Crowson, CS

ObjectiveOur objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN).MethodsWe performed a systematic review and meta‐analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy‐proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta‐analysis of proportions, meta‐regression, and subgroup meta‐analysis were performed at 6 and 12 months for all outcomes.ResultsFifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3–31.5), 3.2% (95% CI 2.4–4.0), and 0.2% (95% CI 0.0–0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9–52.3), 12.1% (95% CI 9.3–14.9), and 2.7% (95% CI 0.0–5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose–response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria.ConclusionA higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Objective To evaluate the incidence and outcomes of large artery (LA) involvement among patients with giant cell arteritis (GCA) and to compare LA involvement to non-GCA patients. Methods The study included Olmsted County, Minnesota, USA residents with incident GCA between 1950 and 2016 with follow-up through 31 December 2020, death or migration. A population-based age-matched/sex-matched comparator cohort without GCA was assembled. LA involvement included aortic aneurysm, dissection, stenosis in the aorta or its main branches diagnosed within 1 year prior to GCA or anytime afterwards. Cumulative incidence of LA involvement was estimated; Cox models were used. Results The GCA cohort included 289 patients (77% females, 81% temporal artery biopsy positive), 106 with LA involvement. Reported cumulative incidences of LA involvement in GCA at 15 years were 14.8%, 30.2% and 49.2% for 1950–1974, 1975–1999 and 2000–2016, respectively (HR 3.48, 95% CI 1.67 to 7.27 for 2000–2016 vs 1950–1974). GCA patients had higher risk for LA involvement compared with non-GCA (HR 3.22, 95% CI 1.83 to 5.68 adjusted for age, sex, comorbidities). Thoracic aortic aneurysms were increased in GCA versus non GCA (HR 13.46, 95% CI 1.78 to 101.98) but not abdominal (HR 1.08, 95% CI 0.33 to 3.55). All-cause mortality in GCA patients improved over time (HR 0.62, 95% CI 0.41 to 0.93 in 2000–2016 vs 1950–1974) but remained significantly elevated in those with LA involvement (HR 1.89, 95% CI 1.39 to 2.56). Conclusions LA involvement in GCA has increased over time. Patients with GCA have higher incidences of LA involvement compared with non-GCA including thoracic but not abdominal aneurysms. Mortality is increased in patients with GCA and LA involvement highlighting the need for continued surveillance.

Abstract Objectives To examine multimorbidity in psoriasis and its association with the development of psoriatic arthritis (PsA). Methods A retrospective cohort study was performed using the Rochester Epidemiology Project. Population-based incidence (2000–09) and prevalence (1 January 2010) cohorts of psoriasis were identified by manual chart review. A cohort of individuals without psoriasis (comparators) were identified (1:1 matched on age, sex and county). Morbidities were defined using two or more Clinical Classification Software codes ≥30 days apart within prior 5 years. PsA was defined using ClASsification of Psoriatic ARthritis (CASPAR) criteria. χ2 and rank-sum tests were used to compare morbidities, and age-, sex- and race-adjusted Cox models to examine the association of baseline morbidities in psoriasis with development of PsA. Results Among 817 incident psoriasis patients, the mean age was 45.2 years with 52.0% females, and 82.0% moderate/severe psoriasis. No multimorbidity differences were found between incident psoriasis patients and comparators. However, in the 1088 prevalent psoriasis patients, multimorbidity was significantly more common compared with 1086 comparators (odds ratio 1.35 and 1.48 for two or more and five or more morbidities, respectively). Over a median 13.3-year follow-up, 23 patients (cumulative incidence: 2.9% by 15 years) developed PsA. Multimorbidity (two or more morbidities) was associated with a 3-fold higher risk of developing PsA. Conclusion Multimorbidity was more common in the prevalent but not incident cohort of psoriasis compared with the general population, suggesting that patients with psoriasis may experience accelerated development of multimorbidity. Moreover, multimorbidity at psoriasis onset significantly increased the risk of developing PsA, highlighting the importance of monitoring multimorbid psoriasis patients for the development of PsA.

ObjectiveWhile thrombosis and pregnancy loss are the best‐known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra‐criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL‐positive patients.MethodsLevels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye‐based platelet assay was used to assess the potential impact of calprotectin on aPL‐mediated thrombocytopenia.ResultsCirculating calprotectin was measured in 112 patients with primary APS and 30 aPL‐positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL‐positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C‐reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL‐mediated thrombocytopenia by engaging platelet surface toll‐like receptor 4 and activating the NLRP3‐inflammasome, thereby reducing platelet viability in a caspase‐1‐dependent manner.ConclusionThese data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia.image

Abstract Objectives The objectives of this study were to assess the prevalence and incidence of multimorbidity and its association with the SLICC/ACR damage index (SDI) among patients with SLE. Methods Using prevalent and incident population–based cohorts of patients with SLE and their matched comparators, we assessed 57 chronic conditions. Chronic conditions were categorized as SDI-related or SDI-unrelated. Multimorbidity was defined as the presence of two or more chronic conditions. The prevalence of multimorbidity for both cohorts was compared using logistic regression. Cox models were used to examine the development of multimorbidity after SLE incidence. Results The prevalent cohort included 449 patients with established SLE on 1 January 2015. They were three times more likely to have multimorbidity compared with non-SLE comparators [odds ratio (OR) 2.98, 95% CI 2.18–4.11]. The incident cohort included 270 patients with new-onset SLE. At SLE incidence, patients with SLE were more likely to have multimorbidity than comparators (OR 2.27, 95% CI 1.59–3.27). After incidence, the risk of developing multimorbidity was 2-fold higher among patients with SLE than among comparators [hazard ratio (HR) 2.11, 95% CI 1.59–2.80]. The development of multimorbidity was higher in patients with SLE based on SDI-related conditions (HR 2.91, 95% CI 2.17–3.88) than on SDI-unrelated conditions (HR 1.73, 95% CI, 1.32–2.26). Conclusion Patients with SLE had a higher burden of multimorbidity, even before the onset of the disease. The risk disparity continued after SLE classification and was also seen in a prevalent SLE cohort. Multimorbidity was driven both by SDI-related and unrelated conditions.

Objectives The objective is to examine utilisation of cardiovascular preventive services in patients with rheumatoid arthritis (RA), compared with a non-RA population, and to examine cardiovascular disease (CVD) screening rates among RA patients without diabetes mellitus (DM), hypertension or hyperlipidaemia to non-RA patients with one of these diagnoses. Methods All ≥18-year-old patients with an RA diagnosis living in one of eight Minnesota counties on 1 January 2015 were included and matched (1:1) by sex, age and county to non-RA comparators. Rates of screening for CVD risk factors, including DM (ie, glucose), hypertension (ie, blood pressure) and hyperlipidaemia (ie, lipids), were compared between groups using Cox models. Results The study included 1614 patients with RA and 1599 non-RA comparators. DM screening was more common among patients with RA (HR: 1.10, 95% CI: 1.01 to 1.19), as was hypertension screening (HR: 1.37, 95% CI: 1.24 to 1.52). Hyperlipidaemia screening in RA was similar to comparators (HR: 0.99, 95% CI: 0.89 to 1.10). Conversely, patients with RA and no CVD risk factors had a lower probability of undergoing diabetes (HR: 0.67, 95% CI: 0.57 to 0.78) and hyperlipidaemia screening (HR: 0.65, 95% CI: 0.54 to 0.79) than non-RA patients with only one CVD risk factor diagnosis. Hypertension screening was similar between both groups. Conclusions RA patients undergo CVD preventive screening at rates at least comparable to the general population. However, patients with RA as their sole CVD risk factor were less likely to undergo screenings, despite an equivalent-to-higher risk as the traditional CVD risk factors. These findings demonstrate opportunities for improvement of RA patient care.

Abstract Objectives Active RA has been associated with an increased risk of both cardiovascular and peripheral vascular disease. We aimed to compare cerebrovascular changes in patients with and without RA, both with and without a neuropathologic diagnosis of neurodegenerative disease. Methods Patients with RA (n = 32) who died and underwent autopsy between 1994 and 2021 were matched to non-RA controls (n = 32) on age, sex and level of neurodegenerative proteinopathy. Routine neuropathologic examination was performed at the time of autopsy. Cerebrovascular disease severity was evaluated using modified Kalaria and Strozyk scales. Clinical dementia diagnoses were manually collected from patients’ medical records. Results Prior to death, 15 (47%) RA patients and 14 (44%) controls were diagnosed with dementia; 9 patients in each group (60% and 64%, respectively) had Alzheimer’s disease. The prevalence of cerebral amyloid angiopathy, microinfarcts, infarcts or strokes was found to be similar between groups. Patients with RA were more likely to have more severe vascular changes in the basal ganglia by Kalaria scale (P = 0.04), but not in other brain areas. There were no significant differences in the presence of large infarcts, lacunar infarcts or leukoencephalopathy by Strozyk scale. Among patients with RA and no clinical diagnosis of dementia, the majority had mild–moderate cerebrovascular abnormalities, and a subset of patients had Alzheimer’s disease neuropathologic changes. Conclusion In this small series of autopsies, patients with and without RA had largely similar cerebrovascular pathology when controlling for neurodegenerative proteinopathies, although patients with RA exhibited more pronounced cerebrovascular disease in the basal ganglia.

Abstract Objectives ANCA-associated vasculitis (AAV) is currently categorized under the small vessel vasculitides. There is limited knowledge about large vessel involvement in AAV (L-AAV), mainly described in case reports and small series. L-AAV can involve temporal arteries (TA-AAV), aorta (A-AAV), and periaortic soft tissue (PA-AAV). We sought to characterize the features of patients with L-AAV. Methods Patients older than 18 years at diagnosis of TA-AAV, A-AAV and PA-AAV seen at the Mayo Clinic, Rochester between 1 January 2000 and 31 December 2021 were identified through a proprietary medical text search algorithm. Patients were included if diagnosed with L-AAV, fulfilled 2022 ACR/EULAR classification criteria for GPA, MPA or EGPA, had positive ANCA test results, and had more than one outpatient or inpatient visit. Results The study cohort consists of 36 patients with L-AAV. Of those, 23 had p-ANCA and/or MPO-ANCA, and 13 had c-ANCA and/or PR3-ANCA. Mean (s.d.) age at AAV diagnosis was 63.4 (12.79) years; 20 (56%) were male. Seventeen patients had TA-AAV, 10 had A-AAV and 9 had PA-AAV. Most patients (n = 25, 69%) were diagnosed with large vessel vasculitis and AAV within a 1-year timespan. Twenty-five (69%) patients had histopathological confirmation of AAV diagnosis in a location other than temporal artery, aorta or periaortic soft tissue. Glucocorticoids (36/36), rituximab (19/36) and methotrexate (18/36) were the most frequent treatments. Conclusion This is the largest single-centre cohort of patients with L-AAV to date. AAV can involve large arteries, albeit infrequent. AAV-targeted therapy should be considered in patients with L-AAV.

Abstract Objectives Multimorbidity is burdensome for people with RA. We investigated differences in multimorbidity and comorbidities by sex and age in the RA population. Methods This cross-sectional analysis used national administrative claims (OptumLabs® Data Warehouse) from people with RA and non-RA comparators (matched on age, sex, race, census region, index year and length of baseline insurance coverage) from 2010–2019. RA was determined using a validated algorithm. Multimorbidity was defined as ≥2 (MM2+) or ≥5 (MM5+) comorbidities from a validated set of 44 chronic conditions. We used logistic regression to assess associations between characteristics and multimorbidity. Results The sample included 154 391 RA patients and 154 391 non-RA comparators. For people aged 18–50 years, RA women (vs RA men) had 7.5 and 4.4 (vs 3.2 and 0.9 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. For people aged 51+ years, RA women (vs RA men) had 2.1 and 2.5 (vs 1.2 and 0.3 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. Interactions revealed that differences in multimorbidity between women and men were exacerbated by RA (vs non-RA) (P &lt; 0.05), with more pronounced effects in people aged 18–50. Men had more cardiovascular-related conditions, whereas RA women had more psychological, neurological and general musculoskeletal conditions. Other comorbidities varied by sex and age. Conclusion Multimorbidity disproportionately impacts women with RA. Research, clinical and policy agendas for rheumatic diseases should acknowledge and support the variation in care needs by sex and gender across the lifespan.

Objective There is a paucity of population‐based studies investigating the epidemiology of lupus nephritis (LN) in the US and long‐term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well‐defined 8‐county region in the US. Methods Patients with incident LN between 1976 and 2018 in Olmsted County, Minnesota (1976–2009) and an 8‐county region in southeast Minnesota (2010–2018) were identified. Age‐ and sex‐specific incidence rates and point prevalence over 4 decades, adjusted to the projected 2000 US population, were determined. Standardized mortality ratios (SMRs), survival rates, and time to end‐stage renal disease (ESRD) were estimated. Results There were 72 patients with incident LN between 1976 and 2018, of whom 76% were female and 69% were non‐Hispanic White. Mean ± SD age at diagnosis was 38.4 ± 16.24 years. Average annual LN incidence per 100,000 population between 1976 and 2018 was 1.0 (95% CI 0.8–1.3) and was highest in patients ages 30–39 years. Between the 1976–1989 and 2000–2018 time periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 per 100,000 in 1985 to 21.2 per 100,000 in 2015. Patients with LN had an SMR of 6.33 (95% CI 3.81–9.89), with no improvement in the mortality gap in the last 4 decades. At 10 years, survival was 70%, and 13% of LN patients had ESRD. Conclusion The incidence and prevalence of LN in this area increased in the last 4 decades. LN patients have poor outcomes, with high rates of ESRD and mortality rates 6 times that of the general population.