piperidines and Rheumatic-Diseases

Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.. 托法替尼是一种Janus激酶抑制剂，能够阻断Janus激酶和相关的信号转导及转录激活因子信号转导通路，减少多种细胞因子的生成与释放，具有治疗多种风湿病的潜力，其优点是起效快、能减少对糖皮质激素的依赖和相关不良事件。托法替尼在成人患者中的治疗作用已被证实，近年来已越来越多应用于儿童患者中，该文就托法替尼在儿童风湿病中的临床应用作一综述。.

Topics: Adult; Child; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Rheumatic Diseases

Tofacitinib is an oral, small molecule JAK inhibitor that targets JAK1/JAK3. Tofacitinib has been approved by the FDA to be used in the treatments of rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ulcerative colitis. Considering the important pathogenic role of the JAK/STAT pathway in autoimmune disease, tofacitinib could be, theoretically, effective in the treatments of other systemic rheumatic diseases. Here we reviewed the published literature to profile the perspectives about the off-label uses of tofacitinib, especially in those refractory cases with poor response to conventional therapies or biologic agents. Tofacitinib can be a new therapeutic option and help reducing hormone dependence and correlated adverse events.

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Janus Kinase 1; Janus Kinase 3; Off-Label Use; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Rheumatic Diseases

Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients.. A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events.. Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated.. Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.

Topics: Animals; Antirheumatic Agents; Biological Products; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Retrospective Studies; Rheumatic Diseases; Risk Factors

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

Patients with rheumatoid arthritis are highly vulnerable to infections because of abnormalities in their immune system, and because of immunosuppressive effects of their medications. Vaccinations in this population are complicated by disease-modifying antirheumatic drugs, which also modulate or suppress the immune system and potentially decrease the immunogenicity and efficacy of the vaccines. We review the available data regarding the impact of rheumatoid arthritis therapy on the immunogenicity of various common vaccines. We also review rheumatoid arthritis-specific vaccination recommendations, live vaccine safety concerns, and current gaps in our understanding of these issues."

Topics: Abatacept; Antirheumatic Agents; Contraindications; Drug Interactions; Herpes Zoster Vaccine; Humans; Immunocompromised Host; Immunogenicity, Vaccine; Influenza Vaccines; Methotrexate; Piperidines; Pneumococcal Vaccines; Pyrimidines; Pyrroles; Rheumatic Diseases; Rheumatologists; Rituximab; Vaccines; Vaccines, Attenuated; Yellow Fever Vaccine

Tofacitinib is the first Janus kinase (JAK) inhibitor commercially approved for the treatment of rheumatoid arthritis. This compound and a number of other JAK inhibitors are currently being tested in phase II and III trials for the treatment of a variety of autoimmune inflammatory diseases. Whereas a characteristic safety profile is emerging for some JAK inhibitors, differences between individual agents might emerge on the basis of distinct potency against their molecular targets. Similarly to biological therapy, JAK inhibition can lead to serious and opportunistic infections, and viral infections seem to be particularly frequent. Although no malignancy signals have been identified to date, long-term follow-up and further research are needed to understand the risk of malignancy associated with these compounds. As is the case for biologic agents, vaccination is important to mitigate the risks of these emerging therapies.

Topics: Azetidines; Humans; Infections; Janus Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Rheumatic Diseases; Signal Transduction; Sulfonamides

Topics: Administration, Oral; Animals; Humans; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rheumatic Diseases

After two decades of research and development activity focussed on orally active kinase inhibitors, the first such drug (the JAK inhibitor Xeljanz, tofacitinib) was approved by the FDA in November 2012 for the treatment of rheumatoid arthritis (RA). There is an intense activity in many companies both on expanding the utility of JAK inhibitors in other auto-immune indications and in discovering inhibitors of the JAK family with different and more selective profiles. Progress is also being made with orally active Syk inhibitors. One such inhibitor (fostamatinib) is currently in large-scale phase 3 trials, and there are others in clinical development. The last two to three years have been transformative for kinase inhibitors in auto-immune diseases, as several inhibitors have finally progressed beyond phase 2 trials after so many failures on other targets. Thus, there are new treatment options for RA patients beyond existing oral DMARDs and parenteral biologics.

Topics: Animals; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinase 3; Mitogen-Activated Protein Kinases; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Rheumatic Diseases; Syk Kinase

Hepatitis B virus (HBV) can reactivate among rheumatology patients initiating tocilizumab (TCZ) or tofacitinib (TOF). HBV screening is recommended by the Centers for Disease Control and Prevention (CDC), the American Association for the Study of Liver Diseases (AASLD), and the Canadian Rheumatology Association, but it is not explicitly recommended by the American College of Rheumatology.. We conducted a cross-sectional study to characterize HBV screening practices for adult rheumatology patients initiating TCZ or TOF before December 31, 2018, in the Greater Boston area. We classified appropriate HBV screening patterns prior to TCZ or TOF (i.e., HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb]) as follows: complete (all 3 tested), partial (any 1 or 2 tests), or none. We determined the frequency of inappropriate HBV testing (HBV e-antigen, anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb) and used multivariable regression to assess factors associated with complete HBV screening.. Among 678 subjects initiating TCZ, 194 (29%) completed appropriate HBV screening, 307 (45%) had partial screening, and 177 (26%) had none. Among 391 subjects initiating TOF, 94 (24%) completed appropriate HBV screening, 195 (50%) had partial screening, and 102 (26%) had none. Inappropriate testing was performed in 22% of subjects. Race was associated with complete HBV screening (White vs non-White: OR 0.74, 95% CI 0.57-0.95), whereas prior immunosuppression was not (conventional synthetic disease-modifying antirheumatic drugs [DMARDs]: OR 1.05, 95% CI 0.72-1.55; biologic DMARDs: OR 0.73, 95% CI 0.48-1.12).. Patients initiating TCZ or TOF are infrequently screened for HBV despite recommendations from the AASLD and CDC.

Topics: Adult; Antibodies, Monoclonal, Humanized; Canada; Cross-Sectional Studies; Hepatitis B; Hepatitis B virus; Humans; Piperidines; Pyrimidines; Rheumatic Diseases

Topics: Aged; Antibodies, Monoclonal, Humanized; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Latent Infection; Male; Middle Aged; Piperidines; Pyrimidines; Retrospective Studies; Rheumatic Diseases

Topics: COVID-19; COVID-19 Vaccines; Humans; Piperidines; Pyrimidines; Rheumatic Diseases; Rheumatology; SARS-CoV-2; United States; Vaccination

Topics: Abatacept; Adult; Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Azetidines; Betacoronavirus; Coronavirus Infections; COVID-19; Disease Susceptibility; Female; Hospitalization; Humans; Interleukin 1 Receptor Antagonist Protein; Italy; Janus Kinase Inhibitors; Logistic Models; Male; Middle Aged; Pandemics; Piperidines; Pneumonia, Viral; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Pyrroles; Rheumatic Diseases; Risk Factors; SARS-CoV-2; Severity of Illness Index; Sulfonamides; Tumor Necrosis Factor Inhibitors; Ustekinumab

Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.. This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.. DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).

Topics: Adult; Aged; Antirheumatic Agents; Clinical Trials as Topic; Female; Humans; Incidence; Male; Middle Aged; Observational Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Thromboembolism

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

The 2016 Annual European Congress of Rheumatology, an annual conference organized by the European League Against Rheumatism (EULAR), took place in London, U.K. Over 4,000 abstracts were submitted this year with over 199 sessions and poster tours on offer. The congress has become a major event in the field of rheumatology with participants attending from around the world. The oral sessions, poster displays and lectures cover a broad spectrum of topics, including the latest understanding of disease processes, as well as recent advances in diagnosis and patient care.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Piperidines; Pyrimidines; Pyrroles; Rheumatic Diseases; Rheumatology

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chronic Disease; Drug Approval; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Switzerland

Janus protein tyrosine kinase (JAK) inhibitors are new therapeutic targets in the treatment of rheumatoid arthritis. Tofacitinib has shown good clinical efficacy in phase II and III studies with American College of Rheumatology (ACR) 20 response rates over 50% for monotherapy and in combination with methotrexate (MTX). Also the safety profile shows similar infection rates as observed with known biologicals. The crude rate of serious infection events was 3/100 patient-years. Often reported adverse events are infections of the upper respiratory tract and urogenital infections.

Topics: Antirheumatic Agents; Drug Delivery Systems; Humans; Janus Kinases; Piperidines; Pyrimidines; Pyrroles; Rheumatic Diseases

Topics: Adult; Benzydamine; Contusions; Dibucaine; Drug Combinations; Female; Humans; Hyaluronoglucosaminidase; Joint Diseases; Male; Middle Aged; Periarthritis; Piperidines; Pyrazoles; Rheumatic Diseases; Sprains and Strains; Torticollis

Topics: Adult; Furans; Humans; Liver; Piperidines; Rheumatic Diseases; Spiro Compounds; Stomach