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Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity.The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing three point mutations in Epitope 15 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen the differential PR3-ANCA binding. A patient-derived monoclonal ANCA (moANCA518) that selectively binds to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 was used as a gauge of remote epitope activation. Selective binding was determined by inhibition experiments.Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518.The preferential binding of PR3-ANCAs from patients like the selective binding of moANCA518 to iHm5 is conferred by increased antigenicity of Epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches. This article is protected by copyright. All rights reserved.

ObjectivesSevere infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial.MethodsData on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models.ResultsEighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis againstPneumocystis jiroveciiwith trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA.ConclusionsThe use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.

Understanding of the pathophysiology of immunoglobulin G4–related disease (IgG4-RD) over the last dozen years has opened the door to a variety of targeted treatment approaches. Glucocorticoids are an effective treatment for IgG4-RD if used at a sufficiently high dose, but disease flares are common during or after glucocorticoid tapers and these medications seldom lead to long-term, treatment-free remissions. Moreover, their long-term use in a disease that frequently affects middle-aged to elderly individuals and often causes major pancreatic damage leads to a narrow therapeutic index. Biological therapies offer the possibility of effective disease control with fewer treatment-associated side effects. Promising avenues of investigation include B-cell depletion, immunomodulation of B-cell subsets, interference with co-stimulation, Bruton’s tyrosine kinase inhibition, and Signaling lymphocytic activation molecule F7-directed treatment.

ObjectivesInflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC.MethodsRh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients’ baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD.ResultsData from 1066 patients with iRMD were analysed. GC doses of 7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28–C reactive protein >3.2).ConclusionsGCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of >7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity.Trial registration numberNCT02719314.

ObjectiveTo evaluate the effect of achieving a negative postinduction antineutrophil cytoplasmic antibody ANCA) assay on the risk of relapse, end-stage renal disease (ESRD) and death in ANCA-associated vasculitis (AAV).MethodsWe emulated a target trial using observational data from the Mass General Brigham AAV cohort comparing patients who achieved versus did not achieve serological remission (negative ANCA assay) within 180 days of induction. Outcomes were relapse, ESRD or death within 5 years, obtained from medical records, the US Renal Data System and the National Death Index. We placed a ‘clone’ of each patient in both trial arms, censored those deviating from their assigned protocol and weighted each by the inverse probability of censoring. Outcomes were assessed by pooled logistic regression.ResultsThe study included 506 patients with AAV. The mean age was 61 years (SD 18) and the majority were women (58%), white (87%), myeloperoxidase-ANCA+ (72%) and had renal involvement (68%). Rituximab (59%) or cyclophosphamide (33%) was most often used for induction treatment. Within 5 years, 81 (16%) died, 51 (10%) had ESRD and 64 (13%) had relapse. Patients treated to a negative ANCA assay within 180 days had HR 0.55 (95% CI 0.38 to 0.81) for relapse and HR 0.87 (95% CI 0.61 to 1.25) for the composite of ESRD or death within 5 years.ConclusionsIn this emulated target trial from a large AAV cohort, achieving serological remission within 180 days of induction was associated with lower risk of relapse, but no statistically significant difference in ESRD or mortality outcomes.

IgG4-related disease-associated hypertrophic pachymeningitis (IgG4RD-HP) is a fibroinflammatory autoimmune disorder in which diagnosis is difficult without biopsy. Guidance on management of disease refractory to glucocorticoids and intravenous rituximab is limited. We present the case of a 68-year-old woman with IgG4RD-HP who developed sensorineural hearing loss with associated bulky basilar pachymeningeal enhancement. Her cerebrospinal fluid was inflammatory and had an elevated IgG4 concentration, strongly suggestive of IgG4RD-HP. Biopsy of involved meninges was not possible due to surgical risk. Over years she developed bilateral optic neuropathies and hydrocephalus, requiring intravenous rituximab and ventriculoperitoneal shunt. Her disease was refractory to glucocorticoids. Despite maintenance intravenous rituximab, she developed slowly progressive symptoms of intracranial hypertension and hydrocephalus with persistently inflammatory spinal fluid. Switching to intrathecal rituximab therapy led to dramatic improvement in gait and headache and reduced pachymeningeal bulk and metabolic activity. In patients with IgG4RD-HP refractory to glucocorticoids and intravenous rituximab, intrathecal rituximab may be an efficacious therapy.

Background Glucocorticoids are the mainstay of treatment for autoimmune blistering diseases (AIBDs). The Glucocorticoid Toxicity Index (GTI) is a novel, outcome-based glucocorticoid-induced adverse effects monitoring instrument. Objective To investigate whether the GTI score was able to accurately quantify the glucocorticoid-induced toxicity in patients with AIBDs. Methods The prospective cohort study included patients with confirmed diagnoses of AIBDs (group1, currently receiving glucocorticoids; and group 2, had glucocorticoids ceased earlier). Data were collected minimally at baseline (V1) and 3 months (V2). Further data from patients who were able to complete the follow-up visits at 6 months (V3) and 12 months (V4) amid the COVID-19 pandemic were also included. GTI scores were calculated after data collection. Results Analysis of data from V1 and V2 found a linear correlation between GTI score and prednisone doses (P

BACKGROUND: There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. METHODS: We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. FINDINGS: The subjects’ median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304–913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint. Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (T(FH2)) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. INTERPRETATION: Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated T(FH2) cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.

Immunoglobulin-G4-related disease (IgG4-RD) is a systemic autoimmune disease that can affect nearly any organ, but its epidemiology remains poorly understood. Validated algorithms to identify cases in claims data will enable studies to describe IgG4-RD epidemiology in the general population.Potential claims-based algorithms were developed by IgG4-RD experts using a combination of International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, 10th Revision (ICD-10) codes, dispensed medications, and procedure codes for immunoglobulin G (IgG) subclass testing. Algorithms were tested using Medicare Parts A, B, and D linked to medical records (2007-2017). Classification of cases as IgG4-RD was determined using the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for IgG4-RD. We estimated the positive predictive value (PPV) of each algorithm; sensitivity was determined using a cohort of patients with IgG4-RD also enrolled in Medicare Parts A, B, and D during the study period.We identified seven algorithms that used a combination of ICD-9 and ICD-10 codes, medication prescriptions, and/or IgG subclass tests to identify patients with IgG4-RD. The PPV of algorithms in the derivation cohort ranged from 57% to 100%, and sensitivity ranged from 0% to 58%. The best performing algorithm in the validation cohort had a PPV of 81% and a sensitivity of 58%. Typical IgG4-RD manifestations were observed in the cohort (n = 36) assembled by this algorithm, including 50% with sialadenitis, 64% with pancreatic disease, 31% with renal disease, and 59% with an elevated IgG4 concentration.We derived and validated a well-performing algorithm to identify IgG4-RD cases with typical manifestations of the disease. The claims-based algorithm can be used in research studies of IgG4-RD.

Objective The objective of this study was to validate the diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as the primary cause of end-stage renal disease (ESRD) in the US Renal Data System (USRDS). Methods We identified patients with ESRD in the Mass General Brigham (MGB) health care system who were enrolled in the USRDS. The health records of those with AAV listed as the primary cause of ESRD in the USRDS were reviewed to confirm the diagnosis and estimate positive predictive value (PPV). Sensitivity was estimated by evaluating the primary cause of ESRD listed in the USRDS for patients with ESRD due to AAV in the MGB AAV cohort. Results We identified 89 MGB patients with ESRD due to AAV in the USRDS. Of these, 85 cases were confirmed to be true cases of AAV (PPV = 94%). Among the patients classified as having AAV, 84 (99%) had an ANCA test, which was predominantly myeloperoxidase/P-ANCA (47 [55%]); 36 (42%) had a renal biopsy, and all biopsies were supportive of the diagnosis. The majority (81 [90%]) was identified as AAV by International Classification of Diseases Ninth Revision or International Classification of Diseases 10th Revision codes for granulomatosis with polyangiitis (446.4 or M313.1). Of the 77 MGB AAV cohort patients with ESRD who were linked to the USRDS, 41 (53%) had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to nonspecific nephritis. Conclusion The diagnosis of AAV as the cause of ESRD in the USRDS has a high PPV; sensitivity was moderate. These findings support the continued use of the USRDS to study ESRD due to AAV.

Background Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) belong to the IgG4-related disease (IgG4-RD) spectrum. Both entities respond to glucocorticoids, but iatrogenic toxicity associated with prolonged steroid therapy and relapse represent relevant clinical concerns in the long-term. Rituximab is increasingly used as an effective alternative strategy to induce remission but data regarding the safety and efficacy of B-cell depletion therapy for pancreato-biliary involvement of IgG4-RD are limited. We performed a systematic review and meta-analysis to estimate the rate of remission, flare, and adverse events (AEs) occurring in pancreato-biliary IgG4-RD following rituximab treatment. Methods The MEDLINE, SCOPUS, and EMBASE databases were searched from inception to December 2020 to identify studies reporting the outcomes of IgG4-related pancreato-biliary disease after treatment with rituximab. Studies involving ≥2 patients were selected. In case of duplicated studies, the most recent or the one with the biggest N were chosen. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effects were calculated using a random-effect model and expressed in terms of pooled remission, relapse, and AEs rates. Results Seven cohort studies met inclusion criteria and 101 patients were included. Reasons for rituximab administration were new disease onset (18.5%), disease flare after glucocorticoids (63.5%), and glucocorticoids intolerance (17.9%). The median follow-up time was 19 months. The pooled rate of complete response at 6 months was 88.9% (95%CI 80.5–93.9) with no heterogeneity (I2 = 0%). The pooled estimate of relapse rate was 21% (95%CI 10.5–40.3) with moderate heterogeneity (I2 = 51%). A higher rate of relapse (35.9%, 95%CI 17.3–60.1) was reported in studies including patients with multiorgan involvement (OOI). The median time to relapse was 10 months. The pooled estimate of rituximab-related AEs was 25% (95%CI 8.8–53) with substantial heterogeneity (I2 = 73.6%). No publication bias was observed. Conclusion Treatment of IgG4-related pancreato-biliary disease with rituximab is associated with high remission rate, a higher relapse rate in the presence of OOI, and limited AEs. Randomized controlled trials with adequate power are needed to confirm these findings.

Giant cell arteritis (GCA) requires treatment with high-dose, long-term glucocorticoids (GCs). A score assessing and quantifying patients' baseline GC-related toxicity may be important to risk stratification and therapeutic decision-making in patients initiating immunosuppression.We analyzed patients with GCA enrolled in the Tocilizumab in Giant Cell Arteritis (GiACTA) trial. Baseline GC-related toxicity scores for 12 domains were derived from the Glucocorticoid Toxicity Index using baseline medications, medical history, vital signs, and laboratory values. The 12 domains examined were body mass index, glucose tolerance, blood pressure, lipid metabolism, bone and/or tendon, GC myopathy, skin toxicity, neuropsychiatric effects, infection, ocular toxicity, gastrointestinal injury, and adrenal function. Potential scores ranged from 0 to 538. We compared differences between those with newly diagnosed versus relapsing disease at baseline.A total of 250 patients were included (75% female, mean age 69 years). The mean ± SD baseline GC-related toxicity score among all patients was 111.3 ± 53.2. The domains that contributed most to the overall scores were blood pressure (24.0% of the overall score), followed by glucose tolerance (22.6%) and neuropsychiatric effects (15.9%). Baseline GC-related toxicity scores were higher in patients with relapsing disease compared with those with newly diagnosed disease (mean of 122.5 vs. 98.9; P 0.001). The body mass index and neuropsychiatric domain scores were significantly higher in patients with relapsing disease.This approach to the assessment of baseline GC-related toxicity distinguished patients with relapsing GCA from those with newly diagnosed disease. Baseline GC-related toxicity scores may be useful in therapeutic decision-making for patients beginning immunosuppressive treatment.

ObjectiveSerum IgG4 concentrations are used to evaluate a diagnosis of IgG4-related disease (IgG4-RD), but the positive predictive value (PPV) of a very high IgG4 level is uncertain. This study evaluated the PPV of a very high IgG4 concentration for diagnosing IgG4-RD.MethodsThe data warehouses of 2 large academic healthcare systems were queried for IgG4 concentration test results. Cases with serum IgG4 concentrations > 5× the upper limit of normal (ULN) were included. Cases of IgG4-RD were determined using the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria. The PPV for IgG4-RD of an IgG4 concentration > 5× ULN was estimated. Other conditions associated with very high IgG4 concentrations and specific features of IgG4-RD cases were characterized.ResultsIgG4 concentrations were available in 32,206 cases. Of these, 3039 (9.4%) had elevated IgG4 concentrations, and a final cohort of 191 (0.6%) cases had IgG4 concentrations > 5× ULN (median age 66 yrs, 72% male). The PPV of an IgG4 concentration > 5× ULN for a diagnosis of IgG4-RD was 75.4% (95% CI 68.7-81.3). In the remaining cases, elevated IgG4 concentrations were observed among patients with malignancies, autoimmune diseases, and infections.ConclusionThe majority of cases with serum IgG4 concentrations > 5× ULN in this study had IgG4-RD. These data support the high weight placed on very high serum IgG4 concentrations in the ACR/EULAR classification criteria. However, 25% of cases with very high IgG4 concentrations had an alternative diagnosis, underscoring the importance of considering the broad differential of etiologies associated with an elevated IgG4 concentration when evaluating a patient.

Sjögren’s syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren’s syndrome were undertaken, including the quantitation of the frequency of selected cell–cell interactions in the disease milieu. Quantitative analyses of CD4+T cell subsets and of CD8+T cells in the labial salivary glands from untreated patients with primary Sjögren’s syndrome revealed that activated CD8+cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren’s syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.

Understanding of the pathophysiology of IgG4-related disease (IgG4-RD) over the last dozen years has opened the door to a variety of targeted treatment approaches. Glucocorticoids are an effective treatment for IgG4-RD if used at a sufficiently high dose, but disease flares are common during or after glucocorticoid tapers and these medications seldom lead to long-term, treatment-free remissions. Moreover, their long-term use in a disease that frequently affects middle-aged to elderly individuals and often causes major pancreatic damage leads to a narrow therapeutic index. Biological therapies offer the possibility of effective disease control with fewer treatment-associated side-effects. Promising avenues of investigation include B cell depletion, immunomodulation of B cell subsets, interference with co-stimulation, BTK inhibition, and SLAMF7-directed treatment.

Autoreactive B cells are responsible for ANCA production in ANCA-associated vasculitis (AAV). Rituximab depletes circulating B cells including autoreactive ones. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.Sequential flow-cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 proteinase-3 (PR3)-ANCAAt B cell recurrence, PR3The composition of autoreactive B cell pool varies significantly following rituximab treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.

Objective To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations. Conclusion This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

Objective To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis. Methods Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions. Conclusion These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.

Objective To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA). Methods We conducted a prospective, open-label trial of UST in patients with active new-onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24-week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone-free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone-free remission definition was performed. Results The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new-onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone-free remission that did not require ESR/CRP level normalization. One serious adverse event occurred. Conclusion UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial.

To study the longitudinal effects of both glucocorticoids (GCs) and tocilizumab, an IL-6 receptor inhibitor, on hemoglobin A1c (HbA1c) during GC tapering.We analyzed patients with complete data from the GiACTA (Tocilizumab in GCA) trial to investigate the impact of both glycemic and non-glycemic factors on changes in HbA1c over the 52-week trial. Patients were randomized to either tocilizumab or placebo in addition to GCs. We used a multivariable mixed-effects model to evaluate associations of HbA1c with daily GC dose, randomization to tocilizumab, and red blood cell count in patients with and without diabetes at baseline over 52 weeks.In 209 patients, the median HbA1c decreased by 0.50% (p0.01) in the tocilizumab/GC group and by 0.10% (p0.01) in the GC-only group. Randomization to tocilizumab/GCs was associated with lower HbA1c (β=-0.209% in those without diabetes, p0.01; β=-0.290% in those with diabetes, p=0.23). These changes had a sizable impact on glucose tolerance classification: 42.5% in the tocilizumab/GC group improved from pre-diabetes status to normal, compared with only 12.5% of patients treated with GC alone. Daily GC dose was associated with HbA1c in patients with (β=0.018%/mg, p0.01) and without baseline diabetes (β=0.005%/mg, p0.01).Tocilizumab treatment was associated with a substantial reduction in HbA1c, independent of GC exposure, which may be achieved through a combination of glycemic and non-glycemic effects.

IgG4-related disease (IgG4-RD) is an increasingly recognized immune-mediated fibroinflammatory disorder that promptly responds to glucocorticoids but commonly relapses during steroid tapering or after discontinuation. In the last few years, B-cell depletion therapy with rituximab (RTX) proved to be effective in the induction of remission and maintenance treatment of IgG4-RD, providing a new powerful tool in the management of this emerging condition. In this review, we outline the pathogenetic rationale for using B-cell depleting agents in IgG4-RD, we summarize available clinical experience with RTX in this disease, and we describe future possible therapies targeting B-lymphocytes that are now in the pipeline.

Sjögren's syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren's syndrome were undertaken, including the quantitation of the frequency of selected cell-cell interactions in the disease milieu. Quantitative analyses of CD4

The randomized, placebo (PBO)-controlled GiACTA trial demonstrated the efficacy and safety of tocilizumab (TCZ) in patients with giant cell arteritis (GCA). The present study evaluated the efficacy of TCZ in patients with GCA presenting with polymyalgia rheumatica (PMR) symptoms only, cranial symptoms only or both PMR and cranial symptoms in the GiACTA trial.In GiACTA, 250 patients with GCA received either TCZ weekly or every other week plus a 26-week prednisone taper or PBO plus a 26- or 52-week prednisone taper. This post hoc analysis assessed baseline characteristics, sustained remission rate, number of flares, annualized flare rate, time to flare, cumulative prednisone dose, methotrexate use and safety in patients with PMR symptoms only, cranial symptoms only or both at baseline.Overall, 52 patients had PMR symptoms only, 94 had cranial symptoms only and 104 had both symptoms at baseline. At Week 52, rates of sustained remission were significantly higher with TCZ vs PBO in all 3 groups (PMR only, 45.2% vs 19.0%, P = 0.0446; cranial only, 60.3% vs 19.4%, P = 0.0001; PMR and cranial, 55.0% vs 11.4%, P 0.0001). Smaller proportions of TCZ-treated patients experienced disease flare than PBO-treated patients across all groups (PMR only, 41.9% vs 57.1%; cranial only, 20.7% vs 47.2%; PMR and cranial, 31.7% vs 81.8%). Annualized flare rate and risk of flare were significantly lower with TCZ vs PBO for patients with cranial symptoms only and both symptoms; they were numerically lower, but did not reach statistical significance, in the smaller group of patients with PMR symptoms only.TCZ improved clinical outcomes in patients who presented with PMR symptoms only, cranial symptoms only or both at baseline, suggesting that TCZ is effective in patients with GCA regardless of the presenting clinical phenotype.

BackgroundIgG4-related disease (IgG4-RD) is an immune-mediated condition that can affect nearly any organ or anatomic site. We sought to describe the epidemiology of IgG4-RD in the USA.MethodsWe used Optum’s deidentified Clinformatics Data Mart Database from 1 January 2009 to 31 December 2021 to identify IgG4-RD cases using a validated algorithm. We estimated the incidence rate and prevalence between 2015 and 2019 (when rates stabilised), standardised to the US population by age and sex. We compared mortality rates among patients with IgG4-RD to the non-IgG4-RD population matched in a 1:10 ratio on age, sex, race/ethnicity and encounter date. We used Cox proportional hazards models to estimate HRs and 95% CIs.ResultsWe identified 524 IgG4-RD cases. The mean age was 56.5 years with 57.6% female and 66% White. The incidence of IgG4-RD increased during the study period from 0.78 to 1.39 per 100 000 person-years in 2015 and 2019, respectively. The point prevalence on 1 Janury 2019 was 5.3/100 000 persons. During follow-up, there were 39 and 164 deaths among 515 IgG4-RD cases and 5160 comparators, resulting in a mortality rate of 3.42 and 1.46/100 person-years, respectively, and adjusted HR of 2.51 (95% CI 1.76 to 3.56).ConclusionsThe incidence of IgG4-RD is similar to that of systemic rheumatic diseases such as ANCA-associated vasculitis and systemic sclerosis but may be increasing as familiarity with this diagnosis grows. Clinicians should be aware of this condition, especially given the excess risk of death. Identification of effective therapies is an important research agenda.