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Eberhard A, Di Giuseppe D, Askling J, Bergman S, Bower H, Chatzidionysiou K, Forsblad‐d'Elia H, Kastbom A, Olofsson T, Frisell T, Turesson C. Effectiveness of JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs on Pain Reduction in Rheumatoid Arthritis: Results From a Nationwide Swedish Cohort Study. Arthritis Rheumatol 2025; 77:253-262. [PMID: 39308007 PMCID: PMC11865685 DOI: 10.1002/art.43014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/25/2024] [Accepted: 08/30/2024] [Indexed: 10/27/2024]
Abstract
OBJECTIVE To compare the effectiveness of JAK inhibitors (JAKis) and biologic disease-modifying antirheumatic drugs (bDMARDs) on pain in patients with rheumatoid arthritis. METHODS In this retrospective study, we investigated patients with a diagnosis of rheumatoid arthritis, starting treatment with a JAKi (n = 1,827), a tumor necrosis factor inhibitor (TNFi; n = 6,422), an interleukin-6 inhibitor (n = 887), abatacept (n = 1,102), or rituximab (n = 1,149) in 2017 to 2019, using data from several linked Swedish national registers. Differences in change in pain, assessed with a visual analog scale (0-100 mm), from baseline to 3 months, as well as proportions of patients remaining on initial treatment with low pain (visual analog scale pain <20) at 12 months, were compared between treatments. Comparisons of treatment responses between JAKis and bDMARDs were evaluated using multivariable linear regression, adjusted for patient characteristics, comorbidities, current comedication, and previous treatment. RESULTS JAKi treatment was associated with a greater decrease in pain at 3 months compared with TNFi treatment (adjusted mean additional decrease 4.0 mm; 95% confidence interval 1.6-6.3), with similar trends in comparisons with non-TNFi bDMARDs. More patients achieved low pain at 12 months on JAKis compared with TNFis, in particular among those previously treated with at least two bDMARDs (adjusted change contrast 5.3 percentage points; 95% confidence interval 1.0-9.6). CONCLUSION JAKis had a slightly better effect on pain outcomes at 3 and 12 months compared with TNFis, with significantly greater differences in patients previously treated with at least two bDMARDs. The effect of JAKis on pain reduction was at least similar to that of non-TNFi bDMARDs.
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Affiliation(s)
| | | | | | - Stefan Bergman
- Institute of Medicine, Sahlgrenska Academy, University of GothenburgGothenburgSweden
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Pearce‐Fisher D, Smith MH, Mehta BY, Spolaore E, DiCarlo E, Sun D, Goodman SM. Patient-Reported Fatigue Associated with Joint Histopathology in Rheumatoid Arthritis. ACR Open Rheumatol 2025; 7:e11772. [PMID: 39846130 PMCID: PMC11755064 DOI: 10.1002/acr2.11772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 08/21/2024] [Accepted: 11/12/2024] [Indexed: 01/24/2025] Open
Abstract
OBJECTIVE Fatigue is important for patients with rheumatoid arthritis (RA) but is poorly understood. We sought to study associations of fatigue with clinical features, disease activity, and synovial histology. METHODS Patients meeting the American College of Rheumatology/EULAR 1987 and/or 2010 RA criteria were recruited before elective total joint replacement. Demographics, RA characteristics, tender and swollen joints, erythrocyte sedimentation rate (ESR) and C-reactive protein, and patient-reported fatigue, categorized as mild, moderate, or severe, were collected. Hematoxylin and eosin stains of sectioned synovium were systematically scored by a pathologist. Relationships between fatigue and studied variables were evaluated with Kendall's tau. A directed acyclic graph (DAG) was used to illustrate associations of exposures, outcome variables, mediators, and confounders. Multivariable ordered logistic regression was used to further study associations. RESULTS Of 160 included patients, 85.6% were women, with a median age of 63.5 (55.25-71.40) and mean disease activity scores in 28 joints using ESR (DAS28-ESR) of 3.91 (SD 1.3). There were no differences in comorbidities across fatigue categories. Fatigue correlated with DAS28-ESR, synovial lining hyperplasia (SLH), anxiety, depression, and pain. In the DAG, DAS28-ESR was associated with fatigue, full mediation by pain, partial mediation by depression and anxiety, and confounding by female sex. SLH was independently associated with fatigue but did not confound the relationship between DAS28-ESR and fatigue. SLH was affected by synovial lymphocytic inflammation. In multivariable models, female sex, DAS28-ESR, and SLH were all associated with higher fatigue. CONCLUSION Although fatigue is associated with DAS28-ESR, it is also associated with SLH independently of disease activity.
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Affiliation(s)
- Diyu Pearce‐Fisher
- Hospital for Special Surgery, New York City, Stony Brook UniversityStony BrookNew York
| | - Melanie H. Smith
- Hospital for Special Surgery and Weill Cornell MedicineNew York CityNew York
| | - Bella Y. Mehta
- Hospital for Special Surgery and Weill Cornell MedicineNew York CityNew York
| | | | - Edward DiCarlo
- Hospital for Special Surgery and Weill Cornell MedicineNew York CityNew York
| | - Dongmei Sun
- Hospital for Special SurgeryNew York CityNew York
| | - Susan M. Goodman
- Hospital for Special Surgery and Weill Cornell MedicineNew York CityNew York
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Wang M, Xiang YH, Liu M, Jiang S, Guo JY, Jin XY, Sun HF, Zhang N, Wang ZG, Liu JX. The application prospects of sacha inchi ( Plukenetia volubilis linneo) in rheumatoid arthritis. Front Pharmacol 2024; 15:1481272. [PMID: 39484157 PMCID: PMC11524839 DOI: 10.3389/fphar.2024.1481272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/04/2024] [Indexed: 11/03/2024] Open
Abstract
Sacha Inchi (Plukenetia volubilis L) (SI) is a traditional natural medicine from tropical rainforests of Amazon region in South America. As a raw material for edible oil, it has various pharmacological effects such as antioxidant, anti-inflammatory, hypolipidemia, and blood pressure lowering, which have attracted increasing attentions of pharmacists. This has prompted researchers to explore its pharmacological effects for potential applications in certain diseases. Among these, the study of its anti-inflammatory effects has become a particularly interesting topic, especially in rheumatoid arthritis (RA). RA is a systemic autoimmune disease, and often accompanied by chronic inflammatory reactions. Despite significant progress in its treatment, there is still an urgent need to find effective anti-RA drugs in regard to safety. This review summarizes the potential therapeutic effects of SI on RA by modulating gut microbiota, targeting inflammatory cells and pathways, and mimicking biologic antibody drugs, predicting the application prospects of SI in RA, and providing references for research aimed at using SI to treat RA.
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Affiliation(s)
- Min Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- Sino-Pakistan Center on Traditional Chinese Medicine, School of Pharmaceutical Sciences, School of Basic Medical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
| | - Yin-Hong Xiang
- Sino-Pakistan Center on Traditional Chinese Medicine, School of Pharmaceutical Sciences, School of Basic Medical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
| | - Mei Liu
- Sino-Pakistan Center on Traditional Chinese Medicine, School of Pharmaceutical Sciences, School of Basic Medical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
- School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan, China
| | - Shan Jiang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Jia-ying Guo
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Xiao-yan Jin
- School of Pharmaceutical Sciences, Xinjiang medical University, Wulumuqi, Xinjiang, China
| | - Hui-feng Sun
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Ning Zhang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- Sino-Pakistan Center on Traditional Chinese Medicine, School of Pharmaceutical Sciences, School of Basic Medical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
| | - Zhi-Gang Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Jian-xin Liu
- Sino-Pakistan Center on Traditional Chinese Medicine, School of Pharmaceutical Sciences, School of Basic Medical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua, Hunan, China
- School of Pharmaceutical Sciences, University of South China, Hengyang, Hunan, China
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Sarzi-Puttini P, Zen M, Arru F, Giorgi V, Choy EA. Reprint of "Residual pain in rheumatoid arthritis: Is it a real problem?". Autoimmun Rev 2024; 23:103516. [PMID: 38272434 DOI: 10.1016/j.autrev.2024.103516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 08/24/2023] [Indexed: 01/27/2024]
Abstract
Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties.
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Affiliation(s)
- Piercarlo Sarzi-Puttini
- IRCCS Galeazzi-S.Ambrogio Hospital, Rheumatology Department, Milan, Italy; Department of Biomedical and Clinical Sciences, Università degli studi di Milano, Milan, Italy.
| | - Margherita Zen
- Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Federico Arru
- Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Valeria Giorgi
- IRCCS Galeazzi-S.Ambrogio Hospital, Rheumatology Department, Milan, Italy
| | - Ernest A Choy
- Rheumatology and Translational Research, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK; Cardiff Regional Experimental Arthritis Treatment and Evaluation (CREATE) Centre, Cardiff University School of Medicine, Cardiff, Wales, UK
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Farisogullari B, Santos EJF, Dures E, Geenen R, Machado PM. Efficacy of pharmacological interventions: a systematic review informing the 2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases. RMD Open 2023; 9:e003349. [PMID: 38056919 DOI: 10.1136/rmdopen-2023-003349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/14/2023] [Indexed: 12/08/2023] Open
Abstract
OBJECTIVE To identify the best evidence on the efficacy of pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and to summarise their safety in the identified studies to inform European Alliance of Associations for Rheumatology recommendations for the management of fatigue in people with I-RMDs. METHODS Systematic review of adults with I-RMDs conducted according to the Cochrane Handbook. Search strategy ran in Medline, Embase, Cochrane Library, CINAHL Complete, PEDro, OTseeker and PsycINFO. Only randomised controlled trials (RCTs) or controlled clinical trials were eligible. Assessment of risk of bias, data extraction and synthesis performed by two reviewers independently and in duplicate. Data pooled in statistical meta-analyses. RESULTS From 4151 records, 455 were selected for full-text review, 99 fulfilled the inclusion criteria and 19 RCTs were included in meta-analyses. Adalimumab was superior to placebo in reducing fatigue at 12 and 52 weeks in rheumatoid arthritis (RA) (n=3 and 2 RCTs; mean difference (MD)= -3.03, p<0.001; MD=-2.25, p=0.03, respectively). Golimumab (n=2 RCTs; 24 weeks: MD=-5.27, p<0.001), baricitinib (n=2 RCTs; 24 weeks: MD=-4.06, p<0.001), sarilumab (n=2 RCTs; 24 weeks: MD=-3.15, p<0.001), tocilizumab (n=3 RCTs; 24 weeks: MD=-3.69, p<0.001) and tofacitinib (n=3 RCTs; 12 weeks: MD=-4.44, p<0.001) were also superior to placebo in reducing fatigue in RA. A dose/effect relationship was observed for sarilumab, tocilizumab and tofacitinib. In spondyloarthritis (excluding psoriatic arthritis), secukinumab was superior to placebo in reducing fatigue at 16 weeks (n=2 RCTs; MD=-4.15, p<0.001), with a dose/effect relationship also observed. The narrative results of the RCTs not included in the meta-analysis indicated that several other pharmacological interventions were efficacious in reducing fatigue, with reassuring safety results. CONCLUSIONS Several pharmacological interventions are efficacious and generally safe for managing fatigue in people with I-RMDs.
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Affiliation(s)
| | - Eduardo José Ferreira Santos
- School of Health, Polytechnic University, Viseu, Portugal
- Health Sciences Research Unit: Nursing (UICiSA:E), Coimbra, Portugal
| | - Emma Dures
- Academic Rheumatology, Bristol Royal Infirmary, Bristol, UK
- School of Health and Social Wellbeing, University of the West of England, Bristol, UK
| | - Rinie Geenen
- Department of Psychology, Utrecht University, Utrecht, The Netherlands
| | - Pedro M Machado
- Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK
- National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK
- Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK
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Sarzi-Puttini P, Zen M, Arru F, Giorgi V, Choy EA. Residual pain in rheumatoid arthritis: Is it a real problem? Autoimmun Rev 2023; 22:103423. [PMID: 37634676 DOI: 10.1016/j.autrev.2023.103423] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties.
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Affiliation(s)
- Piercarlo Sarzi-Puttini
- IRCCS Galeazzi-S.Ambrogio Hospital, Rheumatology Department, Milan, Italy; Department of Biomedical and Clinical Sciences, Università degli studi di Milano, Milan, Italy.
| | - Margherita Zen
- Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Federico Arru
- Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Valeria Giorgi
- IRCCS Galeazzi-S.Ambrogio Hospital, Rheumatology Department, Milan, Italy
| | - Ernest A Choy
- Rheumatology and Translational Research, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK; Cardiff Regional Experimental Arthritis Treatment and Evaluation (CREATE) Centre, Cardiff University School of Medicine, Cardiff, Wales, UK
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Tanaka Y, Genovese MC, Matsushima H. Long-Term Safety, Efficacy, and Patient-Centered Outcomes of Filgotinib in the Treatment of Rheumatoid Arthritis: Current Perspectives. Patient Prefer Adherence 2023; 17:2499-2516. [PMID: 37822545 PMCID: PMC10563783 DOI: 10.2147/ppa.s417677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/01/2023] [Indexed: 10/13/2023] Open
Abstract
Filgotinib is an orally administered, preferential Janus kinase (JAK) inhibitor indicated for the treatment of moderate-to-severe rheumatoid arthritis (RA). The short-term safety, efficacy, and patient-reported outcomes (PROs) with filgotinib from Phase 2b/3 clinical trials (DARWIN 1 and 2; FINCH 1, 2, and 3) are described in patients who inadequately responded to methotrexate (MTX) and biologic disease-modifying antirheumatic drugs or who were naïve to MTX. This article reviews the safety and efficacy from the long-term extension (LTE) trials, DARWIN 3 (N=739) and FINCH 4 (N=2731), and PROs across the filgotinib development program in RA. Overall, in the DARWIN clinical trials (conducted from 2013-2023), patients received their LTE treatment for ≤8 years, while in the FINCH trials (ongoing from 2016-2025), patients received filgotinib treatment for ≤6 years in the LTE. The longer-term safety profile and consistent, sustained efficacy (American College of Rheumatology 20/50/70, Clinical Disease Activity Index, and Disease Activity Scale in 28 joints with C-reactive protein response rates) of filgotinib were largely similar to those observed in the shorter-term parent trials ≤52 weeks. PRO results from the parent trials showed improvements in patients' quality of life with filgotinib treatment, which compared to or exceeded improvements seen with placebo and active comparators (adalimumab, MTX). Filgotinib has a higher specificity for JAK1 compared with other therapeutic treatments, leading to reduced inhibition of JAK2/3-dependent pathways, potentially providing a distinct safety profile. Filgotinib is approved in Europe and Japan for treatment of people with moderate-to-severe RA, though it has not been approved by the US Food and Drug Administration, due to concerns around the benefit/risk profile of the filgotinib 200-mg dosage and the potential impact on semen parameters.
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan
| | - Mark C Genovese
- Division of Immunology and Rheumatology, Stanford University, Stanford, CA, USA
- Gilead Sciences, Inc, Foster City, CA, USA
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Abstract
INTRODUCTION Rheumatoid Arthritis (RA) remains a challenge for rheumatologists and patients despite implementation of intensive treat-to-target strategies in shared decision with patients and an increasing availability of drugs. Janus kinase inhibitors (JAKi) are a new generation of oral targeted drugs. Filgotinib preferentially inhibits JAK1 and is the latest JAKi to be approved for use in RA. AREAS COVERED This narrative review focuses on drug characteristics, efficacy, and safety of filgotinib in patients with RA, summarizing available literature. Trial data are detailed, put into perspective for practice and discussed in regulatory perspective. EXPERT OPINION Preclinical studies demonstrate preferential inhibition of JAK1 and a promising pharmacokinetic profile with few drug-drug interactions. Increase in hemoglobin in line with preferential inhibition of JAK1 over JAK2 is seen in early-phase clinical trials. A phase III program demonstrates efficacy in several disease stages, numerically higher with 200 mg versus 100 mg daily. In the overall RA population such dose-related effect is not observed for safety except for herpes zoster and increases in lipids and creatine phosphokinase. This reassuring safety profile is to be confirmed in future practice. It also needs to be unraveled if JAK1 preferential inhibition plays a key role in this safety profile.
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Affiliation(s)
- Rene Westhovens
- Emeritus Professor KU Leuven, Skeletal Biology and Engineering Research Center Department of Development and Regeneration, Leuven, Belgium
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Alciati A, Di Carlo M, Siragusano C, Palumbo A, Masala IF, Atzeni F. Effect of biological DMARDs and JAK inhibitors in pain of chronic inflammatory arthritis. Expert Opin Biol Ther 2022; 22:1311-1322. [PMID: 36168970 DOI: 10.1080/14712598.2022.2130243] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The advent of biological disease-modifying anti-rheumatic drugs (bDMARDs) and, more recently, of Janus kinase inhibitors (JAKi) has had a major impact on the long-term outcomes of chronic inflammatory arthritis (IA). However, the persistence of pain, even in patients with a complete pharmacological control of peripheral inflammation, represents an important clinical challenge in the treatment of IA. AREAS COVERED In this review, we provide an overview of possible mechanisms underlying pain in IA and its assessment, as well as the effects of bDMARDs and JAKi on pain management. EXPERT OPINION The overall data showed a good effect of bDMARDs and JAKi on pain, more pronounced for JAKi. However, it is challenging to distinguish the effect on the different types of pain (nociceptive, neuropathic, and nociplastic).
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Affiliation(s)
- Alessandra Alciati
- Department of Clinical Neurosciences, Hermanas Hospitalarias, Villa San Benedetto Menni Hospital, Humanitas Clinical and Research Center, Albese con Cassano, via Roma 16, 22032 Como, Italy; Rozzano, Milan, Italy
| | - Marco Di Carlo
- Rheumatology Clinic, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Jesi, Ancona, Italy
| | - Cesare Siragusano
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | - Antonino Palumbo
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | | | - Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
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Shamail GMH, Haridoss M, Natarajan M, Joshua V, Bagepally BS. Association Between Janus Kinase Inhibitors Therapy and Mental Health Outcome in Rheumatoid Arthritis: A Systematic Review and Meta-analysis. Rheumatol Ther 2022; 9:313-329. [PMID: 34902113 PMCID: PMC8964882 DOI: 10.1007/s40744-021-00409-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/24/2021] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic debilitating illness, usually associated with mental health ailments. Literature reports contradictory observations about the association between recent RA pharmacotherapies and mental health. We systematically reviewed RA randomized control trials to synthesize the association between Janus kinases (JAK) inhibitors therapy and mental health. METHODS We systematically searched clinical trials of JAK inhibitor intervention reporting mental health outcomes using short form-36 (SF-36) in PubMed, Embase, and Scopus databases from inception to February 2021. We have selected the studies and extracted the data, adhering to Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We have pooled the mean change of SF-36 mental component score (MCS) between JAK inhibitors and comparator therapy with a 95% confidence interval. RESULTS Of the 2915 searched studies for systematic review, 19 studies involving 14,323 individuals were included for the meta-analysis. The pooled mean reduction in SF-36 MCS scores (after minus before) with JAK inhibitors was 4.95 (4.41-5.48). The pooled mean difference of incremental mean change in SF-36 MCS score between JAK monotherapy and comparator was 1.53 (0.88-2.18). The improvement in SF-36 MCS scores with JAK inhibitor therapy is greater than the minimum clinically important difference (MCID) value of 2.5. However, on separate analysis with comparator drugs like methotrexate and standard treatment, the MCS scores did not exceeded the MCID value and were also not statistically significant. CONCLUSIONS JAK inhibitors results in clinically meaningful improvement in the mental health scores of the RA patients. PROSPERO REGISTRATION ID 2021 CRD42021234466.
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Affiliation(s)
| | - Madhumitha Haridoss
- Health Technology Assessment Resource Centre, ICMR-National Institute of Epidemiology, R-127, Tamil Nadu Housing Board, Phase I and II, Ayapakkam, Chennai, 600077, India
| | - Meenakumari Natarajan
- Health Technology Assessment Resource Centre, ICMR-National Institute of Epidemiology, R-127, Tamil Nadu Housing Board, Phase I and II, Ayapakkam, Chennai, 600077, India
| | - Vasna Joshua
- ICMR-National Institute of Epidemiology, Chennai, India
| | - Bhavani Shankara Bagepally
- ICMR-National Institute of Epidemiology, Chennai, India.
- Health Technology Assessment Resource Centre, ICMR-National Institute of Epidemiology, R-127, Tamil Nadu Housing Board, Phase I and II, Ayapakkam, Chennai, 600077, India.
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Zhao MY, Zhang W, Rao GW. Targeting Janus Kinase (JAK) for Fighting Diseases: The Research of JAK Inhibitor Drugs. Curr Med Chem 2022; 29:5010-5040. [PMID: 35255783 DOI: 10.2174/1568026622666220307124142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/11/2021] [Accepted: 12/21/2021] [Indexed: 11/22/2022]
Abstract
Janus Kinase (JAK), a nonreceptor protein tyrosine kinase, has emerged as an excellent target through research and development since its discovery in the 1990s. As novel small-molecule targeted drugs, JAK inhibitor drugs have been successfully used in the treatment of rheumatoid arthritis (RA), myofibrosis (MF) and ulcerative colitis (UC). With the gradual development of JAK targets in the market, JAK inhibitors have also received very considerable feedback in the treatment of autoimmune diseases such as atopic dermatitis (AD), Crohn's disease (CD) and graft-versus host disease (GVHD). This article reviews the research progress of JAK inhibitor drugs: introducing the existing JAK inhibitors on the market and some JAK inhibitors in clinical trials currently. In addition, the synthesis of various types of JAK inhibitors were summarized, and the effects of different drug structures on drug inhibition and selectivity.
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Affiliation(s)
- Min-Yan Zhao
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P. R. China
| | - Wen Zhang
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P. R. China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P. R. China
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12
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Huang YM, Zhuang Y, Tan ZM. Changes in rheumatoid arthritis under ultrasound before and after sinomenine injection. World J Clin Cases 2022; 10:35-42. [PMID: 35071503 PMCID: PMC8727271 DOI: 10.12998/wjcc.v10.i1.35] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/14/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a prevalent clinical autoimmune disease that is commonly treated with diclofenac and methotrexate. In recent years, the application of traditional Chinese medicine in RA has received widespread attention; it promotes blood circulation, strengthens the immune system, and eliminates evil. The sinomenine preparation of Zhingqeng Fengtongning is studied as a possible treatment for patients with RA.
AIM To explore the value of sinomenine injection into the articular cavity for the treatment of RA.
METHODS A total of 94 patients with RA treated from January 2019 to January 2021 were selected and divided into the study and control groups with 47 patients each using a simple random number table method. Both groups received conventional treatment with diclofenac sodium and methotrexate tablets. The control group received diproxone and lidocaine by intra-articular administration while the study group received an intra-articular administration of the sinomenine preparation of Zhengqing Fengning and lidocaine. χ2 test was used to evaluate the therapeutic effect and synovial thickness, degree of pain through the visual analog scale (VAS), blood flow grade, arthroinflammatory indexes [rheumatoid factor (RF), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)] before and after treatment in the two groups.
RESULTS The total effective rate of the study group (93.62%) was higher than that of the control group (78.72%) (P < 0.05). Before treatment, there were no significant differences between the two groups in terms of synovial thickness, VAS score, blood flow grading, levels of RF, and ESR (P > 0.05). After treatment, the synovial thickness and VAS score were significantly lower (P < 0.05) in the study group than in the control group (2.05 ± 0.59 mm vs 2.87 ± 0.64 mm and 2.11 ± 0.62 vs 2.90 ± 0.79 scores, respectively). The rate of blood flow at grade 0 in the study group (76.60%) was higher than that in the control group (57.45%), and the rate of blood flow at grade I (10.64%) was lower than that in the control group (31.91%) (P < 0.05). Furthermore, the levels of RF (55.61 ± 6.13 U/mL), CRP (11.43 ± 3.59 mg/L), and ESR (29.60 ± 5.56 mm/h) in the study group were lower than those in the control group (73.04 ± 9.23 U/mL, 15.07 ± 4.06 mg/L, 36.64 ± 6.10 mm/h, respectively) (P < 0.05).
CONCLUSION Sinomenine administration of Zhengqing Fengtongning in the articular cavity with conventional treatment of RA can improve ultrasonographic blood flow and synovial thickness, reduce pain, regulate inflammation, and enhance therapeutic effect.
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Affiliation(s)
- Yi-Min Huang
- Department of Rheumatology and Immunology, Huizhou Central People’s Hospital, Huizhou 516001, Guangdong Province, China
| | - Yu Zhuang
- Department of Rheumatology and Immunology, Huizhou Central People’s Hospital, Huizhou 516001, Guangdong Province, China
| | - Zhi-Ming Tan
- Department of Rheumatology and Immunology, Huizhou Central People’s Hospital, Huizhou 516001, Guangdong Province, China
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Giollo A, Fuzzi E, Doria A. Methotrexate in early rheumatoid arthritis: Is the anchor drug still holding? Autoimmun Rev 2022; 21:103031. [PMID: 34995761 DOI: 10.1016/j.autrev.2022.103031] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/02/2022] [Indexed: 12/29/2022]
Abstract
Treat-to-target (T2T) is currently the most fashionable strategy for treatment-naïve, early rheumatoid arthritis (RA) patients. A T2T approach can lead to a complete and drug-free disease remission, whereas failure to obtain remission leads to damage early in the disease course. Hence, one should try to achieve high remission rates as early as possible, implementing the best therapeutic strategies available. Methotrexate (MTX) combined with glucocorticoid bridging is the mainstay of T2T. However, MTX is often used suboptimally in RA patients for many reasons, including poor tolerability, low compliance, and safety issues. Recent evidence has suggested that novel targeted synthetic DMARDs (tsDMARDs) such as the Janus-kinase (JAK) inhibitors in combination with glucocorticoids yielded better outcomes in early RA than conventional treatment. Such an approach may have advantages in terms of patients' outcomes, though some concerns about serious adverse events need to be addressed.
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Affiliation(s)
- Alessandro Giollo
- Division of Rheumatology, Department of Medicine, University of Padova Hospital Trust, Padova, Italy.
| | - Enrico Fuzzi
- Division of Rheumatology, Department of Medicine, University of Padova Hospital Trust, Padova, Italy
| | - Andrea Doria
- Division of Rheumatology, Department of Medicine, University of Padova Hospital Trust, Padova, Italy.
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14
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Luo Y, Alexander M, Gadina M, O'Shea JJ, Meylan F, Schwartz DM. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition. J Allergy Clin Immunol 2021; 148:911-925. [PMID: 34625141 PMCID: PMC8514054 DOI: 10.1016/j.jaci.2021.08.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/04/2021] [Accepted: 08/09/2021] [Indexed: 12/18/2022]
Abstract
Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.
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Affiliation(s)
- Yiming Luo
- Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Madison Alexander
- Translational Immunology Section, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Massimo Gadina
- Office of Science and Technology, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - John J O'Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Francoise Meylan
- Office of Science and Technology, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Daniella M Schwartz
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
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15
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Mease PJ, Stryker S, Liu M, Salim B, Rebello S, Gharaibeh M, Collier DH. Treatment patterns in rheumatoid arthritis patients newly initiated on biologic and conventional synthetic disease-modifying antirheumatic drug therapy and enrolled in a North American clinical registry. Arthritis Res Ther 2021; 23:236. [PMID: 34496952 PMCID: PMC8424897 DOI: 10.1186/s13075-021-02599-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Background Understanding the evolving treatment patterns in patients with rheumatoid arthritis (RA) is important for rheumatologists to make the best practice decisions and optimize treatment. Here, we describe treatment patterns among patients newly initiated on biologic and/or nonbiologic RA therapy over time after enrollment in the US Corrona RA registry. Methods This was a retrospective, cohort study of adult patients with RA enrolled in the Corrona RA registry. Patients were included in this study if they initiated therapy with conventional synthetic disease-modifying antirheumatic drug (csDMARD) monotherapy, TNF inhibitor (TNFi) monotherapy, other (non-TNFi) biologic monotherapy, or combination therapy (index therapy); initiated therapy between January 1, 2004, and December 31, 2015 (index date), after enrollment in the Corrona RA registry; had at least 6 months of follow-up time after the index date; and had at least one follow-up visit. Time periods of interest were based on the year of index therapy initiation: 2004–2007, 2008–2011, and 2012–2015. Results This study included 8027 patients. csDMARD monotherapy and TNFi + csDMARD combination therapy were the most common index therapies in the registry (39.9% and 44.9%, respectively, in the 2004–2007 period; 38.6% and 38.2%, respectively, in the 2008–2011 period; and 35.2% for both in the 2012–2015 period). At therapy initiation, a higher proportion of patients who initiated other biologics, whether as monotherapies (54.0%) or in combination with csDMARD (49.9%), had high disease activity than those who initiated csDMARD monotherapy (28.4%). For 2012–2015 vs 2004–2007 and 2008–2011 periods, persistence on a given therapy appeared to decrease for the TNFi monotherapy cohort (48.2% vs 64.3% and 52.4%) and other biologic monotherapy cohort (52.3% vs 71.4% and 54.5%) over 12 months; switching from one therapy to another was common in the Corrona RA registry. Conclusions Increased switching from one therapy to another and decreased time on a given therapy was observed in the Corrona RA registry in the 2012–2015 period. This observation is most likely due to the increased availability of additional treatment options and/or the change in clinical focus, particularly the emphasis on achievement of treat-to-target goals of remission or low disease activity along with more aggressive treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-021-02599-4.
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Affiliation(s)
- Philip J Mease
- Swedish Medical Center/Providence St. Joseph Health and the University of Washington, Seattle, WA, 98122, USA.
| | | | - Mei Liu
- Corrona LLC., Waltham, MA, USA
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16
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Abstract
Filgotinib (Jyseleca®) is an oral, ATP-competitive, reversible JAK1 preferential inhibitor that is being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, including inflammatory arthritis and inflammatory bowel disease. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In September 2020, filgotinib received its first approvals in the EU and Japan. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). Clinical studies of filgotinib for the treatment of inflammatory autoimmune diseases are ongoing worldwide. This article summarizes the milestones in the development of filgotinib leading to this first approval.
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Affiliation(s)
- Sohita Dhillon
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand
| | - Susan J Keam
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand.
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17
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Tanaka Y, Takeuchi T, Izutsu H, Kaneko Y, Kato D, Fukuda M, Rokuda M, Schultz NM. Patient- and physician-reported outcomes from two phase 3 randomized studies (RAJ3 and RAJ4) of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis. Arthritis Res Ther 2021; 23:221. [PMID: 34429152 PMCID: PMC8383363 DOI: 10.1186/s13075-021-02590-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/23/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety in the treatment of patients with rheumatoid arthritis (RA). This study evaluated the effect of peficitinib on patient- and physician-reported outcomes in Asian patients with RA and an inadequate response to prior disease-modifying antirheumatic drugs (DMARDs). METHODS Patients from two randomized, placebo-controlled, double-blind, phase 3 trials (RAJ3 and RAJ4) received once-daily peficitinib 100 mg, peficitinib 150 mg, or placebo, alone or in combination with DMARDs (RAJ3), or in combination with methotrexate (RAJ4). Mean changes in Work Productivity and Activity Impairment (WPAI) questionnaire domain scores from baseline, and percentages of patients achieving minimal clinically important differences (MCIDs) for patient- and physician-reported outcomes (WPAI, Health Assessment Questionnaire - Disability Index [HAQ-DI], and Subject's Global Assessment of Pain [SGAP]), and Physician's Global Assessment of disease activity (PGA) were evaluated at weeks 4, 8, 12, and 12/early termination (ET). RESULTS Data from 1025 patients were analyzed. At week 12/ET in both studies, patients who received peficitinib 100 mg or 150 mg reported significantly improved WPAI domain scores from baseline (except for absenteeism in RAJ4) compared with placebo (both doses, p<0.05). A higher proportion of peficitinib- versus placebo-treated patients achieved MCID in WPAI, HAQ-DI, SGAP, and PGA in studies RAJ3 and RAJ4. Significant differences with peficitinib versus placebo were evident in both studies as early as week 4 in HAQ-DI (peficitinib 150 mg only), SGAP, and PGA, and week 8 in WPAI loss of work productivity and daily activity impairment. At week 12/ET, significantly higher proportions of patients receiving peficitinib versus placebo achieved MCID in HAQ-DI, SGAP, PGA, and WPAI domains of presenteeism (RAJ3 only), loss of work productivity (RAJ3 only), and daily activity impairment (p<0.05 for all comparisons). CONCLUSIONS Peficitinib 100 mg or 150 mg administered daily over 12 weeks resulted in clinically meaningful improvements in outcomes that are important to RA patients, including pain, physical function, and work productivity and activity. These observations were reinforced through similar improvements in physicians' rating of disease activity. TRIAL REGISTRATION RAJ3: ClinicalTrials.gov, NCT02308163 , registered 4 December 2014. RAJ4: ClinicalTrials.gov, NCT02305849 , registered 3 December 2014.
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.
| | | | | | | | | | | | | | - Neil M Schultz
- Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA
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18
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Avci AB, Feist E, Burmester GR. Early phase studies of JAK1 selective inhibitors in rheumatoid arthritis. Rheumatology (Oxford) 2021; 60:ii11-ii16. [PMID: 33950228 PMCID: PMC8098113 DOI: 10.1093/rheumatology/keaa893] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/07/2020] [Indexed: 01/20/2023] Open
Abstract
The first approved Janus kinase (JAK) inhibitors for treatment of RA targeted more than one JAK molecule. Although this brings an advantage of simultaneous blocking of more cytokines involved in RA, it may also carry an increased risk of toxicity. Subsequently, more selective JAK inhibitors were developed with the aim of improving the safety-efficacy profile and to further increase drug maintenance. With this proposal, early phase trials of selective JAK1 inhibitors, namely upadacitinib, filgotinib and itacitinib, were initiated in recent years to identify the efficacy and adverse effects of these agents and to define their potential role in treatment of inflammatory and autoimmune diseases. Early phase (Phase I-II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit-risk profile for further evaluation in the later successfully performed Phase III trials. Although itacitinib also demonstrated a good efficacy and safety in a Phase II trial in RA patients, it is mainly in development for haematologic and oncologic conditions.
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Affiliation(s)
- Ali Berkant Avci
- Department of Internal Medicine, Rheumatology, Life Hospital, Antalya, Turkey
| | - Eugen Feist
- Department of Rheumatology, Helios Fachklinik Vogelsang-Gommern, Vogelsang-Gommern
| | - Gerd Rüdiger Burmester
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany
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Pope JE. Management of Fatigue in Rheumatoid Arthritis. RMD Open 2021; 6:rmdopen-2019-001084. [PMID: 32385141 PMCID: PMC7299512 DOI: 10.1136/rmdopen-2019-001084] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/04/2020] [Accepted: 04/09/2020] [Indexed: 12/31/2022] Open
Abstract
Fatigue in rheumatoid arthritis is highly prevalent. It is correlated only weakly with disease activity but more so with pain, mood, personality features, poor sleep, obesity and comorbidities. Fatigue can be measured by many standardised questionnaires and more easily with a Visual Analogue Scale or numeric rating scale. Most patients with RA have some fatigue, and at least one in six have severe fatigue. Chronic pain and depressed mood are also common in RA patients with significant fatigue. It affects function and quality of life and is worse on average in women. Evidence-based treatment for fatigue includes treatment of underlying disease activity (with on average modest improvement of fatigue), exercise programmes and supervised self-management programmes with cognitive-behavioural therapy, mindfulness and reinforcement (such as reminders). The specific programmes for exercise and behavioural interventions are not standardised. Some medications cause fatigue such as methotrexate. More research is needed to understand fatigue and how to treat this common complex symptom in RA that can be the worst symptom for some patients.
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Affiliation(s)
- Janet E Pope
- Medicine, Division Rheumatology, Western University, Ontario, Canada
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20
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Erdağ M, Balbaba M, İlhan N, Çalık İ, Ulaş F, Eröksüz Y, Yıldırım H. Protective effect of filgotinib in rat endotoxin-induced uveitis model. Int Ophthalmol 2021; 41:2905-2912. [PMID: 33864579 DOI: 10.1007/s10792-021-01851-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 04/08/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE To investigate the protective effect of filgotinib in endotoxin-induced uveitis model in rats. MATERIALS AND METHOD This study used 24 Wistar Albino rats. Group I (control group) included the healthy controls; in Group II (sham group), only 300 µg/kg intraperitoneal (ip) lipopolysaccharide (LPS) was administered; and in Group III (treatment group), 3 mg/kg/day filgotinib was administered orally for 10 days followed by 300 µg/kg ip LPS. In all groups, clinical activity scores were evaluated after 24 h. Moreover, histopathological and immunological examinations were performed. RESULTS In Groups I, II, and III, the mean clinical activity and histopathological examination scores were 0.00, 3.25 ± 0.70, and 1.89 ± 0.60 and 0.00, 2.88 ± 1.12, and 1.44 ± 0.52, respectively. The clinical activity and histopathological examination scores were significantly increased in the sham group compared to the control group (p < 0.05); these findings were significantly reduced in the treatment group (p < 0.05). The mean TNF-α and IL-6 ELISA levels in all groups were 50.20 ± 3.24, 59.87 ± 2.98, and 54.34 ± 4.62 and 30.88 ± 1.79, 36.77 ± 1.21, and 33.66 ± 1.86, respectively. The TNF-α and IL-6 ELISA levels were significantly decreased in the treatment group compared to the sham group (p < 0.05); there was no significant difference between the treatment group and the control group (p = 0.105, p = 0.067, respectively) CONCLUSION: Filgotinib may be an alternative treatment option in preventing the development of noninfectious uveitis.
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Affiliation(s)
- Murat Erdağ
- Department of Ophthalmology, Van Training and Research Hospital, 65000, Van, Turkey. .,Department of Ophthalmology, Faculty of Medicine, Fırat University, 23119, Elazig, Turkey.
| | - Mehmet Balbaba
- Department of Ophthalmology, Faculty of Medicine, Fırat University, 23119, Elazig, Turkey
| | - Nevin İlhan
- Department of Biochemistry, Faculty of Medicine, Fırat University, 23119, Elazig, Turkey
| | - İlknur Çalık
- Department of Pathology, Faculty of Medicine, Fırat University, 23119, Elazig, Turkey
| | - Fatih Ulaş
- Department of Ophthalmology, Faculty of Medicine, Abant Izzet Baysal University, 14280, Bolu, Turkey
| | - Yesari Eröksüz
- Department of Pathology, Faculty of Veterinary Medicine, Fırat University, 23119, Elazig, Turkey
| | - Hakan Yıldırım
- Department of Ophthalmology, Faculty of Medicine, Fırat University, 23119, Elazig, Turkey
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Raimondo MG, Biggioggero M, Coletto LA, Ramming A, Caporali R, Favalli EG. Clinical pharmacology of filgotinib in the treatment of rheumatoid arthritis: current insights. Expert Rev Clin Pharmacol 2021; 14:661-670. [PMID: 33847204 DOI: 10.1080/17512433.2021.1913050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. AREAS COVERED This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. EXPERT OPINION The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.
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Affiliation(s)
- Maria Gabriella Raimondo
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany
| | - Martina Biggioggero
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy
| | - Lavinia Agra Coletto
- Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università Degli Studi Di Milano, Milano, Italy
| | - Andreas Ramming
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany
| | - Roberto Caporali
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy.,Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università Degli Studi Di Milano, Milano, Italy
| | - Ennio Giulio Favalli
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy
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Strand V, Tundia N, Bergman M, Ostor A, Durez P, Song IH, Enejosa J, Schlacher C, Song Y, Fleischmann R. Upadacitinib improves patient-reported outcomes vs placebo or adalimumab in patients with rheumatoid arthritis: results from SELECT-COMPARE. Rheumatology (Oxford) 2021; 60:5583-5594. [PMID: 33590829 PMCID: PMC8645276 DOI: 10.1093/rheumatology/keab158] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/07/2021] [Indexed: 12/03/2022] Open
Abstract
Objective To evaluate the impact of upadacitinib vs placebo and adalimumab treatment, on patient-reported outcomes (PROs) in SELECT-COMPARE in an active RA population with inadequate responses to MTX (MTX-IR). Methods PROs in patients receiving upadacitinib (15 mg QD), placebo, or adalimumab (40 mg EOW) while on background MTX were evaluated over 48 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA) and pain by visual analogue scale (VAS), the HAQ Disability Index (HAQ-DI), the 36-Item Short Form Survey (SF-36), morning (AM) stiffness duration and severity, the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), and work instability. Least squares mean (LSM) changes and proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and scores ≥ normative values were evaluated. Results Upadacitinib and adalimumab resulted in greater LSM changes from baseline vs placebo across all PROs (P < 0.05) at week 12, and pain and AM stiffness severity (P < 0.05) at week 2. More upadacitinib- vs placebo-treated (P < 0.05) and similar percentages of upadacitinib- vs adalimumab-treated patients reported improvements ≥ MCID across all PROs at week 12. Upadacitinib vs adalimumab resulted in greater LSM changes from baseline in PtGA, pain, HAQ-DI, stiffness severity, FACIT-F, and the SF-36 Physical Component Summary (PCS) (all P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients reported scores ≥ normative values in HAQ-DI and SF-36 PCS (P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients maintained clinically meaningful improvements in PtGA, pain, HAQ-DI, FACIT-F, and AM stiffness through 48 weeks. Conclusion In MTX-IR patients with RA, treatment with upadacitinib resulted in statistically significant and clinically meaningful improvements in PROs equivalent to or greater than with adalimumab. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02629159.
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Affiliation(s)
- Vibeke Strand
- Division of Immunology/Rheumatology, Stanford University, Palo Alto, CA, USA
| | | | - Martin Bergman
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Andrew Ostor
- Cabrini Medical Centre, Monash University, Melbourne, Australia
| | - Patrick Durez
- Rheumatology, Cliniques universitaires Saint-Luc-Université catholique de Louvain-Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
| | | | | | | | - Yan Song
- Analysis Group, Inc, Boston, MA, USA
| | - Roy Fleischmann
- University of Texas Southwestern Medical Center, MCRC, Dallas, TX, USA
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Moura RA, Fonseca JE. JAK Inhibitors and Modulation of B Cell Immune Responses in Rheumatoid Arthritis. Front Med (Lausanne) 2021; 7:607725. [PMID: 33614673 PMCID: PMC7892604 DOI: 10.3389/fmed.2020.607725] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/18/2020] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic, in vitro and in vivo studies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.
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Affiliation(s)
- Rita A Moura
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - João Eurico Fonseca
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisbon Academic Medical Centre, Lisbon, Portugal
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Abstract
PURPOSE OF THE REVIEW Three Janus kinase (JAK) inhibitors are approved for rheumatoid arthritis (RA) with a fourth awaiting approval. Multiple clinical trial results with these molecules have recently been reported. These were the first small molecule oral targeted synthetic DMARDs (tsDMARDs) to be approved for RA. RECENT FINDINGS Preclinical studies have suggested differential affinity for JAK isoform inhibition but it is not presently clear that there is any difference in efficacy in the clinic with these therapies. Preliminary data has suggested that filgotinib may have a modestly different safety profile but lacking direct comparisons, this will be difficult to confirm. Long-term safety studies have suggested similar safety signals to biologics although a possible signal for VTE/PE risk has been noted with tofacitinib and baricitinib. Having an oral small molecule such as the JAK inhibitors with similar or better efficacy than biologics has been a major advance in RA treatment.
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Affiliation(s)
- Virginia Reddy
- Division of Rheumatology, Texas Health Dallas Presbyterian Hospital, Dallas, TX, USA
| | - Stanley Cohen
- UT Southwestern Medical School, Dallas, TX, USA. .,Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 800, Dallas, TX, 75231, USA. .,Texas Health Dallas Presbyterian Hospital, Dallas, TX, USA.
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25
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Kerschbaumer A, Sepriano A, Smolen JS, van der Heijde D, Dougados M, van Vollenhoven R, McInnes IB, Bijlsma JWJ, Burmester GR, de Wit M, Falzon L, Landewé R. Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2020; 79:744-759. [PMID: 32033937 PMCID: PMC7286044 DOI: 10.1136/annrheumdis-2019-216656] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 01/07/2020] [Accepted: 01/08/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). METHODS A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. RESULTS 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. CONCLUSION This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.
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Affiliation(s)
| | - Alexandre Sepriano
- Leiden University Medical Center, Leiden, The Netherlands
- NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
| | | | | | | | | | | | | | | | | | | | - Robert Landewé
- Amsterdam Rheumatology Center, Amsterdam, The Netherlands
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26
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Riedelberger M, Penninger P, Tscherner M, Hadriga B, Brunnhofer C, Jenull S, Stoiber A, Bourgeois C, Petryshyn A, Glaser W, Limbeck A, Lynes MA, Schabbauer G, Weiss G, Kuchler K. Type I Interferons Ameliorate Zinc Intoxication of Candida glabrata by Macrophages and Promote Fungal Immune Evasion. iScience 2020; 23:101121. [PMID: 32428860 PMCID: PMC7232100 DOI: 10.1016/j.isci.2020.101121] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/09/2020] [Accepted: 04/29/2020] [Indexed: 12/16/2022] Open
Abstract
Host and fungal pathogens compete for metal ion acquisition during infectious processes, but molecular mechanisms remain largely unknown. Here, we show that type I interferons (IFNs-I) dysregulate zinc homeostasis in macrophages, which employ metallothionein-mediated zinc intoxication of pathogens as fungicidal response. However, Candida glabrata can escape immune surveillance by sequestering zinc into vacuoles. Interestingly, zinc-loading is inhibited by IFNs-I, because a Janus kinase 1 (JAK1)-dependent suppression of zinc homeostasis affects zinc distribution in macrophages as well as generation of reactive oxygen species (ROS). In addition, systemic fungal infections elicit IFN-I responses that suppress splenic zinc homeostasis, thereby altering macrophage zinc pools that otherwise exert fungicidal actions. Thus, IFN-I signaling inadvertently increases fungal fitness both in vitro and in vivo during fungal infections. Our data reveal an as yet unrecognized role for zinc intoxication in antifungal immunity and suggest that interfering with host zinc homeostasis may offer therapeutic options to treat invasive fungal infections.
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Affiliation(s)
- Michael Riedelberger
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Philipp Penninger
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Michael Tscherner
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Bernhard Hadriga
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Carina Brunnhofer
- Institute of Chemical Technologies and Analytics, TU Wien, Vienna, Austria
| | - Sabrina Jenull
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Anton Stoiber
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Christelle Bourgeois
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Andriy Petryshyn
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Walter Glaser
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria
| | - Andreas Limbeck
- Institute of Chemical Technologies and Analytics, TU Wien, Vienna, Austria
| | - Michael A Lynes
- Department of Molecular and Cell Biology, University of Connecticut, CT, USA
| | - Gernot Schabbauer
- Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Guenter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, and Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Karl Kuchler
- Medical University of Vienna, Center for Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Vienna, Austria.
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Dixit A, Kiran V, Gabani BB, Mullangi R. Validated DBS method for filgotinib quantitation in rat dried blood spots and its application to a pharmacokinetic study in rats. ADMET AND DMPK 2020; 8:139-148. [PMID: 35300367 PMCID: PMC8915582 DOI: 10.5599/admet.796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/23/2020] [Indexed: 11/29/2022] Open
Abstract
Filgotinib is a selective JAK1 (Janus kinase) inhibitor, showed efficacy in patients suffering from moderate-to-severe rheumatoid arthritis. In this paper, we present the data on the development and validation of a sensitive, selective and high-throughput LC-MS/MS (liquid chromatography with tandem mass spectrometry) method for the quantitation of filgotinib from rat dried blood spot (DBS) cards. To the DBS disc cards, 0.2% formic acid enriched with internal standard (IS) was added and sonicated. Thereafter the extraction of filgotinib and the IS (tofacitinib) was accomplished using ethyl acetate as an extraction solvent. The resolution of filgotinib and the IS was achieved on a Gemini C18 column with an isocratic mobile phase, which is a mixture of 0.2% formic acid:acetonitrile (20:80, v/v) at a flow-rate of 0.9 mL/min. The total run time was 2.90 min and the retention time of filgotinib and the IS was ~1.31 and 0.89 min, respectively. Filgotinib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 426.3→291.3 and m/z 313.2→149.2, respectively, for quantitation. The calibration range was 1.37-1937 ng/mL. No matrix effect and carry over were observed. All the validation parameters met the acceptance criteria. The validated method has been applied to a pharmacokinetic study in rats. A good correlation between DBS and plasma concentrations for filgotinib was observed.
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Affiliation(s)
- Abhishek Dixit
- Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India
| | - Vinay Kiran
- Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India
| | - Bhavesh Babulal Gabani
- Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India
| | - Ramesh Mullangi
- Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India
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28
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Khristich AN, Mirkin SM. On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability. J Biol Chem 2020; 295:4134-4170. [PMID: 32060097 PMCID: PMC7105313 DOI: 10.1074/jbc.rev119.007678] [Citation(s) in RCA: 188] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?
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Affiliation(s)
| | - Sergei M Mirkin
- Department of Biology, Tufts University, Medford, Massachusetts 02155.
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29
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30
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Hosseini A, Gharibi T, Marofi F, Javadian M, Babaloo Z, Baradaran B. Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases. J Cell Physiol 2020; 235:5903-5924. [DOI: 10.1002/jcp.29593] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Arezoo Hosseini
- Immunology Research CenterTabriz University of Medical SciencesTabriz Iran
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
- Student Research CommitteeTabriz University of Medical SciencesTabriz Iran
- Aging Research InstituteTabriz University of Medical SciencesTabriz Iran
| | - Tohid Gharibi
- Immunology Research CenterTabriz University of Medical SciencesTabriz Iran
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
- Student Research CommitteeTabriz University of Medical SciencesTabriz Iran
- Aging Research InstituteTabriz University of Medical SciencesTabriz Iran
| | - Faroogh Marofi
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
| | - Mahsa Javadian
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
| | - Zohreh Babaloo
- Immunology Research CenterTabriz University of Medical SciencesTabriz Iran
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
| | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabriz Iran
- Department of Immunology, School of MedicineTabriz University of Medical SciencesTabriz Iran
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31
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Dixit A, Kiran V, Gabani BB, Mohd Z, Trivedi RK, Mullangi R. Validated LC–MS/MS method for quantitation of a selective JAK1 inhibitor, filgotinib in rat plasma, and its application to a pharmacokinetic study in rats. Biomed Chromatogr 2020; 34:e4802. [DOI: 10.1002/bmc.4802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/22/2020] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Affiliation(s)
- Abhishek Dixit
- Drug Metabolism and PharmacokineticsJubilant Biosys Ltd Bangalore India
| | - Vinay Kiran
- Drug Metabolism and PharmacokineticsJubilant Biosys Ltd Bangalore India
| | | | - Zainuddin Mohd
- Drug Metabolism and PharmacokineticsJubilant Biosys Ltd Bangalore India
| | | | - Ramesh Mullangi
- Drug Metabolism and PharmacokineticsJubilant Biosys Ltd Bangalore India
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32
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Keretsu S, Bhujbal SP, Cho SJ. Molecular modeling studies of pyrrolo[2,3-d]pyrimidin-4-amine derivatives as JAK1 inhibitors based on 3D-QSAR, molecular docking, molecular dynamics (MD) and MM-PBSA calculations. J Biomol Struct Dyn 2020; 39:753-765. [PMID: 31916502 DOI: 10.1080/07391102.2020.1714483] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Rheumatoid Arthritis (RA) is an autoimmune disease caused by overproduction of pro-inflammatory cytokines. Janus Kinases (JAKs) mediate cytokines signaling through the Janus Kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. Clinical studies have shown that Janus kinase 1 (JAK1) mediated signaling plays a key role in synovial response in rheumatoid arthritis. Hence, the inhibition JAK1 is considered as an important therapeutic route for treatment of rheumatoid arthritis. In this study, we have performed three-dimensional quantitative structure-activity relationship (3 D-QSAR), molecular docking, molecular dynamics (MD) and free energy calculations on a series of pyrrolo[2,3-d]pyrimidin-4-amine JAK1 inhibitors. Molecular docking studies of the compounds 03, 13, 36 and 49 with JAK1 were performed to study the binding interactions. The binding conformations of the compounds from docking studies were selected based on binding energy and H-bond interactions and were used as initial structure for MD simulations. Using 3 D-QSAR techniques, a ligand-based comparative molecular field analysis (CoMFA) model (q2 = 0.5, r2 = 0.96) and a receptor-based CoMFA model (q2 = 0.78, r2 = 0.98) were developed. Analysis of the MD results of the most active compound (compound 49) with JAK1 showed the formation of H-bond interactions with residues Glu957, Leu959 and Gly887 and water-mediated H-bond interaction with Gly887 and His885. Based on the contour map analyses of the receptor-based CoMFA, a design strategy was proposed and was used for designing new JAK1 inhibitors. Four of the designed compounds (D57, D58, D98 and D99) showed predicted activity values (pIC50> 8.8) greater than the most active compound for JAK1. MM-PBSA based free energy calculations indicated that the designed compounds were able to form stable binding with JAK1 primarily through electrostatic interactions and van der Waal interactions. Collectively, the outcome of this study can be used to further the progress of JAK1 inhibition for the treatment of rheumatoid arthritis. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Seketoulie Keretsu
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, Republic of Korea
| | - Swapnil P Bhujbal
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, Republic of Korea
| | - Seung Joo Cho
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, Republic of Korea.,Department of Cellular Molecular Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea
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33
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Ormaechea MS, Hassan M, Onghanseng N, Park JH, Mahajan S, Al-Kirwi KY, Uludag G, Halim MS, Schlaen A, Sepah YJ, Do DV, Nguyen QD. Safety of systemic therapy for noninfectious uveitis. Expert Opin Drug Saf 2019; 18:1219-1235. [PMID: 31801415 DOI: 10.1080/14740338.2019.1692810] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: The treatment strategies for noninfectious uveitis (NIU) aim to achieve disease remission, prevention of recurrences, and preserving vision, while minimizing the side effects associated with the therapies used.Areas covered: The index review aims to provide a detailed overview of the adverse events and safety parameters associated with the systemic therapies for the management of the NIU.Expert opinion: Despite being the cornerstone of management of acute cases of NIU, long-term corticosteroid use is associated with multi-system side effects, requiring the use of steroid-sparing agents. Adalimumab was recently approved by the FDA for the management of NIU based on the results of VISUAL studies. Similarly, newer drugs targeting various aspects of the inflammatory cascade are being developed. However, until we completely understand the molecular pathways of the inflammatory diseases, the therapeutic profile of these newer agents needs to be broad enough to suppress inflammatory cascade and narrow enough to spare normal cellular processes. Another strategy that has shown some potential in decreasing the systemic side effects is to provide local drug delivery. Therefore, the future of management of NIU is very bright with many novel therapeutic agents and strategies of drug delivery on the horizon.
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Affiliation(s)
- Maria Soledad Ormaechea
- Department of Ophthalmology, Hospital Universitario Austral, Buenos Aires, Argentina.,Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Muhammad Hassan
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Neil Onghanseng
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Jung Hyun Park
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA.,Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | | | - Khalid Yusuf Al-Kirwi
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA.,Department of Ophthalmology, Imamein Khadhimein Medical City University Hospital, Baghdad, Iraq
| | - Gunay Uludag
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | | | - Ariel Schlaen
- Department of Ophthalmology, Hospital Universitario Austral, Buenos Aires, Argentina
| | - Yasir J Sepah
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
| | - Diana V Do
- Byers Eye Institute, Stanford University, Palo Alto, CA, USA
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Wu J, Zhu Z, Yu Q, Ding C. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis: phase I to Ⅱ clinical trials. Expert Opin Investig Drugs 2019; 28:1113-1123. [PMID: 31738612 DOI: 10.1080/13543784.2019.1692812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Introduction: Rheumatoid arthritis (RA) is a chronic, refractory disorder caused by autoimmunity in the synovial joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biologicals offer remission in only two-thirds of RA patients within 3 months, hence new therapeutic approaches are necessary. Tyrosine kinase inhibitors (TKIs) are newly developed small molecule drugs which have demonstrated encouraging results in this disease.Areas covered: The key findings from phase I and II clinical trials that have investigated the use of novel TKIs in the treatment of RA are discussed. We examined the literature published between January 2014 to January 2019 using electronic databases including PubMed, Web of Science, Medline, Embase, and Google Scholar. Additional information about phase I and II trials on the ClinicalTrial.gov website up to January 2019 was also retrieved.Expert opinion: JAK inhibitors are promising drugs with sound efficacy and acceptable safety and may be beneficial to patients who do not respond to DMARDs and biologicals. The response rates among RA patients to TKIs are diverse; genetic and environmental factors may be involved in the varying responses which are closely related to the pathogenesis of RA. Future studies may reveal the underlying mechanisms of resistance and non-response.
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Affiliation(s)
- Jing Wu
- Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhaohua Zhu
- Clinical Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qinghong Yu
- Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Changhai Ding
- Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Clinical Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
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35
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Biggioggero M, Becciolini A, Crotti C, Agape E, Favalli EG. Upadacitinib and filgotinib: the role of JAK1 selective inhibition in the treatment of rheumatoid arthritis. Drugs Context 2019; 8:212595. [PMID: 31692920 PMCID: PMC6821397 DOI: 10.7573/dic.212595] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/29/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint involvement, extra-articular manifestations, comorbidities, and increased mortality. In the last few decades, the management of RA has been dramatically improved by the introduction of a treat-to-target approach aiming to prevent joint damage progression. Moreover, the increasing knowledge about disease pathogenesis allowed the development of a new drug class of biologic agents targeted on immune cells and proinflammatory cytokines involved in RA network. Despite the introduction of several targeted drugs, a significant proportion of RA patients still fail to achieve the clinical target; so, more recently the focus of research has been shifted toward the inhibition of kinases involved in the transduction of the inflammatory signal into immune cells. In particular, two Janus kinase (JAK) inhibitors, baricitinib and tofacitinib, have been licensed for the treatment of RA as a consequence of a very favorable profile observed in randomized controlled trials (RCTs) conducted across different RA subpopulations. Both these new compounds are active on the majority of four JAK family members (JAK1, JAK2, JAK3, and TYK2), whereas the most recent emerging approach is directed toward the development of JAK1 selective inhibitors (upadacitinib and filgotinib) with the aim to improve the safety profile by minimizing the effects on JAK3 and, especially, JAK2. In this narrative review, we discuss the rationale for JAK inhibition in RA, with a special focus on the role of JAK1 selective blockade and a detailed description of available data from the results of clinical trials on upadacitinib and filgotinib.
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Affiliation(s)
| | | | - Chiara Crotti
- Department of Rheumatology, Gaetano Pini Institute, Milan, Italy
| | - Elena Agape
- Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy
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36
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Muller R. JAK inhibitors in 2019, synthetic review in 10 points. Eur J Intern Med 2019; 66:9-17. [PMID: 31178258 DOI: 10.1016/j.ejim.2019.05.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 01/03/2023]
Abstract
JAK inhibitors are recent treatments. Many publications have appeared in recent years, exposing treatment efficiencies in phases 2 and 3 studies, or their tolerance profile in various rheumatological diseases. We propose here a systematic review of JAK inhibitors, from their mechanism of physiological action up to the estimation of their current risk benefit balance, and their possible future applications. In order to better synthesize the data, we organized this review into 10 essential points. 1- What is the role of JAK/Stat pathway? 2- How can a single signaling pathway regulate as many different signals? 3- What are the commercialized JAK inhibitors and their validated indications in humans today? 4- What is the level of efficiency of JAK inhibitors in inflammatory diseases? 5- What is the delay of efficiency of JAK inhibitors? 6- Where is the place of JAK inhibitors in the therapeutic strategy today? 7- What is the infectious tolerance profile of JAK inhibitors? 8- What is the non-infectious safety profile of JAK inhibitors? 9- What is the cost of JAK inhibitors compared to other DMARDs? 10- What future prospects for JAK inhibitors?
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Affiliation(s)
- Romain Muller
- Internal medecine, Assistance Publique-Hôpitaux de Marseille (AP-HM), France.
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Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska-Hanczewska A, Dudek A, Abi-Saab W, Tasset C, Meuleners L, Harrison P, Besuyen R, Van der Aa A, Mozaffarian N, Greer JM, Kunder R, Van den Bosch F, Gladman DD. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392:2367-2377. [PMID: 30360969 DOI: 10.1016/s0140-6736(18)32483-8] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 09/24/2018] [Accepted: 09/28/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis. METHODS The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670. FINDINGS Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p<0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group. INTERPRETATION Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified. FUNDING Galapagos and Gilead Sciences.
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Affiliation(s)
- Philip Mease
- Swedish-Providence-St Joseph Health Systems, Seattle WA, USA; University of Washington, Seattle, WA, USA.
| | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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- Ghent University Hospital, Ghent, Belgium; VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium
| | - Dafna D Gladman
- University of Toronto and Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
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van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, Abi-Saab W, Tasset C, Meuleners L, Besuyen R, Hendrikx T, Mozaffarian N, Liu K, Greer JM, Deodhar A, Landewé R. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet 2018; 392:2378-2387. [PMID: 30360970 DOI: 10.1016/s0140-6736(18)32463-2] [Citation(s) in RCA: 198] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 09/24/2018] [Accepted: 09/28/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis. METHODS In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs. Patients were randomly assigned (1:1) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks. Randomisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy. The patients, study team, and study sponsor were masked to treatment assignment. The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12, which was assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug). Safety was assessed according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT03117270. FINDINGS Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n=58) or placebo (n=58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was -1·47 (SD 1·04) in the filgotinib group and -0·57 (0·82) in the placebo group, with a least squares mean difference between groups of -0·85 (95% CI -1·17 to -0·53; p<0·0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study. INTERPRETATION Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs. Further investigation of filgotinib for ankylosing spondylitis is warranted. FUNDING Galapagos and Gilead Sciences.
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Affiliation(s)
| | | | - Lianne S Gensler
- Division of Rheumatology, University of California, San Francisco, CA, USA
| | | | - Vira Tseluyko
- Department of Rheumatology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
| | | | | | | | | | | | | | | | - Ke Liu
- Gilead Sciences, Foster City, CA, USA
| | | | - Atul Deodhar
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR, USA
| | - Robert Landewé
- Department of Rheumatology & Clinical Immunology, Amsterdam University Medical Center, Amsterdam, Netherlands; Department of Rheumatology, Zuyderland Hospital, Heerlen, Netherlands
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