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Starobova H, Alshammari A, Winkler IG, Vetter I. The role of the neuronal microenvironment in sensory function and pain pathophysiology. J Neurochem 2024; 168:3620-3643. [PMID: 36394416 DOI: 10.1111/jnc.15724] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/10/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022]
Abstract
The high prevalence of pain and the at times low efficacy of current treatments represent a significant challenge to healthcare systems worldwide. Effective treatment strategies require consideration of the diverse pathophysiologies that underlie various pain conditions. Indeed, our understanding of the mechanisms contributing to aberrant sensory neuron function has advanced considerably. However, sensory neurons operate in a complex dynamic microenvironment that is controlled by multidirectional interactions of neurons with non-neuronal cells, including immune cells, neuronal accessory cells, fibroblasts, adipocytes, and keratinocytes. Each of these cells constitute and control the microenvironment in which neurons operate, inevitably influencing sensory function and the pathology of pain. This review highlights the importance of the neuronal microenvironment for sensory function and pain, focusing on cellular interactions in the skin, nerves, dorsal root ganglia, and spinal cord. We discuss the current understanding of the mechanisms by which neurons and non-neuronal cells communicate to promote or resolve pain, and how this knowledge could be used for the development of mechanism-based treatments.
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Affiliation(s)
- Hana Starobova
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
| | - Ammar Alshammari
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
| | - Ingrid G Winkler
- Mater Research Institute, The University of Queensland, Queensland, South Brisbane, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
- The School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia
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Ochi S, Sonomoto K, Nakayamada S, Tanaka Y. Predictors of functional improvement and pain reduction in rheumatoid arthritis patients who achieved low disease activity with disease-modifying antirheumatic drugs: a retrospective study of the FIRST Registry. Arthritis Res Ther 2024; 26:140. [PMID: 39061106 PMCID: PMC11282705 DOI: 10.1186/s13075-024-03369-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) patients sometimes exhibit different levels of improvement in health assessment questionnaire-disability index (HAQ-DI) and subjective pain visual analogue score (VAS) even after achieving low disease activities (LDA). This study aimed to identify factors associated with improvement in HAQ-DI and pain VAS among those who achieved LDA. METHODS Data of the FIRST registry, a multi-institutional cohort of RA patients treated with biological and targeted-synthetic DMARDs (b/tsDMARDs) were analyzed. Patients who were enrolled from August 2013 to February 2023 and who achieved clinical LDA [clinical disease activity index (CDAI) ≤ 10.0] at 6 months after starting treatment were included. Multiple logistic regression analyses were conducted to identify the factors that associated with achieving HAQ-DI normalization (< 0.5), HAQ-DI improvement (by > 0.22), or pain VAS reduction (≤ 40 mm). RESULTS Among 1424 patients who achieved LDA at 6 months, 732 patients achieved HAQ-DI normalization and 454 achieved pain VAS reduction. The seropositivity and the use of JAK inhibitor compared with TNF inhibitor were associated with both HAQ-DI < 0.5 and pain VAS reduction at 6 months. On the other hand, older age, past failure in ≥ 2 classes of b/tsDMARDs, higher HAQ-DI at baseline, and use of glucocorticoid were associated with the lower likelihood of HAQ-DI normalization and pain VAS reduction. Longer disease duration, being female, and higher disease activity at baseline was negatively associated HAQ-DI normalization alone. Comorbidities were not associated with the outcomes. CONCLUSIONS These results suggest some preferable treatment may exist for improvement of HAQ-DI and pain VAS reduction in the early stage of the treatment, which is a clue to prevention of a criteria of difficult-to-treat RA.
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Affiliation(s)
- Sae Ochi
- Department of Laboratory Medicine, The Jikei University School of Medicine, Nishishinbashi 3-25-8, Minato-ku, Tokyo, 105-8461, Japan.
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Iseigaoka1-1, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.
| | - Koshiro Sonomoto
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Iseigaoka1-1, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, Japan, Iseigaoka1-1, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Iseigaoka1-1, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Iseigaoka1-1, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan.
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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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Janus Kinase Inhibitors Improve Disease Activity and Patient-Reported Outcomes in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 24,135 Patients. Int J Mol Sci 2022; 23:ijms23031246. [PMID: 35163173 PMCID: PMC8836107 DOI: 10.3390/ijms23031246] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 12/11/2022] Open
Abstract
Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.
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Chang CK, Chen PK, Chen CC, Chang SH, Chen CH, Chen DY. Increased Levels of Omega-3 Fatty Acids and DHA Are Linked to Pain Reduction in Rheumatoid Arthritis Patients Treated with Janus Kinase Inhibitors. Nutrients 2021; 13:nu13093050. [PMID: 34578928 PMCID: PMC8465317 DOI: 10.3390/nu13093050] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 02/07/2023] Open
Abstract
Although Janus kinase inhibitors (JAKi) could reduce patient-reported pain in rheumatoid arthritis (RA), their mechanism remains unclear. Therefore, we examined lipid metabolites change in JAKi-treated patients and evaluate their association with pain reduction. We used 1H-NMR-based lipid/metabolomics to determine serum levels of lipid metabolites at baseline and week 24 of treatment. Serum levels of significant lipid metabolites were replicated by ELISA in 24 JAKi-treated and 12 tocilizumab-treated patients. Pain was evaluated with patients’ assessment on a 0–100 mm VAS, and disease activity assessed using DAS28. JAKi or tocilizumab therapy significantly reduced disease activity. Acceptable pain (VAS pain ≤20) at week 24 was observed in 66.7% of JAKi-treated patients, and pain decrement was greater than tocilizumab-treated patients (ΔVAS pain 70.0 vs. 52.5, p = 0.0595). Levels of omega-3 fatty acids and docosahexaenoic acid (DHA) were increased in JAKi-treated patients (median 0.55 mmol/L versus 0.71 mmol/L, p = 0.0005; 0.29 mmol/L versus 0.35 mmol/L, p = 0.0004; respectively), which were not observed in tocilizumab-treated patients. ELISA results showed increased DHA levels in JAKi-treated patients with acceptable pain (44.30 µg/mL versus 45.61 µg/mL, p = 0.028). A significant association of pain decrement with DHA change, not with DAS28 change, was seen in JAKi-treated patients. The pain reduction effect of JAKi probably links to increased levels of omega-3 fatty acids and DHA.
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Affiliation(s)
- Ching-Kun Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (C.-K.C.); (P.-K.C.); (S.-H.C.)
- Translational Medicine Laboratory, China Medical University Hospital, Taichung 404, Taiwan
| | - Po-Ku Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (C.-K.C.); (P.-K.C.); (S.-H.C.)
- Translational Medicine Laboratory, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chia-Ching Chen
- School of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan;
| | - Shih-Hsin Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (C.-K.C.); (P.-K.C.); (S.-H.C.)
- Translational Medicine Laboratory, China Medical University Hospital, Taichung 404, Taiwan
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Chu-Huang Chen
- Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan;
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA
- New York Heart Research Foundation, Mineola, New York, NY 11501, USA
| | - Der-Yuan Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan; (C.-K.C.); (P.-K.C.); (S.-H.C.)
- Translational Medicine Laboratory, China Medical University Hospital, Taichung 404, Taiwan
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: ; Tel.: +886-4-22052121 (ext. 4666); Fax: 886-4-22073812
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Yin Y, Liu M, Zhou E, Chang X, He M, Wang M, Wu J. Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol 2021; 40:3989-4005. [PMID: 33990888 DOI: 10.1007/s10067-021-05686-8] [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: 10/14/2020] [Revised: 01/17/2021] [Accepted: 03/08/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To assess the efficacy and safety of jakinibs for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Randomized placebo-controlled trials (RCTs) of jakinibs in RA patients were eligible. The effective outcome was RA improvement to reach an American College of Rheumatology 20%/50%/70% (ACR20/50/70) response rate at weeks 12 and 24 after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events, infections, and serious infections. RESULTS Twenty-eight randomized, double-blind, controlled trials including 14,500 patients were included. At both weeks 12 and 24, the pooled analysis suggested effective treatment with jakinibs, represented as an increased clinical response of ACR20, ACR50, and ACR70. Subgroup analysis based on different types of jakinibs demonstrated that only peficitinib treatment had no impact on the clinical response of ACR50 or ACR70 at week 12. Jakinibs were associated with an increased incidence of infections at week 12 and TEAEs and infections at week 24. No increase in the risk of SAEs, discontinuations due to adverse events, or serious infections was observed in comparisons between treatment with jakinibs and treatment with placebo in these patients. CONCLUSIONS Jakinibs are efficacious and well tolerated in RA patients up to 24 weeks, although they are associated with an increased risk of infectious complications. Key Points • ACR20/50/70 in patients treated with jakinibs was significantly higher than those in patients treated with placebo. • No difference in ACR50/70 was observed in patients with RA treated with peficitinib and placebo. • Jakinibs are beneficial and well tolerated in RA treatment.
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Affiliation(s)
- Yufeng Yin
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China
| | - Mengru Liu
- Department of Rheumatology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Erye Zhou
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China
| | - Xin Chang
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China
| | - Michun He
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China
| | - Mingjun Wang
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China
| | - Jian Wu
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, No. 188 Shizi St, Suzhou, 215006, Jiangsu, China.
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Giraud F, Pereira E, Anizon F, Moreau P. Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors. Molecules 2021; 26:molecules26092696. [PMID: 34064521 PMCID: PMC8124620 DOI: 10.3390/molecules26092696] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022] Open
Abstract
The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR-Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.
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Zhu J, Wang J, Huang J, Du W, He Y, Pan H, Luo J. MicroRNA-140-5p regulates the proliferation, apoptosis and inflammation of RA FLSs by repressing STAT3. Exp Ther Med 2020; 21:171. [PMID: 33456538 PMCID: PMC7792473 DOI: 10.3892/etm.2020.9602] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 04/09/2020] [Indexed: 12/15/2022] Open
Abstract
Ectopic expression of microRNA (miRNA) in rheumatoid arthritis (RA) fibroblast-like synoviocyte (RA FLS) is associated with the development of rheumatoid arthritis. The present study aimed to evaluate the effects of miRNA-140-5p (miR-140) on the properties of RA FLSs. It was found that miR-140 expression was decreased in 33 RA patients and extracted RA FLS samples, when compared to the corresponding healthy controls. Abnormally increased miR-140 expression in RA FLSs attenuated cell proliferation and increased cell apoptosis. Additionally, reduced pro-inflammatory cytokine production was observed in RA FLSs transfected with a miR-140 precursor. Furthermore, the 3'-UTR of the signal transducer and activator of transcription (STAT) 3 gene was identified as a target of miR-140. Notably, restoration of STAT3 expression rescued the regulatory effect of miR-140 on the proliferation, apoptosis and inflammatory cytokine production of RA FLSs. Therefore, the current findings indicated that miR-140 is a crucial modulator of both proliferation and apoptosis, shedding light on the etiology behind RA FLS viability, which is modulated by an interplay between miR-140 and STAT3 in the context of RA.
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Affiliation(s)
- Jiehua Zhu
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jianglin Wang
- School of Laboratory Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jialin Huang
- School of Laboratory Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Wensheng Du
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yingzhong He
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Hongfei Pan
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Junmin Luo
- Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Traditional and modern management strategies for rheumatoid arthritis. Clin Chim Acta 2020; 512:142-155. [PMID: 33186593 DOI: 10.1016/j.cca.2020.11.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/03/2020] [Accepted: 11/03/2020] [Indexed: 12/20/2022]
Abstract
Rheumatoid arthritis (RA) is a serious disorder of the joints affecting 1 or 2% of the population aged between 20 and 50 years worldwide. RA is the foremost cause of disability in developing and Western populations. It is an autoimmune disease-causing inflammation and pain involving synovial joints. Pro-inflammatory markers, including cytokines, such as interleukin -1 (IL-1), IL-6, IL-7, IL-8, and tumor necrosis factor-α (TNF-α) are involved in RA. RA treatment involves TNF-α blockade, B cell therapy, IL-1 and IL-6 blockade, and angiogenesis inhibition. Synthetic drugs available for the treatment of RA include disease-modifying anti-rheumatic drugs (DMARD), such as cyclophosphamide, sulfasalazine, methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), and intramuscular gold. These agents induce adverse hepatorenal effects, hypertension, and gastric ulcers. We found that patients diagnosed with chronic pain, as in RA, and those refractory to contemporary management are most likely to seek traditional medicine. Approximately 60-90% of patients with arthritis use traditional medicines. Therefore, the efficacy and safety of these traditional medicines need to be established. The treatment for RA entails a comprehensive multidisciplinary strategy to reduce pain and inflammation and to restore the activity of joints. The potential medicinal plants exhibiting anti-arthritic and anti-rheumatic pharmacological activity are reviewed here.
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Gwak EH, Yoo HY, Kim SH. Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats. Biomol Ther (Seoul) 2020; 28:361-369. [PMID: 32209733 PMCID: PMC7327145 DOI: 10.4062/biomolther.2020.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/14/2020] [Accepted: 02/21/2020] [Indexed: 12/21/2022] Open
Abstract
Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.
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Affiliation(s)
- Eun Hye Gwak
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea
| | - Hee Young Yoo
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea
| | - So Hee Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea
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Guo X, Jia Y, Han L, Zhao Y, Li W, Zhang Z, Peng Y, Zheng J. Metabolic Activation of Tofacitinib Mediated by Myeloperoxidase in Vitro. Chem Res Toxicol 2019; 32:2459-2465. [PMID: 31725283 DOI: 10.1021/acs.chemrestox.9b00280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tofacitinib (TFT) is used for the treatment of moderately and severely active rheumatoid arthritis. Unfortunately, TFT was reported to induce leukopenia, and the underlying mechanisms remain unclear. The present study demonstrated that TFT was oxidized to a chemically reactive nitrenium ion by myeloperoxidase (MPO) occurring in neutrophils. The electrophilic ion showed chemical reactivity toward N-acetyl-cysteine (NAC) to produce two TFT-NAC conjugates (M1 and M2) in incubation of TFT with leucocytes in the presence of NAC. The generation of the nitrenium ion was verified by HClO-mediated oxidation of TFT. In addition, the nitrenium ion was found to react with sulfhydryl groups of cysteine residues of cellular protein in leucocytes after exposure to TFT. The study facilitates the understanding of the mechanisms of TFT toxic action.
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Affiliation(s)
- Xiucai Guo
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Yudi Jia
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Lingling Han
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Yanhong Zhao
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Wei Li
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Zhengyu Zhang
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Ying Peng
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China
| | - Jiang Zheng
- Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China.,State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province , Guizhou Medical University , Guiyang , Guizhou 550004 , P.R. China
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Mueller RB, Hasler C, Popp F, Mattow F, Durmisi M, Souza A, Hasler P, Rubbert-Roth A, Schulze-Koops H, Kempis JV. Effectiveness, Tolerability, and Safety of Tofacitinib in Rheumatoid Arthritis: A Retrospective Analysis of Real-World Data from the St. Gallen and Aarau Cohorts. J Clin Med 2019; 8:jcm8101548. [PMID: 31561582 PMCID: PMC6832556 DOI: 10.3390/jcm8101548] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/22/2019] [Accepted: 09/24/2019] [Indexed: 12/20/2022] Open
Abstract
: Introduction: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). The efficacy and safety of tofacitinib have been shown in several randomized clinical trials. The study presented here aimed to assess the clinical tolerability and effectiveness of tofacitinib among RA patients in real life. Methods: Consecutive patients between January 2015 and April 2017 with RA who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria were included in a prospectively designed analysis of retrospective data. Patients were initiated on tofacitinib 5 mg bid. The primary objective was to analyze the safety of tofacitinib in a real-life cohort. Safety was assessed by the reasons to stop tofacitinib during follow up and changes of liver enzymes, hemoglobin, and creatinine. The secondary outcome was to analyze the frequency of and time to achieve low disease activity (LDA) and remission as defined by 28 joint count disease activity score (DAS28). Results: A total of 144 patients were treated with tofacitinib. A total of 84.9% of patients were pre-exposed to at least one biological agent. The average DAS28 at the initiation of tofacitinib was 4.43. A total of 50.0% of patients were positive for rheumatoid factor and 49.0% for ACPA. The mean follow up was 1.22 years (range 10d-3.7a) after initiation of tofacitinib treatment. A total of 94 (64.4%) patients remained on tofacitinib during follow-up. The average time to stop tofacitinib was 190.0 days. Reasons to stop tofacitinib were: insufficient response (n = 23), gastrointestinal symptoms (n = 18), infection (n = 5), myalgia (n = 2), remission (n = 2), headache (n = 2), cough, blue finger syndrome, intolerance, heartburn, psoriasis, and increased liver enzymes (all n = 1). Increased alanine amino transferase (ALAT) or aspartate amino transferase (ASAT) > 2× upper limit of normal (ULN) were detected in 3.3% and 4.4% of patients, respectively. Hemoglobin decrease of >10% was detected in 15.1% of the patients and decreased lymphocytes <500/μL in 3.4%. An increase of creatinine >20% was detected in 9.4% of patients. A total of 62.9% and 50.0% of the patients achieved low disease activity (LDA) or remission after a median of 319 and 645 days, respectively. These rates were significantly higher in patients naïve to biologic agents as compared to patients pre-exposed to biologics (LDA: naïve 100% 92 d, pre-exposed 57.0% 434 d, p ≤ 0.001; remission: naïve 86.7% 132 d, pre-exposed 44.1%, 692 d, p = 0.001). Conclusions: Tofacitinib is a safe and effective treatment option for patients with RA. Tofacitinib may induce high rates of LDA and remission in patients with active disease, even after the use of one or more biologics, though the rate appeared higher in patients naïve to biologics. Tofacitinib may be a valuable option in a treat-to-target approach. Our data demonstrate that Janus kinase (JAK) inhibitors are safe and efficacious in real life patients.
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Affiliation(s)
- Ruediger B Mueller
- Division of Rheumatology and Immunology, Department of Internal Medicine, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
- Division of Rheumatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland.
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
| | - Caroline Hasler
- Division of Rheumatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland.
| | - Florian Popp
- Division of Rheumatology and Immunology, Department of Internal Medicine, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
| | - Frederik Mattow
- Division of Rheumatology and Immunology, Department of Internal Medicine, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
| | - Mirsada Durmisi
- Division of Rheumatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland.
| | | | - Paul Hasler
- Division of Rheumatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland.
| | - Andrea Rubbert-Roth
- Division of Rheumatology and Immunology, Department of Internal Medicine, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
| | - Hendrik Schulze-Koops
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
| | - Johannes von Kempis
- Division of Rheumatology and Immunology, Department of Internal Medicine, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
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Guo X, Li W, Li Q, Chen Y, Zhao G, Peng Y, Zheng J. Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4. Chem Res Toxicol 2019; 32:1791-1800. [PMID: 31414593 DOI: 10.1021/acs.chemrestox.9b00141] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Tofacitinib (TFT) is an oral JAK inhibitor which has been approved for the treatment of moderately and severely active rheumatoid arthritis. TFT was found to show concentration-, time-, and NADPH-dependent inhibition of CYP3A4, and irreversibility of the inactivation was also observed. Incubation (40 min, 37 °C) of recombinant CYP3A4 with TFT at 200 μM resulted in >70% loss of CYP3A4 activity. Estimated kinact and KI were 0.037 min-1 and 93.2 μM, respectively. GSH and superoxide dismutase/catalase revealed minor or little protection against the CYP3A4 inactivation. Furthermore, ketoconazole attenuated TFT-mediated CYP3A4 inactivation. Epoxide and α-keto-aldehyde intermediates of TFT were trapped and characterized in microsomal incubations, respectively. The aldehyde intermediate is believed to be the key for the enzyme inactivation. Multiple P450 enzymes, including CYPs2C19, 3A4, 2D6, and 1A2, participated in the metabolism of TFT to the epoxide, while the formation of the aldehyde was mainly catalyzed by CYP3A4. In conclusion, TFT was proven to be a mechanism-based inactivator of CYP3A4.
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Affiliation(s)
| | | | | | | | | | | | - Jiang Zheng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province , Guizhou Medical University , Guiyang , Guizhou 550004 , P. R. China
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15
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Kobayashi T, Ito S, Murasawa A, Ishikawa H, Yoshie H. Effects of tofacitinib on the clinical features of periodontitis in patients with rheumatoid arthritis: two case reports. BMC Rheumatol 2019; 3:13. [PMID: 31020271 PMCID: PMC6474052 DOI: 10.1186/s41927-019-0062-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 03/25/2019] [Indexed: 12/13/2022] Open
Abstract
Background The pathobiology of rheumatoid arthritis (RA) is similar to that of periodontitis in that proinflammatory cytokines play an important pathologic role. There is evidence to suggest that inhibitors of tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor for the treatment of RA ameliorated periodontal inflammation. However, no study has evaluated the effect of tofacitinib, an oral Janus kinase inhibitor for the treatment of RA, on periodontitis. Case presentation The present report cases are 51- and 43-year-old non-smoking women with RA who demonstrated localized moderate chronic periodontitis. Both cases showed improvement in the periodontal inflammatory condition after 3 months of tofacitinib therapy, although the teeth count and supragingival bacterial plaque level were relatively unchanged. Improvements were also observed in the serum levels of IL-6 in both cases as well as in the serum levels of TNF-α and anti-cyclic citrullinated peptide immunoglobulin G in one case and of rheumatoid factor and matrix metalloproteinase-3 in the other case. Patients who received tofacitinib exhibited an inconsistent clinical response, likely due to the low disease activity of RA at the start of the administration. Conclusions These are the first reported cases in which tofacitinib may have a beneficial effect on periodontitis. However, more research is required to understand the relationship between periodontitis and tofacitinib therapy.
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Affiliation(s)
- Tetsuo Kobayashi
- 1General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514 Japan.,2Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514 Japan
| | - Satoshi Ito
- Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata, 957-0054 Japan
| | - Akira Murasawa
- Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata, 957-0054 Japan
| | - Hajime Ishikawa
- Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata, 957-0054 Japan
| | - Hiromasa Yoshie
- 2Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514 Japan
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Bird P, Hall S, Nash P, Connell CA, Kwok K, Witcombe D, Thirunavukkarasu K. Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib. RMD Open 2019; 5:e000742. [PMID: 30886732 PMCID: PMC6397430 DOI: 10.1136/rmdopen-2018-000742] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 11/13/2018] [Accepted: 12/03/2018] [Indexed: 12/20/2022] Open
Abstract
Objectives Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). ‘Serotype’ subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.
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Affiliation(s)
- Paul Bird
- University of New South Wales, Sydney, New South Wales, Australia
| | - Stephen Hall
- Cabrini Health and Monash University, Melbourne, Victoria, Australia
| | - Peter Nash
- University of Queensland, Brisbane, Queensland, Australia
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Bykerk VP, Burmester GR, Combe BG, Furst DE, Huizinga TWJ, Ahmad HA, Emery P. On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate in patients with early rheumatoid arthritis. Rheumatol Int 2018; 38:2225-2231. [PMID: 30341453 DOI: 10.1007/s00296-018-4173-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/05/2018] [Indexed: 11/26/2022]
Abstract
Clinical outcomes in patients with early rheumatoid arthritis (RA) were assessed by baseline symptom duration in the Assessing Very Early Rheumatoid arthritis Treatment trial (ClinicalTrials.gov; NCT01142726). Patients with early, active RA were randomized to subcutaneous (SC) abatacept 125 mg/week plus methotrexate (MTX), SC abatacept alone, or MTX monotherapy for 12 months. All RA treatments were withdrawn after 12 months in patients with Disease Activity Score in 28 joints (C-reactive protein; DAS28-CRP) < 3.2. In this post hoc analysis, the proportion of patients achieving protocol-defined remission (DAS28-CRP < 2.6) or improvement in physical function at 12 and at both 12 and 18 months was assessed according to symptom duration (≤ 3 months, > 3 to ≤ 6 months, or > 6 months) and treatment group. No clinically significant differences were seen in baseline demographics or characteristics across symptom duration groups. Irrespective of baseline symptom duration, a numerically higher proportion of abatacept plus MTX-treated patients achieved DAS-defined remission at month 12 and sustained remission at month 18 compared with MTX monotherapy. A numerically higher proportion of abatacept plus MTX-treated patients with symptom duration ≤ 3 months maintained DAS-defined remission after complete treatment withdrawal from 12 to 18 months compared with longer symptom duration groups. This subgroup also had the fastest onset of clinical response (DAS28-CRP < 2.6) after initiation of treatment. Health Assessment Questionnaire-Disability Index response was similar regardless of baseline symptom duration. Overall, symptom duration of ≤ 3 months was associated with a faster onset of clinical response and higher rates of drug-free remission following treatment with abatacept plus MTX.
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Affiliation(s)
- Vivian P Bykerk
- Department of Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th St, New York, NY, 10021, USA.
| | - Gerd R Burmester
- Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany
| | - Bernard G Combe
- Department of Rheumatology, Service d'Immuno-Rheumatologie, Montpellier, France
| | - Daniel E Furst
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Tom W J Huizinga
- Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
| | - Harris A Ahmad
- Headquarters Medical Immunology, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Paul Emery
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Gadina M, Johnson C, Schwartz D, Bonelli M, Hasni S, Kanno Y, Changelian P, Laurence A, O'Shea JJ. Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol 2018; 104:499-514. [PMID: 29999544 DOI: 10.1002/jlb.5ri0218-084r] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/24/2018] [Accepted: 05/28/2018] [Indexed: 02/06/2023] Open
Abstract
In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.
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Affiliation(s)
- Massimo Gadina
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Catrina Johnson
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Daniella Schwartz
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael Bonelli
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarfaraz Hasni
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Yuka Kanno
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Paul Changelian
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Arian Laurence
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - John J O'Shea
- National Institute of Arthritis, Musculoskeletal and Skin Diseases, Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland, USA
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Guan YY, Zhang Y, Liu LX, Li HD, Xue D, Bao WL, Ye G, Shen X. Suppressive effects of Wang‑Bi Tablet on adjuvant‑induced arthritis in rats via NF‑κB and STAT3 signaling pathways. Int J Mol Med 2018; 42:1666-1674. [PMID: 29901091 DOI: 10.3892/ijmm.2018.3723] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/30/2018] [Indexed: 11/05/2022] Open
Abstract
Rheumatoid arthritis (RA) severely affects the quality life of patients due to its high association with disability. Traditional Chinese medicines have been reported to exert notable therapeutic effects on RA. The Chinese medicinal prescription Wang‑Bi Tablet (WB) has been successfully used to clinically treat RA for many years; however, its pharmacological mechanism of action is largely unclear. In the present study, adjuvant‑induced arthritis (AIA) rats were used to evaluate the anti‑inflammatory effects of WB and western blotting was used to explore the molecular mechanisms. The experimental results demonstrated that WB treatment significantly reduced arthritis score and hind‑paw volume. Furthermore, synovial hyperplasia, inflammatory cell infiltration and joint destruction were ameliorated by WB. The expression levels of the proinflammatory cytokines interleukin (IL)‑1β, tumor necrosis factor‑α and IL‑6, were reduced in the joints of WB‑treated rats. Western blotting revealed that WB could also inhibit excessive activation of nuclear factor (NF)‑κB and Janus kinase (JAK)‑signal transducer and activator of transcription 3 (STAT3) signaling pathways. These results indicated that the therapeutic effects of WB on AIA may be accomplished through inhibition of the NF‑κB and JAK‑STAT3 signaling pathways. These findings provide experimental evidence to support WB as a therapeutic agent for the treatment of patients with RA.
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Affiliation(s)
- Yun-Yun Guan
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
| | - Yeqing Zhang
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, P.R. China
| | - Li-Xin Liu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
| | - Hai-Dong Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
| | - Dan Xue
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, P.R. China
| | - Wei-Lian Bao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
| | - Guan Ye
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, P.R. China
| | - Xiaoyan Shen
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
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Long-Term Radiographic and Patient-Reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses. Rheumatol Ther 2018; 5:341-353. [PMID: 29761420 PMCID: PMC6251846 DOI: 10.1007/s40744-018-0113-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Indexed: 12/12/2022] Open
Abstract
Introduction Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. Methods This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). Results Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (≤ 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA. Conclusion Regardless of treatment, in both MTX-naïve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation. Funding Pfizer Inc. Trial registration Clinicaltrials.gov identifiers: NCT01039688 and NCT00847613. Electronic supplementary material The online version of this article (10.1007/s40744-018-0113-7) contains supplementary material, which is available to authorized users.
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Salaffi F, Giacobazzi G, Di Carlo M. Chronic Pain in Inflammatory Arthritis: Mechanisms, Metrology, and Emerging Targets-A Focus on the JAK-STAT Pathway. Pain Res Manag 2018; 2018:8564215. [PMID: 29623147 PMCID: PMC5829432 DOI: 10.1155/2018/8564215] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022]
Abstract
Chronic pain is nowadays considered not only the mainstay symptom of rheumatic diseases but also "a disease itself." Pain is a multidimensional phenomenon, and in inflammatory arthritis, it derives from multiple mechanisms, involving both synovitis (release of a great number of cytokines) and peripheral and central pain-processing mechanisms (sensitization). In the last years, the JAK-STAT pathway has been recognized as a pivotal component both in the inflammatory process and in pain amplification in the central nervous system. This paper provides a summary on pain in inflammatory arthritis, from pathogenesis to clinimetric instruments and treatment, with a focus on the JAK-STAT pathway.
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Affiliation(s)
- Fausto Salaffi
- Rheumatology Department, Università Politecnica delle Marche, Jesi, Ancona, Italy
| | | | - Marco Di Carlo
- Rheumatology Department, Università Politecnica delle Marche, Jesi, Ancona, Italy
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Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 2017; 77:521-546. [PMID: 28255960 PMCID: PMC7102286 DOI: 10.1007/s40265-017-0701-9] [Citation(s) in RCA: 765] [Impact Index Per Article: 95.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.
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Affiliation(s)
- Shubhasree Banerjee
- Rheumatology Fellowship and Training Branch, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
| | - Ann Biehl
- Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Massimo Gadina
- Translational Immunology Section, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarfaraz Hasni
- Lupus Clinical Research Program, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Daniella M Schwartz
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health, Bethesda, Maryland, USA
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Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Maxwell LJ, Buchbinder R, Lopez‐Olivo MA, Suarez‐Almazor ME, Tugwell P, Wells GA. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD012591. [PMID: 28282491 PMCID: PMC6472522 DOI: 10.1002/14651858.cd012591] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics. OBJECTIVES To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics. METHODS On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer). MAIN RESULTS This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer. Tofacitinib monotherapy versus placeboThere were no published data. Tofacitinib + MTX versus active comparator (MTX)In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer. AUTHORS' CONCLUSIONS Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Lara J Maxwell
- Ottawa Hospital Research Institute (OHRI), The Ottawa Hospital ‐ General CampusCentre for Practice‐Changing Research (CPCR)501 Smyth Road, Box 711OttawaONCanadaK1H 8L6
| | - Rachelle Buchbinder
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash UniversityMonash Department of Clinical Epidemiology, Cabrini HospitalSuite 41, Cabrini Medical Centre183 Wattletree RoadMalvernVictoriaAustralia3144
| | - Maria Angeles Lopez‐Olivo
- The University of Texas, M.D. Anderson Cancer CenterDepartment of General Internal Medicine1515 Holcombe BlvdUnit 1465HoustonTexasUSA77030
| | - Maria E Suarez‐Almazor
- The University of Texas, M.D. Anderson Cancer CenterDepartment of General Internal Medicine1515 Holcombe BlvdUnit 1465HoustonTexasUSA77030
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance. J Immunol Res 2016; 2016:5021537. [PMID: 28070525 PMCID: PMC5187469 DOI: 10.1155/2016/5021537] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/20/2016] [Indexed: 12/12/2022] Open
Abstract
It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.
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Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA. Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA). Cochrane Database Syst Rev 2016; 11:CD012437. [PMID: 27855242 PMCID: PMC6469573 DOI: 10.1002/14651858.cd012437] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND We performed a systematic review, a standard meta-analysis and network meta-analysis (NMA), which updates the 2009 Cochrane Overview, 'Biologics for rheumatoid arthritis (RA)'. This review is focused on biologic monotherapy in people with RA in whom treatment with traditional disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) had failed (MTX/other DMARD-experienced). OBJECTIVES To assess the benefits and harms of biologic monotherapy (includes anti-tumor necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or non-TNF (abatacept, anakinra, rituximab, tocilizumab)) or tofacitinib monotherapy (oral small molecule) versus comparator (placebo or MTX/other DMARDs) in adults with RA who were MTX/other DMARD-experienced. METHODS We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 6, June), MEDLINE (via OVID 1946 to June 2015), and Embase (via OVID 1947 to June 2015). Article selection, data extraction and risk of bias and GRADE assessments were done in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparisons (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We calculated absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). MAIN RESULTS This update includes 40 new RCTs for a total of 46 RCTs, of which 41 studies with 14,049 participants provided data. The comparator was placebo in 16 RCTs (4,532 patients), MTX or other DMARD in 13 RCTs (5,602 patients), and another biologic in 12 RCTs (3,915 patients). Monotherapy versus placeboBased on moderate-quality direct evidence, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in American College of Rheumatology score (ACR50) and physical function, as measured by the Health Assessment Questionnaire (HAQ) versus placebo. RR was 4.68 for ACR50 (95% CI, 2.93 to 7.48); absolute benefit RD 23% (95% CI, 18% to 29%); and NNTB = 5 (95% CI, 3 to 8). The mean difference (MD) was -0.32 for HAQ (95% CI, -0.42 to -0.23; a negative sign represents greater HAQ improvement); absolute benefit of -10.7% (95% CI, -14% to -7.7%); and NNTB = 4 (95% CI, 3 to 5). Direct and NMA estimates for TNF biologic, non-TNF biologic or tofacitinib monotherapy showed similar results for ACR50 , downgraded to moderate-quality evidence. Direct and NMA estimates for TNF biologic, anakinra or tofacitinib monotherapy showed a similar results for HAQ versus placebo with mostly moderate quality evidence.Based on moderate-quality direct evidence, biologic monotherapy was associated with a clinically meaningful and statistically significant greater proportion of disease remission versus placebo with RR 1.12 (95% CI 1.03 to 1.22); absolute benefit 10% (95% CI, 3% to 17%; NNTB = 10 (95% CI, 8 to 21)).Based on low-quality direct evidence, results for biologic monotherapy for withdrawals due to adverse events and serious adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase. The direct estimate for TNF monotherapy for withdrawals due to adverse events showed a clinically meaningful and statistically significant result with RR 2.02 (95% CI, 1.08 to 3.78), absolute benefit RD 3% (95% CI,1% to 4%), based on moderate-quality evidence. The NMA estimates for TNF biologic, non-TNF biologic, anakinra, or tofacitinib monotherapy for withdrawals due to adverse events and for serious adverse events were all inconclusive and downgraded to low-quality evidence. Monotherapy versus active comparator (MTX/other DMARDs)Based on direct evidence of moderate quality, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in ACR50 and HAQ scores versus MTX/other DMARDs with a RR of 1.54 (95% CI, 1.14 to 2.08); absolute benefit 13% (95% CI, 2% to 23%), NNTB = 7 (95% CI, 4 to 26) and a mean difference in HAQ of -0.27 (95% CI, -0.40 to -0.14); absolute benefit of -9% (95% CI, -13.3% to -4.7%), NNTB = 2 (95% CI, 2 to 4). Direct and NMA estimates for TNF monotherapy and NMA estimate for non-TNF biologic monotherapy for ACR50 showed similar results, based on moderate-quality evidence. Direct and NMA estimates for non-TNF biologic monotherapy, but not TNF monotherapy, showed similar HAQ improvements , based on mostly moderate-quality evidence.There were no statistically significant or clinically meaningful differences for direct estimates of biologic monotherapy versus active comparator for RA disease remission. NMA estimates showed a statistically significant and clinically meaningful difference versus active comparator for TNF monotherapy (absolute improvement 7% (95% CI, 2% to 14%)) and non-TNF monotherapy (absolute improvement 19% (95% CrI, 7% to 36%)), both downgraded to moderate quality.Based on moderate-quality direct evidence from a single study, radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologic monotherapy versus active comparator, MD -4.34 (95% CI, -7.56 to -1.12), though the absolute reduction was small, -0.97% (95% CI, -1.69% to -0.25%). We are not sure of the clinical relevance of this reduction.Direct and NMA evidence (downgraded to low quality), showed inconclusive results for withdrawals due to adverse events, serious adverse events and cancer, with wide confidence intervals encompassing the null effect and evidence of an important increase. AUTHORS' CONCLUSIONS Based mostly on RCTs of six to 12-month duration in people with RA who had previously experienced and failed treatment with MTX/other DMARDs, biologic monotherapy improved ACR50, function and RA remission rates compared to placebo or MTX/other DMARDs.Radiographic progression was reduced versus active comparator, although the clinical significance was unclear.Results were inconclusive for whether biologic monotherapy was associated with an increased risk of withdrawals due to adverse events, serious adverse events or cancer, versus placebo (no data on cancer) or MTX/other DMARDs.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Murakoshi M, Kuwabara H, Nagasaki M, Xiong YM, Reagan JD, Maeda H, Nara F. Discovery and pharmacological effects of a novel GPR142 antagonist. J Recept Signal Transduct Res 2016; 37:290-296. [PMID: 27807998 DOI: 10.1080/10799893.2016.1247861] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases.
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Affiliation(s)
- Michiko Murakoshi
- a Biological Research Department , Daiichi Sankyo RD Novare Co. Ltd. , Tokyo , Japan
| | - Harumi Kuwabara
- b Pain & Neuroscience Laboratories, Research Function, R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan
| | - Miyuki Nagasaki
- c Biologics & Immuno-Oncology Laboratories Research Function , R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan
| | - Yu Mei Xiong
- d Department of Cardio-Metabolic Disorders , Amgen, Inc. , South San Francisco , CA , USA
| | - Jeff D Reagan
- d Department of Cardio-Metabolic Disorders , Amgen, Inc. , South San Francisco , CA , USA
| | - Hiroaki Maeda
- e Immunology & Inflammatory Disease Field , Asubio Pharma Co. Ltd. , Kobe , Japan
| | - Futoshi Nara
- c Biologics & Immuno-Oncology Laboratories Research Function , R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan
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Alves CH, Farrell E, Vis M, Colin EM, Lubberts E. Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside-a Comprehensive Review. Clin Rev Allergy Immunol 2016; 51:27-47. [PMID: 26634933 PMCID: PMC4961736 DOI: 10.1007/s12016-015-8522-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions.
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Affiliation(s)
- C Henrique Alves
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Eric Farrell
- Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Marijn Vis
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Edgar M Colin
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Rheumatology, ZGT Almelo, Zilvermeeuw 1, 7600 SZ, Almelo, The Netherlands
| | - Erik Lubberts
- Department of Rheumatology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
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Fleischmann R, Kremer J, Tanaka Y, Gruben D, Kanik K, Koncz T, Krishnaswami S, Wallenstein G, Wilkinson B, Zwillich SH, Keystone E. Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. Int J Rheum Dis 2016; 19:1216-1225. [PMID: 27451980 PMCID: PMC5396326 DOI: 10.1111/1756-185x.12901] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1–30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose‐dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient‐reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.
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Affiliation(s)
| | - Joel Kremer
- Center for Rheumatology, Albany Medical College, Albany, New York, USA
| | - Yoshiya Tanaka
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Singh JA, Hossain A, Tanjong Ghogomu E, Kotb A, Christensen R, Mudano AS, Maxwell LJ, Shah NP, Tugwell P, Wells GA. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2016; 2016:CD012183. [PMID: 27175934 PMCID: PMC7068903 DOI: 10.1002/14651858.cd012183] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA). OBJECTIVES To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR). METHODS We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation. MAIN RESULTS This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Ahmed Kotb
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | - Robin Christensen
- Copenhagen University Hospital, Bispebjerg og FrederiksbergMusculoskeletal Statistics Unit, The Parker InstituteNordre Fasanvej 57CopenhagenDenmarkDK‐2000
| | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Lara J Maxwell
- Ottawa Hospital Research Institute (OHRI), The Ottawa Hospital ‐ General CampusCentre for Practice‐Changing Research (CPCR)501 Smyth Road, Box 711OttawaONCanadaK1H 8L6
| | - Nipam P Shah
- University of Alabama at BirminghamDepartment of Clinical Immunology and RheumatologyFaculty Office Tower, Suite 805, 510 20th Street SouthBirminghamALUSA35294
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Boyce EG, Vyas D, Rogan EL, Valle-Oseguera CS, O'Dell KM. Impact of tofacitinib on patient outcomes in rheumatoid arthritis - review of clinical studies. PATIENT-RELATED OUTCOME MEASURES 2016; 7:1-12. [PMID: 26834501 PMCID: PMC4716749 DOI: 10.2147/prom.s62879] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Rheumatoid arthritis is a chronic, progressive autoimmune disease associated with inflammation and destruction of joints and systemic effects, which result in significant impact on patient's quality of life and function. Tofacitinib was approved for the treatment of rheumatoid arthritis in the USA in 2012 and subsequently in other countries, but not by the European Medicines Agency. The goal of this review was to evaluate the impact of tofacitinib on patient-reported and patient-specific outcomes from prior clinical studies, focusing on quality of life, functionality, pain, global disease assessment, major adverse consequences, and withdrawals. A total of 13 reports representing 11 clinical studies on tofacitinib in rheumatoid arthritis were identified through PubMed and reference lists in meta-analyses and other reviews. Data on improvements in patient-driven composite tools to measure disease activity in rheumatoid arthritis, such as the Health Assessment Questionnaire, served as a major outcome evaluated in this review and were extracted from each study. Additional data extracted from those clinical studies included patient assessment of pain (using a 0-100 mm visual analog scale), patient global assessment of disease (using a 0-100 mm visual analog scale), patient withdrawals, withdrawals due to adverse effects or lack of effect, and risk of serious adverse effects, serious infections, and deaths. Tofacitinib 5 mg bid appears to have a favorable impact on patient outcomes related to efficacy and safety when compared with baseline values and with comparator disease-modifying antirheumatic drugs and placebo. Improvements were seen in the composite and individual measures of disease activity. Serious adverse effects, other adverse consequences, overall withdrawals, and withdrawals due to adverse effects and lack of efficacy are similar or more favorable for tofacitinib versus comparator disease-modifying antirheumatic drugs and placebo. At this point, tofacitinib appears to have an important role in the treatment of rheumatoid arthritis through improvement in these patient outcomes. However, it may require years of additional clinical studies and postmarketing surveillance to fully characterize the benefit-to-risk ratio of tofacitinib in a larger and diverse patient population.
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Affiliation(s)
- Eric G Boyce
- Department of Pharmacy Practice, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
| | - Deepti Vyas
- Department of Pharmacy Practice, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
| | - Edward L Rogan
- Department of Pharmacy Practice, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
| | - Cynthia S Valle-Oseguera
- Department of Pharmacy Practice, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
| | - Kate M O'Dell
- Department of Pharmacy Practice, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
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Asakawa M, Yoshida H, Sakai R, Saeki K, Okada M, Kanamori M, Kotani H, Wei X, Yoshimura A. A novel JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl(2,6-dichlorophenyl)acetate, suppresses helper T cell differentiation in vitro and collagen-induced arthritis in vivo. Biochem Biophys Res Commun 2015; 468:766-73. [DOI: 10.1016/j.bbrc.2015.11.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 11/05/2015] [Indexed: 10/22/2022]
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Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Arch Immunol Ther Exp (Warsz) 2015; 63:435-49. [PMID: 26062902 PMCID: PMC4633446 DOI: 10.1007/s00005-015-0344-z] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 05/26/2015] [Indexed: 02/07/2023]
Abstract
The end of twentieth century has introduced some changes into T helper (Th) cells division. The identification of the new subpopulation of T helper cells producing IL-17 modified model of Th1-Th2 paradigm and it was named Th17. High abilities to stimulate acute and chronic inflammation made these cells ideal candidate for crucial player in development of autoimmune disorders. Numerous publications based on animal and human models confirmed their pivotal role in pathogenesis of human systemic and organ-specific autoimmune diseases. These findings made Th17 cells and pathways regulating their development and function a good target for therapy. Therapies based on inhibition of Th17-dependent pathways are associated with clinical benefits, but on the other hand are frequently inducing adverse effects. In this review, we attempt to summarize researches focused on the importance of Th17 cells in development of human autoimmune diseases as well as effectiveness of targeting IL-17 and its pathways in pre-clinical and clinical studies.
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Affiliation(s)
- Jacek Tabarkiewicz
- Centre for Innovative Research in Medical and Natural Sciences, Medical Faculty, University of Rzeszów, Rzeszow, Poland.
| | - Katarzyna Pogoda
- Centre for Innovative Research in Medical and Natural Sciences, Medical Faculty, University of Rzeszów, Rzeszow, Poland
| | | | - Piotr Pozarowski
- Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland
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Tanimoto A, Shinozaki Y, Nozawa K, Kimoto Y, Amano W, Matsuo A, Yamaguchi T, Matsushita M. Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis. BMC Musculoskelet Disord 2015; 16:339. [PMID: 26546348 PMCID: PMC4636776 DOI: 10.1186/s12891-015-0802-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 11/03/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction, disability, and decreased quality of life (QOL). Inhibition of Janus kinase (JAK) signaling ameliorates articular inflammation and joint destruction in animal models of RA, but its effects on behaviors indicating well-being are poorly understood. In this study, we evaluated the effect of JAK inhibition on spontaneous locomotor activity in rats with adjuvant-induced arthritis, a rodent model of RA. METHODS Arthritis was induced in male Lewis rats by a single subcutaneous injection of Freund's complete adjuvant. The novel JAK inhibitor JTE-052 was orally administered for 7 days after the onset of arthritis. RESULTS Induction of arthritis suppressed the spontaneous locomotor activity of the rats. Administration of JTE-052 completely improved the spontaneous locomotor activity, with partial reductions in articular inflammation and joint destruction. Hyperalgesia and motor functions were also improved, but the efficacy was not complete. However, serum interleukin (IL)-6 levels were completely decreased at 4 h after administration of the first dose of JTE-052. CONCLUSIONS This study demonstrated that JAK inhibition improved the spontaneous locomotor activity of rats with adjuvant-induced arthritis, in association with amelioration of pain and physical dysfunction as a consequence of suppression of joint inflammation. Moreover, although further studies are needed, there was possible participation of IL-6 downregulation in the improvement of locomotor activity by JAK inhibition.
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Affiliation(s)
- Atsuo Tanimoto
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Yuichi Shinozaki
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Keisuke Nozawa
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Yukari Kimoto
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Wataru Amano
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Akira Matsuo
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Takayuki Yamaguchi
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
| | - Mutsuyoshi Matsushita
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
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Therapeutic potential of IL-15 in rheumatoid arthritis. Hum Immunol 2015; 76:812-8. [PMID: 26429323 DOI: 10.1016/j.humimm.2015.09.041] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 12/02/2014] [Accepted: 09/28/2015] [Indexed: 01/10/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic, destructive inflammatory autoimmune disease. Cytokine-mediated immunity has been found to play an important role in the pathogenesis of autoimmune diseases including RA. Recently, much attention has been paid on the role of IL-15, which is a member of the 4 α-helix bundle cytokine family. IL-15 was detected in serum and synovial fluid from RA patients and arthritis mice models. Moreover, administration of IL-15 leads to the development of severe inflammatory arthritis, suggesting that IL-15 may be therapeutically relevant in RA. Therefore, targeting IL-15 may be significantly important and valuable. In this article, we discuss the biological features and effects of IL-15 and summarize recent advances on the pathological roles of IL-15 in RA and treatment for RA.
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da Mota LMH, Cruz BA, de Albuquerque CP, Gonçalves DP, Laurindo IMM, Pereira IA, de Carvalho JF, Pinheiro GDRC, Bertolo MB, Pinto MRDC, Louzada-Junior P, Xavier RM, Giorgi RDN, Lima RAC. Update on the 2012 Brazilian Society of Rheumatology Guidelines for the treatment of rheumatoid arthritis: position on the use of tofacitinib. REVISTA BRASILEIRA DE REUMATOLOGIA 2015; 55:512-21. [PMID: 26456224 DOI: 10.1016/j.rbr.2015.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 08/11/2015] [Indexed: 02/06/2023] Open
Abstract
In 2014, tofacitinib, a target-specific, synthetic disease modifying anti rheumatic drug (DMARD) and a selective inhibitor of Janus kinase (JAK) was approved for use in Brazil. This position paper aims to update the recommendations of the Brazilian Society of Rheumatology (SBR) on the treatment of rheumatoid arthritis (RA) in Brazil, specifically regarding the use of target-specific synthetic DMARDs. The method of this recommendation consisted of a literature review of scientific papers held on the Medline database. After this review, a text was produced, answering questions in Pico structure, considering efficacy and safety issues of tofacitinib use for RA treatment in different scenarios (such as first-line treatment after failure with methotrexate [MTX] or other conventional synthetic DMARDs after failure with biological therapy). Based on existing evidence, and considering the available data on efficacy, safety and cost of medications available to treat the disease in Brazil, the RA Commission of SBR, after a process of discussion and voting on proposals, established the following position on the use of tofacitinib for treatment of RA in Brazil: "Tofacitinib, alone or in combination with MTX, is an alternative for RA patients with moderate or high activity after failure of at least two different synthetic DMARDs and one biological DMARD." The level of agreement with this recommendation was 7.5. This position may be reviewed in the coming years, in the face of a greater experience with the use of this medication.
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Affiliation(s)
- Licia Maria Henrique da Mota
- Hospital Universitário de Brasília, Universidade de Brasília (UnB), Brasília, DF, Brasil; Programa de Pós-graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brasil.
| | | | | | - Deborah Pereira Gonçalves
- Serviço de Reumatologia, Hospital Universitário Walter Cantídio, Fortaleza, CE, Brasil; Serviço de Reumatologia, Hospital Geral Dr. César Cals, Fortaleza, CE, Brasil; Programa de Residência Médica em Reumatologia, Hospital Geral Dr. César Cals, Fortaleza, CE, Brasil
| | | | - Ivanio Alves Pereira
- Disciplina de Reumatologia, Universidade do Sul de Santa Catarina (Unisul), Florianópolis, SC, Brasil; Núcleo de Reumatologia, Hospital Universitário, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brasil
| | | | | | - Manoel Barros Bertolo
- Disciplina de Reumatologia, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil; Departamento de Clínica Médica, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil
| | - Maria Raquel da Costa Pinto
- Ambulatório de Artrite Reumatoide, Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil; Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil
| | - Paulo Louzada-Junior
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brasil
| | - Ricardo Machado Xavier
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil; Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - Rina Dalva Neubarth Giorgi
- Serviço de Reumatologia, Hospital do Servidor Público Estadual Francisco Morato de Oliveira (HSPE-FMO), São Paulo, SP, Brasil
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Gao W, McCormick J, Connolly M, Balogh E, Veale DJ, Fearon U. Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis. Ann Rheum Dis 2015; 74:1275-83. [PMID: 24525913 DOI: 10.1136/annrheumdis-2013-204105] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 01/24/2014] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To examine the effect of hypoxia on Signal Transducer and Activator of Transcription 3 (STAT3)-induced pro-inflammatory pathways in rheumatoid arthritis (RA). METHODS Detection of phospho-STAT3 was assessed in RA synovial tissue and fibroblasts (RASFC) by immunohistology/immunofluorescence. Primary RASFCs and a normal synoviocyte cell line (K4IM) were cultured under hypoxic and normoxic conditions±Stat3-siRNA, HIF-siRNA or WP1066 (JAK2-inhibitor). HIF1α, p-STAT3, p-STAT1 and Notch-1IC protein expression were analysed by western blot. Functional mechanisms were quantified by invasion chamber, matrigel and migration assays. IL-6, IL-8, IL-10 and matrixmetalloproteinases (MMP)-3 were quantified by ELISA. Notch-1 receptor, its DLL-4 ligand and downstream target genes (hrt-1, hrt-2) were quantified by real-time PCR. The effect of WP1066 on spontaneous secretion of pro/anti-inflammatory cytokines and Notch signalling was examined in RA synovial explants ex vivo. RESULTS p-STAT3 was increased in RA synovium compared with control (p<0.05). Hypoxia induced p-STAT3, p-STAT1 and HIF1α expression, an effect blocked by Stat3-siRNA and WP1066. Hypoxia-induced cell invasion, migration and cytokine production were inhibited by Stat3-siRNA (p<0.05) and WP1066 (p<0.05). While HIF1α siRNA inhibited hypoxia-induced p-STAT3 detection, Stat3-siRNA also inhibited hypoxia-induced HIF1α. Furthermore, hypoxia-induced Notch-1IC, DLL4, hrt-1 and -2 expression were significantly inhibited by WP1066 (p<0.05). Finally, in RA synovial explant cultures ex vivo, WP1066 decreased spontaneous secretion of IL-6, IL-8 and MMP3 (p<0.05), Notch-1 mRNA (p<0.05) and induced IL-10 (p<0.05). CONCLUSIONS This is the first study to provide evidence of a functional link between HIF1α, STAT3 and Notch-1 signalling in the regulation of pro-inflammatory mechanisms in RA, and further supports a role for STAT blockade in the treatment of RA.
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Affiliation(s)
- Wei Gao
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
| | - Jennifer McCormick
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
| | - Mary Connolly
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
| | - Emese Balogh
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
| | - Douglas J Veale
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
| | - Ursula Fearon
- Translational Research Group, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland
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Ward MM, Guthrie LC, Alba MI. Clinically important changes in short form 36 health survey scales for use in rheumatoid arthritis clinical trials: the impact of low responsiveness. Arthritis Care Res (Hoboken) 2014; 66:1783-9. [PMID: 24980417 PMCID: PMC4245332 DOI: 10.1002/acr.22392] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 06/24/2014] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Despite wide use of the Short-Form 36 (SF-36) health survey in clinical trials of rheumatoid arthritis (RA), estimates of minimum clinically important improvement (MCII) for its scales are not well-established. We estimated MCIIs for SF-36 scales in patients with active RA. METHODS In this prospective longitudinal study, we studied 243 patients who had active RA and who completed the SF-36 before and after treatment escalation. We first assessed responsiveness with standardized response means (SRMs). For scales with adequate responsiveness (SRM ≥0.50), we used patient judgments of improvement in arthritis status as anchors for estimating MCIIs. We used receiver operating characteristic curve analysis to identify the MCIIs as the change associated with a specificity of 0.80 for improvement. RESULTS Patients had substantial improvement in RA activity with treatment. However, among SF-36 scales, only the physical functioning and bodily pain scales and the physical component summary had adequate responsiveness. Using 0.80 specificity for improvement as the criterion, the MCIIs were 7.1 for the physical functioning scale, 4.9 for the bodily pain scale, and 7.2 for the physical component summary. CONCLUSION Low responsiveness precluded estimation of valid MCIIs for many SF-36 scales in patients with RA, particularly the scales assessing mental health. Although the SF-36 has been included in many clinical trials to broaden the assessment of health status, low responsiveness limits the interpretation of changes in its mental health-related scales.
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Affiliation(s)
- Michael M Ward
- Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
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Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S, Tanaka Y. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis 2014; 73:2192-8. [PMID: 24013646 DOI: 10.1136/annrheumdis-2013-203756] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. METHODS The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. RESULTS Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. CONCLUSIONS Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.
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Affiliation(s)
- Satoshi Kubo
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Kunihiro Yamaoka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Masahiro Kondo
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Kaoru Yamagata
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Jidong Zhao
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Shigeru Iwata
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
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Small-molecule therapeutics in rheumatoid arthritis: scientific rationale, efficacy and safety. Best Pract Res Clin Rheumatol 2014; 28:605-24. [PMID: 25481553 DOI: 10.1016/j.berh.2014.10.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Rheumatoid arthritis (RA) remains a formidable clinical challenge. This is despite remarkable recent advances in our understanding of pathogenesis and the introduction of a variety of novel agents, particularly biologic therapeutics that are potent inhibitors of extracellular immune pathways. Whereas the latter have brought substantial improvements in efficacy and thus outcomes, there remain significant numbers of non- or partial responders to current standard of care. The discovery of key intracellular pathways, particularly kinases that subserve the function of these pivotal cytokine and immune cell receptors implicated in RA pathogenesis, has facilitated the advent of a new phase of RA drug development. Thus, a range of kinase inhibitors has entered clinical trials and one agent has been licenced for use in some regions. Herein we summarise the chequered history of kinase inhibitor development in RA, describing successes and failures alike, and thereafter examine future trends in this exciting field.
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de Vicente J, Lemoine R, Bartlett M, Hermann JC, Hekmat-Nejad M, Henningsen R, Jin S, Kuglstatter A, Li H, Lovey AJ, Menke J, Niu L, Patel V, Petersen A, Setti L, Shao A, Tivitmahaisoon P, Vu MD, Soth M. Scaffold hopping towards potent and selective JAK3 inhibitors: Discovery of novel C-5 substituted pyrrolopyrazines. Bioorg Med Chem Lett 2014; 24:4969-75. [DOI: 10.1016/j.bmcl.2014.09.031] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 09/08/2014] [Accepted: 09/10/2014] [Indexed: 10/24/2022]
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Lundquist LM, Cole SW, Sikes ML. Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop 2014; 5:504-511. [PMID: 25232526 PMCID: PMC4133456 DOI: 10.5312/wjo.v5.i4.504] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 03/26/2014] [Accepted: 06/03/2014] [Indexed: 02/06/2023] Open
Abstract
Tofacitinib is the first in a new class of nonbiologic disease-modifying antirheumatic drugs (DMARDs), a targeted, synthetic DMARD, approved for the treatment of rheumatoid arthritis (RA) as monotherapy or in combination with methotrexate or other non-biologic DMARD. Tofacitinib, an orally administered Janus kinase (JAK) inhibitor, decreases T-cell activation, pro-inflammatory cytokine production, and cytokine signaling by inhibiting binding of type I cytokine receptors family and γ-chain cytokines to paired JAK1/JAK3 receptors. The net effect of tofacitinb’s mechanism of action is decreased synovial inflammation and structural joint damage in RA patients. To date, six phase 3 trials have been conducted to evaluate the safety and efficacy of tofacitinib under the oral rheumatoid arthritis triaLs (ORAL) series. This review describes the pharmacology of the novel agent, tofacitinib, and details the safety and efficacy data of the ORAL trials.
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Malemud CJ, Blumenthal DE. Protein kinase small molecule inhibitors for rheumatoid arthritis: Medicinal chemistry/clinical perspectives. World J Orthop 2014; 5:496-503. [PMID: 25232525 PMCID: PMC4133455 DOI: 10.5312/wjo.v5.i4.496] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 02/28/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
Medicinal chemistry strategies have contributed to the development, experimental study of and clinical trials assessment of the first type of protein kinase small molecule inhibitor to target the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. The orally administered small molecule inhibitor, tofacitinib, is the first drug to target the JAK/STAT pathway for entry into the armamentarium of the medical therapy of rheumatoid arthritis. The introduction of tofacitinib into general rheumatologic practice coupled with increasing understanding that additional cellular signal transduction pathways including the mitogen-activated protein kinase and phosphatidylinositide-3-kinase/Akt/mammalian target of rapamycin pathways as well as spleen tyrosine kinase also contribute to immune-mediated inflammatory in rheumatoid arthritis makes it likely that further development of orally administered protein kinase small molecule inhibitors for rheumatoid arthritis will occur in the near future.
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Song GG, Bae SC, Lee YH. Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials. Korean J Intern Med 2014; 29:656-63. [PMID: 25228842 PMCID: PMC4164730 DOI: 10.3904/kjim.2014.29.5.656] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/19/2013] [Accepted: 12/23/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/AIMS The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). METHODS A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. RESULTS Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. CONCLUSIONS Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
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Affiliation(s)
- Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang-Cheol Bae
- Hospital for Rheumatic Diseases, Hanyang University College of Medicine, Seoul, Korea
| | - Young Ho Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, Sakai T, Nakamura M, Motokawa S, Nakamura T, Kawakami A. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol 2014; 175:208-14. [PMID: 24665995 DOI: 10.1111/cei.12234] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2013] [Indexed: 12/18/2022] Open
Abstract
The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 μg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 μg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib.
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Affiliation(s)
- K Migita
- Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Omura, Japan
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Does signaling pathway inhibition hold therapeutic promise for osteoarthritis? Joint Bone Spine 2014; 81:281-3. [PMID: 24709002 DOI: 10.1016/j.jbspin.2014.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2013] [Indexed: 01/15/2023]
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Meier FMP, Frerix M, Hermann W, Müller-Ladner U. Current immunotherapy in rheumatoid arthritis. Immunotherapy 2014; 5:955-74. [PMID: 23998731 DOI: 10.2217/imt.13.94] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Rheumatoid arthritis is a common autoimmune disease primarily manifesting as chronic synovitis, subsequently leading to a change in joint integrity. Progressive disability and systemic complications are strongly associated with a decreased quality of life. To maintain function and health in patients with rheumatoid arthritis, early, aggressive and guided immunosuppressive therapy is required to induce clinical remission. Antirheumatic drugs are capable of controlling synovial inflammation and are therefore named 'disease-modifying antirheumatic drugs' (DMARDs). This article aims to bridge the beginning of DMARD therapy with agents such as methotrexate, leflunomide, sulfasalazine, injectable gold and (hydroxy)chloroquine with biological therapies, and with the new era of kinase inhibitors. Mechanisms of action, as well as advantages and disadvantages of DMARDs, are discussed with respect to the current literature and current recommendations.
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Affiliation(s)
- Florian M P Meier
- Department of Internal Medicine & Rheumatology, Justus-Liebig-University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany
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Abstract
Tofacitinib (Xeljanz(®)) is the first approved drug in a new class of disease modifying antirheumatic drugs (DMARDs), the Janus kinase (JAK) inhibitors. JAKs have a pivotal role in triggering cytokine-induced signal transduction pathways that influence normal and pathological cellular processes of haematopoiesis and immune cell function, including pathogenic mechanisms involved in rheumatoid arthritis (RA). Selective inhibition of JAKs by tofacitinib potentially modulates inflammatory processes and provides a novel approach for the treatment of RA. Oral tofacitinib is indicated for the treatment of adult patients with active RA who have had an inadequate response to methotrexate and/or other DMARDs. In several large well designed trials, tofacitinib, in combination with methotrexate or other nonbiological DMARDs or as monotherapy, was an effective and generally well tolerated DMARD for the treatment of adult patients with moderately to severely active RA who had had an inadequate response to previous DMARDs, including tumour necrosis factor-α inhibitors. Direct head-to-head trials and/or further clinical experience (including long-term safety data), along with robust pharmacoeconomic studies, are required to more definitively position tofacitinib relative to other currently available DMARDs. In the meantime, tofacitinib (alone or in combination with nonbiological DMARDs) is an emerging option for the treatment of DMARD-experienced adult patients with moderately to severely active RA who have had an inadequate response to or are intolerant of methotrexate or other DMARDs.
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Affiliation(s)
- Lesley J Scott
- Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand.
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Zhang X, Liang F, Yin X, Xiao X, Shi P, Wei D, Yao L, Wang Q, Chen Y. Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis. Clin Rheumatol 2014; 33:165-73. [PMID: 24389749 DOI: 10.1007/s10067-013-2452-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 11/24/2013] [Indexed: 10/25/2022]
Abstract
The aim of this systematic review and meta-analysis is to assess the efficacy and safety of tofacitinib for the treatment of patients with acute rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drug (DMARD). Randomized controlled trials were searched in MEDLINE (1966-2013), Embase (1947-2013), the Cochrane Central Register of Controlled Trials (1948-2013), WHO International Clinical Trial Registration Platform (2004-2013), Clinical Trial.gov (1999-2013), and China Biology Medicine disc (1978-2013). The review included 10 studies involving 4,929 patients. A pooled analysis of six studies showed that tofacitinib had a superior effect over placebo (both with background therapy) at weeks 12 and 24. Also, the pooled results of three studies showed that tofacitinib monotherapy had a significantly greater effect over placebo. Compared to adalimumab, tofacitinib was found to be more efficacious as well. For safety, tofacitinib monotherapy had less serious adverse events (sAE) than placebo but not other adverse effects (oAE). In the comparison of tofacitinib and placebo both with background therapy, no difference in sAE and oAE were found. However, the quality of the evidence was quite low when evaluated using GRADE. Tofacitinib alone, or together with non-biologic DMARDs, was associated with more favorable remission in the signs and symptoms of RA than adalimumab or placebo. Also, tofacitinib monotherapy was safer than placebo with regards to reported sAE, but not oAE. However, the quality of evidence is exceedingly low; long-term, large-scale, and high-quality post-marketing research is suggested to further verify the conclusion.
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Affiliation(s)
- Xingming Zhang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China
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Tanaka Y, Yamaoka K. JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Mod Rheumatol 2014. [DOI: 10.3109/s10165-012-0799-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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