To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA).
Using ...health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV.
A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81).
The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.
Objective
To evaluate gastrointestinal (GI) perforation in rheumatoid arthritis (RA) patients receiving tofacitinib, tocilizumab, or other biologic agents.
Methods
Using health plan data from 2006 ...through 2014, RA patients without prior GI perforation were identified. Those in whom treatment with tofacitinib or a biologic agent was being initiated were followed up for incident GI perforation with hospitalization. Crude incidence rates were calculated by exposure. Adjusted Cox proportional hazards models were used to evaluate the association between GI perforation and exposures. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated.
Results
A cohort of 167,113 RA patients was analyzed. Among them, 4,755 began treatment with tofacitinib, 11,705 with tocilizumab, 115,047 with a tumor necrosis factor inhibitor (TNFi), 31,214 with abatacept, and 4,392 with rituximab. Compared to TNFi recipients, abatacept recipients were older, tofacitinib and rituximab recipients were younger, and tocilizumab recipients were similar in age. Patients beginning treatment with a non‐TNFi agent were more likely to have previously received biologic agents than patients beginning treatment with a TNFi. The incidence of GI perforation per 1,000 patient‐years was 0.86 (tofacitinib), 1.55 (tocilizumab), 1.07 (abatacept), 0.73 (rituximab), and 0.83 (TNFi). Most perforations occurred in the lower GI tract: the incidence of lower GI tract perforation per 1,000 patient‐years was 0.86 (tofacitinib), 1.26 (tocilizumab), 0.76 (abatacept), 0.48 (rituximab), and 0.46 (TNFi). Lower GI tract perforation risk was significantly elevated with tocilizumab treatment, and numerically elevated with tofacitinib treatment, versus treatment with TNFi. Adjusted HRs were 2.51 (95% CI 1.31–4.80) for tocilizumab and 1.94 (95% CI 0.49–7.65) for tofacitinib. Older age (HR 1.16 per 5 years 95% CI 1.10–1.22), diverticulitis/other GI conditions (HR 3.25 95% CI 1.62–6.50), and prednisone use at >7.5 mg/day (HR 2.29 95% CI 1.39–3.78) were associated with lower GI tract perforation. The incidence of upper GI tract perforation was similar among all drug exposures.
Conclusion
The risk of lower GI tract perforation associated with tocilizumab treatment, and possibly tofacitinib treatment, is elevated compared to that associated with TNF blockade.
Objective
Increased incidence of herpes zoster (HZ) has been observed with JAK inhibitors such as tofacitinib. However, whether concomitant methotrexate (MTX) and/or glucocorticoids confer additional ...(additive or multiplicative) risk is unclear. We evaluated HZ risk in tofacitinib users with and without MTX and glucocorticoids.
Methods
Within MarketScan and Medicare data (2011–2016), we identified all patients with rheumatologist‐diagnosed rheumatoid arthritis initiating treatment with tofacitinib (index date); demographics and baseline covariates were evaluated in the year prior to the index date. HZ was ascertained using International Classification of Diseases, Ninth Revision or Tenth Revision codes with antiviral drug use (±7 days). Multivariable Cox regression was used to evaluate hazard ratios (HRs) for HZ in tofacitinib users with and without current concomitant MTX and glucocorticoids, controlling for baseline covariates.
Results
We studied 8,030 new tofacitinib users (83.3% women). The mean ± SD age was 60.3 ± 12.6 years. HZ incidence in tofacitinib users was numerically lowest in the absence of glucocorticoids (3.4 per 100 patient‐years with MTX; 3.7 per 100 patient‐years without MTX). An approximately 2‐fold increased incidence of HZ was observed for tofacitinib users receiving either glucocorticoids alone (6.0 per 100 patient‐years) or both MTX plus glucocorticoids (6.5 per 100 patient‐years). The adjusted HR for HZ in tofacitinib users was unchanged (HR 0.99 95% confidence interval (95% CI) 0.64–1.54) when given only with MTX, but was increased (HR 1.96 95% CI 1.33–2.88) for tofacitinib plus glucocorticoids. Older age and female sex were also risk factors, while prior vaccination was associated with a strong trend for lower risk.
Conclusion
In tofacitinib users, HZ occurred at a rate of approximately 4% per year and was further doubled with glucocorticoid exposure. Concomitant MTX did not confer additional risk. Zoster vaccination may decrease risk.
Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine ...pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.
This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.
12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the
average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.
DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).
Purpose
Inpatient mortality is an important variable in epidemiology studies using claims data. In 2016, MarketScan data began obscuring specific hospital discharge status types for patient privacy, ...including inpatient deaths, by setting the values to missing. We used a machine learning approach to correctly identify hospitalizations that resulted in inpatient death using data prior to 2016.
Methods
All hospitalizations from 2011 to 2015 with discharge status of missing, died, or one of the other subsequently obscured values were identified and divided into a training set and two test sets. Predictor variables included age, sex, elapsed time from hospital discharge until last observed claim and until healthcare plan disenrollment, and absence of any discharge diagnoses. Four machine learning methods were used to train statistical models and assess sensitivity and positive predictive value (PPV) for inpatient mortality.
Results
Overall 1 307 917 hospitalizations were included. All four machine learning approaches performed well in all datasets. Random forest performed best with 88% PPV and 93% sensitivity for the training set and both test sets. The two factors with the highest relative importance for identifying inpatient mortality were having no observed claims for the patient on days 2–91 following hospital discharge and patient disenrollment from the healthcare plan within 60 days following hospital discharge.
Conclusion
We successfully developed machine learning algorithms to identify inpatient mortality. This approach can be applied to obscured data to accurately identify inpatient mortality among hospitalizations with missing discharge status.
Objective
The herpes zoster (HZ) vaccine is recommended for adults in the US ages ≥60 years who do not have weakened immune systems. It is unclear how the risk of HZ varies according to age and ...disease conditions in younger patients with autoimmune or inflammatory (AI) diseases. This study was undertaken to evaluate the age‐stratified incidence of HZ in patients with AI diseases as compared to older adults for whom the HZ vaccine is currently recommended by the US Centers for Disease Control and Prevention.
Methods
Using linked data obtained from patients who were insured by US commercial and government health care plans during the period 2007–2010, 7 cohorts of patients with AI diseases were assembled: systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), ankylosing spondylitis (AS), and gout. Two comparator cohorts were also assembled as controls: adult patients with diabetes and adult subjects without AI diseases or diabetic conditions. HZ was identified using diagnostic codes. Age‐specific incidence rates (IRs) of HZ were calculated and compared to the IRs of HZ in control subjects ages 61–70 years who were without AI diseases or diabetic conditions.
Results
After review of the linked data, the following number of enrollment periods were identified: 8,395 for patients with SLE, 7,916 for patients with IBD, 50,646 for patients with RA, 2,629 for patients with PsA, 4,299 for patients with PsO, 1,019 for patients with AS, 58,934 for patients with gout, 214,631 for control patients with diabetes, and 330,727 for control subjects without AI diseases and diabetic conditions. The respective highest and lowest IRs of HZ during the study were 19.9 per 1,000 person‐years in the SLE cohort and 6.8 per 1,000 person‐years in the gout cohort, as compared to an IR of 5.3 per 1,000 person‐years in control subjects without AI diseases or diabetic conditions. The age‐specific IRs of HZ in patients with RA and those with SLE ages ≥40 years were 1.5–2 times greater than those observed in older healthy adults (IR 8.5 per 1,000 person‐years), for whom the vaccine is currently recommended.
Conclusion
SLE, IBD, and RA are AI diseases associated with a higher risk of HZ compared to that in older adults for whom vaccination is currently recommended, suggesting that individuals with these conditions who are as young as age 40 years could potentially benefit from the HZ vaccine.
Abstract
Background
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody tests are often measured at the time of rheumatoid arthritis (RA) diagnosis but may not be repeated and ...therefore not available in electronic health record (EHR) data; lab test results are unavailable in most administrative claims databases. ICD10 coding allows discrimination between rheumatoid factor positive (M05) (“seropositive”) and seronegative (M06) patients, but the validity of these codes has not been examined.
Methods
Using the ACR’s Rheumatology Informatics System for Effectiveness (RISE) EHR-based registry and U.S. MarketScan data where some patients have lab test results, we assembled two cohorts. Seropositive RA was defined having a M05 diagnosis code on the second rheumatologist encounter, M06 similarly identified seronegative RA, and RF and anti-CCP lab test results were the gold standard. We calculated sensitivity (Se) and positive predicted value (PPV) of the M05/M06 diagnosis codes.
Results
We identified 43,581 eligible RA patients (RISE) and 1185 (MarketScan) with RF or anti-CCP lab test results available. Using M05 as the proxy for seropositive RA, sensitivity = 0.76, PPV = 0.82 in RISE, and Se = 0.73, PPV = 0.84 in MarketScan. Results for M06 as a proxy for seronegative RA were comparable in RISE, albeit somewhat lower in MarketScan. Over 3 consecutive visits, approximately 90% of RA patients were coded consistently using either M05 or M06 at each visit.
Conclusion
Under ICD10, M05 and M06 diagnosis codes are reasonable proxies to identify seropositive and seronegative RA with high sensitivity and positive predictive values if lab test results are not available.
Objective
Multiple studies have shown seemingly unfavorable changes in lipid profiles associated with interleukin‐6 receptor (IL‐6R) antagonists and some other therapies for rheumatoid arthritis. The ...aim of this study was to assess the real‐world cardiovascular disease (CVD) risk associated with tocilizumab, the first anti–IL‐6R medication approved for the treatment of RA.
Methods
We conducted a cohort study using 2006–2015 Medicare and MarketScan claims for patients with RA in whom treatment with biologic disease‐modifying antirheumatic drugs was initiated after January 1, 2010. The primary outcome was a composite of myocardial infarction, stroke, and fatal CVD, assessed using a validated method. The influence of potential confounding due to RA disease activity was assessed in a subgroup analysis (~5–10% of biologic therapy initiations) using the multi‐biomarker disease activity (MBDA) score.
Results
A total of 88,463 patients with RA were included. The crude incidence rate (IR) per 1,000 patient‐years for composite CVD events among Medicare patients ranged from 11.8 (95% confidence interval 95% CI 9.7–14.4) for etanercept users to 17.3 (95% CI 15.2–19.7) for infliximab users. The crude IR for pooled users of a tumor necrosis factor inhibitor was 15.0 (95% CI 13.9–16.3). Compared to tocilizumab, the corresponding adjusted hazard ratios (HRs) were 1.01 (95% CI 0.79–1.28) for abatacept, 1.16 (95% CI 0.89–1.53) for rituximab, 1.10 (95% CI 0.80–1.51) for etanercept, 1.33 (95% CI 0.99–1.80) for adalimumab, and 1.61 (95% CI 1.22–2.12) for infliximab. There were no statistically significant differences in the risk of CVD between tocilizumab and any other biologic when MarketScan data were used. Results were robust in numerous subgroup analyses and after external adjustment to control for RA disease activity in the subgroup of patients with linked MBDA test results (n = 4,156).
Conclusion
Tocilizumab was associated with a CVD risk comparable to that for etanercept as well as a number of other biologics used for the treatment of RA.
Objective
Despite strong recommendations for routine measurement of rheumatoid arthritis (RA) disease activity and associated treatment changes to attain remission/low disease activity, the ...measurement tools that clinicians use to evaluate RA patients’ disease activity and frequency of treatment change have not been well characterized. Therefore, we evaluated different measurement tools that physicians used to assess RA disease activity and associated RA treatment changes.
Methods
Using data from the Rheumatology Informatics System for Effectiveness (RISE) registry from January 2016 through June 2017, and using the following criteria: age ≥18 years, diagnosis of RA (International Classification of Diseases, Ninth and Tenth Revision, codes), ≥2 RISE visits, and ≥1 RA disease activity measure scored in 2016, we classified eligible patients’ drug use at the index visit as monotherapy or combination therapy with conventional synthetic (cs) and biologic disease‐modifying antirheumatic drugs (bDMARDs). Outcomes include change in treatment over 12 months. Mixed models identified factors associated with treatment change.
Results
Among 50,996 eligible patients, 27,274 had longitudinal data. The most commonly used measures were RAPID3 (78.9%) and the Clinical Disease Activity Index (CDAI) (34.2%). The frequency of treatment change during follow‐up was relatively low (35.6–54.6%), even for patients with moderate/high disease activity according to RAPID3 or CDAI scores. Older patients (age ≥75 years; adjusted odds ratio ORadj 0.63 95% confidence interval (95% CI) 0.50–0.78) and those already receiving combination therapy with csDMARDs (ORadj 0.45 95% CI 0.33–0.61) or combination therapy with bDMARDs (ORadj 0.30 95% CI 0.24–0.38) were less likely to change RA treatment even after multivariable adjustment.
Conclusion
Using the American College of Rheumatology's national RISE registry, one‐ to two‐thirds of RA patients failed to change their treatment, even when experiencing moderate/high disease activity. Multimodal interventions directed at both patients and providers are needed to encourage shared decision‐making, goal‐directed care, and to overcome barriers to treatment escalation.
To compare the coronary heart disease risk among patients with rheumatoid arthritis (RA) initiating common biologic disease-modifying antirheumatic drugs of different mechanisms.
We conducted a ...retrospective cohort study of patients with RA enrolled in Medicare, a public health plan covering >90% of US residents 65 years or older, from 2006 to 2012 who (1) initiated a biologic, (2) had complete medical and pharmacy coverage for at least 12 months before biologic initiation and (3) were free of coronary heart disease at the time of initiation. We compared the incidence rates (IRs) of (1) acute myocardial infarction (AMI) and (2) a composite outcome of AMI or coronary revascularisation and used multivariable adjusted Cox regression models to examine the associations between the type of biologic and the two outcomes.
We identified 47 193 eligible patients with RA with mean age 64 (SD 13) years; 85% were women. Crude IRs for AMI ranged from 5.7 to 8.8 cases per 1000 person-years (PYs). AMI risk was significantly elevated among antitumour necrosis factor (anti-TNF) initiators overall (adjusted HR (aHR) 1.3; 95% CI 1.0 to 1.6) and individually among etanercept (aHR 1.3; 95% CI 1.0 to 1.8) and infliximab (aHR 1.3; 95% CI 1.0 to 1.6) compared with abatacept initiators. Crude IRs for the composite outcome ranged from 7.6 to 14.5 per 1000 PYs. Tocilizumab initiators were at reduced risk of the composite outcome compared with abatacept initiators (aHR 0.64, 95% CI 0.41 to 0.99).
Findings from this observational study of patients with RA suggested that anti-TNF biologics may be associated with higher AMI risk compared with abatacept.
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