New molecular targets in the treatment of rheumatoid arthritis.

PURPOSE OF REVIEW: This review will discuss selected emerging molecular targets and associated potential therapeutic agents for rheumatoid arthritis (RA)-directed treatment. RECENT FINDINGS: Agents in active development for RA treatment include those targeted to CD40 and CD40 ligand, programmed death protein 1 (PD-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Several other molecules with a strong theoretical role in RA pathogenesis and/or demonstrated efficacy in other autoimmune diseases are also being evaluated as potential drug targets in preclinical or translational studies in RA. These targets include interleukin 1 receptor associated kinases 1 and 4 (IRAK1, IRAK4), tyrosine kinase 2 (Tyk2), bradykinin receptor 1 (B1R), OX40 and OX40 ligand. SUMMARY: Identification of molecular targets for RA treatment remains an active area of investigation, with multiple therapeutic agents in clinical and preclinical development.

Development of a Machine Learning Model to Predict the Use of Surgery in Patients With Rheumatoid Arthritis.

OBJECTIVE: One in five patients with rheumatoid arthritis (RA) rely on surgery to restore joint function. However, variable response to disease-modifying antirheumatic drugs (DMARDs) complicates surgical planning, and it is difficult to predict which patients may ultimately require surgery. We used machine learning to develop predictive models for the likelihood of undergoing an operation related to RA and which type of operation patients who require surgery undergo. METHODS: We used electronic health record data to train two extreme gradient boosting machine learning models. The first model predicted patients' probabilities of undergoing surgery ≥5 years after their initial clinic visit. The second model predicted whether patients who underwent surgery would undergo a major joint replacement versus a less intensive procedure. Predictors included demographics, comorbidities, and medication data. The primary outcome was model discrimination, measured by area under the receiver operating characteristic curve (AUC). RESULTS: We identified 5,481 patients, of whom 278 (5.1%) underwent surgery. There was no significant difference in the frequency of DMARD or steroid prescriptions between patients who did and did not have surgery, though nonsteroidal anti-inflammatory drug prescriptions were more common among patients who did have surgery (P = 0.03). The model predicting use of surgery had an AUC of 0.90 ± 0.02. The model predicting type of surgery had an AUC of 0.58 ± 0.10. CONCLUSIONS: Predictive models using clinical data have the potential to facilitate identification of patients who may undergo rheumatoid-related surgery, but not what type of procedure they will need. Integrating similar models into practice has the potential to improve surgical planning.

Association between antenatal corticosteroid treatment and severe adverse events in pregnant women.

BACKGROUND: Antenatal corticosteroids are considered the standard of care for pregnant women at risk for preterm birth, but studies examining their potential risks are scarce. We aimed to estimate the associations of antenatal corticosteroids with three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding, in pregnant women. METHODS: Of 2,157,321 pregnant women, 52,119 at 24 weeks 0/7 days to 36 weeks 6/7 days of gestation were included in this self-controlled case series study during the study period of 2009-2018. We estimated incidence rates of three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding. Conditional Poisson regression was used to calculate incidence rate ratios (IRRs) for comparing incidence rates of the adverse events in each post-treatment period compared to those during the baseline period among pregnant women exposed to a single course of antenatal corticosteroid treatment. RESULTS: Among 52,119 eligible participants who received antenatal corticosteroid treatment, the estimated incidence rates per 1000 person-years were 0.76 (95% confidence interval (CI): 0.69-0.83) for sepsis, 0.31 (95% CI: 0.27-0.36) for heart failure, and 11.57 (95% CI: 11.27-11.87) for gastrointestinal bleeding. The IRRs at 5 ~ 60 days after administration of antenatal corticosteroids were 5.91 (95% CI: 3.10-11.30) for sepsis and 4.45 (95% CI: 2.63-7.55) for heart failure, and 1.26 (95% CI: 1.02-1.55) for gastrointestinal bleeding; and the IRRs for days 61 ~ 180 were 2.00 (95% CI: 1.01-3.96) for sepsis, 3.65 (95% CI: 2.14-6.22) for heart failure, and 1.81 (95% CI: 1.56-2.10) for gastrointestinal bleeding. CONCLUSIONS: This nationwide population-based study suggests that a single course of antenatal corticosteroids is significantly associated with a 1.3- to 5.9-fold increased risk of sepsis, heart failure, and gastrointestinal bleeding in pregnant women. Maternal health considerations, including recommendations for adverse event monitoring, should be included in future guidelines for antenatal corticosteroid treatment.

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.

Prevalence and prescribing patterns of oral corticosteroids in the United States, Taiwan, and Denmark, 2009-2018.

Oral corticosteroids (OCS) are commonly prescribed for acute, self-limited conditions, despite studies demonstrating toxicity. Studies evaluating longitudinal OCS prescribing in the general population are scarce and do not compare use across countries. This study investigated and compared OCS prescription patterns from 2009 to 2018 in the general populations of the United States, Taiwan, and Denmark. This international population-based longitudinal cohort study used nationwide claims databases (United States: Optum Clinformatics Data Mart; de-identified; Taiwan: National Health Insurance Research Database; and Denmark: National Prescription and Patient Registries/Danish National Patient Registry) to evaluate OCS prescribing. We classified annual OCS duration as short-term (1-29 days), medium-term (30-89 days), or long-term (≥90 days). Longitudinal change in annual prevalence of OCS use and physician prescribing patterns were reported. Among 54,630,437 participants, average annual percentage of overall OCS use was 6.8% in the United States, 17.5% in Taiwan, and 2.2% in Denmark during 2009-2018. Prevalence of OCS prescribing increased at an average annual rate of 0.1%-0.17%, mainly driven by short-term prescribing to healthy adults. One-quarter to one-fifth of OCS prescribing was associated with a diagnosis of respiratory infection. Family practice and internal medicine physicians were among the highest OCS prescribers across countries and durations. Age- and sex-stratified trends mirrored unstratified trends. This study provides real-world evidence of an ongoing steady increase in OCS use in the general populations of the United States, Taiwan, and Denmark. This increase is largely driven by short-term OCS prescribing to healthy adults, a practice previously viewed as safe but recently shown to incur substantial population-level risk.

Lowering Expectations: Glucocorticoid Tapering Among Veterans With Rheumatoid Arthritis Achieving Low Disease Activity on Stable Biologic Therapy.

OBJECTIVE: In the Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial, 65% of patients with rheumatoid arthritis (RA) in low disease activity (LDA) on stable biologic therapy successfully tapered glucocorticoids. We aimed to evaluate real-world rates of glucocorticoid tapering among similar patients in the Veterans Affairs Rheumatoid Arthritis registry. METHODS: Within a multicenter, prospective RA cohort, we used registry data and linked pharmacy claims from 2003 to 2021 to identify chronic prednisone users achieving LDA after initiating a new biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). We defined the index date as first LDA occurring 60 to 180 days after b/tsDMARD initiation. The primary outcome of successful tapering, assessed at day 180 after LDA, required a 30-day averaged prednisone dose both less than or equal to 5mg/day and at least 50% lower than at the index date. The secondary outcome was discontinuation, defined as a prednisone dose of 0 mg/day at days 180 through 210. We used univariate statistics to compare patient characteristics by fulfillment of the primary outcome. RESULTS: We evaluated 100 b/tsDMARD courses among 95 patients. Fifty-four courses resulted in successful tapering; 33 resulted in discontinuation. Positive rheumatoid factor, higher erythrocyte sedimentation rate, more background DMARDs, shorter time from b/tsDMARD initiation to LDA, and higher glucocorticoid dose 30 days before LDA were associated with greater likelihood of successful tapering. CONCLUSION: In a real-world RA cohort of chronic glucocorticoid users in LDA, half successfully tapered and a third discontinued prednisone within 6 months of initiating a new b/tsDMARD. Claims-based algorithms of glucocorticoid tapering and discontinuation may be useful to evaluate predictors of tapering in administrative data sets.

Characteristics of Facilities With Early and Rapid Ustekinumab Adoption for Patients With Inflammatory Bowel Disease.

INTRODUCTION: To examine which facility characteristics, including teamwork, are associated with early or rapid inflammatory bowel disease-related ustekinumab adoption. METHODS: We examined the association between ustekinumab adoption and the characteristics of 130 Veterans Affairs facilities. RESULTS: Mean ustekinumab adoption increased by 3.9% from 2016 to 2018 and was higher in urban compared with rural facilities (ß = 0.03, P = 0.033) and among facilities with more teamwork (ß = 0.11, P = 0.041). Compared with nonearly adopters, early adopters were more likely be high-volume facilities (46% vs 19%, P = 0.001). DISCUSSION: Facility variation in medication adoption provides an opportunity for improving inflammatory bowel disease care through targeted dissemination strategies to improve medication uptake.

Rheumatic disease patient decision-making about COVID-19 vaccination: a qualitative analysis.

BACKGROUND: Although patients with rheumatic and musculoskeletal diseases (RMDs) are at increased risk for adverse outcomes of COVID-19 illness compared to healthy controls, they also have lower rates of willingness to be vaccinated. Previous research has identified reasons for vaccine hesitancy among patients with RMDs (such as concerns about side effects and flares), but little is known about what these reasons mean in the context of patients' lives, or how vaccine decision making is experienced from a patient perspective. Our objective was to describe decision-making about COVID-19 vaccination among RMD patients. METHODS: Participants in a RMD registry were invited to complete monthly online surveys regarding COVID-19 vaccination from March-June 2021. We qualitatively analyzed comments from two open-ended survey questions reporting general experiences with vaccination and side effects. Comments were coded for attitudes towards COVID-19 vaccination, vaccine access, rheumatologic medication management around vaccination, and vaccine side effects. Themes were identified for the process and context of COVID-19 vaccine decisions, patient motivations for receiving or avoiding vaccination, and consistency of peri-vaccine medication management with current ACR guidelines. RESULTS: We analyzed 710 comments from 537 respondents. Commenting respondents had a mean age of 64 years, were 87% female, 94% white, and 93% received/intended to receive ≥ 1 dose of a COVID-19 vaccine. Desire for protection and a return to normal routines motivated some commenters to get vaccinated, while concerns about vaccine side effects motivated others to delay or avoid vaccination. Several commenters reported disease flares following vaccination. Some commenters did not consult their providers about vaccination and failed to withhold immunomodulatory medications during vaccination, while others withheld medications more conservatively than recommended by current ACR guidelines, either on their own or directed by their provider. CONCLUSIONS: While most commenters were vaccine-accepting, challenges to COVID-19 vaccine uptake in the RMD population may include fears of side effects, including worsened RMD symptoms, and perceptions that vaccination is unnecessary. Addressing these concerns and beliefs may be critical for promoting vaccination in this population.

Correlation of Fibromyalgia Survey Questionnaire and Quantitative Sensory Testing Among Patients With Active Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing associated with high pain sensitization. Pain sensitization is often assessed using quantitative sensory testing (QST), which is burdensome to patients. The self-administered Fibromyalgia Survey Questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of central pain sensitization. We examined the correlation between FSQ and QST in patients with active RA. METHODS: Participants in the Central Pain in Rheumatoid Arthritis (CPIRA) cohort underwent FSQ and QST evaluation at enrollment. QST measures included pressure pain threshold (PPT) at the thumb, trapezius, wrist, and knee; temporal summation (TS) at the wrist and arm; and conditioned pain modulation (CPM). Partial Spearman correlation between FSQ and each QST measure was assessed, adjusted for demographic factors, study site, disease characteristics, and pain catastrophizing. Sensitivity analyses included (1) stratified analysis by sex and (2) evaluation of how each component of FSQ associates with the QST measures. RESULTS: Among 285 participants with active RA, FSQ was weakly but statistically significantly correlated with PPT (r range = -0.31 to -0.21), and TS (r range = 0.13-0.15) at all sites in unadjusted analyses. After adjustment, statistically significant correlations persisted for TS at the wrist and PPT at all sites (except the thumb). Sensitivity analyses did not identify differences in association based on sex or with individual FSQ components. CONCLUSION: FSQ and QST were correlated among participants with active RA, but the strength of association was weak. QST and FSQ are not interchangeable measures of pain sensitization.

Fibromyalgianess and glucocorticoid persistence among patients with rheumatoid arthritis.

OBJECTIVES: Over one-third of patients with RA exhibit evidence of fibromyalgianess, which is associated with higher rates of disability and inadequate responsiveness to RA treatment. Patients with RA often remain on glucocorticoids long-term, despite the known risk of dose-dependent morbidity. We undertook this study to examine the relationship between fibromyalgianess and glucocorticoid persistence among RA patients. METHODS: We followed participants with active RA on oral prednisone for ∼3 months after initiating a new DMARD. Fibromyalgianess was measured using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key FM features often superimposed upon RA. Severity of fibromyalgianess was stratified as follows: FSQ <8 low, FSQ 8-10 moderate and FSQ >10 high/very high. The association between baseline fibromyalgianess and glucocorticoid persistence, defined as prednisone use at 3-month follow-up visit after DMARD initiation, was assessed using multiple logistic regression adjusted for baseline demographics, RA duration, serostatus and inflammatory activity assessed using swollen joint count and CRP. RESULTS: Of the 97 participants on prednisone at baseline, 65% were still taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent glucocorticoid use, compared with 84% of participants with high or very high fibromyalgianess. After adjustment for non-inflammatory factors and inflammatory activity, participants with high/very high baseline fibromyalgianess were more likely to be taking prednisone at follow-up relative to those with low fibromyalgianess [odds ratio 4.99 (95% CI 1.20, 20.73)]. CONCLUSION: High fibromyalgianess is associated with persistent glucocorticoid use, independent of inflammatory activity.

Association of Anti-Tumor Necrosis Factor Therapy With Mortality Among Veterans With Inflammatory Bowel Disease.

Importance: Inflammatory bowel disease (IBD) is commonly treated with corticosteroids and anti-tumor necrosis factor (TNF) drugs; however, medications have well-described adverse effects. Prior work suggests that anti-TNF therapy may reduce all-cause mortality compared with prolonged corticosteroid use among Medicare and Medicaid beneficiaries with IBD. Objective: To examine the association between use of anti-TNF or corticosteroids and all-cause mortality in a national cohort of veterans with IBD. Design, Setting, and Participants: This cohort study used a well-established Veteran's Health Administration cohort of 2997 patients with IBD treated with prolonged corticosteroids (≥3000-mg prednisone equivalent and/or ≥600 mg of budesonide within a 12-month period) and/or new anti-TNF therapy from January 1, 2006, to October 1, 2015. Data were analyzed between July 1, 2019, and December 31, 2020. Exposures: Use of corticosteroids or anti-TNF. Main Outcomes and Measures: The primary end point was all-cause mortality as defined by the Veterans Health Administration vital status file. Marginal structural modeling was used to compare associations between anti-TNF therapy or corticosteroid use and all-cause mortality. Results: A total of 2997 patients (2725 men [90.9%]; mean [SD] age, 50.0 [17.4] years) were included in the final analysis, 1734 (57.9%) with Crohn disease (CD) and 1263 (42.1%) with ulcerative colitis (UC). All-cause mortality was 8.5% (n = 256) over a mean (SD) of 3.9 (2.3) years' follow-up. At cohort entry, 1836 patients were new anti-TNF therapy users, and 1161 were prolonged corticosteroid users. Anti-TNF therapy use was associated with a lower likelihood of mortality for CD (odds ratio [OR], 0.54; 95% CI, 0.31-0.93) but not for UC (OR, 0.33; 95% CI, 0.10-1.10). In a sensitivity analysis adjusting prolonged corticosteroid users to include patients receiving corticosteroids within 90 to 270 days after initiation of anti-TNF therapy, the OR for UC was statistically significant, at 0.33 (95% CI, 0.13-0.84), and the OR for CD was 0.55 (95% CI, 0.33-0.92). Conclusions and Relevance: This study suggests that anti-TNF therapy may be associated with reduced mortality compared with long-term corticosteroid use among veterans with CD, and potentially among those with UC.

Glucocorticoid and opioid use in rheumatoid arthritis management.

PURPOSE OF REVIEW: Glucocorticoids and opioids are longstanding, common treatments for rheumatoid arthritis (RA) symptoms. High-quality clinical trials have established that glucocorticoids improve outcomes in RA, but debate continues as to whether their benefits outweigh their risks. We reviewed recent studies on patterns of glucocorticoid and opioid prescribing in RA, and associated harms. RECENT FINDINGS: At present, a large proportion of RA patients remain on glucocorticoids and/or opioids long-term. Likelihood and risk of both glucocorticoid and opioid exposure vary across the population, and are influenced by provider factors. Opioids are also associated with delays in disease-modifying treatment initiation. Recent evidence increasingly demonstrates toxicity associated with even low-dose glucocorticoids (≤7.5 mg/day). Up to two-thirds of RA patients may be able to discontinue chronic low-dose glucocorticoids without flare or adrenal insufficiency. These new data have led to changes in clinical practice guidelines for glucocorticoid use in RA. SUMMARY: Although low-dose and short-term glucocorticoid use is extremely common and effective in RA management, increasing evidence of toxicity has led experts to begin recommending that such exposure be minimized. Despite a lack of data to suggest opioids improve RA disease activity, they are used commonly, continued long-term, and associated with delayed effective therapy.

Association of Continuity of Care With Outcomes in US Veterans With Inflammatory Bowel Disease.

Importance: Health care fragmentation is associated with inefficiency and worse outcomes. Continuity of care (COC) models were developed to address fragmentation. Objective: To examine COC and selected outcomes in US veterans with inflammatory bowel disease (IBD). Design, Setting, and Participants: This retrospective cohort study used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify veterans with IBD who received care in the VHA health care system between January 1, 2002, and December 31, 2014. Included patients were veterans with IBD who had a primary care physician and at least 4 outpatient visits with key physicians (gastroenterologist, primary care physician, and surgeon) within the first year after an index IBD encounter. Data were analyzed from November 2018 to May 2020. Exposures: Care continuity was measured with the Bice-Boxerman COC index to define care density and dispersion within year 1 after the initial presentation. Main Outcomes and Measures: A Cox proportional hazards regression model was used to quantify the association between a low level of COC in year 1 (defined as ≤0.25 on a 0 to 1 scale) and subsequent IBD-related outcomes in years 2 and 3 (outpatient flare, hospitalization, and surgical intervention). Results: Among the 20 079 veterans with IBD who met the inclusion criteria, 18 632 were men (92.8%) and the median (interquartile range [IQR]) age was 59 (48-66) years. In the first year of follow-up, substantial variation in the dispersion of care was observed (median [IQR] COC, 0.24 [0.13-0.46]). In a Cox proportional hazards regression model, a low level of COC was associated with a higher likelihood of outpatient flares that required corticosteroids (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.01-1.22), hospitalizations (aHR, 1.25; 95% CI, 1.06-1.47), and surgical interventions (aHR, 1.72; 95% CI, 1.43-2.07). Conclusions and Relevance: Results of this cohort study showed a wide variation in dispersion of IBD care and an association between a lower level of COC and active IBD and worse outcomes. The findings suggest that investigating the barriers to COC in integrated systems that have invested in care coordination is key to not only better understanding COC but also identifying opportunities to improve care fragmentation.

Mapping the relationships between inflammatory bowel disease and comorbid diagnoses to identify disease associations.

BACKGROUND: Massive amounts of patient data are captured daily in electronic medical records (EMR). Utilizing the power of such large data may help identify disease associations and generate hypotheses that can lead to a better understanding of disease associations and mechanisms. We aimed to comprehensively identify and validate associations between inflammatory bowel disease (IBD) and concurrent comorbid diagnoses. METHODS: We performed a cross-sectional study using EMR data collected between 1986 and 2009 at a large tertiary referral center to identify associations with a diagnosis of IBD. The resulting associations were externally validated using the Truven MarketScan database, a large nationwide dataset of private insurance claims. RESULTS: A total of 6225 IBD patients and 31 125 non-IBD controls identified using EMR data were used to abstract 41 comorbid diagnoses associated with an IBD diagnosis. The strongest associations included Clostridiodes difficile infection, pyoderma gangrenosum, parametritis, pernicious anemia, erythema nodosum, and cytomegalovirus infection. Two IBD association clusters were found, including diagnoses of nerve conduction abnormalities and nonspecific inflammatory conditions of organs outside the gut. These associations were validated in a national cohort of 80 907 patients with IBD and 404 535 age- and sex-matched controls. CONCLUSION: We leveraged a big data approach to identify several associations between IBD and concurrent comorbid diagnoses. EMR and big data provide the opportunity to explore disease associations with large sample sizes. Further studies are warranted to refine the characterization of these associations and evaluate their usefulness for increasing our understanding of disease associations and mechanisms.

Patterns of glucocorticoid prescribing and provider-level variation in a commercially insured incident rheumatoid arthritis population: A retrospective cohort study.

OBJECTIVE: Glucocorticoids are common in RA management despite an unfavorable, exposure-dependent risk profile impacted by patient and provider-level factors. Existing work describing glucocorticoid use in RA is not generalizable and does not adequately examine provider factors. We aim to describe how providers prescribe glucocorticoids to commercially insured, newly diagnosed RA patients in the United States. METHODS: This was a retrospective cohort study which used the national Optum© administrative database. We identified 9221 adults ages 18-65 with RA diagnosed 2010-2014. We assessed glucocorticoid dispensing 3 months pre-diagnosis through 12months post-diagnosis ("study period"), cumulatively stratified by calendar quarter and prescriber specialty (rheumatologist, primary care, other). We examined prescribing variation among individual rheumatologists by dividing quarterly distribution of per-patient dose and days' supply into quartiles. RESULTS: 6717 (72.8%) patients filled ≥1 glucocorticoid prescription during the study period. 2890 (31.3%) patients received ≥3 months' supply, with median (IQR) daily dose 10 (6.6) mg/day and days' supply 189 (143) days. 52.6% of patients received glucocorticoids 1-3 months post-diagnosis; 29.2% received glucocorticoids 10-12 months post-diagnosis. Among glucocorticoid users post-diagnosis, quarterly median daily dose and days' supply were consistently ≥10 mg/day and ≥30 days, respectively. Rheumatologists prescribed most glucocorticoids, with median per-quarter daily dose and days' supply 10 mg/day and 43-60 days. Individual rheumatologists' prescribing varied widely across all quarters. CONCLUSION: Among commercially insured incident RA patients, receipt of ≥10 mg/day prednisone equivalent for months is common, typically prescribed by rheumatologists, and persists a year post-diagnosis in 29.2% of patients. Glucocorticoid prescribing varies widely across rheumatologists. Further work is warranted to identify provider factors explaining variation in glucocorticoid prescribing, and assess how these affect health outcomes.

Anti-tumour necrosis factor-α therapy and recurrent or new primary cancers in patients with inflammatory bowel disease, rheumatoid arthritis, or psoriasis and previous cancer in Denmark: a nationwide, population-based cohort study.

BACKGROUND: Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy. METHODS: In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration. FINDINGS: Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11). INTERPRETATION: Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications. FUNDING: None.