glpg0634 and tofacitinib

The relative efficacy of Janus kinase (JAK) inhibitors in producing remission and low disease activity (LDA) states remains unknown since there are currently no trials that provide direct comparisons among JAK inhibitors in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA).. This study aimed to assess the relative remission and LDA rates of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) in DMARD-naive patients with RA.. We conducted Bayesian network meta-analysis and included information from direct and indirect comparisons from randomized controlled trials that examined remission (Disease Activity Score in 28 Joints using C-reactive protein level [DAS28-CRP] <2.6) and LDA (DAS28-CRP ≤ 3.2) produced by tofacitinib, baricitinib, upadacitinib, filgotinib monotherapy, and MTX in patients with DMARD-naive RA.. Four randomized controlled trials, comprising 2,185 patients, met the inclusion criteria. This network meta-analysis showed that treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved a significantly higher remission rate than that with MTX (odds ratio [OR] = 4.13, 95% CI = 2.88-6.02; OR = 2.12, 95% CI = 1.17-4.13; OR = 1.95, 95% CI = 1.10-3.50; OR = 1.79, 95% CI = 1.27-3.53). The ranking probability based on the surface under the cumulative ranking curve indicated that upadacitinib 15 mg had the highest probability of achieving remission (SUCRA = 0.985), followed by tofacitinib 5 mg (SUCRA = 0.574), baricitinib 4 mg (SUCRA = 0.506), filgotinib 200 mg (SUCRA = 0.431), and MTX (SUCRA = 0.004). Moreover, treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significantly higher LDA rate than that with MTX. The ranking probability for LDA was similar to that for remission; upadacitinib 15 mg had the highest probability of achieving LDA, followed by tofacitinib 5 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX.. Upadacitinib seems to be one of most effective interventions for achieving remission and LDA in DMARD-naive patients with RA based on the comparative analysis, and there are differences in remission and LDA rates induced by different JAK inhibitors.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Drug Therapy, Combination; Humans; Janus Kinase Inhibitors; Methotrexate; Treatment Outcome

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

Topics: Adamantane; Colitis; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Piperidines; Pyridines; Pyrimidines; Pyrroles; Triazoles

The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib were assessed in patients with rheumatoid arthritis (RA) with inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARDs).. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib in RA patients with inadequate responses to bDMARDs.. Four RCTs comprising 1399 patients met the inclusion criteria. Tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significant American College of Rheumatology 20% (ACR20) responses versus placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by filgotinib 200 mg, baricitinib 4 mg, filgotinib 100 mg, tofacitinib 5 mg, and placebo. The ranking in SUCRA based on the ACR50 response rate indicated that baricitinib 4 mg had the highest probability of achieving the ACR50 response rate, followed by filgotinib 200 mg, tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 100 mg, and placebo. Tofacitinib 5 mg showed a significantly higher ACR70 response rate than filgotinib 100 mg and upadacitinib 15 mg. Tofacitinib 5 mg, filgotinib 200 mg, and placebo showed a significantly lower serious adverse event rate than upadacitinib 15 mg.. Tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for RA patients with an inadequate response to bDMARDs but with different efficacy and safety profiles.. ZIEL: Bei Patienten mit rheumatoider Arthritis (RA) und inadäquater Reaktion auf biologische krankheitsmodizifierende Antirheumatika (bDMARD) wurde die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib ermittelt.. Eine Bayes-Netzwerk-Metaanalyse wurde durchgeführt, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib bei RA-Patienten mit inadäquatem Ansprechen auf bDMARD zu untersuchen.. Die Einschlusskriterien wurden von 4 RCT mit 1399 Patienten erfüllt. Unter Tofacitinib, Baricitinib, Upadacitinib und Filgotinib zeigte sich eine signifikant höhere ACR20-Ansprechrate (gemäß American College of Rheumatology) als unter Placebo. Wie die Rangfolgewahrscheinlichkeit, basierend auf der Oberfläche unter der kumulativen Rangfolgenkurve (SUCRA, „surface under the cumulative ranking curve“), ergab, stellte Upadacitinib 15 mg mit größter Wahrscheinlichkeit die beste Behandlung zur Erzielung der ACR20-Ansprechrate dar, es folgten Filgotinib 200 mg, Baricitinib 4 mg, Filgotinib 100 mg, Tofacitinib 5 mg und Placebo. Die auf der ACR50-Ansprechrate basierende SUCRA-Rangfolge zeigte, dass für Baricitinib 4 mg die höchste Wahrscheinlichkeit bestand, die ACR50-Ansprechrate zu erzielen, es folgten Filgotinib 200 mg, Tofacitinib 5 mg, Upadacitinib 15 mg, Filgotinib 100 mg und Placebo. Tofacitinib 5 mg wies eine signifikant höhere ACR70-Ansprechrate auf als Filgotinib 100 mg und Upadacitinib 15 mg. Für Tofacitinib 5 mg, Filgotinib 200 mg und Placebo zeigte sich eine signifikant niedrigere Rate schwerer unerwünschter Ereignisse als für Upadacitinib 15 mg.. Für RA-Patienten mit inadäquater Reaktion auf bDMARD erwiesen sich Tofacitinib, Baricitinib, Upadacitinib und Filgotinib als wirksame Therapieoptionen, jedoch mit unterschiedlichen Wirksamkeits- und Sicherheitsprofilen.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Biological Products; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles

An assessment of the relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) was performed in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) so as to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and MTX in DMARD-naïve RA patients. Four RCTs comprising 2185 patients met the inclusion criteria. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of achieving the American College of Rheumatology 20% (ACR20) response rate, followed by baricitinib 4 mg, tofacitinib 5 mg, filgotinib 200 mg, and MTX. Tofacitinib, baricitinib, upadacitinib, and filgotinib treatments achieved significantly higher ACR50 and ACR70 responses compared to MTX. Tofacitinib 5 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. The safety analysis based on serious adverse events, adverse events (AEs), and withdrawals due to AEs revealed no statistically significant differences between the respective intervention groups. In conclusion, tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for DMARD-naïve RA patients, suggesting a difference in efficacy and safety among the different JAK inhibitors.. Die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib wurde im Vergleich zu Methotrexat (MTX) bei DMARD-naiven („disease-modifying antirheumatic drug“) Patienten mit rheumatoider Arthritis (RA) untersucht. Die Autoren führten eine Netzwerk-Metaanalyse nach Bayes durch, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib, Filgotinib und MTX bei DMARD-naiven RA-Patienten zu ermitteln. Die Einschlusskriterien wurden von 4 RCT mit 2185 Patienten erfüllt. Die Ranking-Wahrscheinlichkeit auf Grundlage der Fläche unter der kumulativen Ranking-Kurve („surface under the cumulative ranking curve“, SUCRA) zeigte, dass unter Upadacitinib 15 mg die höchste Wahrscheinlichkeit zur Erzielung der Responserate gemäß American College of Rheumatology 20 % (ACR20) bestand, dann folgten Baricitinib 4 mg, Tofacitinib 5 mg, Filgotinib 200 mg und MTX. Die Behandlung mit Tofacitinib, Baricitinib, Upadacitinib und Filgotinib führten zu signifikant höheren ACR50- und ACR70-Therapieantworten als MTX. Tofacitinib 5 mg wies die höchste Wahrscheinlichkeit für die Erzielung der ACR50- und ACR70-Responseraten auf, es folgten Upadacitinib 15 mg, Baricitinib 4 mg, Filgotinib 200 mg und MTX. Die Sicherheitsanalyse basierte auf den Parametern schwere unerwünschte Ereignisse, unerwünschte Ereignisse („adverse events“, AE) und Therapieabbruch aufgrund von AE, aber es waren keine statistisch signifikanten Unterschiede zwischen den jeweiligen Interventionsgruppen festzustellen. Als Fazit ist festzuhalten, dass Tofacitinib, Baricitinib, Upadacitinib und Filgotinib wirksame Therapieoptionen bei DMARD-naiven RA-Patienten waren, dabei ergaben sich Hinweise auf Unterschiede zwischen der Wirksamkeit und Sicherheit zwischen den verschiedenen JAK-Inhibitoren.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Sulfonamides; Treatment Outcome; Triazoles

Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.. Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.. The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.. The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

Topics: Adamantane; Advisory Committees; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Cytokines; Drug Therapy, Combination; Europe; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Niacinamide; Piperidines; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Rheumatology; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles

JAK inhibitor therapies are effective treatment options for immune-mediated inflammatory diseases (IMIDs), but their use has been limited by venous thromboembolism (VTE) risk warnings from licensing authorities. We undertook this study to evaluate the VTE risk of JAK inhibitors in patients with IMIDs.. Systematic searches of Medline and Embase databases from inception to September 30, 2020 were conducted. Phase II and phase III double-blind, randomized controlled trials (RCTs) of JAK inhibitors at licensed doses were included in our analyses. RCTs with no placebo arm, long-term extension studies, post hoc analyses, and pooled analyses were excluded. Three researchers independently extracted data on exposure to JAK inhibitors or placebo and VTE events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]) and assessed study quality.. A total of 42 studies were included, from an initial search that yielded 619. There were 6,542 JAK inhibitor patient exposure years (PEYs) compared to 1,578 placebo PEYs. There were 15 VTE events in the JAK inhibitor group and 4 in the placebo group. The pooled incidence rate ratios (IRRs) of VTE, PE, and DVT in patients receiving JAK inhibitors were 0.68 (95% confidence interval [95% CI] 0.36-1.29), 0.44 (95% CI 0.28-0.70), and 0.59 (95% CI 0.31-1.15), respectively.. This meta-analysis of RCT data defines the VTE risk with JAK inhibitors as a class in IMID patients. The pooled IRRs do not provide evidence that support the current warnings of VTE risk for JAK inhibitors. These findings will aid continued development of clinical guidelines for the use of JAK inhibitors in IMIDs.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pulmonary Embolism; Purines; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles; Venous Thromboembolism; Venous Thrombosis

Primary non-response and secondary loss of response remain a significant issue with the currently available treatment options for a significant proportion of patients with inflammatory bowel disease (IBD). There are multiple unmet needs in the IBD treatment algorithm and new treatment options are required. As our understanding of the pathogenesis of IBD evolves, new therapeutic targets are being identified. The JAK-STAT pathway has been extensively studied. Tofacitinib, a JAK1 inhibitor, is now licensed for use in the induction and maintenance of ulcerative colitis and there are a large number of molecules currently under investigation. These new small molecule drugs (SMDs) will challenge current treatment pathways at a time when clinical therapeutic outcomes are rapidly evolving and becoming more ambitious. This is a review of the current JAK1 inhibitors in IBD including the current evidence from clinical trials.

Topics: Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase 1; Janus Kinase Inhibitors; Piperidines; Pyridines; Pyrimidines; Triazoles

Inhibition of Janus kinases [JAKs] in Crohn's disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

Topics: Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Piperidines; Pyridines; Pyrimidines; Treatment Failure; Treatment Outcome; Triazoles

We compared the efficacy and safety of tofacitinib and filgotinib in patients with rheumatoid arthritis (RA) showing inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs).. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and filgotinib in combination with methotrexate (MTX) in patients with RA exhibiting inadequate cs- or bDMARD response.. Nine RCTs consisting of 5466 patients met the inclusion criteria. We obtained 15 pairwise comparisons, including 11 direct comparisons from 6 interventions. Tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were among the most effective treatments for active RA showing an inadequate cs- or bDMARD response, followed by tofacitinib 5 mg + MTX, filgotinib 100 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX showed the highest probability of being the best treatment options in terms of ACR20 response rate (SUCRA = 0.898, 0.782), followed by tofacitinib 5 mg + MTX (SUCRA = 0.602), filgotinib 100 mg + MTX (SUCRA = 0.359), adalimumab + MTX (SUCRA = 0.358), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, filgotinib + MTX, adalimumab + MTX, or placebo + MTX.. In patients with RA exhibiting an inadequate response to cs- or bDMARDs, tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were the most efficacious interventions and risks of serious adverse events did not differ between tofacitinib and filgotinib groups.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Drug Therapy, Combination; Humans; Methotrexate; Network Meta-Analysis; Piperidines; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles

Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.. We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.. We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37).. In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Topics: Arthritis, Rheumatoid; Azetidines; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Incidence; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Placebos; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing; Sulfonamides; Survival Analysis; Treatment Outcome; Triazoles

Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.

Topics: Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Triazoles

Janus kinase (JAK) inhibitors are novel small molecules with a mechanism of action in multiple signaling pathways that allows their application in a broad spectrum of autoimmune and autoinflammatory diseases. As far as the field of dermatology is concerned, chronic plaque psoriasis is currently one of the most studied indications regarding the potential use of JAK inhibitors. The purpose of this review is to provide a summarized overview of the existing information on the efficacy and safety of JAK inhibitors in plaque psoriasis, with a focus on tofacitinib, ruxolitinib, baricitinib, peficitinib and filgotinib. Although the published data on the therapeutic benefit of these agents in the therapy of this chronic condition are promising, further prospective studies and real-life data are necessary in order to sufficiently evaluate their role as an adequate treatment option for psoriatic patients.

Topics: Adamantane; Azetidines; Humans; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Nitriles; Piperidines; Prospective Studies; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Triazoles

Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed.. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA.. Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo.. All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.

Topics: Adamantane; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Heterocyclic Compounds, 3-Ring; Humans; Niacinamide; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Triazoles

Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK) are tyrosine kinases that act by linkage with different intracellular receptors, regulating cytokines gene transcription implicated in the inflammatory burden seen in IBD patients.. A comprehensive literature search was performed to retrieve studies on JAKi and IBD to discuss the latest developments and how the selectivity of these drugs is changing the natural course of IBD.. Available data on efficacy and safety of JAKi in IBD are highly encouraging and because of their selectivity, these drugs might become among the foremost options in the treatment algorithm.

Topics: Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinase Inhibitors; Naphthyridines; Nitriles; Piperidines; Pyridines; Pyrimidines; Signal Transduction; Triazoles; TYK2 Kinase

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

Topics: Acetates; Animals; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Indans; Indoles; Janus Kinase Inhibitors; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Quinolones; Sphingosine-1-Phosphate Receptors; Triazoles

Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use.

Topics: Adamantane; Arthritis, Rheumatoid; Azetidines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 3; Janus Kinase Inhibitors; Niacinamide; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles; Valine

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Drug Discovery; Heterocyclic Compounds, 3-Ring; Humans; Indans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Mesalamine; Oxadiazoles; Phosphodiesterase Inhibitors; Piperidines; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Lysosphingolipid; Triazoles

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease.

Topics: B-Lymphocytes; Colitis, Ulcerative; Crohn Disease; Humans; Indans; Janus Kinase 1; Janus Kinase Inhibitors; Oligonucleotides; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; Smad7 Protein; T-Lymphocytes; Triazoles

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins. Among these kinases, the non-receptor tyrosine kinase family Janus kinase (JAK) plays a pivotal role in the pathological processes of RA. Several JAK inhibitors have been developed as new therapies for patients with RA. These are oral synthetic DMARDs that inhibit JAK1, 2, and 3. One JAK inhibitor, tofacitinib, has already been approved in many countries. Results of phase III clinical trials using a JAK1/2 inhibitor, baricitinib, have shown feasible efficacy and tolerable safety. Both drugs are effective in patients who showed inadequate response to biological DMARDs as well as synthetic DMARDs. In addition, clinical phase III trials using filgotinib and ABT-494, specific JAK1 inhibitors, are currently underway. JAK inhibitors are novel therapies for RA, but further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Triazoles

The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Autoimmune Diseases; Clinical Trials as Topic; Cytokines; Humans; Inflammation; Inflammatory Bowel Diseases; Janus Kinases; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context.. We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines.. We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR -18.4% [IC95% -33.4 to -3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data.. In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; C-Reactive Protein; Humans; Janus Kinase Inhibitors; Methotrexate

Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.. In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.. JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.. Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Cells, Cultured; Cytokines; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Sulfonamides; Triazoles

The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to adalimumab were assessed in rheumatoid arthritis (RA) patients with inadequate responses to methotrexate (MTX).. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients with inadequate responses to MTX.. Four RCTs comprising 5451 patients met the inclusion criteria. Baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than adalimumab 40 mg + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + MTX had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by upadacitinib 15 mg + MTX, tofacitinib 5 mg + MTX, filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, and placebo + MTX. Upadacitinib 15 mg + MTX and baricitinib 4 mg + MTX showed significantly higher ACR50 and ACR70 response rates than adalimumab 40 mg + MTX. For herpes zoster infection, the ranking probability based on SUCRA indicated that placebo + MTX was likely to be the safest treatment, followed by filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, tofacitinib 5 mg + MTX, upadacitinib 15 mg + MTX, and baricitinib 4 mg + MTX. No statistically significant differences were found between the intervention groups in terms of safety.. In RA patients with an inadequate response to MTX, baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed the highest ACR response rates, suggesting a difference in efficacy among the different JAK inhibitors.. ZIEL DER ARBEIT: Bei Patienten mit rheumatoider Arthritis (RA) und inadäquatem Ansprechen auf Methotrexat (Mtx) wurde die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib im Vergleich zu Adalimumab untersucht.. Die Autoren führten eine Bayes-Netzwerk-Metaanalyse durch, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib, Filgotinib und Adalimumab bei RA-Patienten mit inadäquatem Ansprechen auf MTX zu untersuchen.. Die Einschlusskriterien wurden von 4 RCT mit 5451 Patienten erfüllt. Unter Baricitinib 4 mg + MTX und Upadacitinib 15 mg + MTX zeigte sich eine signifikant höhere ACR20-Ansprechrate (gemäß American College of Rheumatology) als unter Adalimumab 40 mg + MTX. Wie die Rangfolgewahrscheinlichkeit, basierend auf der Oberfläche unter der kumulativen Rangfolgenkurve (SUCRA, „surface under the cumulative ranking curve“), ergab, stellte Baricitinib 4 mg + MTX mit größter Wahrscheinlichkeit die beste Behandlung zur Erzielung der ACR20-Ansprechrate dar, es folgten Upadacitinib 15 mg + MTX, Tofacitinib 5 mg + MTX, Filgotinib 200 mg + MTX, Filgotinib 100 mg + MTX, Adalimumab 40 mg + MTX und Placebo + MTX. Upadacitinib 15 mg + MTX und Baricitinib 4 mg + MTX wiesen signifikant höhere ACR50- und ACR70-Ansprechraten auf als Adalimumab 40 mg + MTX. In Bezug auf eine Herpes-zoster-Infektion ergab die auf SUCRA basierende Rangfolgewahrscheinlichkeit, dass Placebo + MTX am ehesten die sicherste Therapie darstellte, dem folgten Filgotinib 200 mg + MTX, Filgotinib 100 mg + MTX, Adalimumab 40 mg + MTX, Tofacitinib 5 mg + MTX, Upadacitinib 15 mg + MTX und Baricitinib 4 mg + MTX. Es wurden keine statistisch signifikanten Unterschiede zwischen den Interventionsgruppen hinsichtlich der Sicherheit festgestellt.. Bei RA-Patienten mit inadäquatem Ansprechen auf MTX ergaben Baricitinib 4 mg + MTX und Upadacitinib 15 mg + MTX die höchsten ACR-Ansprechraten, was ein Hinweis auf einen Unterschied in der Wirksamkeit der verschiedenen JAK-Inhibitoren sein könnte.

Topics: Adalimumab; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor-mediated signaling of multiple cytokines and growth factors, including those with pro-inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK-dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head-to-head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long-term clinical data, and when available, real-world experience.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Cell Line; Cytokines; Enzyme Assays; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Janus Kinase 1; Janus Kinase Inhibitors; Male; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Receptors, Cytokine; Sulfonamides; Triazoles