Teaming up to overcome challenges toward translation of new therapeutics for osteoarthritis.

As a leading global cause of musculoskeletal-related disability, osteoarthritis (OA) represents a public health urgency. Understanding of disease pathogenesis has advanced substantially in the past decade, yet no disease-modifying therapeutics have advanced to the clinic. To address this challenge, the CARE-AP (Cartilage Repair strategies to alleviate Arthritis Pain) collaborative research team was convened to bring together relevant multidisciplinary expertise and perspectives from across the VA research community nationwide. The first CARE-AP Annual Research Symposium took place (virtually) in February 2022 with roughly 90 participants. A number of innovative and therapeutic strategies were discussed, including siRNA approaches coupled with novel nanoparticle-based delivery systems, cellular engineering approaches to develop reparative cells that can probe the joint environment and respond to disease-specific cues, and novel biofabrication techniques to improve tissue engineering and effect "biological joint replacement." In addition, challenges and advances in rehabilitation approaches, imaging outcomes, and clinical studies were presented, which were integrated into a framework of recommendations for running "preclinical trials" to improve successful clinical translation.

The Risk of Lung Cancer in Rheumatoid Arthritis and Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: To evaluate lung cancer risk in rheumatoid arthritis (RA) and RA-interstitial lung disease (ILD). METHODS: We performed a retrospective, matched cohort study of RA and RA-ILD within the Veterans Health Administration (VA) between 2000-2019. RA and RA-ILD patients were identified with validated administrative-based algorithms then matched (up to 1:10) on age, gender, and VA enrollment year to individuals without RA. Lung cancers were identified from a VA oncology database and the National Death Index. Conditional Cox regression models assessed lung cancer risk adjusting for race, ethnicity, smoking status, Agent Orange exposure, and comorbidity burden among matched individuals. Several sensitivity analyses were performed. RESULTS: We matched 72,795 RA to 633,937 non-RA persons (mean age 63 years; 88% male). Over 4,481,323 patient-years, 17,099 incident lung cancers occurred. RA was independently associated with an increased lung cancer risk (aHR 1.58 [1.52, 1.64]), which persisted in never-smokers (aHR 1.65 [1.22, 2.24]) and incident RA (aHR 1.54 [1.44, 1.65]). Compared to non-RA controls, prevalent RA-ILD (n=757) was more strongly associated with lung cancer risk (aHR 3.25 [2.13, 4.95]) than RA without ILD (aHR 1.57 (1.51, 1.64]). Analyses of both prevalent and incident RA-ILD produced similar results (RA-ILD vs. non-RA aHR 2.88 [2.45, 3.40]). CONCLUSION: RA was associated with a >50% increased risk of lung cancer, and RA-ILD represented a particularly high-risk group with an approximate 3-fold increased risk. Increased lung cancer surveillance in RA, and especially RA-ILD, may be a useful strategy for reducing the burden posed by the leading cause of cancer death.

Association of Cardiovascular Outcomes With Low-Dose Glucocorticoid Prescription in Patients With Rheumatoid Arthritis.

OBJECTIVE: Many guidelines recommend limiting glucocorticoids in patients with rheumatoid arthritis (RA), but 40% of patients remain on glucocorticoids long term. We evaluated the cardiovascular risk of long-term glucocorticoid prescription by studying patients on stable disease-modifying antirheumatic drugs (DMARDs). METHODS: Using two claims databases, we identified patients with RA on stable DMARD therapy for >180 days. Proportional hazards models with inverse-probability weights and clustering to account for multiple observations were used to estimate the effect of glucocorticoid dose on composite cardiovascular outcomes (stroke or myocardial infarction [MI]). RESULTS: There were 135,583 patients in Medicare and 39,272 in Optum's de-identified Clinformatics Data Mart (CDM) database. Medicare and CDM patients had an incidence of 1.3 and 0.8 composite cardiovascular outcomes per 100 person-years, respectively. In the older, comorbid Medicare cohort, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes in adjusted models with predicted one-year incidence of 1.4% (95% confidence interval [CI] 1.2%-1.6%) for ≤5 mg, 1.6% (95% CI 1.4%-1.9%) for >5 to 10 mg, and 1.8% (95% CI 1.2%-2.5%) for >10 mg versus 1.1% (95% CI 1.1%-1.2%) among patients not receiving glucocorticoids. There was no significant association among the CDM cohort. However, in the subgroup of younger patients with RA and higher cardiovascular risk, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes. CONCLUSION: Among older patients with more comorbidities and younger patients with higher cardiovascular risk with RA on stable DMARD therapy, glucocorticoids were associated with a dose-dependent increased risk of MI and stroke, even at doses ≤5 mg/day. By contrast, no association was noted among younger, healthier patients with RA.

Antibodies to Malondialdehyde-Acetaldehyde Adduct Are Associated With Prevalent and Incident Rheumatoid Arthritis-Associated Interstitial Lung Disease in US Veterans.

OBJECTIVE: The objective of this study is to determine the associations of protein-specific anti-malondialdehyde-acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: Within a multicenter, prospective cohort of US veterans with RA, RA-ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA-albumin, MAA-collagen, MAA-fibrinogen, and MAA-vimentin (IgA, IgM, and IgG) were measured by a standardized enzyme-linked immunosorbent assay. Associations of anti-MAA antibodies with prevalent and incident RA-ILD were assessed using multivariable regression models adjusting for established RA-ILD risk factors. RESULTS: Among 2,739 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA-ILD (average time to diagnosis: 6.6 years). Higher IgM anti-MAA-collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02-1.61), IgA anti-MAA-fibrinogen (aOR 1.48, 95% CI 1.14-1.92), and IgA (aOR 1.78, 95% CI 1.34-2.37) and IgG (aOR 1.48, 95% CI 1.14-1.92) anti-MAA-vimentin antibodies were associated with prevalent RA-ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11-1.76) and IgM (aHR 1.29, 95% CI 1.04-1.60) anti-MAA-albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16-3.90) or IgM (aHR 1.98, 95% CI 1.08-3.64) anti-MAA-albumin antibody concentrations in the highest quartile had an approximately two-fold increased risk of incident RA-ILD. Across all isotypes, anti-MAA-fibrinogen, anti-MAA-collagen, and anti-MAA-vimentin antibodies were not significantly associated with incident RA-ILD. CONCLUSION: Protein-specific anti-MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA-ILD. IgA and IgM anti-MAA-albumin antibodies were associated with a higher risk of incident RA-ILD. These findings suggest that MAA modifications and resultant immune responses may contribute to RA-ILD pathogenesis.

Prevalence of Cardiovascular and Cancer Risk Factors Among Rheumatoid Arthritis Patients Prescribed Janus Kinase Inhibitors and Tumor Necrosis Factor Inhibitors: A Cross-Sectional Study.

OBJECTIVE: The study was to determine the prevalence of baseline risk factors for cardiovascular outcomes and cancer among commercially-insured patients with rheumatoid arthritis (RA) during their first dispensed treatment for either tumor necrosis factor inhibitors (TNFi) or JAK inhibitors (JAKi). METHODS: Patients with RA from August 16, 2019 to March 31, 2022 were identified in the Merative MarketScan Commercial and Medicare databases. The first date that a TNFi or JAKi was dispensed was the index date, and baseline risk factors were assessed among patients continuously eligible for 12 months before the index date. Patients who had the following were stratified into an elevated risk category: age ≥65 years, smoking, or a history of a major adverse cardiovascular event, venous thromboembolism, or cancer. The prevalence of modifiable risk factors was also reported: hypertension, hyperlipidemia, obesity, and diabetes. The crude prevalence and prevalence difference (PD) were reported. RESULTS: A total of 12,673 patients (TNFi [n = 7,748; 61%] and JAKi [n = 4,925; 39%]) met inclusion criteria. The prevalence of elevated risk was the same for all patients using TNFi (n = 2,051; 26%) and JAKi (n = 1,262; 26%). Compared with patients having low risk, patients with an elevated risk also had a higher prevalence of at least one primary modifiable risk factor for both patients using JAKi (79% vs 58%; PD 21%, 95% confidence interval [CI] 18%-24%) and TNFi (81% vs 60%; PD 21%, 95% CI 19%-23%). CONCLUSION: In recent years, JAKi and TNFi were used in similar proportions to treat RA among commercially-insured patients at elevated cardiovascular and cancer risk. Because uncontrolled disease, modifiable comorbidities, and treatment with JAKi are associated with these adverse events, future studies evaluating how practice patterns may be affected by the emergence of safety data will be of value.

Characteristics and 6-Month Outcomes in Patients with Rheumatoid Arthritis Initiating Infliximab Biosimilar IFX-dyyb in a Real-World Setting.

INTRODUCTION: Real-world studies describing biosimilar initiation or switching in patients with rheumatoid arthritis (RA) are limited. The aim of this study was to assess treatment patterns and effectiveness of real-world patients with RA initiating infliximab biosimilar IFX-dyyb (CT-P13; Inflectra®) in the USA. METHODS: This observational study evaluated patients with RA from the CorEvitas RA Registry who initiated IFX-dyyb and had Clinical Disease Activity Index (CDAI) recorded at baseline and 6 months. The primary outcome was reaching low disease activity (LDA; CDAI ≤ 10) at 6 months in patients with moderate or high disease activity (CDAI > 10) at baseline. Secondary outcomes were change at 6 months in CDAI and certain patient-reported outcomes (PROs). Patient data were stratified by prior treatment: biologic/targeted synthetic disease-modifying antirheumatic drug (tsDMARD)-naïve, reference infliximab (IFX-REF) or IFX biosimilar, or a non-IFX biologic or tsDMARD. RESULTS: Of 318 patients initiating IFX-dyyb, 176 had baseline and 6-month CDAI scores; 73 (41%) switched from IFX, 61 (35%) switched from another non-IFX/biologic/tsDMARD, 32 (18%) were naïve to biologics/tsDMARDs, and 10 (6%) switched from an IFX biosimilar. Among patients with moderate or high disease activity at baseline, 32.9% (95% CI 22.9, 42.9) achieved LDA at 6 months. Mean 6-month change from baseline in CDAI was - 1.8 (95% CI - 3.3, - 0.3) overall; - 4.7 (- 7.6, - 1.7) in patients who switched from a non-IFX biologic/tsDMARD, - 4.1 (- 7.8, - 0.3) in biologic/tsDMARD-naïve patients, and 1.1 (- 0.4, 2.6) in patients who switched from IFX-REF/IFX biosimilar. Other clinical outcomes/PROs improved at 6 months. Of the IFX-dyyb initiators, 68% remained on IFX-dyyb at 6 months. CONCLUSION: In this real-world population of patients with RA initiating IFX-dyyb, the majority switched from IFX-REF or a non-IFX biologic/tsDMARD. CDAI remained stable in patients switching from IFX-REF/IFX biosimilar and improved in patients switching from a non-IFX biologic/tsDMARD and in biologic/tsDMARD-naïve patients.

Infliximab is an effective treatment for rheumatoid arthritis (RA). Biosimilars­biologic drugs designed to be very similar to the originator products­are now available that may be more affordable with matching efficacy and safety. IFX-dyyb is a US Food and Drug Administration-approved infliximab biosimilar but little is known about its use in real-world clinical practice in patients with RA in the USA. This study used data from a large observational registry to look at treatment patterns and effectiveness of IFX-dyyb in adults with RA. One hundred and seventy-six patients were included who had data available at both baseline and at 6 months. Most patients (47%) switched to IFX-dyyb from the originator infliximab or another infliximab biosimilar; 35% switched from another RA treatment, and 18% were new to treatment. Six months after starting IFX-dyyb, 68% of patients were still receiving treatment. A measure of clinical disease activity remained stable in patients who switched from originator infliximab or another biosimilar, while this measure improved in patients switching to IFX-dyyb from other treatments or starting treatment for the first time. Other clinical measures and patient-reported outcomes such as pain and fatigue also improved over 6 months with IFX-dyyb. This real-world study of patients with RA initiating IFX-dyyb in the USA adds to our knowledge of the use of biosimilars in this patient population.

Real-World Use and Effectiveness Outcomes in Patients with Rheumatoid Arthritis Treated with Upadacitinib: An Analysis from the CorEvitas Registry.

INTRODUCTION: Data assessing longer-term real-world effectiveness and treatment patterns with upadacitinib (UPA), a Janus kinase inhibitor, in rheumatoid arthritis (RA) are lacking. We assessed improvement in clinical and patient-reported outcomes and treatment patterns for up to 12 months among adult patients with RA initiating UPA. METHODS: Data were collected from the CorEvitas® RA Registry (08/2019-04/2022). Eligible patients had moderate to severe RA (Clinical Disease Activity Index [CDAI] > 10) and follow-up visits at 6 or 12 months after UPA initiation. Outcomes were mean change from baseline, percentage achieving minimal clinically important differences (MCID) in clinical and patient-reported outcomes, and disease activity at follow-up. We evaluated clinical outcomes and therapy changes among patients with tumor necrosis factor inhibitor (TNFi) experience and among those receiving UPA as first-line therapy, as well as those receiving UPA as monotherapy versus as part of combination therapy. We further evaluated whether outcomes were similar among those that remained on therapy. RESULTS: Patients treated with UPA (6-month cohort, N = 469; 12-month cohort, N = 263) had statistically significant improvements (p < 0.001) in mean CDAI, tender/swollen joint counts, pain, and fatigue at follow-up. At 12 months, 46.0% achieved MCID in CDAI and 40.0% achieved low disease activity/remission. Overall, 43.0% discontinued UPA at 12 months; of those receiving combination treatment (N = 90) with conventional therapies and UPA, 42.2% (N = 38) discontinued conventional therapy. Findings were similar in the 6-month cohort and among subgroups. Changes from baseline and proportions of patients achieving MCID or clinical outcomes tended to be numerically lower among patients with TNFi experience and numerically higher among those receiving UPA as first-line therapy. CONCLUSIONS: UPA initiation was associated with improvements in clinical and patient-reported outcomes, with meaningful clinical improvements regardless of prior TNFi experience, line of therapy, or concomitant use of conventional therapies. Further research is needed to better understand sustained response of UPA over longer treatment periods.

Combined Orbital and Cranial Vessel Wall Magnetic Resonance Imaging for the Assessment of Disease Activity in Giant Cell Arteritis.

OBJECTIVE: Acute visual impairment is the most feared complication of giant cell arteritis (GCA) but is challenging to predict. Magnetic resonance imaging (MRI) evaluates orbital pathology not visualized by an ophthalmologic examination. This study combined orbital and cranial vessel wall MRI to assess both orbital and cranial disease activity in patients with GCA, including patients without visual symptoms. METHODS: Patients with suspected active GCA who underwent orbital and cranial vessel wall MRI were included. In 14 patients, repeat imaging over 12 months assessed sensitivity to change. Clinical diagnosis of ocular or nonocular GCA was determined by a rheumatologist and/or ophthalmologist. A radiologist masked to clinical data scored MRI enhancement of structures. RESULTS: Sixty-four patients with suspected GCA were included: 25 (39%) received a clinical diagnosis of GCA, including 12 (19%) with ocular GCA. Orbital MRI enhancement was observed in 83% of patients with ocular GCA, 38% of patients with nonocular GCA, and 5% of patients with non-GCA. MRI had strong diagnostic performance for both any GCA and ocular GCA. Combining MRI with a funduscopic examination reached 100% sensitivity for ocular GCA. MRI enhancement significantly decreased after treatment (P < 0.01). CONCLUSION: In GCA, MRI is a sensitive tool that comprehensively evaluates multiple cranial structures, including the orbits, which are the most concerning site of pathology. Orbital enhancement in patients without visual symptoms suggests that MRI may detect at-risk subclinical ocular disease in GCA. MRI scores decreased following treatment, suggesting scores reflect inflammation. Future studies are needed to determine if MRI can identify patients at low risk for blindness who may receive less glucocorticoid therapy.

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

OBJECTIVE: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). METHODS: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors. RESULTS: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005). CONCLUSION: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Associations between Adiponectin and the Development of Diabetes in Rheumatoid Arthritis.

PURPOSE: We evaluated associations between adiponectin and the risk of diabetes among patients with rheumatoid arthritis (RA), a systemic inflammatory disease associated with metabolic disturbance. METHODS: This prospective cohort study included adults with RA from the Veteran's Affairs Rheumatoid Arthritis Registry. Adiponectin and inflammatory cytokines/chemokines were measured at enrollment on stored serum samples. Adiponectin levels were categorized and clinical variables were described across categories (<10 µg/mL; 10-40 µg/mL; > 40 µg/mL. Multivariable Cox proportional hazard models evaluated associations between adiponectin and incident diabetes adjusting for age, sex, race, smoking status, body mass index (BMI), disease-modifying therapy use, calendar year, and comorbidity. Testing for modification of effect in the context of elevated cytokines/chemokines was performed. RESULTS: Among 2595 patients included in the analysis, those with adiponectin levels >40 µg/mL (N = 379; 15%) were older and had lower BMI. There were 125 new cases of diabetes among 1,689 patients without prevalent disease at enrollment. There was an inverse association between adiponectin and incident diabetes, however, the association was positive among patients with adiponectin levels >40 µg/mL. Patients with levels >40 µg/mL were at higher risk compared to those with levels 10-40 µg/mL [HR: 1.70 (1.34,2.16) p < 0.001]. Those with adiponectin levels >40 µg/mL had significantly higher levels of inflammatory cytokines with evidence of a modified effect of adiponectin on diabetes risk in the setting of inflammation. CONCLUSIONS: The relationship between adiponectin and incident diabetes risk is U-shaped in RA. Patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk.

Development and Internal Validation of a Clinical and Genetic Risk Score for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. METHODS: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). RESULTS: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. CONCLUSION: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Changes in Characteristics of Patients Initiating and Discontinuing Advanced Therapies for Rheumatoid Arthritis Following the Release of Safety Data.

OBJECTIVE: The objective of this study was to determine the impact of emerging safety data on practice patterns by describing the characteristics of patients initiating and discontinuing advanced therapies for rheumatoid arthritis (RA) before and after January 2021. METHODS: This cohort study evaluated US veterans with RA between April 2019 and September 2022. This period was divided into two 664-day periods before and after January 2021. Eligible patients had ≥1 diagnosis code for RA and initiated a tumor necrosis factor inhibitor (TNFi), non-TNFi biologic, or JAK inhibitor (JAKi). We tested for interaction within regression models to determine whether changes in patient characteristics for tofacitinib recipients were different from changes observed for other therapies. We also evaluated factors associated with therapy discontinuation in Cox models adjusted for age, sex, and duration on therapy, including assessment for effect modification. RESULTS: When comparing patients with RA initiating tofacitinib before (n = 2,111) with those initiating tofacitinib after (n = 1,664) January 2021, there was a decrease in mean age (64.1 vs 63.0 years) and in the proportion with cardiovascular comorbidities (all P < 0.01). These changes were significantly different from those observed for patients initiating TNFi or non-TNFi biologics. Among active advanced therapy recipients, the likelihood of discontinuation was higher for tofacitinib than TNFi (hazard ratio 1.18, 95% confidence interval 1.10-1.26, P < 0.001). The higher rate of tofacitinib discontinuation was more pronounced in the presence of cardiovascular comorbidities (P < 0.05). CONCLUSION: Recent safety data significantly affected prescribing practices for advanced therapies, with a reduction in JAKi initiation and an increase in JAKi discontinuation among older patients and those at high cardiovascular risk.

Extracting forced vital capacity from the electronic health record through natural language processing in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE: To develop a natural language processing (NLP) tool to extract forced vital capacity (FVC) values from electronic health record (EHR) notes in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: We selected RA-ILD patients (n = 7485) in the Veterans Health Administration (VA) between 2000 and 2020 using validated ICD-9/10 codes. We identified numeric values in proximity to FVC string patterns from clinical notes in the EHR. Subsequently, we performed processing steps to account for variability in note structure, related pulmonary function test (PFT) output, and values copied across notes, then assigned dates from linked administrative procedure records. NLP-derived FVC values were compared to values recorded directly from PFT equipment available on a subset of patients. RESULTS: We identified 5911 FVC values (n = 1844 patients) from PFT equipment and 15 383 values (n = 4982 patients) by NLP. Among 2610 date-matched FVC values from NLP and PFT equipment, 95.8% of values were within 5% predicted. The mean (SD) difference was 0.09% (5.9), and values strongly correlated (r = 0.94, p < 0.001), with a precision of 0.87 (95% CI 0.86, 0.88). NLP captured more patients with longitudinal FVC values (n = 3069 vs. n = 1164). Mean (SD) change in FVC %-predicted per year was similar between sources (-1.5 [30.0] NLP vs. -0.9 [16.6] PFT equipment; standardized response mean = 0.05 for both). CONCLUSIONS: NLP of EHR notes increases the capture of accurate, longitudinal FVC values by three-fold over PFT equipment. Use of this NLP tool can facilitate pharmacoepidemiologic research in RA-ILD and other lung diseases by capturing this critical measure of disease severity.

Frailty and Risk of Serious Infections in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted-Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted-synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. METHODS: Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients' baseline frailty risk score was calculated using a Claims-Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time-to-any infection and all-cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. RESULTS: A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non-TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2-1.9) and 40% higher risk of inpatient admissions (1.4 [1.3-1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1-1.3]) or non-TNFi (1.2 [1.0-1.4]) or JAKi (1.4 [1.0-2.0]). CONCLUSION: Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted-synthetic DMARDs.

H. Ralph Schumacher.

Dr Schumacher was a force in rheumatology for more than half a century through his multiple roles as a researcher, clinician, mentor, and educator. He is not likely to be soon forgotten by the rheumatology community; however, it is hoped that this chapter can provide a faithful recollection that will help bring his memory to life for some and that rings true to those who knew him and learned from him.

2023 American College of Rheumatology and American Association of Hip and Knee Surgeons Clinical Practice Guideline for the Optimal Timing of Elective Hip or Knee Arthroplasty for Patients With Symptomatic Moderate-to-Severe Osteoarthritis or Advanced Symptomatic Osteonecrosis With Secondary Arthritis for Whom Nonoperative Therapy Is Ineffective.

OBJECTIVE: To develop evidence-based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient-important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA). METHODS: We developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations. RESULTS: The panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality. CONCLUSION: This guideline provides evidence-based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient-important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.

Serum alarmins and the risk of incident interstitial lung disease in rheumatoid arthritis.

OBJECTIVES: To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: Using serum collected at enrolment, three alarmins (interleukin [IL]-33, thymic stromal lymphopoietin [TSLP], and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score, and anti-cyclic citrullinated antibody positivity. RESULTS: Of 2,835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (HR 0.73 per log-fold increase; 95% CI 0.57-0.95; p= 0.018) and adjusted (HR 0.77; 95% CI 0.59-1.00, p= 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. CONCLUSIONS: In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA.

2023 American College of Rheumatology and American Association of Hip and Knee Surgeons Clinical Practice Guideline for the Optimal Timing of Elective Hip or Knee Arthroplasty for Patients With Symptomatic Moderate-to-Severe Osteoarthritis or Advanced Symptomatic Osteonecrosis With Secondary Arthritis for Whom Nonoperative Therapy Is Ineffective.

OBJECTIVE: To develop evidence-based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient-important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA). METHODS: We developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations. RESULTS: The panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality. CONCLUSION: This guideline provides evidence-based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient-important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.