior tumor necrosis factor (TNF) inhibitor exposure.
A total of 1,039 patients received > or =1 course of rituximab. Of these, 570 received 2 courses, 191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years. Irrespective of prior TNF inhibitor exposure, ACR20 responses were comparable at week 24 after course 1 and at week 24 after course 2 (65% versus 72%), as were ACR50 and ACR70 responses. EULAR moderate/good responses were also comparable in course 2 relative to course 1 (88% versus 79%), with EULAR remission occurring in a 2-fold higher proportion of patients after course 2 than after course 1 (13% versus 6%). The most common adverse events, which were mild-to-moderate acute infusion-related events, decreased with each course. The serious infection rate after course 1 (5.1 per 100 patient-years) remained stable through additional courses. The proportion of patients with circulating IgM and IgG levels below the lower limit of normal (LLN) increased with subsequent courses; however, serious infection rates in these patients (5.6 per 100 patient-years in patients with low IgM levels and 4.8 per 100 patient-years in patients with low IgG levels were comparable with those in patients with immunoglobulin levels above the LLN (4.7 per 100 patient-years). Patients with human antichimeric antibody (9.2%) did not exhibit decreasing efficacy or present additional safety concerns.
These findings indicate that patients treated with repeated courses of rituximab have sustained clinical responses with no new adverse events.
Tokyo: Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan
- M Yoshida
Tokyo: Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan
- N Tsusaka
Long-term safety of patients receiving rituximab in rheumatoid arthritis clinical trials
- R F Van Vollenhoven
- P Emery
- C O Bingham
- Iii
- E C Keystone
- R Fleischmann
- D E Furst
Tokyo: Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan
- K Nakabayashi
- H Hashimoto
- Microscopic
Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis
- K De Groot
- N Rasmussen
- P A Bacon
- J W Tervaert
- C Feighery
- G Gregorini
Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients
- P Charles
- A Néel
- N Tieulié
- A Hot
- G Pugnet
- O Decaux
Epidemiology about the ANCA-related vasculitis
- S Kobayashi