Baricitinib: From Rheumatoid Arthritis to COVID-19.
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ABSTRACT:
SUBMITTER: Assadiasl S
PROVIDER: S-EPMC8250677 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately-to-severely active rheumatoid arthritis (RA).MethodsData were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long-term extension study. The data analysis set designated "All-bari-RA" included all baricitinib exposures at any dose.ResultsOverall, 3,492 RA patients received baricitinib (7,860 patient-years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient-years for placebo and 0.8 per 100 patient-years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient-years for placebo and 0.5 per 100 patient-years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient-years for placebo and 2.4 per 100 patient-years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo-controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg-4 mg-extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient-years in those receiving 2 mg baricitinib and 0.6 per 100 patient-years in those receiving 4 mg baricitinib). In the All-bari-RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient-years.ConclusionIn RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer-term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.
| S-EPMC6618316 | biostudies-literature
Project description: Not available
| S-EPMC8009616 | biostudies-literature
Project description:Baricitinib is an innovative small-molecule drug that reversibly inhibits continuous activation of JAK/STAT pathway, thus reducing joint inflammation. The drug was approved for use as monotherapy or in combination with methotrexate (MTX) in the treatment of adults with moderately to severely active rheumatoid arthritis (RA). The aim of this paper was to review the studies on pharmacology, mode of action, pharmacokinetics, efficacy, and safety of baricitinib in patients with RA. Baricitinib provides an innovative approach to modulating the immune and inflammatory response in patients with RA, which is especially important in individuals who do not respond to disease-modifying antirheumatic drugs or standard biologic drugs (tumor necrosis factor inhibitors) or who lose response over time. Baricitinib therapy reduces symptoms of RA and improves the quality of life. Moreover, it has shown high efficacy and an acceptable safety profile in Phase III randomized controlled trials (RCTs) and become another JAK inhibitor approved for RA treatment, providing a useful alternative option. RCTs have revealed a significant benefit of baricitinib over placebo, MTX, and adalimumab in terms of standard efficacy outcomes, especially the American College of Rheumatology ACR20, ACR50, and ACR70 response rates. Additionally, a clinically meaningful improvement in patient-reported outcomes, including the quality of life, compared with placebo has been reported. The safety profile seems acceptable, although some rare but potentially severe adverse events have been observed, such as serious infections, opportunistic infections (eg, herpes zoster), malignancies, and cardiac or hepatic disorders. Baricitinib administered at an approved dose of 2 or 4 mg once daily offers a novel and promising alternative to parenterally administered biologic drugs used in RA treatment.
| S-EPMC6385775 | biostudies-literature
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.
| S-EPMC7046961 | biostudies-literature
Project description:Baricitinib is a Janus kinase (JAK) 1 and 2 inhibitor approved for treating rheumatoid arthritis (RA). The JAK/STAT system is essential in the intracellular signaling of different cytokines and in the activation process of the monocyte lineage. This study verifies the effects of baricitinib on STAT phosphorylation in monocytes of RA patients and evaluates the correlation between STAT phosphorylation and response to therapy. We evaluated the disease activity of patients (DAS28CRP) at baseline (T0) and after 4 and 12 weeks (T1-T3) of treatment with baricitinib, dividing them into responders (n = 7) and non-responders (n = 7) based on the reduction of DAS28CRP between T0 and T1 of at least 1.2 points. Through flow cytometry, STAT1 phosphorylation was analyzed at T0/T1/T3 in monocytes, at basal conditions and after IL2, IFNα, and IL6 stimulation. We showed that monocyte frequency decreased from T0 to T1 only in responders. Regarding the phosphorylation of STAT1, we observed a tendency for higher basal pSTAT1 in monocytes of non-responder patients and, after 4 weeks, a significant reduction of cytokine-induced pSTAT1 in monocytes of responders compared with non-responders. The single IFNα stimulation only partially recapitulated the differences in STAT1 phosphorylation between the two patient subgroups. Finally, responders showed an increased IFN signature at baseline compared with non-responders. These results may suggest that monocyte frequency and STAT1 phosphorylation in circulating monocytes could represent early markers of response to baricitinib therapy.
| S-EPMC9357974 | biostudies-literature
Project description:Vitamin D is an immunomodulatory hormone with an established role in calcium and phosphate metabolism and skeletal mineralization. Evidence showing its immunological benefits by regulating essential components of the innate and adaptive immune system is prevalent. Vitamin D deficiency is reported worldwide and is thereby found to be associated with various immune-related diseases. Rheumatoid Arthritis and COVID-19 are two such diseases, sharing a similar hyperinflammatory response. Various studies have found an association of lower Vitamin D levels to be associated with both these diseases. However, contrasting data is also reported. We review here the available scientific data on risk factor association and supplementation benefits of Vitamin D in Rheumatoid Arthritis and COVID-19, intending to critically evaluate the literature.
| S-EPMC8401347 | biostudies-literature
Project description:Objective:RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. Methods:RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ?10. An interaction P-value ?0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results:The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ?10 by disease duration (larger effect ?10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion:Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration:ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.
| S-EPMC5913638 | biostudies-literature
Project description:Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.
| S-EPMC7784289 | biostudies-literature
Project description:Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.
| S-EPMC7303585 | biostudies-literature
Project description:In March 2020, COVID-19 infection caused by SARS-CoV-2 has been declared to be a global pandemic, where its complications, severity and mortality are reported to be due to the released inflammatory cytokines or the so-called cytokine storm. This is quite similar to that observed in the autoimmune and chronic inflammatory rheumatic disease, rheumatoid arthritis (RA). It was hypothesized that RA patients are at a higher risk of acquiring COVID-19; however, recent studies reported that they are not when compared to the rest of the population. In this review, we aim to highlight the mutual pathological features, cytokine profiles and risk factors between COVID-19 and RA. Also, many researchers are currently working to explore therapeutic agents that could aid in the eradication of COVID-19 infection. Due to the similarity between the inflammation status in COVID-19 and RA, many anti-rheumatic drugs such as hydroxychloroquine, tocilizumab, baricitinib and anakinra were proposed to be therapeutic modalities for COVID-19 infection.
| S-EPMC8040489 | biostudies-literature