Multimorbidity phenotypes in ankylosing spondylitis and their association with disease activity and functional impairment: Data from the prospective study of outcomes in ankylosing spondylitis cohort.

OBJECTIVES: To examine the association of multimorbidity phenotypes at baseline with disease activity and functional status over time in ankylosing spondylitis (AS). METHODS: Patient-reported AS morbidities (comorbidities, N = 28 and extra-musculoskeletal manifestations, EMMs, N = 3) within 3 years of enrollment with a prevalence ≥1 %, were included from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort. We defined multimorbidity as ≥2 morbidities (MM2+) and substantial multimorbidity as ≥5 morbidities (MM5+). Multimorbidity clusters or phenotypes were identified using K-median clustering. Disease activity (ASDAS-CRP) and functional status (BASFI) measures were collected every 6 months. Generalized estimating equation method was used to examine the associations of multimorbidity counts and multimorbidity clusters with measures of disease activity and functional status over time. RESULTS: Among 1,270 AS patients (9,885 visits) with a median follow-up of 2.9 years (IQ range: 1.0-6.8 years), the prevalence of MM2+ and MM5+ was 49 % and 9 % respectively. We identified five multimorbidity clusters: depression (n = 321, 25 %), hypertension (n = 284, 22 %), uveitis (n = 274, 22 %), no morbidities (n = 238, 19 %), and miscellaneous (n = 153, 12 %). Patients in the depression cluster were more likely to be female and had significantly more morbidities and worse disease activity and functional status compared to those with no morbidities. CONCLUSION: Approximately 49 % of AS patients in the PSOAS cohort had multimorbidity and five distinct multimorbidity phenotypes were identified. In addition to the number of morbidities, the type of morbidity appears to be important to longitudinal outcomes in AS. The depression cluster was associated with worse disease activity and function.

Prevalence and predictors of sustained remission/low disease activity after discontinuation of induction or maintenance treatment with tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic and scoping review.

BACKGROUND: To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor inhibitors (TNFi), separately in induction treatment and maintenance treatment studies, and to identify predictors of successful discontinuation. METHODS: We performed a systematic literature review of studies published from 2005 to May 2022 that reported outcomes after TNFi discontinuation among patients in remission/LDA. We computed prevalences of successful discontinuation by induction or maintenance treatment, remission criterion, and follow-up time. We performed a scoping review of predictors of successful discontinuation. RESULTS: Twenty-two induction-withdrawal studies were identified. In pooled analyses, 58% (95% confidence interval (CI) 45, 70) had DAS28 < 3.2 (9 studies), 52% (95% CI 35, 69) had DAS28 < 2.6 (9 studies), and 40% (95% CI 18, 64) had SDAI ≤ 3.3 (4 studies) at 37-52 weeks after discontinuation. Among patients who continued TNFi, 62 to 85% maintained remission. Twenty-two studies of maintenance treatment discontinuation were also identified. At 37-52 weeks after TNFi discontinuation, 48% (95% CI 38, 59) had DAS28 < 3.2 (10 studies), and 47% (95% CI 33, 62) had DAS28 < 2.6 (6 studies). Heterogeneity among studies was high. Data on predictors in induction-withdrawal studies were limited. In both treatment scenarios, longer duration of RA was most consistently associated with less successful discontinuation. CONCLUSIONS: Approximately one-half of patients with RA remain in remission/LDA for up to 1 year after TNFi discontinuation, with slightly higher proportions in induction-withdrawal settings than with maintenance treatment discontinuation.

Syndesmophyte Growth in Ankylosing Spondylitis: from Laboratory to Bedside.

PURPOSE OF REVIEW: This study aims to review recent studies on risk factors for syndesmophyte growth in ankylosing spondylitis (AS) and on treatment effects. RECENT FINDINGS: New genetic studies, including a genome-wide association study, provided only limited evidence of specific genetic associations with radiographic severity. Measures of inflammation, including vertebral osteitis and C-reactive protein level, were strongly associated with radiographic progression, while studies of adipokines had mixed results. Mesenchymal stem cells from HLA-B27 positive AS patients were found to promote vertebral ossification via a pathway of B27 misfolding, retinoic acid receptor-ß activation, and increased bone alkaline phosphatase. Low vertebral trabecular bone density is associated with syndesmophyte growth, with reciprocal effects when bridged. Several observational studies suggested radiographic severity was reduced by treatment with tumor necrosis factor inhibitors, particularly when longer than 2 years. Syndesmophyte development in AS is the result of a complex, incompletely understood, interplay of inflammatory and mechanical factors.

Risk of Hematologic Malignancies in Elderly Patients With Ankylosing Spondylitis: A Cohort Study and Systematic Review.

OBJECTIVE: To examine the risk of hematologic malignancies in older adults with ankylosing spondylitis (AS). PATIENTS AND METHODS: We used US Medicare data from January 1, 1999, to December 31, 2010, to identify a population-based cohort of beneficiaries with AS. We also included beneficiaries with inflammatory bowel disease (IBD) as disease controls and beneficiaries without AS or IBD as unaffected controls. We excluded those treated with tumor necrosis factor inhibitors in this period. We followed up each group for new diagnosis claims for hematologic malignancies until September 30, 2015. RESULTS: We included 12,451 beneficiaries with AS, 234,905 with IBD, and 10,975,340 unaffected controls, with a mean follow-up of 9.9, 9.3, and 8.0 years, respectively. We identified 297 hematologic malignancies in the AS group, 4538 malignancies in the IBD group, and 128,239 malignancies in unaffected controls. The standardized incidence ratio in AS vs unaffected controls was 1.39 (95% CI, 1.05 to 1.61) for non-Hodgkin lymphoma, 1.50 (95% CI, 1.17 to 1.92) for chronic lymphocytic leukemia, and 1.52 (95% CI, 1.12 to 2.06) for multiple myeloma. Risks of acute myeloid leukemia and chronic myeloid leukemia were not elevated in AS, and there were too few cases of Hodgkin lymphoma to compute risks. Risks were comparable to those of beneficiaries with IBD. We also performed a systematic literature review of the risk of hematologic malignancy in AS, focusing on age associations, which have not been previously examined. We identified 21 studies in the systematic literature review, which included mainly young or middle-aged patients. Results suggested that AS was largely not associated with an increased risk of hematologic malignancies. Two cohort studies reported an increased risk of multiple myeloma in AS. CONCLUSION: The risks of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma are increased among elderly patients with AS.

Why Do Some Patients Have Severe Sacroiliac Disease But No Syndesmophytes in Ankylosing Spondylitis? Data From a Nested Case-Control Study.

OBJECTIVE: Sacroiliac (SI) joint and spinal inflammation are characteristic of ankylosing spondylitis (AS), but some patients with AS have been identified who have discordant radiographic disease. We studied an AS subgroup with long-standing disease and fused SI joints. We identified factors associated with discrepant degrees of radiographic damage between the SI joints and spine. METHODS: From the Prospective Study of Outcomes in AS (PSOAS) cohort, patients with a disease duration ≥ 20 years and fused SI joints were included in a nested case-control design. Patients with and without syndesmophytes were used as cases and controls for analysis. We used classification and regression tree (CART) analysis to determine risk factors for syndesmophytes presence and reexamined the validity of the risk factors using univariable logistic regression models. RESULTS: There were 354 patients in the subgroup, 23 of whom lacked syndesmophytes. CART analysis showed females were less likely to have syndesmophytes. The next important predictor was age of symptom onset in males, with age of onset ≤ 16 years being less likely to have syndesmophytes. Univariable analysis confirmed females were less likely to have syndesmophytes (odds ratio [OR] 0.17, 95% CI 0.07-0.41). Syndesmophyte presence was associated with HLA-B27 positivity (P = 0.03) and age of symptom onset > 16 years old (OR 2.72, 95% CI 1.15-6.45). All 23 patients who lacked syndesmophytes were HLA-B27 positive. CONCLUSION: Using CART analysis and univariable modeling, women were less likely to have syndesmophytes despite advanced disease duration and SI joint disease. Patients with younger age of symptom onset were less likely to have syndesmophytes. All patients without syndesmophytes were HLA-B27 positive, indicating HLA-B27 positivity may be more associated with SI disease than spinal disease.

Predicting Probability of Response to Tumor Necrosis Factor Inhibitors for Individual Patients With Ankylosing Spondylitis.

Importance: Tumor necrosis factor inhibitors (TNFis) have revolutionized the management of ankylosing spondylitis (AS); however, the lack of notable clinical responses in approximately one-half of patients suggests important heterogeneity in treatment response. Identifying patients likely to respond or not respond to TNFis could provide opportunities to personalize treatment strategies. Objective: To develop models of the probability of short-term response to TNFi treatment in individual patients with active AS. Design, Setting, and Participants: This is a retrospective cohort study using data of the TNFi group (ie, treatment group) from 10 randomized clinical trials (RCTs) of TNFi treatment among patients with active AS, conducted from 2002 to 2016. Participants were adult patients with active AS who failed nonsteroidal anti-inflammatory drugs. Included RCTs were phase 3 and 4 studies that assessed the efficacy of an originator TNFi at week 12 and/or week 24, either compared with placebo or an antirheumatic drug. The cohort was divided into a training and a testing set. Data analysis was conducted from July 1, 2019, to November 30, 2020. Exposures: All included patients received an originator TNFi for at least 12 weeks. Main Outcomes and Measures: Outcomes included major response and no response based on the change of AS Disease Activity Score at 12 weeks. Machine learning algorithms were applied to estimate the probability of having major response and no response for individual patients. Results: The study included 1899 participants from 10 trials. The training set included 1207 individuals (mean [SD] age, 39 [12] years; 908 [75.2%] men), of whom 407 (33.7%) had major response and 414 (34.3%) had no response. In the reduced logistic regression models, accuracy was 0.74 for major response and 0.75 for no response. The probability of major response increased with higher C-reactive protein (CRP) level, patient global assessment (PGA), and Bath AS Disease Activity Index (BASDAI) question 2 score and decreased with higher body mass index (BMI) and Bath AS Functional Index (BASFI) score. The probability of no response increased with age and BASFI score, and decreased with higher CRP level, BASDAI question 2 score, and PGA. In the testing set (692 participants; mean [SD] age, 38 [11] years; 533 [77.0%] men), models demonstrated moderate to high accuracy. Conclusions and Relevance: In this cohort study, the probability of initial response to TNFi was predicted from baseline variables, which may facilitate personalized treatment decision-making.

Vertebral Bone Mineral Density, Vertebral Strength, and Syndesmophyte Growth in Ankylosing Spondylitis: The Importance of Bridging.

OBJECTIVE: To examine the relationship between vertebral trabecular bone mineral density (tBMD), vertebral strength, and syndesmophytes in patients with ankylosing spondylitis (AS) using quantitative computed tomography (QCT). METHODS: We performed QCT of the spine to measure syndesmophytes and tBMD in 5 vertebrae (T11-L3) in 61 patients with AS. Finite element analysis was performed to measure vertebral strength in compressive overload, including in trabecular and cortical compartments. In cross-sectional analyses, we examined associations of syndesmophyte height with tBMD and vertebral strength in each vertebra. In 33 patients followed up for 2 years, we investigated whether baseline tBMD and vertebral strength predicted syndesmophyte growth in the same vertebra, and vice versa. RESULTS: In the cross-sectional analyses, 126 vertebrae had bridging, 77 vertebrae had nonbridging syndesmophytes, and 83 vertebrae had no syndesmophytes. There were strong inverse associations between syndesmophyte height and tBMD, total strength, and trabecular strength only among bridged vertebrae. In the longitudinal analysis, nonbridged vertebrae with low tBMD (adjusted ß = -0.01 [95% confidence interval (95% CI) -0.019, -0.0012]) and low strength (adjusted ß = -0.0003 [95% CI -0.0004, -0.0002]) had more syndesmophyte growth over time. Similar associations were absent among bridged vertebrae. Conversely, vertebrae with bridging at baseline had a significant loss in percent tBMD over time (adjusted ß = -0.001 [95% CI -0.0017, -0.0004]). CONCLUSION: Associations between syndesmophytes and vertebral density and strength in AS differ between bridged and nonbridged vertebrae. Among nonbridged vertebrae, low tBMD and strength are associated with syndesmophyte growth. Bridging is associated with large subsequent losses in tBMD, possibly due to mechanical offloading.

EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVE: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion. RESULTS: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering. CONCLUSION: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.

Geographic Differences in Rates of Primary Total Knee Arthroplasty in Young and Older Adults: A Comparison of 3 US States.

OBJECTIVE: Rates of total knee arthroplasty (TKA) among Medicare beneficiaries (adults aged ≥ 65 yrs) vary across the United States, with higher rates in the Midwest and West than in the South. It is not known if a similar variation is present among younger patients, or if findings in Medicare reflect selective postponement of TKA in some regions. METHODS: Data on all primary TKA performed in adults aged ≥ 20 years in 3 states (Iowa, Utah, and Florida) in 2016 were obtained from state inpatient databases. Rates of TKA were computed based on population census data. Age-, sex-, and race-standardized rates were compared between Iowa and Florida, and between Utah and Florida, among adults aged 20-64 years and adults aged ≥ 65 years. RESULTS: There were 10,074, 8954, and 43,908 primary TKAs in Iowa, Utah, and Florida, respectively. Standardized rates were higher in Iowa and Utah than in Florida among both adults aged 20-64 years (Iowa:Florida rate ratio [RR] 1.89, 95% CI 1.79-1.99; Utah:Florida RR 2.31, 95% CI 2.18-2.45) and those aged ≥ 65 years (Iowa:Florida RR 1.41, 95% CI 1.35-1.47; Utah:Florida RR 1.77, 95% CI 1.70-1.85). Results were similar in sensitivity analyses limited to White patients, urban residents, and those with a diagnosis of knee osteoarthritis. CONCLUSION: TKA rates were higher in Iowa and Utah than in Florida among both younger adults and those aged ≥ 65 years, indicating that geographic differences are not specific to elderly patients.

Risk of 30-day Readmission After Knee or Hip Replacement in Rheumatoid Arthritis and Osteoarthritis by Non-Medicare and Medicare Payer Status.

OBJECTIVE: To determine the indication and risk of 30-day rehospitalization after hip or knee replacement among patients with rheumatoid arthritis (RA) and osteoarthritis (OA) by Medicare and non-Medicare status. METHODS: Using the Nationwide Readmission Database (2010-2014), we defined an index hospitalization as an elective hospitalization with a principal procedure of total hip (THR) or knee replacement (TKR) among adults aged ≥ 18 years. Primary payer was categorized as Medicare or non-Medicare. Survey logistic regression provided the odds of 30-day rehospitalization in RA relative to OA. We calculated the rates for principal diagnoses leading to rehospitalization. RESULTS: Overall, 3.53% of 2,190,745 index hospitalization had a 30-day rehospitalization. Patients with RA had a higher adjusted risk of rehospitalization after TKR (OR 1.11, 95% CI 1.02-1.21) and THR (OR 1.39, 95% CI 1.19-1.62). Persons with RA and OA did not differ with respect to rates of infections, cardiac events, or postoperative complications leading to the rehospitalization. After TKR, RA patients with Medicare had a lower venous thromboembolism (VTE) risk (OR 0.58, 95% CI 0.58-0.88), whereas those with RA had a greater VTE risk (OR 2.41, 95% CI 1.04-5.57) after THR. CONCLUSION: Patients with RA had a higher 30-day rehospitalization risk than OA after TKR and THR regardless of payer type. While infections, postoperative complications, and cardiac events did not differ, there was a significant difference in VTE as the principal diagnosis of rehospitalization.

Trends in Permanent Work Disability Associated With Rheumatoid Arthritis in the United States, 1999-2015.

OBJECTIVE: Advances in treatment over the past 20 years have resulted in improved control of rheumatoid arthritis (RA). The objective of our study was to investigate whether there has been a decrease in permanent work disability associated with RA in the US. METHODS: Medicare data from 1999 to 2015 were used to identify beneficiaries age 20-59 years with RA who became eligible for Medicare coverage under Social Security Disability Insurance. Diagnosis of RA was based on physician claims in the first year of enrollment. Annual rates of enrollment were sex- and age-standardized to the 2000 US population. RESULTS: The study included 97,787 beneficiaries with RA and Social Security Disability Insurance across all years. Medicare enrollment was 26.0 per million in 1999 and 26.0 per million in 2015. Rates increased following the Great Recession of 2008-2009 before returning to prerecession levels. There was no linear trend over time after adjusting for the annual national unemployment rate (relative risk 0.99 per year [95% confidence interval 0.99-1.00]; P = 0.69). Risks of work disability were much higher among workers over age 50 years. CONCLUSION: Based on Medicare enrollment by recipients of Social Security Disability Insurance, there was no decrease in permanent work disability among young and middle-age workers with RA in the US between 1999 and 2015.

The Association of Tumor Necrosis Factor Inhibitor Use With Incident Hypertension in Ankylosing Spondylitis: Data From the PSOAS Cohort.

OBJECTIVE: Individuals with ankylosing spondylitis (AS) have a greater cardiovascular (CV) risk than those in the general population. The effect of tumor necrosis factor inhibitors (TNFis) on CV risk, including on the development of hypertension (HTN), remains unclear, with some data suggesting higher risk. We assessed the association of TNFi use with incident HTN in a longitudinal AS cohort. METHODS: Adults with AS enrolled in a prospective cohort in 2002-2018 were examined every 4-6 months. TNFi use during the preceding 6 months was ascertained at each study visit. We defined HTN by patient-reported HTN, antihypertensive medication use, or, on 2 consecutive visits, systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. We evaluated the association between TNFi use and the development of HTN with marginal structural models, estimated by inverse probability-of-treatment weighting, to account for time-dependent confounders and informative censoring. Potential confounders included age, sex, race, site, nonsteroidal antiinflammatory drug use, and disease activity. RESULTS: We included 630 patients without baseline HTN and with at least 1 year of follow-up. Of these, 72% were male, mean age was 39 ± 13 years, and 43% used TNFi at baseline. On follow-up (median 5 yrs), 129 developed incident HTN and 163 started on TNFi during follow-up. TNFi use was not associated with incident HTN (adjusted HR 1.10, 95% CI 0.83-1.37). CONCLUSION: In our prospective AS cohort, TNFi use was not significantly associated with incident HTN.

Estimates of minimal clinically important improvments vary with the responsiveness of the sample.

OBJECTIVE: Minimal clinically important improvements (MCII) are known to vary with the baseline level in the sample. We examined if MCIIs are also larger in samples with higher responsiveness. STUDY DESIGN AND SETTING: In a prospective longitudinal study of patients with active rheumatoid arthritis, we assessed arthritis activity before and after new treatments. We estimated anchor-based MCIIs for three outcomes (pain severity, physical functioning by the Health Assessment Questionnaire, and Simplified Disease Activity Index, a composite measure) using receiver operating characteristic curves. We compared MCIIs among patients treated with three interventions of different impact (dose escalation, new disease-modifying medication, or prednisone). Separately, we used simulations to estimate MCIIs in five groups of responsiveness. RESULTS: Among 250 patients, standardized response means (SRMs) increased across the dose escalation, disease-modifying treatment, and prednisone treatment groups (-0.74, -1.00, and -1.53, respectively). MCIIs were also highest in the prednisone group. For example, corresponding MCIIs were -5.5, -8.9, and -13.8 for the composite measure. In the simulations, MCIIs (range -4.6 to -11.9) varied directly with SRMs (range -0.40 to -1.33). Results were similar for pain and the Health Assessment Questionnaire. CONCLUSION: The MCII is not an intrinsic measurement property but varies directly with sample responsiveness.