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Gastroenterology May 2020Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.
METHODS
We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.
RESULTS
We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37).
CONCLUSIONS
In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.
Topics: Arthritis, Rheumatoid; Azetidines; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Incidence; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Placebos; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing; Sulfonamides; Survival Analysis; Treatment Outcome; Triazoles
PubMed: 31926171
DOI: 10.1053/j.gastro.2020.01.001 -
The British Journal of Dermatology Sep 2023On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked... (Meta-Analysis)
Meta-Analysis
BACKGROUND
On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked to the occurrence of major adverse cardiovascular events (MACE). However, these inflammatory diseases are proatherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden.
OBJECTIVES
To perform a systematic review and meta-analysis of MACE in patients with AD treated with JAKi.
METHODS
We systematically searched PubMed, Embase, Cochrane Library and Google Scholar from their inception to 2 September 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAKi for AD were selected. We included patients aged ≥ 12 years. We built a 'controlled-period' cohort (n = 9309; 6000 exposed to JAKi and 3309 exposed to comparators) and an 'all-JAKi' cohort (n = 9118 patients exposed to a JAKi in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischaemic or haemorrhagic), transient ischaemic attack and CV death. The frequency of primary and secondary MACE was assessed in both cohorts. A fixed-effects meta-analysis using the Peto method was used to calculate the odds ratio (OR) for MACE in the 'controlled-period' cohort. Evaluation of the risk of bias was done using the Cochrane risk-of-bias tool (version 2). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
RESULTS
Eight per cent of the records identified initially met the selection criteria, corresponding to 23 records included in the 'all-JAKi' cohort. Patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (three with JAKi and one with placebo) and five secondary events (four with JAKi and one with placebo) occurred among 9309 patients in the 'controlled-period' cohort (MACE frequency 0.04% and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9118 patients in the 'all-JAKi' cohort (MACE frequency 0.08% and 0.14%, respectively). The OR for primary MACE in patients with AD treated with JAKi vs. placebo or dupilumab was 1.35 (95% confidence interval 0.15-12.21; I2 = 12%, very low certainty of evidence).
CONCLUSIONS
Our review highlights rare cases of MACE among JAKi users for AD. JAKi may have little-to-no effect on the occurrence of MACE in patients with AD vs. comparators, but the evidence is uncertain. Real-life long-term population-level safety studies are needed.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Brain Ischemia; Stroke; Inflammatory Bowel Diseases
PubMed: 37410552
DOI: 10.1093/bjd/ljad229 -
Journal of the European Academy of... Jan 2024Janus kinase (JAK) inhibitors have been recently approved by the FDA and are widely used in the treatment of patients with atopic dermatitis. However, a comprehensive... (Meta-Analysis)
Meta-Analysis Review
Janus kinase (JAK) inhibitors have been recently approved by the FDA and are widely used in the treatment of patients with atopic dermatitis. However, a comprehensive safety profile of JAK inhibitors in patients with atopic dermatitis has not been analysed. This study aimed to establish clinical evidence for the safety of systemic JAK inhibitors in patients with atopic dermatitis. Medline, Embase, Clinicaltrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and International Clinical Trials Registry Platform (ICTRP) were considered for search databases. Randomized controlled trials reporting the adverse events of systemic therapy in patients with atopic dermatitis were included. The risk of 11 adverse events was compared between the JAK inhibitors and placebo groups. Fourteen randomized controlled trials were analysed published between 2019 and 2022. The JAK inhibitors included in the analysis were abrocitinib (10, 30, 100 and 200 mg), baricitinib (1, 2 and 4 mg) and upadacitinib (7.5, 15 and 30 mg). The risk of herpes zoster, headache, acne, elevated blood creatinine phosphokinase and nausea was significantly increased, but the risk of serious infection, non-melanoma skin cancer (NMSC), malignancies other than NMSC, major adverse cardiovascular event, venous thromboembolism and nasopharyngitis was not increased. This study provides comprehensive clinical evidence on the risk of various adverse events in patients with atopic dermatitis. However, since the follow-up periods of the studies analysed in this review were mostly limited to 16 weeks or less, it is recommended that comprehensive long-term observational studies be conducted to determine any potential adverse events associated with major cardiovascular events or malignancies, which typically have prolonged courses.
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Randomized Controlled Trials as Topic; Herpes Zoster; Neoplasms; Treatment Outcome
PubMed: 37597261
DOI: 10.1111/jdv.19426 -
Journal of the American Academy of... Jun 2022Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist;... (Review)
Review
BACKGROUND
Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist; however, their evidence in pediatric AA patients is lacking.
OBJECTIVE
To evaluate the evidence of current treatment modalities for pediatric AA.
METHODS
We conducted a systematic review on the PubMed database in October 2019 for all published articles involving patients <18 years old. Articles discussing AA treatment in pediatric patients were included, as were articles discussing both pediatric and adult patients, if data on individual pediatric patients were available.
RESULTS
Inclusion criteria were met by 122 total reports discussing 1032 patients. Reports consisted of 2 randomized controlled trials, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles assessed the use of aloe, apremilast, anthralin, anti-interferon gamma antibodies, botulinum toxin, corticosteroids, contact immunotherapies, cryotherapy, hydroxychloroquine, hypnotherapy, imiquimod, Janus kinase inhibitors, laser and light therapy, methotrexate, minoxidil, phototherapy, psychotherapy, prostaglandin analogs, sulfasalazine, topical calcineurin inhibitors, topical nitrogen mustard, and ustekinumab.
LIMITATIONS
English-only articles with full texts were used. Manuscripts with adult and pediatric data were only incorporated if individual-level data for pediatric patients were provided. No meta-analysis was performed.
CONCLUSION
Topical corticosteroids are the preferred first-line treatment for pediatric AA, as they hold the highest level of evidence, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA and to promote the potential use of pre-existing, low-cost, and novel therapies, including Janus kinase inhibitors.
Topics: Adolescent; Adrenal Cortex Hormones; Alopecia; Alopecia Areata; Autoimmune Diseases; Child; Humans; Janus Kinase Inhibitors; Prospective Studies
PubMed: 33940103
DOI: 10.1016/j.jaad.2021.04.077 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2021To develop updated guidelines for the pharmacologic management of rheumatoid arthritis.
OBJECTIVE
To develop updated guidelines for the pharmacologic management of rheumatoid arthritis.
METHODS
We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.
RESULTS
The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).
CONCLUSION
This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Drug Therapy, Combination; Glucocorticoids; Humans; Janus Kinase Inhibitors; Rheumatology; Severity of Illness Index; Societies, Medical; Tumor Necrosis Factor Inhibitors; United States
PubMed: 34101376
DOI: 10.1002/art.41752 -
Journal of the American Academy of... Jul 2023New evidence has emerged since the 2014 guidelines that further informs the management of atopic dermatitis (AD) with topical therapies. These guidelines update the 2014...
BACKGROUND
New evidence has emerged since the 2014 guidelines that further informs the management of atopic dermatitis (AD) with topical therapies. These guidelines update the 2014 recommendations for management of AD with topical therapies.
OBJECTIVE
To provide evidence-based recommendations related to management of AD in adults using topical treatments.
METHODS
A multidisciplinary workgroup conducted a systematic review and applied the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for assessing the certainty of evidence and formulating and grading recommendations.
RESULTS
The workgroup developed 12 recommendations on the management of AD in adults with topical therapies, including nonprescription agents and prescription topical corticosteroids (TCS), calcineurin inhibitors (TCIs), Janus kinase (JAK) inhibitors, phosphodiesterase-4 inhibitors (PDE-4), antimicrobials, and antihistamines.
LIMITATIONS
The pragmatic decision to limit the literature review to English-language randomized trials may have excluded data published in other languages and relevant long-term follow-up data.
CONCLUSIONS
Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors. Conditional recommendations are made for the use of bathing and wet wrap therapy and against the use of topical antimicrobials, antiseptics, and antihistamines.
Topics: Adult; Humans; Dermatitis, Atopic; Calcineurin Inhibitors; Dermatologic Agents; Administration, Topical; Glucocorticoids; Anti-Infective Agents, Local; Histamine Antagonists
PubMed: 36641009
DOI: 10.1016/j.jaad.2022.12.029 -
The Journal of Allergy and Clinical... Dec 2023Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes.
OBJECTIVE
We sought to systematically synthesize the benefits and harms of AD systemic treatments.
METHODS
For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna).
RESULTS
The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain.
CONCLUSIONS
Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.
Topics: Humans; Dermatitis, Atopic; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Eczema; Asthma; Treatment Outcome
PubMed: 37678577
DOI: 10.1016/j.jaci.2023.08.029 -
EBioMedicine Mar 2023To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing...
BACKGROUND
To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy.
METHODS
The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence.
FINDINGS
PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects.
INTERPRETATION
This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.
FUNDING
None.
Topics: Male; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Autoimmune Diseases; Biomarkers; Psoriasis; Polymorphism, Single Nucleotide; TYK2 Kinase
PubMed: 36842216
DOI: 10.1016/j.ebiom.2023.104488 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2021Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL (BCP-ALL) with a gene expression profile analogous to... (Review)
Review
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL (BCP-ALL) with a gene expression profile analogous to Philadelphia-positive ALL and recurrent IKAROS Family Zinc Finger 1 (IKZF1) gene deletion despite lacking BCR-ABL1 (Breakpoint cluster region-ABL protooncogene) translocation. Although recognized to occur at all ages, the proportion of cases among BCP-ALL varies (< 10% in children and up to 30% in adolescents). In all age groups, males are more commonly affected. Generally, Ph-like ALL is associated with adverse clinical features and an increased risk of treatment failure with conventional approaches. Genetic alterations such as aberrant expression, point mutations, or fusion translocations lead to activation of cytokine receptors and signaling kinases, which affect the ABL1 (ABL class fusion) or Janus Kinase (JAK) signaling pathways. Several clinical trials are being conducted to understand whether specific tyrosine kinase inhibitor therapy can improve cure rates. This review summarizes the current literature available about this entity.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 33485429
DOI: 10.1016/j.clml.2020.08.011 -
Clinical Rheumatology Jan 2022Corticosteroid-sparing disease-modifying anti-rheumatic drugs are an area of active exploration in large vessel vasculitis (LVV), i.e., Takayasu arteritis (TAK) and... (Review)
Review
Corticosteroid-sparing disease-modifying anti-rheumatic drugs are an area of active exploration in large vessel vasculitis (LVV), i.e., Takayasu arteritis (TAK) and Giant Cell Arteritis (GCA). The role of Janus kinase (JAK) inhibitors has been recently identified in different inflammatory rheumatic diseases. We conducted a systematic review of the use of JAK inhibitors in LVV across MEDLINE, Scopus, Web of Science, EMBASE, PubMed Central, Cochrane database of controlled trials, clinicaltrials.gov, and major recent international conferences. We identified four cohort studies and ten case reports. The JAK inhibitors used in these studies were tofacitinib, baricitinib, and ruxolitinib. A cohort study in TAK compared 27 patients treated with tofacitinib with 26 others treated with methotrexate, with better clinical outcomes with tofacitinib but similar angiographic stabilization, relapses, corticosteroid-sparing effect, and adverse events in both groups. Most of the other studies favored clinical responses with JAK inhibitors in LVV but with a paucity of data on other outcomes. Most of the included studies were of moderate quality. Evidence from pre-clinical models of LVV as well as limited in vivo data in patients with TAK appears to suggest that JAK inhibition reduces adventitial fibrosis, intimal proliferation, and inflammatory T lymphocyte infiltration in the media as well as reduces resident memory T cells in the vascular wall (which are otherwise resistant to corticosteroids). Ongoing clinical trials of tofacitinib, baricitinib, and upadacitinib in LVV shall help to further clarify the potential promise of JAK inhibitors for LVV (PROSPERO registration number CRD42021273359). KEY POINTS : •Tofacitinib appeared to associate with better clinical outcomes than methotrexate in TAK. •JAKinibs reduce adventitial fibrosis, intimal proliferation, and inflammatory vascular infiltrate in pre-clinical models of LVV. •Tofacitinib downregulates resident memory vascular T lymphocytes in pre-clinical models of LVV.
Topics: Antirheumatic Agents; Cohort Studies; Giant Cell Arteritis; Humans; Janus Kinase Inhibitors; Memory T Cells; Takayasu Arteritis
PubMed: 34729652
DOI: 10.1007/s10067-021-05973-4