Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Reported Prevalence of Radiographic Cam Deformity Based on Sport: A Systematic Review of the Current Literature.

BACKGROUND: Repetitive loading and shear stress across the proximal femur account for the high prevalence of cam deformity in athletes. PURPOSE: To systematically review the literature to identify the reported number, age, mean alpha angle measurements, and differences between male and female athletes with radiographic cam deformity based on sport. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was conducted of studies in the literature between January 1990 and March 2018 that reported on athletes with radiographic cam deformity based on sport. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed, and PubMed, Biosis Previews, SPORTDiscus, PEDro, and EMBASE databases were used. Inclusion criteria included studies documenting radiographic cam deformity based on alpha angle measurements categorized according to the athlete's primary sport and according to sex. Exclusion criteria were (1) studies not documenting primary sport, (2) studies not reporting total number of athletes with radiographic cam deformity, and (3) studies not separating cam deformity based on sex or using alpha angle measurements. Statistical analysis was used to compare mean reported age and alpha angle measurements between males and females. RESULTS: A total of 28 studies consisting of 1160 male and 53 female athletes with radiographic cam deformity were identified. Cam lesions were most commonly reported in soccer athletes among both males and females, followed by hockey and American football. Male athletes had significantly higher mean alpha angle measurements (59.9° ± 5.5°) compared with female athletes (48.3° ± 6.9°) (P = .001). No significant difference in age was appreciated between males (21.1 ± 4.0 years) and females (21.7 ± 3.0 years) (P = .62). CONCLUSION: Radiographic cam deformity is most commonly reported in athletes participating in soccer and hockey. Males possessed significantly greater mean alpha angle measurements compared with females, whereas no significant difference in mean age at the time of diagnosis was appreciated between sexes.

From chronic kidney disease to kidney transplantation: The impact of obesity and its treatment modalities.

Obesity is associated with worse short-term outcomes after kidney transplantation but the effect on long-term outcomes is unknown. Although some studies have reported worse outcomes for obese recipients when compared to recipients with a BMI in the normal range, obese recipients who receive a transplant have better outcomes than those who remain wait-listed. Whether transplant candidates should be advised to lose weight before or after transplant has been debated and this is mainly due to the gap in the literature linking pre-transplant weight loss with better outcomes post-transplantation. The issue is further complicated by the use of BMI as a metric of body fat, the obesity paradox in dialysis patients and the different ethical viewpoints of utility versus equity. Measures used to reduce weight loss, including orlistat and bariatric surgery (in particular those with a malabsorptive component), have been associated with enteric hyperoxaluria with consequent risk of nephrolithiasis and oxalate nephropathy. In this review, we discuss the evidence regarding the use of weight loss measures in the kidney transplant candidate and recipient with a view to recommending whether weight loss should be pursued before or after kidney transplantation.

Calcineurin Inhibitor-Sparing Strategies in Renal Transplantation: Where Are We? A Comprehensive Review of the Current Evidence.

The introduction of the calcineurin inhibitors cyclosporine and tacrolimus in the immunosuppressive regimens for kidney transplant has been associated with substantial reductions in the incidence of acute rejection, with a subsequent improvement in 1-year graft survival. However, this has not directly correlated with improvements in long-term allograft survival. Immunosuppressive medications are associated with toxicities related directly to immunosuppressive effects, and these are similar among different agents. In addition, there are other toxicities that are unique for each drug. Immunosuppressive minimization strategies have attempted to address both of these toxicities. Calcineurin inhibitors have been associated with chronic nephrotoxicity, and various calcineurin inhibitor-sparing strategies have been used to address this issue with the aim of improving long-term outcomes. However, there has been a paradigm shift over the past 10 to 15 years, with the appreciation that calcineurin inhibitor nephrotoxicity is not the major cause of late graft failure. Studies have now shown that chronic immune injury mediated by donor-specific antibodies may account for most late graft losses. Although some patients do benefit from calcineurin inhibitor-sparing approaches, others may have late allograft loss from chronic and subacute immune-mediated injury. Unfortunately, the vast majority of calcineurin inhibitor-sparing studies have short-term follow-up and have not explored the change in the donor-specific antibody profile. One of the biggest challenges that we face is being able to distinguish among patients who will benefit from this strategy and those who will not. In this study, we review the various strategies used to limit or avoid the use of calcineurin inhibitors and address the benefits and pitfalls associated in pursuing such strategies.