The effects of age and frailty on the risks of end-stage renal disease, death, and severe infection in older adults with antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study.

BACKGROUND: Frailty, a measure of biological age, might predict poor outcomes in older adults better than chronological age. We aimed to compare the effect of age and frailty on end-stage renal disease, death, and severe infection within 2 years of diagnosis in older adults with incident antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: This retrospective cohort study included individuals aged 65 years or older from the Mass General Brigham ANCA-associated vasculitis cohort in the USA who were treated between Jan 1, 2002, and Dec 31, 2019. Individuals with a diagnosis of eosinophilic granulomatosis with polyangiitis were excluded from the analysis. Baseline frailty was measured with a claims-based frailty index using data collected in the year before the date of treatment initiation in individuals with at least one health-care encounter before baseline; individuals who did not have an encounter within the 12 months before baseline were classified as pre-frail. Incidence rates of end-stage renal disease or death and severe infections (ie, infections leading to hospital admission or death) at 2 years were estimated, and multivariable analyses were performed to compare the association of age and frailty with these outcomes. Cumulative incidence rates and an additive interaction analysis were used to assess the interaction of age and frailty groupings. FINDINGS: Of the 234 individuals included, 136 (58%) were women, 98 (42%) were men, 198 (85%) were White, and 198 (85%) were positive for myeloperoxidase-specific ANCA. Frailty was present in 25 (22%) of 116 individuals aged 65-74 years and 44 (37%) of 118 aged 75 years or older. In the multivariable analysis, an age of 75 years or older was associated with an increased risk of end-stage renal disease or death (hazard ratio [HR] 4·50 [95% CI 1·83-11·09]), however, frailty was not (1·08 [0·50-2·36]). Both an age of 75 years or older (HR 2·52 [95% CI 1·26-5·04]) and frailty (8·46 [3·95-18·14]) were independent risk factors for severe infections. The effect of frailty on the incidence of end-stage renal disease or death was greater in individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 7·5 cases vs 2·0 cases per 100 person-years) than in those aged 75 years or older (13·5 cases vs 16·0 cases per 100 person-years). The effect of frailty on the incidence of serious infections varied by age, with large differences observed among both individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 38·9 cases vs 0·8 cases per 100 person-years) and individuals aged 75 years or older (61·9 cases vs 12·3 cases per 100 person-years). Despite the observed differences between the age groups, the additive interaction terms were not statistically significant for either frailty and end-stage renal disease or death (p for interaction=0·276) or frailty and serious infections (p for interaction=0·650). INTERPRETATION: Adults with ANCA-associated vasculitis aged 75 years or older had a higher incidence of end-stage renal disease, death, and severe infections within 2 years of diagnosis than adults aged 65-74 years. Frailty, an approximation of biological age, was a risk factor for severe infection. Assessment beyond chronological age could better inform management decisions in older adults with ANCA-associated vasculitis. FUNDING: National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Immune Checkpoint Inhibitor-induced Polymyalgia Rheumatica.

Polymyalgia rheumatica (PMR) immune-related adverse events (ICI-PMRs) represent a novel, distinct entity, despite many clinical, laboratory, and imaging similarities to classical PMR. Important questions remain in differentiating ICI-PMR from classical PMR, as well as other immune-related adverse events and PMR mimics. Despite this, ICI-PMR currently takes treatment cues from classical PMR, albeit with considerations relevant to cancer immunotherapy. Comparisons between ICI-PMR and classical PMR may provide further bidirectional insights, especially given that important questions remain unanswered about both diseases. The cause of classical PMR remains poorly understood, and ICI-PMR may represent a model of induced PMR, with important therapeutic implications.

Incidence of dementia in patients with rheumatoid arthritis and association with disease modifying anti-rheumatic drugs - Analysis of a national claims database.

OBJECTIVE: To evaluate the risk of incident dementia associated with the use of biologics or targeted synthetic DMARDs (b/tsDMARD) compared to conventional synthetic (cs) DMARDS only in patients with rheumatoid arthritis (RA). METHODS: We analyzed claims data from the Center for Medicare & Medicare Services (CMS) from 2006-2017. Patients with RA were identified as adults ≥40 years old and two RA diagnoses by a rheumatologist > 7 and < 365 days apart. Patients with a prior diagnosis of dementia were excluded. Use of cs/b/tsDMARDs was the exposure of interest. Person-time was classified as either: 1) b/tsDMARD exposed, which included tumor necrosis factor alpha inhibitors (TNFi)-bDMARDs, non-TNFi-bDMARDs or tsDMARDs with or without csDMARDs; 2) csDMARD-exposed: any csDMARD without b/tsDMARD. Patients could contribute time to different exposure groups if they changed medications. Incident dementia was defined as: 1 inpatient OR 2 outpatients ICD-9-CM or ICD-10 claims for dementia, OR prescription of a dementia-specific medication (rivastigmine, galantamine, memantine, donepezil, tacrine). Age-adjusted incident rates (IR) were calculated, and univariate and multivariate Cox proportional hazard models were used to calculate Hazard Ratios (HR) and 95% confidence intervals (CI). RESULTS: We identified 141,326 eligible RA patients; 80% female and 75.3% white, median age 67 years and mean (SD) exposure time of 1.1 (1.5) years. There were 233,271 initiations of c/b/tsDMARDS and 3,794 cases of incident dementia during follow up. The crude IR of dementia was 2.0 (95% CI 1.9-2.1) per 100 person-years for patients on csDMARDs and 1.3 (95% CI 1.2-1.4) for patients on any b/tsDMARD. Patients on b/tsDMARDs had an adjusted 19% lower risk for dementia than patients on csDMARDs [HR 0.81 (95% CI 0.76-0.87)]. Subgroup analysis found comparable risk reductions between TNFi, non-TNFi, and tsDMARDs. on the risk of dementia. CONCLUSIONS AND RELEVANCE: The incidence of dementia in patients with RA was lower in patients receiving b/tsDMARDs when compared to patients on csDMARD only. No differences were observed between different classes of b/tsDMARDs, suggesting that decreased risk is possibly explained by the overall decrease in inflammation rather than a specific mechanism of action of these drugs.

Comparing cardiovascular risk of patients with rheumatoid arthritis within the Social Security Disability Insurance with those commercially insured.

OBJECTIVE: To compare cardiovascular disease (CVD) rates in rheumatoid arthritis (RA) beneficiaries of the Social Security Disability Insurance (SSDI) with commercially insured RA patients. METHOD: We created three cohorts of RA patients aged < 65 years for SSDI and three for Marketscan using claims data from 2006 to 2016. The cohort definitions were as follows: (1) cohort 1: ≥ 2 diagnosis codes for RA occurring 7-365 days apart with ≥ 1 diagnosis code from a rheumatologist; (2) cohort 2: ≥ 1 diagnosis code for RA from a rheumatologist and a disease-modifying antirheumatic drugs (DMARDS); and (3) cohort 3: cohort 2, plus initiation of a new biologic/tofacitinib. We used Cox regression to determine the CVD risk comparing SSDI vs. Marketscan. Models were sequentially adjusted for age and sex (model 1); model 1 + diabetes, smoking, and high CVD risk (model 2); and model 2 + dual eligible (Medicare and Medicaid), subsidy, and state buy in (model 3). RESULTS: There were 380,336 RA patients, mean age 53.3 (SD 8.1) years, 21-24% male. Prevalence of comorbidities was higher in SSDI vs. Marketscan. SSDI RA patients in cohort 2 (model 3) had higher CVD risk (HR 1.23 (1.14-1.33). In cohort 3 (model 3), CVD risk was not statistically significantly different between SSDI and Marketscan (HR 0.89 (0.69-1.15). CONCLUSION: RA patient beneficiaries of the SSDI had higher risk for CVD events than those employed. The differences in CVD events between SSDI and Marketscan were partially attributable to differences in CVD risk factors.

Clinical Features of ANCA-Associated Vasculitis in African American Patients in the United States: A Single-Center Medical Records Review Study.

BACKGROUND/PURPOSE: The aim of this study was to compare the clinical features at presentation of ANCA-associated vasculitis (AAV) between African American (AA) and White patients. METHODS: This is a chart review of cases between January 2003 and December 2018. African American patients with AAV were identified and matched in a 1:2 ratio with White comparators based on the year of diagnosis (±4 years). Data on demographics, clinical, and laboratory features and outcomes at presentation were collected. Descriptive statistics were used to compare the characteristics between groups. RESULTS: Thirty-two of 56 AA patients with AAV had complete data and were included for analysis. When compared with 64 matched White patients with AAV, AA patients were younger (47.5 vs 61.0 years, p = 0.001). Compared with White patients, AA patients with granulomatosis with polyangiitis (GPA) (35 vs 55 years, p = 0.0006) and microscopic polyangiitis (MPA) (55.5 vs 65.0 years, p = 0.05) were younger. African American patients with GPA were more frequently female (p = 0.008), whereas AA patients with MPA were more frequently male (p = 0.03). No differences in disease manifestations, disease activity, and outcomes were observed between AA and White patients with AAV. CONCLUSIONS: In this single-center study, AA patients with AAV were diagnosed at a younger age than Whites; this was found in both the GPA and MPA disease phenotypes. No other significant differences were observed. Future studies are needed to confirm our findings and better describe differences of AAV in racial/ethnic minorities.

Prevalence of Frailty in Ankylosing Spondylitis, Psoriatic Arthritis, and Rheumatoid Arthritis: Data from a National Claims Dataset.

OBJECTIVE: Frailty is associated with disability and mortality independent of age. Although studies have evaluated frailty in rheumatoid arthritis (RA), information on the prevalence of frailty in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) is limited. We aimed to determine the prevalence of frailty in AS and PsA and to evaluate whether characteristics known to be associated with frailty, including anxiety, differ among these three types of inflammatory arthritis. METHODS: We performed a cross sectional study of Centers for Medicare & Medicaid Services (CMS) beneficiaries aged 65 years or older with AS, PsA, or RA enrolled in 2014. We operationalized frailty using a validated claims-based frailty index. We also explored the prevalence of frailty among CMS beneficiaries younger than age 65 years with work disability, a younger population that also may be at risk of frailty. RESULTS: The prevalence of frailty in beneficiaries aged 65 years or older with AS and PsA was 45.2% and 46.7%, respectively, significantly lower than in RA (65.9%, P < 0.05). The prevalence of frailty in beneficiaries less than 65 years old was much lower overall, though still highest in RA; 11.7%, 4.4%, and 7.0% in RA, AS, and PsA, respectively (P < 0.05). Anxiety was significantly associated with frailty in subjects of all ages, particularly among those less than 65 years old (P < 0.05). CONCLUSION: Almost half of beneficiaries with AS or PsA aged 65 years old or older were frail, higher than in younger disabled beneficiaries. Further studies are needed to understand the risks of developing frailty in these diseases. Frailty was associated with anxiety, particularly in the younger age groups.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Immediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours: results from an international survey of people with rheumatic diseases.

BACKGROUND: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. METHODS: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. FINDINGS: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). INTERPRETATION: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. FUNDING: American College of Rheumatology.

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial.

OBJECTIVE: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.

Localized Granulomatous with Polyangiitis (GPA): Varied Clinical Presentations and Update on Treatment.

PURPOSE OF REVIEW: Granulomatosis with polyangiitis is a primary systemic vasculitis commonly described with the typical triad of upper airway, lung, and kidney involvement. Upper and lower airway involvement is characteristic in patients with granulomatosis with polyangiitis and can sometimes represent the initial or in some instances the sole manifestation. The objective of this review is to summarize the various clinical manifestations of localized disease in GPA and their treatment. RECENT FINDINGS: Sinonasal disease is seen in up to 90% of patients. Otologic and ocular involvement is also commonly seen. Laryngeal and tracheal disease although less common is associated with significant morbidity and can be therapeutically challenging. Clinicians need to be aware of these localized GPA manifestations as they may be presenting disease features in the absence of other systemic findings. Treatment of localized GPA involves both immunosuppressive and surgical interventions for specific manifestations. Collaboration between specialists including rheumatologists, otolaryngologists, and ophthalmologists is often crucial to ensure optimal outcomes for patients. This is a narrative review that provides a comprehensive overview of localized granulomatosis with polyangiitis and current treatment options.

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.

The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

BACKGROUND: The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP). PURPOSE: To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study. METHODS: SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure≥120 and <160mmHg or diastolic blood pressure≥80 and <100mmHg, and serum urate ≥5.0mg/dL or ≥4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate>60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels. RESULTS: Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama. LIMITATIONS: The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.

Systematic review of tumor necrosis factor inhibitor discontinuation studies in rheumatoid arthritis.

BACKGROUND: Anti-tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at a substantial cost. It has been postulated that discontinuation of these medications among patients with RA in remission or LDA may be possible without an associated increase in RA disease activity. OBJECTIVE: The goal of this systematic literature review was to summarize published articles regarding discontinuation of anti-TNFs in patients with RA. METHODS: A systematic literature review was conducted to identify English-language articles indexed in PubMed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include 1 of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or proportion of patients in LDA or remission at the end of the study. RESULTS: Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) before discontinuation being attempted. Results from larger studies (eg, >100 patients) suggest that the proportion of patients who discontinued anti-TNF and did not have an increase in disease activity ranged from 24% to 81%. In 3 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 17 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage. CONCLUSIONS: Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion criteria and highly variable outcome definitions across studies make it difficult to efficiently summarize the literature on this topic or to conduct a meta-analysis. There is a lack of evidence regarding how to best predict which patients have the greatest likelihood of continuing to do well after discontinuation of anti-TNF therapy.