Mikuls, Ted R.

Objective Individuals with serum elevations of anti–cyclic citrullinated peptide (anti‐CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such at‐risk individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence. Methods In this phase 2 randomized trial, individuals at risk for RA with anti‐CCP3 ≥2 times the upper limit of normal (ULN) were assigned to receive HCQ or placebo for 12 months, with up to 24 months of postdrug follow‐up. The primary outcome was the development of clinical RA, as defined in the protocol, at 36 months. Secondary outcomes included safety, development of inflammatory arthritis (IA), and participant‐reported joint symptoms. Results Of 144 randomized participants, 71 were assigned to HCQ and 73 to placebo. In the modified intent‐to‐treat population, clinical RA occurred in 21 of 69 (30.4%) participants in the HCQ group and 24 of 73 (32.9%) in the placebo group. The risk of clinical RA at 36 months was 0.336 with HCQ and 0.394 with placebo (difference −0.058; 95% confidence interval −0.336 to 0.220; P = 0.52). Results for IA were similar. The occurrence and severity of joint symptoms were not observed to differ between groups. Adverse event incidence was similar between groups. Conclusion In this trial involving individuals with anti‐CCP3 levels ≥2 times the ULN, 12 months of HCQ did not prevent the development of clinical RA at 36 months. image

Objective The aim of this study was to determine whether pollutants such as fire smoke–related particulate matter <2.5 μm (PM 2.5 ) are associated with incident rheumatoid arthritis (RA) and RA‐associated interstitial lung disease (RA‐ILD). Methods This patient–control study used Veterans Affairs (VA) data from October 1, 2009, to December 31, 2018. We identified patients with incident RA and RA‐ILD using validated algorithms, matching each patient to ≤10 controls on age, sex, and VA enrollment year. We obtained pollutants including fire smoke PM 2.5 , carbon monoxide, nitrogen oxides (NOx), ozone, overall PM 2.5 , PM 10 , and sulfur dioxide (SO 2 ) at least one year before the index date. We fit conditional logistic regression models to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for incident RA and RA‐ILD, adjusted for confounders. Results We identified 9,701 patients with incident RA (mean age 65 years, 86% male), including 531 patients with RA‐ILD (mean age 69 years, 91% male), and 68,852 matched controls. Fire smoke PM 2.5 was not associated with RA (aOR 1.07, 95% CI 0.92–1.23) but was associated with RA‐ILD (aOR 1.98, 95% CI 1.08–3.62, per 1 μg/m 3 ). Increased levels of NOx were associated with RA (aOR 1.16, 95% CI 1.06–1.27, highest vs lowest quartile). The highest quartiles of ozone (aOR 1.19, 95% CI 1.06–1.34) and PM 10 (aOR 1.25, 95% CI 1.10–1.43) were associated with seronegative RA. Carbon monoxide, overall PM 2.5 , and SO 2 were not, or negatively, associated with RA and RA‐ILD. Conclusion Increased fire smoke PM 2.5 was associated with RA‐ILD, whereas NOx, ozone, and PM 10 were associated with RA risk. Thus, air pollution may increase the risk of RA and RA‐ILD. image

ObjectiveWe aimed to evaluate lung cancer risk in patients with rheumatoid arthritis (RA) and RA‐interstitial lung disease (ILD).MethodsWe performed a retrospective, matched cohort study of RA and RA‐ILD within the Veterans Health Administration (VA) between 2000 and 2019. Patients with RA and RA‐ILD 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.ResultsWe matched 72,795 patients with RA with 633,937 patients without RA (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 (adjusted hazard ratio [aHR] 1.58 [95% confidence interval (CI) 1.52–1.64]), which persisted in never smokers (aHR 1.65 [95% CI 1.22–2.24]) and in those with incident RA (aHR 1.54 [95% CI 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 [95% CI 2.13–4.95]) than RA without ILD (aHR 1.57 [95% CI 1.51–1.64]). Analyses of both prevalent and incident RA‐ILD produced similar results (RA‐ILD vs non‐RA aHR 2.88 [95% CI 2.45–3.40]).ConclusionRA was associated with a >50% increased risk of lung cancer, and those with RA‐ILD represented a particularly high‐risk group with an approximate three‐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.

Objectives Compare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in Oral Rheumatoid Arthritis Trial (ORAL) Surveillance. Methods Patients with RA aged ≥50 years and with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. MACE (non-fatal myocardial infarction (MI), non-fatal stroke or CV death (MACE-3)) was extended by sequential addition of CV events (hospitalisation for unstable angina (MACE-4), coronary revascularisation (MACE-5), transient ischaemic attack (MACE-6), peripheral vascular disease (MACE-7)), heart failure (HF) hospitalisation (MACE-8) and venous thromboembolism (VTE; (MACE-8 plus VTE)). HRs (tofacitinib vs TNFi) were evaluated for MACE and individual components. Results HRs for MACE-4 to MACE-8 with combined and individual tofacitinib doses versus TNFi were similar. Risk of MACE-8 plus VTE appeared similar with tofacitinib 5 mg two times per day versus TNFi (HR 1.12 (0.82 to 1.52)), but higher with tofacitinib 10 mg two times per day versus TNFi (HR 1.38 (1.02 to 1.85)). Risk of MI was higher with tofacitinib versus TNFi, but difference in risk of other individual CV events was not suggested. Across extended MACE definitions, risk appeared higher with tofacitinib versus TNFi in those with atherosclerotic CV disease or age ≥65 years. Conclusion In ORAL Surveillance, risk of composite CV endpoints combining all ischaemic CV events and HF did not appear different with tofacitinib versus TNFi. The totality of CV risk was higher with tofacitinib 10 mg two times per day versus TNFi, driven by an increase in VTE. Trial registration number NCT02092467.

Objective The ORAL Surveillance trial found a dose‐dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. Methods Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient‐years) by 6‐month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. Results Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6‐month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m 2 , older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. Conclusion Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Background: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). Objectives: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). Design: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. Methods: In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Results: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2–9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. Conclusion: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. Registration: NCT02092467.

Abstract PURPOSE: Rheumatoid arthritis (RA) has been associated with an increased risk of non-Hodgkin’s lymphoma (NHL). We describe the characteristics of NHL patients with antecedent RA. METHODS: Records of the Nebraska Lymphoma Study Group (NLSG) registry between 1982–2004 and the Mayo Clinic lymphoma registry between 1988–1998 were systematically reviewed for RA diagnosis and classified by the quality of supporting evidence. We abstracted available follow-up data through July 1, 2004. Definite cases had either a documented RA diagnosis from a trained rheumatologist or met 4 of 7 American College of Rheumatology criteria. Probable RA cases had a non-rheumatologist diagnosis of RA in addition to one of the following: 1) radiographic joint erosions; 2) disease-modifying anti-rheumatic drug (DMARD) use or; 3) RA-associated deformities (i.e., ulnar drift, swan-neck deformities). Five-year overall survival (OAS), event-free survival (EFS), and rates of treatment response were determined. RESULTS: We identified 74 RA cases (54 definite and 20 probable) with concomitant NHL. These patients had a mean age of 67 + 8 years and were predominantly Caucasian (82%) and female (64%). Of the probable RA cases, a majority had documented DMARD use (n=17). Approximately half of the cases used methotrexate (55%) and were deceased (52%) by the common closing date. The most common NHL subtypes included B-DLCL (n=31), B-FL-1/B-FL-2 (n=12), B-FL-3 (n=6), and B-BL/B-BLL (n=4). Of the remaining 21 cases, most were of B-cell origin (n=13) and included B-EMZL (n=3), B-LPL (n=3), B-UCL (n=2), B-UCL-LG (n=2), B-DFL-2 (n=1), B-MCL (n=1), and B-SLL (n=1). The remaining NHL subtypes included NHL-NOS (n=7) or T-PTCL-LC (n=1). B-symptoms were present for 6 (19%) patients with B-DLCL and none of the patients with B-FL-1/B-FL-2. Complete response rates to NHL treatment were 48% in B-DLCL and 33% in B-FL-1/B-FL-2. For B-DLCL and B-FL-1/B-FL-2, respectively, the five-year OAS was 54% (95% CI 36%–69%) and 65% (95% CI 31%–85%) while the five-year EFS was 48% (95% CI 36%–69%) and 56% (95% CI 24%–79%). For all NHL cases the 5-year OAS was 58% (95% CI 47%–69%) and the 5-year EFS was 49% (95% CI 37%–59%). CONCLUSIONS: Lymphomas developing in the context of RA most often include diffuse large B-cell and follicular subtypes. Complete response rates to standard treatment for these major subtypes ranged from 33 to 48%. For RA patients developing NHL, five-year overall- and event-free survival rates are approximately 50%.