Real-World Analysis of Therapeutic Patterns in Patients Affected by Rheumatoid Arthritis in Italy: A Focus on Baricitinib.
ABSTRACT: INTRODUCTION:The objective of this study was to evaluate treatment patterns in patients with rheumatoid arthritis (RA), with a focus on the utilization of baricitinib, an oral highly selective Janus kinase 1 and 2 inhibitor, in an Italian real-world setting. METHODS:This observational retrospective analysis was based on data collected in selected Italian administrative databases. Patients aged ??18 years with a diagnosis of RA defined by hospitalization discharge diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) or by disease exemption code 006 for RA in 2018 were included. The index date (ID) was defined as the date of first prescription for a drug indicated for RA during the inclusion period. Patients without a prescription for biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) before the ID were considered to be b/tsDMARD naïve. A further analysis was performed on patients only receiving baricitinib. RESULTS:A total of 41,290 RA patients were enrolled, of whom 55.6% were not treated with conventional synthetic DMARDs (csDMARDs) or b/tsDMARDs, 39.4% were receiving therapy with csDMARDs, and 5.0% were using b/tsDMARDs. In the latter group, 2.7% (n?=?56) were receiving therapy with baricitinib. In 2018, 13.2% of csDMARD-treated patients switched to b/tsDMARDs, of whom 4.3% (n?=?93) of these switched to baricitinib. In total, 149 patients (mean age?± standard deviation 57.6?±?12.1; 12.8% male) had a baricitinib prescription, of whom 51% were b/tsDMARD naïve. At baseline, 61.7% of baricitinib users were receiving combination therapy with csDMARDs plus corticosteroids, 26.2% were receiving combination therapy with corticosteroids, and 8.1% were receiving combination therapy with csDMARDs; 4% were receiving baricitinib monotherapy. During follow-up, the proportion of patients receiving baricitinib monotherapy increased to 38.9%, while 26.9, 18.8, and 15.4% of baricitinib users received combination therapy with corticosteroids, csDMARDs plus corticosteroids, and csDMARDs, respectively. CONCLUSION:This study provides a current view of the treatment patterns in Italian patients with RA in a real-world setting of daily clinical practice, with a focus on baricitinib utilization.
Project description:OBJECTIVES:Abatacept, a biologic DMARD, was associated with respiratory adverse events in a small subgroup of RA patients with chronic obstructive pulmonary disease (COPD) in a trial. Whether this potential risk is specific to abatacept or extends to all biologics and targeted synthetic DMARDs (tsDMARDs) is unclear. We assessed the risk of adverse respiratory events associated with biologic and tsDMARDs compared with conventional synthetic DMARDs (csDMARDs) among RA patients with concomitant COPD in a large, real-world cohort. METHODS:We used a prevalent new-user design to study RA patients with COPD in the US-based MarketScan databases. New users of biologic DMARDs and/or tsDMARDs were matched on time-conditional propensity scores to new users of csDMARDs. Adverse respiratory events were estimated using Cox models comparing current use of biologic/tsDMARDs with csDMARDs. RESULTS:The cohort included 7424 patients initiating biologic/tsDMARDs and 7424 matched patients initiating csDMARDs. The adjusted hazard ratio of hospitalized COPD exacerbation comparing biologic/tsDMARD vs csDMARD was 0.76 (95% CI: 0.55, 1.06), while it was 1.02 (95% CI: 0.82, 1.27) for bronchitis, 1.21 (95% CI: 0.92, 1.58) for hospitalized pneumonia or influenza and 0.99 (95% CI: 0.87, 1.12) for outpatient pneumonia or influenza. The hazard ratio of the combined end point of COPD exacerbation, bronchitis and hospitalized pneumonia or influenza was 1.04 (95% CI: 0.89, 1.21). CONCLUSION:In this large, real-world comparative safety study, biologic and tsDMARDs, including abatacept, were not associated with an increased risk of adverse respiratory events when compared with csDMARDs in patients with RA and COPD.
Project description:Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE®, Embase®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010-2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA. FUNDING:Pfizer.Plain Language Summary: Plain language summary available on the journal website.
Project description:OBJECTIVES:To investigate changes in BMD in RA patients receiving 3-year biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) or conventional synthetic DMARD (csDMARD). METHODS:Patients with RA were recruited from September 2014 until March 2019. Clinical characteristics, BMD and evidence of fragility fractures at enrolment were documented. Participants were treated according to the National Institute for Health and Care Excellence (NICE) guidelines over a 3-year observation period. Repeated BMD was measured at the end of the study period. Participants were grouped into those receiving b/tsDMARD or csDMARD and by propensity score matching (1:2). RESULTS:A total of 388 participants completed the 3-year follow-up. After propensity score matching, 92 and 184 participants were allocated to the b/tsDMARD (Group I) and csDMARD (Group II), respectively. After 3?years, BMD remained stable at the femoral neck (FN), hip (total) (TH) and lumbar vertebra (L1-4) (P =0.09, 0.15, 0.87) in Group I. However, BMD decreased significantly in Group II (P=0.045, <0.001, 0.004) at corresponding sites. Participants receiving combined b/tsDMARD and anti-osteoporosis therapy experienced a greater BMD preserving effect than other subgroups. CONCLUSION:Long-term b/tsDMARDs therapy had protective effects on bone loss for patients with RA. Patients receiving concomitant anti-osteoporosis therapy and b/tsDMARDs therapy experienced the greatest BMD preserving effect.
Project description:INTRODUCTION:This study assessed if concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids altered the response or safety outcomes to baricitinib in rheumatoid arthritis (RA) patients. METHODS:Patients with???6 swollen/tender joints and no prior biologic DMARD were eligible for study inclusion. In RA-BUILD, csDMARD-inadequate responder (IR) patients were randomized to placebo or baricitinib (2 or 4 mg) once daily (QD). In RA-BEAM, methotrexate (MTX)-IR patients were randomized to placebo QD, baricitinib 4-mg QD, or adalimumab 40-mg biweekly. Patients continued background csDMARD (including MTX) therapy. This post hoc analysis of placebo and baricitinib 4-mg patients assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. RESULTS:From 716 placebo patients, 71, 21, and 6% were taking MTX alone, MTX?+???1 csDMARD, and non-MTX csDMARDs, respectively; from 714 baricitinib patients, the rates were 74, 18, and 6%; 56% of placebo and 55% of baricitinib patients used corticosteroids at baseline (mean dose, 6.0 mg/day for both groups); patients continued use throughout the studies. The odds ratios for achieving American College of Rheumatology response at the 20% improvement level (ACR20) and Clinical Disease Activity Index (CDAI)???10 at week 12 favored baricitinib for most subgroups; no significant interactions were observed. Rates of adverse events were similar regardless of csDMARD group or corticosteroid use. There were numerically more serious adverse events in placebo patients taking corticosteroids (4.2 vs. 1.6%) and a higher rate of discontinuations in baricitinib patients taking corticosteroids (4.1 vs. 1.2%). CONCLUSIONS:Baricitinib was efficacious regardless of concomitant use of csDMARDs or corticosteroids; the incidence of adverse events was similar across all groups of patients. FUNDING:Eli Lilly and Company and Incyte Corporation.
Project description:Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs are important in rheumatoid arthritis (RA) treatment. The risk of hospitalized infection associated with bDMARDs/tsDMARDs in RA patients is unclear.We retrospectively analyzed the cases of the 275 RA patients with 449 treatment episodes who were administered a bDMARD/tsDMARD at Nagasaki University Hospital in July 2003-January 2015. We determined the incidence and risk factors of infection requiring hospitalization in the patients during a 3-year observation period.Thirty-five (12.7%) of the patients experienced a hospitalized infection. The hospitalized infection risk did not differ significantly among several bDMARDs/tsDMARDs. A multivariate analysis revealed that the comorbidities of chronic lung disease (adjusted HR 5.342, 95% CI 2.409-12.42, p < 0.0001) and the initiation of bDMARDs/tsDMARDs before 2010 (adjusted HR 4.266, 95% CI 1.827-10.60, p = 0.0007) are significant independent risk factors for hospitalized infection. Compared to the before-2010 group, the group of patients whose treatment initiated in 2010 or later showed higher patient ages at the initiation of bDMARD/tsDMARD treatment and a higher rate of the use of prophylaxis with an antituberculosis agent, whereas the disease activities and number of the patients who received >5?mg of prednisolone were lower in the after-2010 group.This is the first report that the frequency of hospitalized infection significantly decreased when the patients were treated with a bDMARD or tsDMARD after 2010. Our results indicate that the updated announcement of diagnosis and treatment criteria might contribute to a reduced risk of hospitalized infection and a better understanding of the use of bDMARDs/tsDMARDs by rheumatologists.
Project description:BACKGROUND:Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS:Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and?HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS:In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at?some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (?29?IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ?100?IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION:HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.
Project description:BACKGROUND:Clinical guidelines recommend pneumococcal and tetanus vaccinations in patients with rheumatoid arthritis (RA). Baricitinib is an oral, selective Janus kinase (JAK) 1/JAK 2 inhibitor and is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan. This substudy evaluated pneumococcal conjugate and tetanus toxoid vaccine (TTV) responses in patients with RA receiving baricitinib. These vaccines elucidate predominantly T cell-dependent humoral antibody response. METHODS:Eligible RA patients receiving baricitinib 2 mg or 4 mg with or without concomitant methotrexate (MTX) were enrolled in a phase 3 long-term extension trial (RA-BEYOND; ClinicalTrials.gov, NCT01885078) in USA/Puerto Rico. Patients were vaccinated with 13-serotype pneumococcal conjugate vaccine (PCV-13) and TTV. Primary endpoints were the proportion of patients achieving a satisfactory humoral response for PCV-13 (≥ 2-fold increase in anti-pneumococcal antibody concentrations in ≥ 6 serotypes) and TTV (≥ 4-fold increase in anti-tetanus concentrations) at 5 weeks post-vaccination. Secondary endpoints included humoral responses at 12 weeks and functional responses of serotypes 4, 6B, 14, and 23F (twofold and fourfold increases in opsonic indexes at 5 and 12 weeks). RESULTS:Of 106 patients with a mean duration of RA of approximately 12 years, 80% were female, 30% were taking corticosteroids, and 89% (N = 94) were taking baricitinib plus MTX; most patients (97% PCV-13/96% TTV) completed the evaluations. Overall, 68% (95% CI 58.4, 76.2) of patients achieved a satisfactory response to PCV-13, 43% (34.0, 52.8) achieved a ≥ 4-fold increase in anti-tetanus concentrations, and 74% (64.2, 81.1) achieved a ≥ 2-fold increase. PCV-13 response was similar for patients taking corticosteroids (71%; 53.4, 83.9) vs those not (67%; 55.2, 76.5). The percentage of sera with a ≥ 2-fold increase in post-vaccination opsonic indexes at week 5 ranged from 47% (serotype 14) to 76% (serotype 6B). Through 12 weeks post-vaccination, seven patients (6.6%) reported injection-site events. There were no deaths during the substudy, and three patients experienced a serious adverse event. CONCLUSIONS:Approximately two thirds of patients on long-term baricitinib achieved satisfactory humoral and functional responses to PCV-13 vaccination, while TTV responses were less robust. PCV-13 response was not diminished in those taking concomitant corticosteroids. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01885078 . Registered on 24 June 2013.
Project description:Fatigue is a common and debilitating symptom in patients with RA. Since 2007, fatigue has been included as one of the core outcome measures in RA. Clinical trials of biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) have included fatigue as a secondary endpoint. A Cochrane review in 2016 concluded that the bDMARDs have a moderate effect on improving fatigue in RA. More recent clinical trials of the new biologic agent sarilumab and the Janus kinase inhibitors tofacitinib and baricitinib showed similar benefits. It remains unclear whether the effect of bDMARDs and tsDMARDs on fatigue is mediated by direct effects or through a reduction in inflammation. As fatigue was a secondary endpoint, many analyses did not adjust for potential confounding factors, including pain, mood and anaemia, which is a significant limitation.
Project description:We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
Project description:The aim of this study was to investigate the association between body-mass index (BMI) and remission in RA patients receiving conventional synthetic (cs-) or the biological Disease-Modifying Antirheumatic Drug (DMARD), tocilizumab. Individual participant data (IPD) were pooled from five trials investigating tocilizumab and/or csDMARDs therapy (primarily methotrexate) for RA. Time to first remission was recorded according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). BMI was classified according to WHO definitions. Associations between baseline BMI and remission were assessed by Cox-proportional hazard analysis. IPD were available from 5428 patients treated with tocilizumab?±?csDMARDs (n?=?4098) or csDMARDs alone (n?=?1330). Of these, 1839 (33.9%) had normal BMI, 1780 (32.8%) overweight, 1652 (30.4%) obese and 157 (2.9%) were underweight. Obesity, compared to normal BMI, was associated with less frequent remission using SDAI (adjusted HR 0.80 [95% CI 0.70-0.92]) and CDAI (adjusted HR 0.77 [0.68-0.87]). As continuous variable, increased BMI was associated with less frequent SDAI (P?=?0.001) and CDAI (P?=?0.001) defined remission. No heterogeneity in identified associations was observed between studies (P?=?0.08) or treatments (P?=?0.22). Obesity was negatively associated with RA disease remission regardless of RA therapy, suggesting that baseline BMI should be considered as a stratification factor in future RA trials.