The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis.

We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.

Analysis of the B cell receptor repertoire in six immune-mediated diseases.

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Plasma exchange induces vitamin D deficiency.

BACKGROUND: Plasma exchange is used in the treatment of diseases mediated by pathogenic circulating proteins, or for transplant desensitization. Its non-targeted nature results in the depletion of physiologically important molecules, and it is often complicated by hypocalcaemia. AIM: To determine the effects of plasma exchange on vitamin D binding protein (DBP) and associated vitamin D metabolites. DESIGN: Single-centre prospective cohort study of 11 patients. METHODS: DBP and vitamin D metabolites were measured before and immediately after five plasma exchanges, and 7 and 28 days after discontinuation of plasma exchange. RESULTS: Plasma exchange reduced plasma DBP concentration from 196.9 ± 53.2 to 98.5 ± 34 µg/ml (P = 0.0001), 1,25-dihydroxyvitamin D from 103 ± 52 to 42 ± 4 pmol/l (P = 0.003) and 25-hydroxyvitamin D from 49.7 ± 29 to 22 ± 9.4 nmol/l (P = 0.0017), through their removal in effluent. After 7 days, DBP and 1,25-dihydroxyvitamin D were not significantly different from baseline, but 25-hydroxyvitamin D remained significantly lower after 7 days (26.4 ± 9.8 nmol/l, P = 0.02) and 28 days (30.8 ± 15.5 nmol/l, P = 0.048). Corrected calcium decreased from 2.23 ± 0.11 to 1.98 ± 0.08 mmol/l (P = 0.0007) immediately after five treatments. Plasma calcium was significantly associated with 1,25-dihydroxyvitamin D (r(2) = 0.79, P < 0.0001). CONCLUSION: Plasma exchange induced an acute reversible decrease in plasma 1,25-dihydroxyvitamin D, DBP, calcium and a sustained decrease in plasma 25-hydroxyvitamin D.

Changes in proteinase 3 anti-neutrophil cytoplasm autoantibody levels in early systemic granulomatosis with polyangiitis (Wegener's) may reflect treatment rather than disease activity.

OBJECTIVES: To investigate the nature of the relationship between proteinase 3 anti-neutrophil cytoplasm autoantibody (PR3-ANCA) and relapse in patients with early systemic granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: Clinical data from 16 relapsing and 12 non-relapsing patients with early systemic GPA from a randomised clinical trial were correlated to monthly PR3-ANCA values over 18 months. Each sample was examined using 9 different enzyme-linked immunosorbent assays (ELISAs) to ensure reliability of ANCA results. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays in samples after remission. RESULTS: A PR3-ANCA peak was identified in all relapsing and non-relapsing patients and coincided with relapse in all 14 evaluable relapsing patients. The monthly increment before the peak, however, was similar in relapsing and non-relapsing patients in all assays. Increments from remission to peak were higher in relapsing patients in 2/9 assays. PR3-ANCA values at entry and peak PR3-ANCA values were higher in relapsing patients in 3/9 and 2/9 assays, respectively. However, large overlaps of PR3-ANCA values prevented a distinction between relapsing and non-relapsing patients. The median time to reach peak values was 14 months in relapsing and 12 months in non-relapsing patients with scheduled termination of treatment at 12 months. CONCLUSIONS: The predictive value for relapses of PR3-ANCA determinations confirm and extend previous reports. Although all relapses were related to PR3-ANCA increases, reduction or withdrawal of immunosuppression without relapse was also related to increases and may explain the lack of predictive value of sequential PR3-ANCA determinations.

Long-term outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: a retrospective cohort study.

OBJECTIVES: Alveolar haemorrhage (AH) is a major cause of early death in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). There is a paucity of information regarding the outcomes of AAV patients presenting with severe AH. METHOD: A retrospective cohort study. Patients with severe AH were identified from a case review of 824 AAV patients. Demography, presenting features, treatment, and outcomes are described. RESULTS: Fifty-three patients (33 males, 20 females; median age 59 years) with severe AH were identified: 37 (69.8%) with granulomatosis with polyangiitis (Wegener's) and 16 with microscopic polyangiitis [36 proteinase 3 (PR3)-ANCA positive and 17 myeloperoxidase (MPO)-ANCA positive]. AH was the first disease manifestation in 46 (86.8%) patients. Assisted ventilation was required in 36 (67.9%), renal involvement was present in 52 (98.1%), and 28 (52.8%) required dialysis. Forty (75.5%) received plasma exchange. At 3 months, 44/53 (83.0%) were alive. The mean follow-up was 49 months when 31 (58.5%) were alive and 24 (45.3%) dialysis independent. Mortality was higher in those requiring dialysis at entry (57.1% vs. 24%, p = 0.02) and in patients aged > 65 years (71.4% vs. 30.8%, p = 0.01), and tended to be higher in those requiring intubation (54.5% vs. 32.2%, p = 0.1). CONCLUSIONS: Severe AH was more commonly associated with PR3-ANCA (vs. MPO-ANCA) and strongly correlated with renal vasculitis. Current treatment of severe AH leads to remission but long-term mortality remains high. Concurrent renal failure and older age were associated with higher mortality.

Rituximab for ANCA-associated vasculitis in the setting of severe infection.

OBJECTIVES: The combination of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and severe infection presents a challenge because current therapies with high-dose glucocorticoids and cyclophosphamide (CYC) are immunosuppressive and increase the risk of infection. Thus, coincident infection delays and complicates the introduction of treatment. Rituximab (RTX) is an alternative to CYC in AAV and may be preferable in the setting of severe infection. METHOD: From 2005 to July 2011, 100 patients with AAV were treated with RTX at our institution and those who received RTX instead of CYC because of concomitant infection were studied. RESULTS: Eight patients were identified. The mean follow-up was 12 months (range 6-30 months). All patients achieved remission by 6 months that was sustained to the end of follow-up. There were no deaths or further severe infections. CONCLUSIONS: RTX can be considered for patients with generalized AAV and concomitant severe infection.

EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD). METHODS: A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force. RESULTS: Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. CONCLUSION: Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases.

OBJECTIVES: To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD). METHODS: AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible. RESULTS: Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive. CONCLUSION: Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

Deoxyspergualin in relapsing and refractory Wegener's granulomatosis.

OBJECTIVES: Conventional therapy of Wegener's granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease. METHODS: A prospective, international, multicentre, single-limb, open-label study. Entry required active Wegener's granulomatosis with a Birmingham vasculitis activity score (BVAS) > or =4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5 mg/kg per day, was self-administered by subcutaneous injection in six cycles of 21 days with a 7-day washout between cycles. Cycles were stopped early for white blood count less than 4000 cells/mm(3). The primary endpoint was complete remission (BVAS 0 for at least 2 months) or partial remission (BVAS <50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for 6 months. RESULTS: 42/44 patients (95%) achieved at least partial remission and 20/44 (45%) achieved complete remission. BVAS fell from 12 (4-25), median (range) at baseline to 2 (0-14) at the end of the study (p<0.001). Prednisolone doses were reduced from 20 to 8 mg/day (p<0.001). Relapses occurred in 18 (43%) patients after a median of 170 (44-316) days after achieving remission. Severe or life-threatening (> or = grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. CONCLUSIONS: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener's granulomatosis. Adverse events were common but rarely led to treatment discontinuation.

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

A comparative study of the diagnostic accuracy of ELISA systems for the detection of anti-neutrophil cytoplasm antibodies available in Japan and Europe.

OBJECTIVES: Primary systemic vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA) differs in its frequency and clinical expression between Japan and Europe. We sought to ascertain whether such differences arise from the performance of enzyme-linked immunosorbent assays (ELISAs) for ANCA. METHODS: Plasma samples from 64 consecutive Japanese patients with a clinical and histological diagnosis of primary systemic vasculitis including microscopic polyangiitis (MPA; n=52), Churg-Strauss syndrome (CSS; n=1), and Wegener's granulomatosis (WG; n=11), or those from disease controls with non-vasculitic glomerulonephritis (n=54) and healthy controls (n=55) were tested for the presence of myeloperoxidase (MPO) by ELISAs available in Japan (Nipro and MBL) and compared with those in Europe (Wieslab). The sensitivity and specificity were calculated for each ELISA, and its diagnostic performance was assessed by receiver operating characteristic curve analysis. RESULTS: The sensitivity and specificity of either MPO-ANCA assays for a diagnosis of MPA were 90.4% and 98.2% (Nipro), 88.2% and 96.3% (MBL), and 86.5% and 99.1% (Wieslab). The overall diagnostic performance, assessed as the area under curve of the MPO-ANCA ELISAs for MPA were 0.946+/-0.022 (Nipro), 0.970+/-0.017 (MBL), and 0.971+/-0.017 (Wieslab), while that of PR3-ANCA ELISAs for WG were 0.986+/-0.025 (Nipro), 0.993+/-0.017 (MBL), and 0.916+/-0.059 (Wieslab). CONCLUSIONS: The MPO-ANCA ELISAs commercially available in Japan exhibited high sensitivity and specificity for the diagnosis of ANCA-associated vasculitides and provided similar diagnostic value to those in Europe. These results facilitate further international comparison of ANCA-associated vasculitides between Japanese and European populations.

The cost-effectiveness of mycophenolate mofetil as firstline therapy in active lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect any system of the body. Involvement of the kidneys, lupus nephritis (LN), affects up to 50% of SLE patients during the course of their disease, and is characterized by periods of active disease (flares) and remission. For more severe nephritis, an induction course of immunosuppressive therapy is recommended. Options include intravenous cyclophosphamide (IVC) or mycophenolate mofetil (MMF), followed by a maintenance course, typically of azathioprine. The objective of this study is to determine which therapy results in better quality of life (QoL) for patients and which represents best value for money for finite health service resources. METHODS: A patient-level simulation model is developed to estimate the costs and quality-adjusted life-years (QALYs) of a patient treated with IVC or MMF for an induction period of six months. Efficacy, QoL, resource use and cost data are extracted from the literature and standard databases and supplemented with expert opinion where necessary. RESULTS: On average, the model predicts MMF to result in improved QoL compared with IVC. MMF is also less expensive than IVC, costing pound 1600 (euro 2400; US$ 3100) less over the period, based on 2005 NHS prices. The major determinant and cost driver of this result is the requirement for a day-case procedure to administer IVC. Sensitivity analysis shows an 81% probability that MMF will be cost-effective compared with IVC at a willingness to pay of pound 30,000 (euro 44,700; US$ 58,500) per QALY gained. CONCLUSION: MMF is likely to result in better QoL and be less expensive than IVC as induction therapy for LN.

Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment.

OBJECTIVE: Current treatments for systemic lupus erythematosus (SLE) and vasculitis contribute to mortality and incapacity and are only partially effective; thus, newer therapies are clearly needed. Depletion of B cells has led to disease control in patients with autoimmune disorders. We sought to assess the long-term efficacy and safety of a B cell-depleting therapy in patients with SLE and patients with vasculitis. METHODS: In a prospective study with a median followup of 24 months, 11 patients with active or refractory SLE and 11 patients with active or refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) received a course of therapy with rituximab (an anti-CD20 monoclonal antibody) along with a single dose of intravenous cyclophosphamide. RESULTS: Remission followed rapid B cell depletion, with response rates of 100% among the 11 patients with SLE (6 patients had a complete response, and 5 patients had a partial response) and 91% among the 11 patients with AAV (9 patients had a complete response, and 1 patient had partial remission). A renal response occurred in all 6 patients with lupus nephritis. Clinical improvement was accompanied by significant reductions in the daily dose of prednisolone. Relapse occurred in 64% of the patients with SLE and in 60% of those with AAV. B cell return preceded relapse in the majority of patients, and further treatment with rituximab proved effective. IgG and IgM levels were maintained in the normal range. The incidence of infective complications was low; however, infusion reactions were common, and human antichimeric antibodies developed in 5 of 14 patients. CONCLUSION: B cell depletion offers the prospect of sustained disease remission and improved disease control combined with low toxicity in patients with active or refractory SLE or AAV. Relapse following treatment is common, but re-treatment is rapidly effective.

The role of biologic therapies in the management of systemic vasculitis.

The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionised the treatment of inflammatory arthritides. The steady increase in use of biologic agents coupled with the expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. These agents may have a role in addition to or in place of conventional immunosuppression and also be effective when the latter fails to induce remission. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. While the advent of biologics heralds a new era in the management of the systemic vasculitis, evidence for their efficacy is still in its infancy and has yet to match that of conventional immunosuppressants. In this review, we examine the up-to-date evidence for the use of biologics in systemic vasculitis, including TNF-alpha inhibitors, and highlight the challenges facing their use. We examine the rationale for using biologics based on the pathophysiology of vasculitis. Issues of toxicity and pharmacovigilance with the use of biologics are also discussed. Finally, future directions and predictions are presented.