The C5a receptor inhibitor avacopan was superior to a tapering schedule of prednisone with respect to remission of ANCA-associated vasculitis at 52 weeks. There were fewer glucocorticoid-associated ...adverse events in the avacopan group than in the prednisone group, and serious infections did not differ substantially between the two groups.
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody ...(ANCA)-associated vasculitis and renal involvement. Rates of sustained remission were high in both groups.
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and renal involvement.
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis, is a multisystem autoimmune syndrome characterized by vasculitis predominantly affecting microscopic vessels and circulating autoantibodies to neutrophil cytoplasmic antigens. Renal involvement occurs in 70% of affected patients and is manifested as rapidly progressive glomerulonephritis with pauci-immune necrotizing, crescentic glomerulonephritis on biopsy. The current standard of care for ANCA-associated vasculitis is cyclophosphamide with high-dose glucocorticoids
1–4
; such regimens are effective in 70 to 90% of patients. However, cyclophosphamide is associated with leukopenia, severe infections, cancer, and ovarian failure.
5
Mortality at 1 year exceeds 15%; infection and active vasculitis are . . .
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to ...significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The main histological feature in the kidneys of patients with ...AAV is pauci-immune necrotizing crescentic glomerulonephritis with little immunoglobulin and complement deposition in the glomerular capillary walls. The complement system was not, therefore, initially thought to be associated with the development of AAV. Accumulating evidence from animal models and clinical observations indicate, however, that activation of the complement system - and the alternative pathway in particular - is crucial for the development of AAV, and that the complement activation product C5a has a central role. Stimulation of neutrophils with C5a and ANCA not only results in the neutrophil respiratory burst and degranulation, but also activates the coagulation system and generates thrombin, thus bridging the inflammation and coagulation systems. In this Review, we provide an overview of the clinical, in vivo and in vitro evidence for a role of complement activation in the development of AAV and discuss how targeting the complement system could provide opportunities for therapy.
Summary Background Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of ...patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function. Methods This randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18–75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692. Findings We randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 58% of 33 patients reached endpoint vs 31 84% of 37, hazard ratio HR 0·44 95% CI 0·24–0·78; p=0·0042); risk did not differ between the ciclosporin (29 81% of 36) and supportive treatment only groups (HR 1·17 0·70–1·95; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048). Interpretation For the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset. Funding Medical Research Council, Novartis, Renal Association, Kidney Research UK.
Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We ...determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%;
=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%;
=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.
Abstract Rituximab (RTX), a chimeric, monoclonal anti-CD20 antibody, is increasingly used in immune-mediated renal diseases. While licensed in the induction treatment of ANCA-associated vasculitis, ...it represents one of the most commonly prescribed off-label drugs. Much of the information regarding its safety has been drawn from experience in hematology and rheumatology. Ample evidence illustrates the safety of RTX, however, rare but serious adverse events have emerged that include progressive multifocal leucoencephalopathy and hepatitis B reactivation. Moderate to severe hypogammaglobulinemia and late-onset neutropenia following RTX therapy confer an increased infectious risk and factors predicting these side effects (i.e. a genetic basis) need to be identified. Nephrologists initiating RTX need to bear in mind that long-term risks and optimal dosing for many renal indications remain unclear. Special considerations must be given when RTX is used in women of childbearing age. We summarize practical aspects concerning the use of RTX. This review will provide nephrologists with information to guide their use of RTX alerting them to safety risks and the need for patient counselling.
We aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab.
192 patients with AAV were ...identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0.
95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim-sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections.
We found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim-sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections.
Patients with antineutrophil cytoplasm antibody–associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a ...trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53–1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40–1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.
Objectives. The epidemiological manifestations of ANCA-associated vasculitis (AAV) differ geographically. However, there have been no prospective studies comparing the incidence of AAV between Japan ...and Europe over the same time period using the same case definitions.
Methods. The incidence of AAV was determined by a population-based method in Miyazaki prefecture, Japan, and Norfolk, UK, between 2005 and 2009. Patients with AAV were defined and classified according to the European Medicines Agency (EMEA) algorithm.
Results. The number of incident cases of AAV in Japan and the UK were 86 and 50, respectively, and the average annual incidence over the 5-year period was 22.6/million (95% CI 19.1, 26.2) and 21.8/million (95% CI 12.6, 30.9) in Japan and the UK, respectively. The average age was higher in patients in Japan than in patients in the UK mean (median), 69.7 (72) vs 60.5 (61) years. Microscopic polyangiitis (MPA) was the predominant subtype in Japan (83%), while granulomatosis with polyangiitis (Wegener's) was more frequent in the UK (66%). As for the pattern of ANCA positivity, >80% of Japanese patients were pANCA/MPO positive, whereas two-thirds of UK patients were cANCA/PR3 positive. Renal involvement in MPA was very common in both countries, but was much less common in granulomatosis with polyangiitis in Japan compared with the UK.
Conclusion. There was no major difference in AAV incidence between Japan and the UK, but this prospective study found MPA and MPO-ANCA to be more common in Japan and granulomatosis with polyangiitis and PR3-ANCA to be more common in the UK, in line with earlier reports.
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