piperidines and Arthritis--Juvenile

Alopecia areata is a common autoimmune condition that disproportionately affects children and can significantly hinder quality of life. Few safe and effective therapies are available for the treatment of severely affected pediatric patients. JAK inhibitors have been recently established as an effective and well-tolerated therapy in adults, but there are limited data regarding the use of JAK inhibitors to treat alopecia areata in children. Here, we review the available literature regarding the use of JAK inhibitors in children in dermatology and across other medical disciplines.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Alopecia Areata; Arthritis, Juvenile; Child; Child, Preschool; Humans; Janus Kinase Inhibitors; Neoplasms; Nitriles; Piperidines; Pyrazoles; Pyrimidines

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA).. A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences.. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence.. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

Topics: Antirheumatic Agents; Arthritis, Juvenile; Arthritis, Psoriatic; Arthritis, Rheumatoid; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Elective Surgical Procedures; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Perioperative Care; Piperidines; Pyrimidines; Pyrroles; Rheumatic Diseases; Rheumatology; Spondylarthritis; Spondylitis, Ankylosing; Surgeons; United States

Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).. This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.. Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.. The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.. Pfizer.

Topics: Administration, Oral; Adolescent; Arthritis, Juvenile; Child; Child, Preschool; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Treatment Outcome

The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.

Topics: Arthritis, Juvenile; Humans; Janus Kinase Inhibitors; Lipid Metabolism; Macrophages; Piperidines

Biological disease-modifying antirheumatic drugs (bDMARDs) are treatment options for refractory juvenile idiopathic arthritis (JIA) cases which cannot be afforded by the majority. Tofacitinib is a novel Janus kinase inhibitor, which is reported to be a cost-effective oral alternative to biologics. This prospective observational study was carried out to observe the efficacy and safety of tofacitinib in refractory polyarticular course JIA patients.. The study was conducted in the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. Twenty-seven refractory polyarticular course JIA patients were included in this study. Patients received tofacitinib at recommended doses. Disease activity level was assessed by Juvenile Arthritis Disease Activity Score (JADAS) 27. Cases were evaluated at baseline and at the 6th, 12th and 24th weeks. Safety was monitored from history, examination findings and laboratory reports. Data were analyzed using appropriate statistical tests.. Enthesitis-related arthritis was the commonest type (37%) followed by polyarticular (rheumatoid factor+) and systemic JIA. There was significant improvement in JADAS 27 in all the subtypes of JIA except oligoarticular extended type. Among 100% high disease activity state cases at baseline, 70.4% were inactive at 24 weeks. It was also possible to significantly reduce the dose of steroid. Few side effects like headache and vomiting, elevation of alanine aminotransferase and anemia were observed at 6 weeks. These side effects subsequently improved.. Significant reduction of disease activity score was observed from baseline to follow up in this study. Tofacitinib was well tolerated with minimum side effects.

Topics: Antirheumatic Agents; Arthritis, Juvenile; Bangladesh; Child; Humans; Piperidines; Pyrimidines; Treatment Outcome

Topics: Arthritis, Juvenile; Humans; Piperidines; Pyrimidines

Topics: Arthritis, Juvenile; Humans; Piperidines; Pyrimidines

Topics: Arthritis, Juvenile; Humans; Piperidines; Pyrimidines

Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Juvenile; Child; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; NF-KappaB Inhibitor alpha; Piperidines; Pyrimidines; Severity of Illness Index; Sirolimus; Treatment Failure; Tumor Necrosis Factor Inhibitors

To present our preliminary experience with JAK inhibitors in treating patients affected by juvenile idiopathic arthritis (JIA) and associated uveitis. Case series. Four consecutive patients with long-term history of juvenile idiopathic arthritis and severe associated uveitis were included in the study. Indication for treatment with JAK inhibitors was uncontrolled arthritis and/or uveitis despite different treatments with conventional and biologic disease modifying antirheumatic drugs (DMARDs). While on treatment with JAK inhibitors, namely, baricitinib (three cases) and tofacitinib (one case), all our patients showed improvement of uveitis defined as a reduction of intraocular inflammation according to Standardized Uveitis Nomenclature criteria. However, we observed a different response to treatment between the uveitis and the articular disease, as the latter did not respond as favorably as the former. Overall, the treatment was well tolerated by all patients and no ocular discomfort, ocular side effects, or allergic reactions were registered. JAK inhibitors may provide a new valuable treatment option in the therapeutic armamentarium for patients affected with JIA-associated uveitis, particularly in those refractory cases that are not adequately responding to conventional or biologic DMARDs.Key Points• A subset of patients with JIA uveitis either remain unresponsive or experience loss of efficacy• JAK inhibitors may provide a new valuable treatment option in JIA patients with uveitis• The safety profile was good with no occurrence of systemic side effects.

Topics: Adolescent; Adult; Arthritis, Juvenile; Azetidines; Female; Humans; Janus Kinase Inhibitors; Male; Piperidines; Purines; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome; Uveitis; Visual Acuity; Young Adult

Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.

Topics: Adolescent; Arthritis, Juvenile; Female; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome

Topics: Administration, Oral; Arthritis, Juvenile; Female; Humans; Janus Kinase Inhibitors; Macula Lutea; Macular Edema; Piperidines; Pyrimidines; Pyrroles; Tomography, Optical Coherence; Uveitis, Anterior; Visual Acuity; Young Adult

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA).. A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences.. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence.. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

Topics: Antirheumatic Agents; Arthritis, Juvenile; Arthritis, Psoriatic; Arthritis, Rheumatoid; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biological Products; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Orthopedics; Perioperative Care; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Rheumatology; Societies, Medical; Spondylitis, Ankylosing; United States