Baricitinib: From Rheumatoid Arthritis to COVID-19.
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ABSTRACT:
SUBMITTER: Assadiasl S
PROVIDER: S-EPMC8250677 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Baricitinib: From Rheumatoid Arthritis to COVID-19.
Assadiasl Sara S Fatahi Yousef Y Mosharmovahed Banafsheh B Mohebbi Bahareh B Nicknam Mohammad Hossein MH
Journal of clinical pharmacology 20210612 10
Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, ato ...[more]
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Project description:ObjectiveRheumatoid factors (RFs) are a hallmark of rheumatoid arthritis but also arise in infections, including COVID-19. Moreover, infections, again including COVID-19, are associated with rheumatoid arthritis development, positioning RFs as a potential link between infection and rheumatoid arthritis. RFs traditionally have been thought to be relatively uniform in their reactivity across conditions apart from some increased reactivity in rheumatoid arthritis. Recently, however, IgG RFs that bind citrulline- and homocitrulline-containing IgG epitopes were identified in rheumatoid arthritis, but not other autoimmune diseases, whereas IgM RFs that bind specific native linear IgG epitopes were found uniquely post-COVID-19. The objective of this study was to determine if rheumatoid arthritis-associated RFs develop post-COVID-19 in order to provide new insights into post-infection immune tolerance loss.MethodsCOVID-19 convalescent, rheumatoid arthritis, and control sera (n=20) were used in enzyme-linked immunosorbent assay to evaluate IgG, IgM, and IgA binding to eight IgG1-derived peptides in their native, citrulline-containing, and homocitrulline-containing forms. Antibody levels were compared by Kruskal-Wallis test with Dunn's multiple comparisons test, and the number of participants with binding greater than all controls was compared by Fisher's exact test.ResultsIgG binding to seven of the eight IgG1-derived peptides was increased in a citrulline- or homocitrulline-specific manner only in rheumatoid arthritis. IgA binding was increased to five of eight IgG1-derived peptides in a citrulline- or homocitrulline-specific manner in rheumatoid arthritis and to one homocitrulline-containing peptide post-COVID-19. More post-COVID-19 participants than controls had elevated IgG or IgA binding to two IgG1-derived peptides in a homocitrulline-specific manner.ConclusionRheumatoid arthritis-associated RFs are primarily restricted to rheumatoid arthritis, but some individuals post-COVID-19 generate moderate levels of a few rheumatoid arthritis-associated RFs, especially of the IgA isotype and homocitrulline-reactive. These findings refine our understanding of RFs, provide novel insights into loss of immune tolerance post-infection, and reveal new possibilities for biomarker development in preclinical rheumatoid arthritis.
| S-EPMC11864925 | biostudies-literature
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:ObjectiveThis study investigates the efficacy and safety of baricitinib, an oral targeted synthetic disease-modifying antirheumatic drugs (DMARDs), in patients with difficult-to-treat rheumatoid arthritis (D2T RA) compared to those without, aiming to determine its potential as an alternative treatment for D2T RA.Subject and methodsA total of 78 patients participated in this retrospective cohort study, with 33 meeting the D2T RA criteria and 45 in the non-D2T RA group. Various clinical and laboratory parameters, adverse events, and disease activity indices were assessed, alongside drug efficacy and survival rates.ResultsPatients with D2T RA exhibited higher seronegativity, prior use of b-DMARDs and c-DMARDs, and longer disease duration. Both groups experienced reductions in VAS and DAS28 scores, as well as SDAI, CDAI, HAQ, CRP, and ESR levels at baseline and 3, 6, and 12 months post-baricitinib initiation, with sustained efficacy observed over 12 months. The most prevalent adverse event was infection (28.21%). Although initial drug survival rates were similar between groups, the non-D2T RA group demonstrated higher rates at 24 months (46.70% vs. 59.40%). Subgroup analyses showed comparable survival rates between D2T RA and non-D2T RA groups, whether treated with baricitinib alone or in combination with methotrexate or leflunomide.ConclusionDespite potential treatment resistance, patients meeting the D2T RA criteria shared similar safety and efficacy profiles with those non-D2T RA. Baricitinib emerges as a promising treatment option for D2T RA patients, offering effectiveness and safety comparable to the non-D2T RA group.ObjectiveThis study investigates the efficacy and safety of baricitinib, an oral targeted synthetic disease-modifying antirheumatic drugs (DMARDs), in patients with difficult-to-treat rheumatoid arthritis (D2T RA) compared to those without, aiming to determine its potential as an alternative treatment for D2T RA.Subject and methodsA total of 78 patients participated in this retrospective cohort study, with 33 meeting the D2T RA criteria and 45 in the non-D2T RA group. Various clinical and laboratory parameters, adverse events, and disease activity indices were assessed, alongside drug efficacy and survival rates.ResultsPatients with D2T RA exhibited higher seronegativity, prior use of b-DMARDs and c-DMARDs, and longer disease duration. Both groups experienced reductions in VAS and DAS28 scores, as well as SDAI, CDAI, HAQ, CRP, and ESR levels at baseline and 3, 6, and 12 months post-baricitinib initiation, with sustained efficacy observed over 12 months. The most prevalent adverse event was infection (28.21%). Although initial drug survival rates were similar between groups, the non-D2T RA group demonstrated higher rates at 24 months (46.70% vs. 59.40%). Subgroup analyses showed comparable survival rates between D2T RA and non-D2T RA groups, whether treated with baricitinib alone or in combination with methotrexate or leflunomide.ConclusionDespite potential treatment resistance, patients meeting the D2T RA criteria shared similar safety and efficacy profiles with those non-D2T RA. Baricitinib emerges as a promising treatment option for D2T RA patients, offering effectiveness and safety comparable to the non-D2T RA group.
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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.
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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: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:ObjectiveRA 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.MethodsRA-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.ResultsThe 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.ConclusionBaricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.
| S-EPMC5913638 | biostudies-literature