CD36 regulates macrophage and endothelial cell activation and multinucleate giant cell formation in anti neutrophil cytoplasm antibody vasculitis.

OBJECTIVE: To investigate CD36 in ANCA-associated vasculitis (AAV), a condition characterized by monocyte/macrophage activation and vascular damage. METHODS: CD36 expression was assessed in AAV patients and healthy controls (HC). The impact of palmitic acid (PA) stimulation on multinucleate giant cell (MNGC) formation, macrophage, and endothelial cell activation, with or without CD36 knockdown, was examined. RESULTS: CD36 was overexpressed on AAV patients' monocytes compared to HC, regardless of disease activity. AAV patients exhibited elevated soluble CD36 levels in serum and plasma and PR3-ANCA patients' monocytes demonstrated increased MNGC formation following PA stimulation compared to HC. PA stimulation of macrophages or endothelial cells resulted in heightened CD36 expression, cell activation, increased macrophage migration inhibitory factor (MIF) production, and c-Myc expression, with attenuation upon CD36 knockdown. CONCLUSION: CD36 participates in macrophage and endothelial cell activation and MNGC formation, features of AAV pathogenesis. AAV treatment may involve targeting CD36 or MIF.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

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.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [ß (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [ß (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [ß (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]. CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses.

Decreased renal function is associated with incident dementia: An IMRD-THIN retrospective cohort study in the UK.

INTRODUCTION: Decreased renal function is a potential risk factor for dementia. METHODS: This retrospective cohort study of 2.8 million adults aged ≥50 years used the IMRD-THIN database, representative of UK primary care, from January 1, 1995 to February 24, 2020. The associations between estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (ACR) with incident all-cause dementia were analyzed using Cox regression. RESULTS: In the eGFR cohort (n = 2,797,384), worsening renal dysfunction was associated with increased hazard of all-cause dementia, with greatest hazard at eGFR 15-30 ml/min/1.73min2 (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.19-1.33). In the ACR cohort (n = 641,912), the hazard of dementia increased from ACR 3-30 mg/mmol (HR 1.13, 95% CI 1.10-1.15) to ACR > 30 mg/mmol (HR 1.25, 95% CI 1.18-1.33). DISCUSSION: Worsening eGFR and albuminuria have graded associations with the risk of dementia, which may have significant implications for the care of patients with kidney disease.

Latent Cytomegalovirus Infection and Previous Capsular Polysaccharide Vaccination Predict Poor Vaccine Responses in Older Adults, Independent of Chronic Kidney Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are more prone to severe infection. Vaccination is a key strategy to reduce this risk. Some studies suggest vaccine efficacy may be reduced in patients with CKD, despite preserved maintenance of long-term responses to some pathogens and vaccines. Here, we investigated immune responses to 2 vaccines in patients with CKD to identify predictors of immunological responsiveness. METHODS: Individuals >65 years old, with or without nondialysis CKD (n = 36 and 29, respectively), were vaccinated with a nonadjuvanted seasonal influenza vaccine (T-dependent) and Pneumovax23 (23-valent pneumococcal polysaccharide [PPV23], T-independent). Humoral responses were measured at baseline, day 28, and 6 months. Lymphocyte subset and plasma cell/blast analyses were performed using flow cytometry. Cytomegalovirus (CMV) serotyping was assessed by enzyme-linked immunosorbent assay. RESULTS: Only modest responsiveness was observed to both vaccines, independent of CKD status (25% adequate response in controls vs. 12%-18% in the CKD group). Unexpectedly, previous immunization with PPV23 (median 10-year interval) and CMV seropositivity were associated with poor PPV23 responsiveness in both study groups (P < .001 and .003, respectively; multivariable linear regression model). Patients with CKD displayed expanded circulating populations of T helper 2 and regulatory T cells, which were unrelated to vaccine responses. Despite fewer circulating B cells, patients with CKD were able to mount a similar day 7 plasma cell/blast response to controls. CONCLUSION: Patients with nondialysis CKD can respond similarly to vaccines as age- and sex-matched healthy individuals. CKD patients display an immune signature that is independent of vaccine responsiveness. Prior PPV23 immunization and CMV infection may influence responsiveness to vaccination. Clinical Trials Registration. NCT02535052.

Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2).

OBJECTIVE: To evaluate the impact of anti-Tumour Necrosis Factor-α (anti-TNF) treatment on the occurrence of vasculitic ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). METHODS: A retrospective analysis of DADA2 patients referred from six centres to Great Ormond Street Hospital for Children was conducted. Ischaemic events, vasculitic disease activity, biochemical, immunological, and radiological features were compared, before and after anti-TNF treatment. RESULTS: A total of 31 patients with genetically confirmed DADA2 were included in the study. The median duration of active disease activity prior to anti-TNF treatment was 73 months (inter-quartile range [IQR] 27.5-133.5 months). Twenty seven/31 patients received anti-TNF treatment for a median of 32 months (IQR 12.0-71.5 months). The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months (IQR 1.25-3.63); compared with 0.00 per 100 patient-months (IQR 0.0-0.0) post-treatment (p< 0.0001). Paediatric vasculitis activity score (PVAS) was also significantly reduced: median score of 20/63 (IQR 13.0-25.8/63) pre-treatment vs. 2/63 (IQR 0.0-3.8/63) following anti-TNF treatment (p< 0.0001), with mild livedoid rash being the main persisting feature. Anti-TNF treatment was not effective for severe immunodeficiency or bone marrow failure, which required haematopoietic stem cell transplantation (HSCT). CONCLUSION: Anti-TNF treatment significantly reduced the incidence of ischaemic events and other vasculitic manifestations of DADA2, but was not effective for immunodeficiency or bone marrow failure.

Management of fatigue with physical activity and behavioural change support in vasculitis: a feasibility study.

OBJECTIVE: Patients with ANCA-associated vasculitis (AAV) experience high levels of fatigue, despite disease remission. This study assessed the feasibility and acceptability of a definitive randomized controlled trial of a behavioural-based physical activity intervention to support fatigue self-management in AAV patients. METHODS: AAV patients in disease remission with fatigue (Multidimensional Fatigue Inventory-20 general fatigue domain ≥14) were randomly allocated to intervention or standard care in this single-centre open-label randomized controlled feasibility study. The intervention lasted 12 weeks and comprised eight face-to-face physical activity sessions with a facilitator and 12 weekly telephone calls. Participants were encouraged to monitor their physical activity using a tracker device (Fitbit). Standard care involved sign-posting to fatigue websites. The primary outcome was feasibility of a phase III trial assessed against three stop/go traffic light criteria, (recruitment, intervention adherence and study withdrawal). A qualitative study assessed participant views about the intervention. RESULTS: A total of 248 patients were screened and 134 were eligible to participate (54%). Stop/go criteria were amber for recruitment; 43/134 (32%, 95% CI: 24, 40) eligible participants randomized, amber for adherence; 73% of participants attended all eight physical activity sessions, but only 11/22 (50%, 95% CI: 29, 71%) completed the intervention as per the intended schedule, and green for study withdrawal; 2/43 participants withdrew before 24 weeks (5%, 95% CI: 0, 11). Qualitative results suggested the intervention was acceptable. CONCLUSION: This study suggests a behavioural-based physical activity intervention targeting fatigue self-management was acceptable to patients with AAV, although recruitment and protocol adherence will need modification prior to a definitive trial. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN11929227.

Eosinophilic Granulomatosis with Polyangiitis Presenting as Unilateral Acute Anterior Ischaemic Optic Neuropathy.

Eosinophilic granulomatosis with polyangiitis (eGPA) is a rare vasculitis of small-medium sized vessels that can cause both anterior and posterior ischaemic optic neuropathies. Herein, the authors present a rare case of eGPA presenting initially as an acute unilateral anterior ischaemic optic neuropathy from short posterior ciliary artery vasculitis. The diagnosis presented a challenge as clinical and histopathological evidence suggested allergic rhinosinusitis, and no invasive fungal sinusitis was found. The high serum eosinophilia, asthma, optic neuropathy and paranasal sinus abnormalities fulfilled the criteria for a diagnosis of eGPA. Furthermore serum was positive for myeloperoxidase antibodies. Subsequently the case was successfully treated with oral glucocorticoids and intravenous rituximab.

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.

Epidemiology, morbidity and mortality in Behçet's disease: a cohort study using The Health Improvement Network (THIN).

OBJECTIVES: The epidemiology of Behçet's disease (BD) has not been well characterized in the UK. Evidence on the risk of cardiovascular disease, thromboembolic disease and mortality in patients with BD compared with the general population is scarce. METHODS: We used a large UK primary care database to investigate the epidemiology of BD. A retrospective matched cohort study was used to assess the following outcomes: risk of cardiovascular, thromboembolic disease and mortality. Controls were selected at a 1:4 ratio (age and gender matched). Cox proportional hazard models were used to derive adjusted hazard ratios (aHR). RESULTS: The prevalence of BD was 14.61 (95% CI 13.35-15.88) per 100 000 population in 2017. A total of 1281 patients with BD were compared with 5124 age- and gender-matched controls. There was significantly increased risk of ischaemic heart disease [aHR 3.09 (1.28-7.44)], venous thrombosis [aHR 4.80 (2.42-9.54)] and mortality [aHR 1.40 (1.07-1.84)] in patients with BD compared with corresponding controls. Patients with BD were at higher risk of pulmonary embolism compared with corresponding controls at baseline [adjusted odds ratio 4.64 (2.66-8.09), P < 0.0001]. The majority of patients with pulmonary embolism and a diagnosis of BD had pulmonary embolism preceding the diagnosis of BD, not after (87.5%; n = 28/32). CONCLUSION: BD has a higher prevalence than previously thought. Physicians should be aware of the increased risk of developing ischaemic heart disease, stroke/transient ischaemic attack and deep venous thrombosis in patients with BD at an earlier age compared with the general population. Risk of embolism in patients with BD might vary across the disease course.

Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Background: Infection is the leading cause of death in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Expansion of CD4+CD28null T cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus (CMV)-seropositive individuals. We hypothesized that subclinical CMV reactivation drives CD4+CD28null T-cell expansion, that this is associated with impaired immune response to heterologous antigens, and that antiviral therapy may ameliorate this. Methods: In a proof-of-concept open-label clinical trial, 38 CMV-seropositive AAV patients were randomized to receive valacyclovir for 6 months or no intervention. CMV reactivation was measured monthly in plasma and urine. CD4+CD28null T cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific immunoglobulin G was assayed before and 4 weeks postvaccination to calculate the antibody response ratio. Results: Valacyclovir treatment suppressed subclinical CMV reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whereas CMV reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T cells was associated with a reduction in the functional capacity of the CD4 compartment. Conclusions: Suppression of CMV may improve the immune response to a T-cell-dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit. Clinical Trials Registration: NCT01633476.

Cardiovascular, thromboembolic and renal outcomes in IgA vasculitis (Henoch-Schönlein purpura): a retrospective cohort study using routinely collected primary care data.

BACKGROUND: IgA vasculitis (IgAV, Henoch-Schönlein purpura) is a small-vessel vasculitis most common in children but also occurring in adults. Case series have suggested that IgAV may be associated with cardiovascular disease and venous thromboembolism, but this has not been evaluated in population-based studies. Renal disease and hypertension are possible complications of the disease with unknown incidence. METHODS: Using a large UK primary care database, we conducted an open retrospective matched cohort study of cardiovascular, venous thrombotic and renal outcomes in adult-onset and childhood-onset IgAV. Control participants were selected at a 2:1 ratio, matched for age and sex. Adjusted HRs (aHRs) were calculated using Cox proportional hazards models. RESULTS: 2828 patients with adult-onset IgAV and 10 405 patients with childhood-onset IgAV were compared with age-matched and sex-matched controls. There was significantly increased risk of hypertension (adult-onset aHR 1.42, 95% CI 1.19 to 1.70, p < 0.001; childhood-onset aHR 1.52, 95% CI 1.22 to 1.89, p < 0.001) and stage G3-G5 chronic kidney disease (adult-onset aHR 1.54, 95% CI 1.23 to 1.93, p < 0.001; childhood-onset aHR 1.89, 95% CI 1.16 to 3.07, p=0.010). There was no evidence of association with ischaemic heart disease, cerebrovascular disease or venous thromboembolism. All-cause mortality was increased in the adult-onset IgAV cohort compared with controls (aHR 1.27, 95% CI 1.07 to 1.50, p=0.006). CONCLUSIONS: Patients with IgAV are at increased risk of hypertension and chronic kidney disease (CKD) compared with individuals without IgAV; analysis restricted to adult-onset IgAV patients showed increased mortality. Appropriate surveillance and risk factor modification could improve long-term outcomes in these patients.

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases.

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.

Glucocorticoid activation by 11ß-hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross-sectional study.

OBJECTIVE: Patients with chronic kidney disease (CKD) have dysregulated cortisol metabolism secondary to changes in 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzymes. The determinants of this and its clinical implications are poorly defined. METHODS: We performed a cross-sectional study to characterize shifts in cortisol metabolism in relation to renal function, inflammation and glycaemic control. Systemic activation of cortisol by 11ß-HSD was measured as the metabolite ratio (tetrahydrocortisol [THF]+5α-tetrahydrocortisol [5αTHF])/tetrahydrocortisone (THE) in urine. RESULTS: The cohort included 342 participants with a median age of 63 years, median estimated glomerular filtration rate (eGFR) of 28 mL/min/1.73 m2 and median urine albumin-creatinine ratio of 35.5 mg/mmol. (THF+5αTHF)/THE correlated negatively with eGFR (Spearman's ρ = -0.116, P = 0.032) and positively with C-reactive protein (ρ = 0.208, P < 0.001). In multivariable analysis, C-reactive protein remained a significant independent predictor of (THF+5αTHF)/THE, but eGFR did not. Elevated (THF+5αTHF)/THE was associated with HbA1c (ρ = 0.144, P = 0.008) and diabetes mellitus (odds ratio for high vs low tertile of (THF+5αTHF)/THE 2.57, 95% confidence interval 1.47-4.47). Associations with diabetes mellitus and with HbA1c among the diabetic subgroup were independent of eGFR, C-reactive protein, age, sex and ethnicity. CONCLUSIONS: In summary, glucocorticoid activation by 11ß-HSD in our cohort comprising a spectrum of renal function was associated with inflammation and impaired glucose control.

Glucocorticoid induced adrenal insufficiency is common in steroid treated glomerular diseases - proposed strategy for screening and management.

BACKGROUND: Glucocorticoids (GCs) are frequently used to treat glomerular diseases but are associated with multiple adverse effects including hypothalamic-pituitary-adrenal axis inhibition that can lead to adrenal insufficiency (AI) on withdrawal. There is no agreed GC tapering strategy to minimise this risk. METHODS: This is a single centre retrospective study, between 2013 to 2016, of patients with glomerular disease on GC therapy for more than 3 months screened for GC induced AI with short synacthen stimulation tests (SSTs) done prior to complete GC withdrawal. We investigated the prevalence of AI, predictors, choice of screening tool and recovery. RESULTS: Biochemical evidence of GC induced AI was found in 57 (46.3%) patients. Total duration of GC did not differ between those with and without AI (p = 0.711). Patients with GC induced AI had a significantly lower pre-synacthen baseline cortisol as compared to patients without AI. A cut off pre-synacthen baseline cortisol of ≥223.5 nmol/l had a specificity of 100% for identifying individuals without biochemical AI. Patients with GC induced AI took a mean of 8.7 ± 4.6 months (mean ± SD) to recover. Patients with persistent AI had a significantly lower index post-synacthen cortisol measurement. CONCLUSIONS: We demonstrate that biochemically proven GC induced AI is common in patients with glomerular diseases, is not predicted by daily dose or duration and takes a considerable time to recover. The study supports the use of morning basal cortisol testing as an appropriate means to avoid the need for SSTs in all patients and should be performed in all patients prior to consideration of GC withdrawal after 3 months duration.

Intravenous pulse methylprednisolone for induction of remission in severe ANCA associated Vasculitis: a multi-center retrospective cohort study.

BACKGROUND: Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. METHODS: We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 µmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. RESULTS: Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4-5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94-20.63], p = 0.002), after adjustment for confounding factors. CONCLUSIONS: The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

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%; P=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%; P=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.