piperidines and Infections

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized controlled studies that will in turn help lead to the recommendation of evidence-based treatments for GA.

Topics: Anti-Infective Agents; Antimalarials; Biological Therapy; Comorbidity; Dermatologic Agents; Diabetes Complications; Diagnosis, Differential; Glucocorticoids; Granuloma Annulare; Humans; Iatrogenic Disease; Infections; Methotrexate; Neoplasms; Pentoxifylline; Phosphodiesterase 4 Inhibitors; Phototherapy; Piperidines; Pyrimidines; Thalidomide

Bruton´s tyrosine kinase (BTK) inhibitor (BTKi)s block the B-cell receptor (BCR) signaling cascade by binding to the BTK enzyme preventing the proliferation and survival of malignant and normal B cells. During the past decade, the clinical use of BTKis for the treatment of B-cell malignancies has exponentially grown, changing the treatment landscape for chronic lymphocytic leukemia (CLL) in particular. At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases. The combined inhibition of BTK ("on-target" effect) and other kinases ("off-target" effect) can have additive or synergistic anti-tumor effects but also induce undesired side effects which might be treatment-limiting. Such "off-target" effects are expected to be more limited for second-generation BTKis. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Humans; Infection Control; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies has been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient's underlying disease as well as concomitant or previous therapies have an impact on the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated with a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated with severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and histone deacetylase inhibitors do not seem to be associated with a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Communicable Disease Control; Humans; Immune Checkpoint Inhibitors; Infections; Lymphoproliferative Disorders; Piperidines; Purines; Pyrazines; Quinazolinones; Risk; Rituximab; Sulfonamides; Syndrome

Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) in 2014. Ibrutinib is often used to treat patients who are younger than the patients originally included in theclinical trials have additional unfavorable prognostic factors and suffer from additional comorbidities excluded from the original phase III trials. Our objective was to examine current clinical practices and their impact in this expanded population of CLL patients who often require adjustments in the standard prescribed dose and schedule of therapy.. An extensive review of the medical literature was conducted to establish the consensus on ibrutinib dose modifications in patients with CLL. Twenty-nine studies were reviewed including fourteen clinical trials and fifteen "real-world practice" studies.. The average discontinuation rate was similar between clinical trials and "real-world practice" studies though the reasons for discontinuation differed. CLL progression was a more common reason for discontinuation in clinical trial studies while toxicity was a more common reason for discontinuation in "real-world practice" studies. Some studies have suggested worse outcomes in patients requiring dose reductions in ibrutinib while others have shown no change in treatment efficacy in patients requiring dose reductions due to concomitant CYP medications or increased immunosuppression post-transplant.. The impact of ibrutinib dose modifications on clinical outcome remains unclear. Patients on concomitant CYP3A inhibitors should be prescribed a lower dose than the standard 420 mg daily, in order to maintain comparable pharmacologic properties. Further research is required to establish definitive clinical practice guidelines.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Biotransformation; Clinical Studies as Topic; Clinical Trials as Topic; Cohort Studies; Cytochrome P-450 CYP3A; Disease Susceptibility; Dose-Response Relationship, Drug; Early Termination of Clinical Trials; Hematologic Diseases; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Proteins; Pilot Projects; Piperidines; Practice Patterns, Physicians'; Protein Kinase Inhibitors

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Arrhythmias, Cardiac; Arthralgia; Benzamides; Diarrhea; Hemorrhage; Humans; Hypertension; Infection Control; Infections; Male; Piperidines; Protein Kinase Inhibitors; Pyrazines

We performed a systematic review and meta-analysis to evaluate the comparative risk of serious infections with tumor necrosis factor (TNF) antagonists, non-TNF targeted biologics, tofacitinib, and immunosuppressive agents in patients with inflammatory bowel diseases (IBDs).. In a systematic search of publications, through March 18, 2018, we identified 15 observational studies (>500 person-years) of patients with IBD treated with TNF antagonists, non-TNF targeted biologics, tofacitinib, and/or immunosuppressive agents (thiopurines, methotrexate) that reported risk of serious infections. Only studies with active comparators were included, to allow appropriate comparative synthesis. We performed random-effects meta-analysis and estimated relative risk (RR) and 95% CIs.. Compared with anti-TNF monotherapy, risk of serious infection increased with the combination of anti-TNF and an immunosuppressive agent (in 6 cohorts: RR, 1.19; 95% CI, 1.03-1.37), with anti-TNF and a corticosteroid (in 4 cohorts: RR, 1.64; 95% CI, 1.33-2.03), or with all 3 drugs (in 2 cohorts: RR, 1.35; 95% CI, 1.04-1.77); there was minimal heterogeneity among studies. In contrast, monotherapy with an immunosuppressive agent was associated with a lower risk of serious infections than monotherapy with a TNF antagonist (7 cohorts: RR, 0.61; 95% CI 0.44-0.84) or a TNF antagonist with an immunosuppressive agent (2 cohorts: RR, 0.56; 95% CI, 0.39-0.81). Infliximab-based therapy was associated with a lower risk of serious infections compared with adalimumab-based therapy in patients with ulcerative colitis (4 cohorts: RR, 0.57; 95% CI, 0.33-0.97), but not Crohn's disease (4 cohorts: RR, 0.91; 95% CI, 0.49-1.70). Few data were available on the comparative safety of biologic agents that do not inhibit TNF and tofacitinib.. Combination therapies for IBD that include TNF antagonists, especially with corticosteroids, are associated with a higher risk of serious infection, whereas monotherapy with an immunosuppressive agent is associated with a lower risk, compared with monotherapy with a TNF antagonist. Studies are needed to evaluate the comparative safety of non-TNF targeted biologics and small molecules for treatment of IBD.

Topics: Biological Products; Humans; Immunosuppressive Agents; Infections; Inflammatory Bowel Diseases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Tumor Necrosis Factor-alpha

With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies.. Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Demyelinating Diseases; Deprescriptions; Drug Substitution; Gastrointestinal Agents; Humans; Infections; Inflammatory Bowel Diseases; Lymphoma; Melanoma; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk; Risk Assessment; Skin Neoplasms; Tumor Necrosis Factor-alpha; Ustekinumab

Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib's adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.

Topics: Adenine; Aged; Anti-Infective Agents; Anticoagulants; Arthralgia; Atrial Fibrillation; Drug Resistance, Neoplasm; Female; Hemorrhage; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines

To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.. We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.. Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.. The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.. Prospero 2017 CRD4201707879.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Incidence; Infections; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL), including the new kinase inhibitors (KIs) ibrutinib and idelalisib, has changed the therapeutic landscape of the disease. The new KIs have also changed frequency and epidemiology of infections, that represent a major cause of morbidity and mortality of the disease. Hence, the great strides in the indications and use of new KIs need parallel amelioration of prophylaxis and supportive treatment for infections. Moving from the recognition that infection control represents an unmet need, the Italian Society of Hematology (SIE) convened a panel of experts who had published and/or expressed an interest in infection complications in CLL. The goal of the project was to provide practice recommendations for the management of the infectious complications of CLL during ibrutinib or idelalisib therapy. The present publication represents the results of a series of email correspondences and meetings held during 2017 and 2018. Three domains of infectious complications during KIs therapy for CLL were explored: risk assessment, risk management and risk monitoring. We hope these recommendations will help to minimize infectious adverse events, and we believe that an optimal management of them will be rewarded by better outcomes, and better quality of life.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Hematology; Humans; Infection Control; Infections; Italy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Practice Guidelines as Topic; Purines; Pyrazoles; Pyrimidines; Quality of Life; Quinazolinones

Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated.. The published literature and conference abstracts of prospective clinical trials using ibrutinib in hematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc.org per PRISMA guidelines. Infectious events with a focus on pneumonia were collated per the Common Terminology Criteria for Adverse Events Version 4.03 grading.. Infectious complications are common, occurring in 56% of patients taking single-agent ibrutinib and 52% of those on combination therapy. Approximately one in 5 patients developed pneumonia, which was the major contributor to a 2% rate of death from infections. Many of the cases of pneumonia were due to opportunistic pathogens.. Ibrutinib use requires prudent consideration of the impacts on host immunity. We identified a high rate of serious adverse infectious events within prospective clinical trials. Data suggest a role of both BTK and ITK inhibition for the increased events. There was considerable variability in the reporting of adverse events between trials, journals, and conference reports.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Infections; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Acalabrutinib, a selective Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken. Serious adverse reactions are rare with acalabrutinib; however, patients should be made aware of common adverse events such as headaches, which usually resolve within one month without medical treatment. Interaction with other drugs appears to be less of an issue with acalabrutinib than with ibrutinib; however, patients receiving acalabrutinib therapy must be advised not to take any additional medications without first consulting with their treating physician. A key unmet medical need is treatment options for patients in whom BTK inhibitors are discontinued, because of either intolerance or refractory disease. Patients not tolerating ibrutinib could be switched to acalabrutinib, which has improved selectivity and increased tolerability. First-line treatment with acalabrutinib is being investigated.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Humans; Infection Control; Infections; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cell Communication; Humans; Immunosuppressive Agents; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment

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

To determine the rate of infection and all-cause mortality across tofacitinib phase II, phase III, and long-term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).. Pooled data from studies of tofacitinib in patients with RA were analyzed. In these studies, tofacitinib was administered as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. The cutoff date for inclusion of data was April 19, 2012.. Across phase II, phase III, and LTE studies, 4,789 patients received tofacitinib (8,460 patient-years of exposure). The overall rate of serious infection was 3.09 events per 100 patient-years (95% confidence interval [95% CI] 2.73-3.49), and rates were stable over time. A Cox proportional hazards model showed that age, corticosteroid dose, diabetes, and tofacitinib dose were independently linked to the risk of serious infection. Lymphocyte counts of <0.5 × 10(3) /mm(3) were rare but were associated with an increased risk of treated and/or serious infection. Overall, all-cause mortality rates were 0.30 events per 100 patient-years (95% CI 0.20-0.44).. The overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Humans; Infections; Longitudinal Studies; Male; Methotrexate; Middle Aged; Piperidines; Prevalence; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome; Young Adult

Tofacitinib (tositinib, CP-690,550) is a small molecule inhibitor of Janus associated kinases, primarily JAK3 and JAK2, which inhibits cytokine signaling through the IL-2Rγ chain. In this article, we review the mechanism of action of tofacitinib, and pre-clinical and clinical data regarding its use in solid organ transplantation thus far. It is hoped that tofacitinib may form the basis for calcineurin-free immunosuppression, improving renal function while eliminating calcineurin inhibitor renal toxicity. Current studies suggest that tofacitinib is an effective immunosuppressive agent for renal transplantation, but it's use in current protocols carries an increased risk of CMV, BK, and EBV viral infection, anemia and leukopenia, and post-transplant lymphoproliferative disorder.

Topics: Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk Factors

The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention.. We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided.. Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001).. NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Confidence Intervals; Humans; Infections; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Odds Ratio; Piperazines; Piperidines; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.. Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event].. In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death.. During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Topics: Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Janus Kinase Inhibitors; Male; Medication Therapy Management; Opportunistic Infections; Piperidines; Pyrimidines; Risk Assessment; Severity of Illness Index

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prognosis; Rituximab; Survival Rate

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Cardiovascular Diseases; Female; Follow-Up Studies; Hematologic Diseases; Humans; Infections; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Risk; Salvage Therapy; Treatment Outcome

Topics: Adenine; Adolescent; Adult; Child; Female; Follow-Up Studies; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prevalence; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Risk Factors

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Atrial Fibrillation; Diarrhea; Drug Tolerance; Fatigue; Female; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Safety

To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort.. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics.. Primary and secondary care medical centers in the United States, Canada, Europe, and India.. A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis.. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications.. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs).. There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant.. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Topics: Accidental Falls; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Drug Therapy, Combination; Edema; Female; Humans; Hypotension, Orthostatic; Infections; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Stroke; Thromboembolism; Urea

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; B-Lymphocytes; Bone Marrow; Female; Follow-Up Studies; Humans; Immunity, Humoral; Immunoglobulins; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recovery of Function; Time Factors

To assess the effects of tofacitinib on T lymphocytes in RA patients with a special focus on efficacy and infectious adverse events (iAEs).. Forty-four RA patients participated in 12-month phase II/III randomized clinical trials and an open-label extension trial. Peripheral lymphocyte subsets and in vitro CD4(+) T lymphocyte proliferation were measured in 23 patients of 44 at baseline and at the end of the 12-month trial.. Forty-four patients [35 females, age 54.3 years, disease duration 84.3 months, simplified disease activity index (SDAI) 36.5, CRP 24.9 mg/l, ESR 53 mm/h, MMP-3 284 pg/ml, RF 172.6 IU/ml, neutrophil count 4842 per μl, lymphocyte count 1410 per μl] were treated with tofacitinib. At the end of the study, the SDAI improved to 6.2, but the peripheral lymphocyte count and absolute numbers of CD4(+) and CD8(+) subpopulations did not change during this period. However, CD4(+) T lymphocyte proliferation was suppressed, which correlated with the improvement in SDAI, but not with iAEs (n = 19) during the 12-month treatment. Receiver operating characteristic analysis identified a CD8(+) T lymphocyte count ≤ 211 per μl at baseline as a significant predictor of clinically significant iAEs.. The efficacy of tofacitinib is mediated through the suppression of CD4(+) T lymphocyte proliferation without affecting the absolute number of these cells in the periphery. A low CD8(+) T cell count at baseline correlated with the development of iAEs during the treatment of RA patients.

Topics: Adult; Aged; Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell Proliferation; Double-Blind Method; Female; Humans; In Vitro Techniques; Infections; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk Factors; Severity of Illness Index; Treatment Outcome

Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax).. Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020.. Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed.. A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.

Topics: Adenine; Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunocompromised Host; Infections; Lymphopenia; Lymphoproliferative Disorders; Male; Middle Aged; Piperidines; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazines; Quinazolinones; Retrospective Studies; Risk Factors; Sulfonamides; Young Adult

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Humans; Immunoglobulin A; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prospective Studies

Topics: Adalimumab; Age Factors; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Female; Humans; Incidence; Infections; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Proportional Hazards Models; Pyrimidines; Registries; Risk Factors; United States

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA.. In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12-24 months; n = 717-958) and phase I/II/III/long-term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5-6 months' exposure; n = 236-486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55-1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs.. Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm. Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA.

Topics: Arthritis, Rheumatoid; B-Lymphocytes; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Humans; Incidence; Infections; Janus Kinase Inhibitors; Killer Cells, Natural; Lymphocyte Count; Piperidines; Pyrimidines; Pyrroles; T-Lymphocyte Subsets; T-Lymphocytes; Time Factors

Tofacitinib is the first oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA). We compared the effectiveness and safety of tofacitinib, disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor inhibitors (TNFi), and non-TNF biologics in patients with RA previously treated with methotrexate.. We used MarketScan® databases (2011-2014) to study methotrexate-exposed patients with RA who were newly prescribed tofacitinib, DMARDs other than methotrexate, and biologics. The date of first prescription was defined as the cohort entry. The therapy was considered effective if all of the following criteria from a claims-based algorithm were achieved at the first year of follow-up: high adherence, no biologic or tofacitinib switch or addition, no DMARD switch or addition, no increase in dose or frequency of index drug, no more than one glucocorticoid joint injection, and no new/increased oral glucocorticoid dose. The safety outcome was serious infections requiring hospitalization. Non-TNF biologics comprised the reference group.. We included 21,832 patients with RA, including 0.8% treated with tofacitinib, 24.7% treated with other DMARDs, 61.2% who had started therapy with TNFi, and 13.3% treated with non-TNF biologics. The rates of therapy effectiveness were 15.4% for tofacitinib, 11.1% for DMARDs, 18.6% for TNFi, and 19.8% for non-TNF biologics. In adjusted analyses, tofacitinib and non-TNF biologics appeared to have similar effectiveness rates, whereas DMARD initiators were less effective than non-TNF biologics. We could not clearly establish if tofacitinib was associated with a higher rate of serious infections.. In patients with RA previously treated with methotrexate, our comparisons of tofacitinib with non-TNF biologics, though not definitive, did not demonstrate differences with respect to hospitalized infections or effectiveness.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cohort Studies; Female; Humans; Infections; Male; Methotrexate; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Retrospective Studies; Treatment Outcome

Topics: Adenine; Clinical Trials, Phase III as Topic; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Meta-Analysis as Topic; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.. Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.. 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.. This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.. NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Clinical Trials as Topic; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Time Factors; Tuberculosis; Young Adult

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Female; France; Gastrointestinal Diseases; Hematologic Diseases; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome