Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper.

BACKGROUND: More than half of patients with polymyalgia rheumatica have a relapse during tapering of glucocorticoid therapy. Previous studies have suggested that interleukin-6 blockade may be clinically useful in the treatment of polymyalgia rheumatica. Sarilumab, a human monoclonal antibody, binds interleukin-6 receptor α and efficiently blocks the interleukin-6 pathway. METHODS: In this phase 3 trial, we randomly assigned patients in a 1:1 ratio to receive 52 weeks of a twice-monthly subcutaneous injection of either sarilumab (at a dose of 200 mg) plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. The primary outcome at 52 weeks was sustained remission, which was defined as the resolution of signs and symptoms of polymyalgia rheumatica by week 12 and sustained normalization of the C-reactive protein level, absence of disease flare, and adherence to the prednisone taper from weeks 12 through 52. RESULTS: A total of 118 patients underwent randomization (60 to receive sarilumab and 58 to receive placebo). At week 52, sustained remission occurred in 28% (17 of 60 patients) in the sarilumab group and in 10% (6 of 58 patients) in the placebo group (difference, 18 percentage points; 95% confidence interval, 4 to 32; P = 0.02). The median cumulative glucocorticoid dose at 52 weeks was significantly lower in the sarilumab group than in the placebo group (777 mg vs. 2044 mg; P<0.001). The most common adverse events with sarilumab as compared with placebo were neutropenia (15% vs. 0%), arthralgia (15% vs. 5%), and diarrhea (12% vs. 2%). More treatment-related discontinuations were observed in the sarilumab group than in the placebo group (12% vs. 7%). CONCLUSIONS: Sarilumab showed significant efficacy in achieving sustained remission and reducing the cumulative glucocorticoid dose in patients with a relapse of polymyalgia rheumatica during glucocorticoid tapering. (Funded by Sanofi and Regeneron Pharmaceuticals; SAPHYR ClinicalTrials.gov number, NCT03600818.).

Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism.

BACKGROUND: The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes. METHODS: DNA variant calling for SNP rs351111 (chr.19:844020, c.355G>A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab in ANCA-Associated Vasculitis trial. This was followed by RNA-seq variant calling to characterise the mRNA expression. We compared clinical outcomes between patients homozygous for PRTN3-Ile119 or PRTN3-Val119. RESULTS: Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val119Ile and 13 homozygous for PRTN3-Ile119. RNA-seq was available for 89 patients and mRNA corresponding to the allelic variant was found in 32 patients with PR3-AAV: 25 heterozygous PRTN3-Val119Ile and 7 homozygous for PRTN3-Ile119. The agreement between the DNA calling results and mRNA expression of the 86 patients analysed by both methods was 100%. We compared the clinical outcomes of 64 patients with PR3-AAV: 51 homozygous for PRTN3-Val119 and 13 homozygous for PRTN3-Ile119. The frequency of severe flares at 18 months in homozygous PRTN3-Ile119 was significantly higher when compared with homozygous PRTN3-Val119 (46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile119 as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030). CONCLUSION: In patients with PR3-AAV, homozygosity for PRTN3-Val119Ile polymorphism appears associated with higher frequency of severe relapse. Further studies are necessary to better understand the association of this observation with the risk of severe relapse.

Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3.

OBJECTIVE: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3-targeting ANCAs (PR3-ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. METHODS: The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen for differential PR3-ANCA binding. A patient-derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation-free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. RESULTS: Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared to 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. CONCLUSION: The preferential binding of PR3-ANCAs from patients, such as 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 MCPR2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches.

Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA-associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV. METHODS: Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)-ANCA-positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long-term follow-up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3-specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/µl after RTX treatment. RESULTS: At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05). CONCLUSION: The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.

Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.

Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

Mental Health Care Use and Associated Factors in Systemic Sclerosis: A Scleroderma Patient-Centered Intervention Network Cohort Study.

OBJECTIVE: Systemic sclerosis (SSc) has significant psychosocial implications. We aimed to evaluate the proportion of participants in a large international SSc cohort who used mental health services in a 3-month period and to evaluate demographic, psychological, and disease-specific factors associated with use. METHODS: Baseline data of participants enrolled in the Scleroderma Patient-Centered Intervention Network Cohort were analyzed. We determined the proportion that used mental health services and the source of services in the 3 months prior to enrollment. Multivariable logistic regression was used to identify variables associated with service use. RESULTS: Of the 2319 participants included in the analysis, 417 (18%) used mental health services in the 3 months prior to enrollment. General practitioners were the most common mental health service providers (59%), followed by psychologists (25%) and psychiatrists (19%). In multivariable analysis, mental health service use was independently associated with higher education (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.03-1.11), smoking (OR 1.06, 95% CI 1.02-1.11), being retired (OR 0.60, 95% CI 0.38-0.93), having limited SSc (OR 1.39, 95% CI 1.02-1.89), and having higher anxiety symptom scores (OR 1.04, 95% CI 1.03-1.06) and lower self-efficacy scores (OR 0.90, 95% CI 0.83-0.97). Variables not significantly associated included age, race, disease manifestations, depression symptom scores, and body image distress. CONCLUSION: About 18% of participants in a large international cohort received mental health services in a 3-month period, of whom the majority received these services from a general practitioner.

Rho Kinase Expression in Giant Cell Arteritis: Validating Phosphorylated Ezrin/Radixin/Moesin Intensity Score to Increase Sensitivity of Temporal Artery Biopsy.

OBJECTIVE: Aberrant Rho-associated protein kinase (ROCK) activity is implicated in several vascular and immunologic disorders. We previously demonstrated increased ROCK activity in histopathologically negative temporal artery biopsies (TABs) in subjects with clinical giant cell arteritis (GCA) compared to those without GCA. This current study aimed to examine ROCK activity in a larger cohort of biopsy-negative GCA subjects and to validate the prior findings. METHODS: Based on clinical data 6 months after TAB, subjects were categorized into 2 groups: biopsy-negative GCA and controls without GCA. Paraffin-embedded TABs were stained for phosphorylated ezrin/radixin/ moesin (pERM), a surrogate of ROCK activity, and scored by 2 pathologists blinded to clinical diagnosis using a previously derived scoring system measuring staining intensity in 3 areas of the vessel. RESULTS: Thirty-six subjects with biopsy-negative GCA and 43 controls were analyzed. The mean (SD) pERM intensity score in non-GCA subjects was 3.9 (1.4), compared to 5.0 (1.4) in those with GCA (P = 0.002). Using the predetermined cut-off of 4 to define high pERM intensity, subjects with GCA were significantly more likely to have a high pERM intensity score compared to non-GCA (odds ratio 3.67, 95% CI 1.19-11.36; P = 0.02. The sensitivity of high pERM intensity score for diagnosis of GCA in histologically negative TABs was 86% (95% CI 70-95). CONCLUSION: In this well-characterized cohort, those with biopsy-negative GCA had significantly higher pERM intensity scores compared to subjects without GCA. pERM staining has diagnostic significance in enhancing the sensitivity of TAB and may help to define the clinically important group of biopsy-negative GCA.

Prevalence of frailty in patients with polymyalgia rheumatica and association with health-related quality of life, cognition and sarcopenia.

OBJECTIVE: To describe the prevalence of frailty in a single-centre cohort of patients with PMR and describe its association with health-related quality of life (HRQoL), cognition and sarcopenia. METHODS: This was a cross-sectional study of patients with PMR, according to 2012 EULAR/ACR Classification Criteria, presenting within 12 months of diagnosis and on treatment with glucocorticoids. Frailty was defined according to the Fried frailty criteria. HRQoL was assessed using Patient-Reported Outcomes Measurement Information System Computerized Adaptive Test (PROMIS-CAT) and cognition was assessed using the Mini-Mental State Examination. Sarcopenia was measured by DXA. RESULTS: Forty-one patients were enrolled. Prevalence of frailty and pre-frailty was 17% and 59%, respectively. Frail patients had higher inflammatory markers at diagnosis compared with pre-frail and robust patients. Of 27 patients with DXA results, 26% were sarcopenic. Frail patients had worse physical function, and more pain behaviour and interference compared with pre-frail and robust patients. In univariable analyses, frail patients were more likely to have worse physical function, and more pain behaviour and pain interference, which remained significant after adjusting for age. There were no significant associations between cognition or sarcopenia and frailty. CONCLUSIONS: In this cohort of PMR patients, there was a higher prevalence of frailty and pre-frailty compared with that reported in community-dwelling elderly. Frailty was associated with worse physical function, and increased pain behaviour and pain interference, differences that were also clinically meaningful. Larger prospective studies are needed to confirm these findings and analyse the association of frailty with other PMR disease outcomes.

Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis.

BACKGROUNDLittle is known about the autoreactive B cells in antineutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3-reactive (PR3+) B cells.METHODSMulticolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets).RESULTSThe frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%-6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%-5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%-2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001).CONCLUSIONThis study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells.Trial registrationClinicalTrials.gov NCT00104299.FundingThe Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.

Clinical Manifestations and Long-Term Outcomes of Eosinophilic Granulomatosis With Polyangiitis in North America.

OBJECTIVE: To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. METHODS: Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. RESULTS: The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow-up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow-up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow-up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow-up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. CONCLUSION: This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long-term remission to limit the accrual of disease-related damage.

Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-Associated Vasculitis.

Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.

Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: This study aimed to evaluate the safety of avacopan, an orally administered C5a receptor inhibitor, for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in addition to standard-of-care (SOC) treatment with glucocorticoids with cyclophosphamide or rituximab. METHODS: In this randomized 12-week study, twice daily avacopan (10 mg or 30 mg) plus SOC was assessed versus SOC only in patients with newly diagnosed/relapsing ANCA-associated vasculitis. Efficacy measurements included 50% or greater reduction in Birmingham Vasculitis Activity Score (BVAS) at day 85, rapid reduction (day 29) of BVAS to a score of 0 that was sustained through day 85, change in Vasculitis Damage Index (VDI), renal response (improvement in estimated glomerular filtration rate [eGFR], hematuria, and albuminuria), and health-related quality of life (HRQoL). RESULTS: Forty-two patients were randomized (n = 13 SOC, n = 13 avacopan 10 mg, and n = 16 avacopan 30 mg). Serious adverse events occurred in 15% and 17% of patients receiving SOC only and patients receiving avacopan with SOC, respectively. In the intent-to-treat population, BVAS response was high across arms (11 of 13 SOC, 11 of 12 avacopan 10 mg, and 12 of 15 avacopan 30 mg); increases in mean VDI were greater with SOC only than with avacopan plus SOC (0.3 versus 0.1). Avacopan 30 mg was numerically superior to placebo and avacopan 10 mg in early remission (15%, 8%, and 20% for SOC only, avacopan 10 mg, and avacopan 30 mg, respectively), improved eGFR (+2.0 ml/min/1.73m2 , +1.3 ml/min/1.73m2 , and +6.2 ml/min/1.73m2 , respectively), renal response (17%, 40%, and 63%, respectively), and measures of HRQoL. CONCLUSION: Avacopan in addition to SOC for ANCA-associated vasculitis was well tolerated, and at the higher study dose, it appeared to improve time to remission (ClinicalTrials.gov identifier NCT02222155).

The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes. METHODS: sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases. RESULTS: At baseline, sIL6 levels were detectable in 81% of patients; 73% (n = 57) of subjects were proteinase 3 (PR3)-ANCA positive, sIL-6 levels were higher in subjects with PR3-ANCAs and positively correlated with their levels (rs = 0.36,p < 0.01), but not with levels of myeloperoxidase (MPO)-ANCA (rs = -0.17,p = 0.47). Higher baseline sIL-6 levels were associated with PR3-ANCA positivity, fever, pulmonary nodules/cavities, conductive deafness, and absence of urinary red blood cell casts (p < 0.05). Baseline sIL6 levels did not predict CR at month 6 (p = 0.71), and the median sIL-6 level declined from baseline with induction therapy, regardless of CR achievement. An increase in sIL-6 during CR was a predictor for subsequent severe relapse in RTX-treated patients (hazard ratio (HR):7.24,p = 0.01), but not in CYC/AZA-treated patients (HR:0.62,p = 0.50). In contrast, a sIL-6 increase did not predict B cell repopulation or ANCA titer increase in either treatment arm (p > 0.05). CONCLUSION: At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Is There Still a Role for Cyclophosphamide?

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic necrotizing vasculitides that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Treatment of these conditions has improved during the past 2 decades with better understanding of these conditions and availability of newer agents. Cyclophosphamide (CYC) was the first drug demonstrated to afford successful treatment and improvement in AAV. With the emergence of newer agents with more favorable safety profiles, CYC is no longer the cornerstone of management of AAV. This article reviews existing data for treatment and the current role of CYC in the management of AAV.

Physical or Occupational Therapy Use in Systemic Sclerosis: A Scleroderma Patient-centered Intervention Network Cohort Study.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by significant disability because of musculoskeletal involvement. Physical and occupational therapy (PT/OT) have been suggested to improve function. However, the rate of PT/OT use has been shown to be low in SSc. We aimed to identify demographic, medical, and psychological variables associated with PT/OT use in SSc. METHODS: Participants were patients with SSc enrolled in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort. We determined the rate and indication of PT/OT use in the 3 months prior to enrollment. Multivariable logistic regression was used to identify variables independently associated with PT/OT use. RESULTS: Of the 1627 patients with SSc included in the analysis, 23% used PT/OT in the preceding 3 months. PT/OT use was independently associated with higher education (OR 1.08, 95% CI 1.04-1.12), having moderately severe small joint contractures (OR 2.09, 95% CI 1.45-3.03), severe large joint contractures (OR 2.33, 95% CI 1.14-4.74), fewer digital ulcerations (OR 0.70, 95% CI 0.51-0.95), and higher disability (OR 1.54, 95% CI 1.18-2.02) and pain scores (OR 1.04, 95% CI 1.02-1.06). The highest rate of PT/OT use was reported in France (43%) and the lowest, in the United States (17%). CONCLUSION: Despite the potential of PT/OT interventions to improve function, < 1 in 4 patients with SSc enrolled in a large international cohort used PT/OT services in the last 3 months. Patients who used PT/OT had more severe musculoskeletal manifestations and higher pain and disability.

Arterial lesions in giant cell arteritis: A longitudinal study.

OBJECTIVES: To evaluate large-vessel (LV) abnormalities on serial imaging in patients with giant cell arteritis (GCA) and discern predictors of new lesions. METHODS: Clinical and imaging data from patients with GCA (including subjects diagnosed by LV imaging) enrolled in a prospective, multicenter, longitudinal study and/or a randomized clinical trial were included. New arterial lesions were defined as a lesion in a previously unaffected artery. RESULTS: The study included 187 patients with GCA, 146 (78%) female, mean (±SD) age at diagnosis 68.5 ± 8.5 years; 39% diagnosed by LV imaging. At least one arterial lesion was present in 123 (66%) on the first study. The most frequently affected arteries were subclavian (42%), axillary (32%), and thoracic aorta (20%). In 106 patients (57%) with serial imaging, new arterial lesions were noted in 41 patients (39%), all of whom had a baseline abnormality, over a mean (±SD) follow-up of 4.39 (2.22) years. New abnormalities were observed in 33% patients by year 2; clinical features of active disease were present at only 50% of these cases. There were no differences in age, sex, temporal artery biopsy positivity, or disease activity in patients with or without new lesions. CONCLUSIONS: In this cohort of patients with GCA, LV abnormalities on first imaging were common. Development of new arterial lesions occurred in patients with arterial abnormalities at first imaging, often in the absence of symptoms of active disease. Arterial imaging should be considered in all patients with GCA at diagnosis and serial imaging at least in patients with baseline abnormalities.

Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8.

Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients.

Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial.

OBJECTIVE: To assess the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF). METHODS: In this 52-week, investigator-initiated, single-center, double-blind, placebo-controlled, pilot study, 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo. We assessed safety, efficacy, and differential gene expression. RESULTS: In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) (P = 0.039). In the placebo group, the median MRSS decreased from 28 (IQR 22, 28) to 21 (IQR 14, 25) (P = 0.023). The median change in MRSS was -10 (IQR -13, -9) in the belimumab group and -3.0 (IQR -15, -1) in the placebo group (P = 0.411). There were no significant differences between the groups in the number of adverse events (AEs). A significant decrease in expression of B cell signaling and profibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group. CONCLUSION: Patients in both treatment groups experienced significant improvements in MRSS. The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study. AEs were similar between the groups. Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab is associated with a significant decrease in profibrotic genes and pathways. Additional studies are needed to determine the role of belimumab in the treatment of dcSSc.