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Gianfrancesco M, Awofeso A, Branquinho D, Guo X, McDonnell A, Jacobs W, Regueiro M. A narrative literature review of the incidence and prevalence of safety outcomes in patients with ulcerative colitis. Expert Rev Gastroenterol Hepatol 2025:1-18. [PMID: 40331585 DOI: 10.1080/17474124.2025.2501224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 04/06/2025] [Accepted: 04/29/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Information on rates of safety outcomes in patients with ulcerative colitis [UC] is helpful to better understand the benefit-risk profile of more recent therapies approved for UC. AREAS COVERED This narrative review provides an updated examination of the incidence and prevalence of safety outcomes in the UC patient population. Incidence and prevalence estimates were determined for outcomes including cardiac conduction disorders, infections, and malignancies from published literature [2013-2023]. EXPERT OPINION While information for certain outcomes was more frequently recorded, such as herpes viral infection (incidence rate [IR] 0.0-4.47 per 100 person-years [PY]) and malignancies [all; IR 0.0-1.77 per 100 PY], rarer outcome estimates such as bradycardia [IR 0.2 per 100 PY] and macular edema [IR 0.2 per 100 PY] were limited. Our knowledge of certain, uncommon safety outcomes and concomitant medical conditions in the UC population remains limited given the lack of data available. Even though larger cohorts with longer follow-up are warranted, estimates provided in this review will contribute to an improved understanding of the safety profile of UC therapies.
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Affiliation(s)
| | - Abiola Awofeso
- School of Community Health & Policy, Morgan State University, Baltimore, MD, USA
| | | | | | | | | | - Miguel Regueiro
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
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2
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Okamoto N, Atsumi T, Takagi M, Takahashi N, Takeuchi T, Tamura N, Nakajima A, Nakajima A, Fujii T, Matsuno H, Ishii T, Tsujimoto N, Nishikawa A, Minatoya M, Tanaka Y, Kuwana M. Safety of baricitinib in Japanese patients with rheumatoid arthritis in clinical use: 3-year data of all-case postmarketing surveillance study. Mod Rheumatol 2025; 35:215-224. [PMID: 39119689 DOI: 10.1093/mr/roae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/23/2024] [Accepted: 08/06/2024] [Indexed: 08/10/2024]
Abstract
OBJECTIVES To assess safety of baricitinib in Japanese patients with rheumatoid arthritis (RA) in real-world clinical practice. METHODS This all-case postmarketing surveillance study included patients initiating baricitinib for RA from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from initiation (up to 4 weeks postdiscontinuation in discontinuing patients). RESULTS Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3-year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients [incidence rate (IR) 10.42/100 patient-years (PY); 95% confidence interval, 9.76-11.09]. There were 39 deaths [IR 0.43 (0.30-0.57)/100 PY]. Adverse events of special interest IRs per 100 PY were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48), and venous thromboembolism 0.25 (0.15-0.36). IRs did not increase with prolonged exposure. CONCLUSIONS No new safety concerns were identified during this 3-year postmarketing surveillance study of baricitinib in Japanese patients with RA. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.
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Affiliation(s)
- Nami Okamoto
- Department of Paediatrics, Osaka Rosai Hospital, Osaka, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan
| | - Michiaki Takagi
- Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Nobunori Takahashi
- Department of Orthopedic Surgery, Aichi Medical University, Aichi, Japan
| | - Tsutomu Takeuchi
- Saitama Medical University, Saitama, Japan
- Keio University School of Medicine, Tokyo, Japan
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Atsuo Nakajima
- Department of Rheumatology, Ueno Dialysis Clinic, Tokyo, Japan
| | - Ayako Nakajima
- Center for Rheumatic Diseases, Mie University Hospital, Mie, Japan
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan
| | | | - Taeko Ishii
- Japan Drug Development & Medical Affairs, Eli Lilly Japan K.K., Kobe, Japan
| | - Naoto Tsujimoto
- Japan Drug Development & Medical Affairs, Eli Lilly Japan K.K., Kobe, Japan
| | - Atsushi Nishikawa
- Japan Drug Development & Medical Affairs, Eli Lilly Japan K.K., Kobe, Japan
| | - Machiko Minatoya
- Japan Drug Development & Medical Affairs, Eli Lilly Japan K.K., Kobe, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
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Shimizu K, Yanai R, Yamamoto K, Michizu Y, Ikari Y, Yajima N. Melanoma Differentiation-associated Gene 5-Positive Rapidly Progressive Interstitial Lung Disease Successfully Treated with Tofacitinib. Intern Med 2025; 64:609-612. [PMID: 38987190 PMCID: PMC11904449 DOI: 10.2169/internalmedicine.3467-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 05/19/2024] [Indexed: 07/12/2024] Open
Abstract
Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody-positive dermatomyositis is associated with rapidly progressive interstitial lung disease (RP-ILD). We encountered a man in his 40s who presented with a history of a fever and dry cough. Based on laboratory tests and computed tomography scans of his chest, he was diagnosed with anti-MDA-5 antibody-positive dermatomyositis with RP-ILD refractory to antimicrobial agents. Although the patient was treated with glucocorticoids, calcineurin inhibitors, intravenous cyclophosphamide, and plasma exchange, ventilatory management was still required. The patient survived additional therapy with tofacitinib; however, he developed a catheter-related pulmonary embolism as a complication.
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Affiliation(s)
- Kunika Shimizu
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
| | - Ryo Yanai
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
| | - Kie Yamamoto
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
| | - Yuta Michizu
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
| | - Yuzo Ikari
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
| | - Nobuyuki Yajima
- Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Japan
- Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University, Japan
- Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Japan
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4
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Bernardes TP, Paula TAF, Sales GTM, Calais PV, Foresto RD, Moura LA, Durão MDS, Pesquero JB, Kirsztajn GM. Collapsing glomerulopathy associated with parvovirus B19 and systemic lupus erythematosus in a patient with APOL1 high-risk variant for nephropathy. J Bras Nefrol 2025; 47:e20240104. [PMID: 39792859 PMCID: PMC11723606 DOI: 10.1590/2175-8239-jbn-2024-0104en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/11/2024] [Indexed: 01/12/2025] Open
Abstract
Collapsing glomerulopathy (CG) has a severe course typically associated with viral infections, especially HIV and parvovirus B19, systemic lupus erythematosus (SLE), among other etiologies. A 35-year-old woman with recent use of a JAK inhibitor due to rheumatoid arthritis presented with a 2-week history of fever, cervical adenopathy, and facial erythema. After admission, anemia, hypoalbuminemia, proteinuria, and severe acute kidney injury were noted. SLE was diagnosed and parvovirus B19 DNA was detected in serum samples. Kidney biopsy showed CG without any typical features of lupus nephritis. The patient was treated with prednisone and presented marked improvement of anemia and kidney function after a few weeks. In this case, the patient with SLE presented CG possibly caused by parvovirus B19 infection associated with homozygous apolipoprotein 1 (APOL1) G1 genotype, which has been described as a determinant risk factor for this glomerulopathy. It is not clear whether SLE had a causal relationship with glomerular disease or was a concurrent cause. Treatment can be challenging in such a context, as no antiviral drug is efficient and immunosuppression has no discernable benefit, although steroid use was efficient in treating renal manifestations in this case.
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Affiliation(s)
| | | | | | - Patrícia Varela Calais
- Universidade Federal de São Paulo, Departamento de Biofísica, Centro de Pesquisa e Diagnóstico em Doenças Genéticas, São Paulo, SP, Brazil
| | | | - Luiz Antonio Moura
- Universidade Federal de São Paulo, Departamento de Medicina, São Paulo, SP, Brazil
- Fundação Oswaldo Ramos, Hospital do Rim, São Paulo, SP, Brazil
| | | | - João Bosco Pesquero
- Universidade Federal de São Paulo, Departamento de Biofísica, Centro de Pesquisa e Diagnóstico em Doenças Genéticas, São Paulo, SP, Brazil
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Ahmed S, Yesudian R, Ubaide H, Coates LC. Rationale and concerns for using JAK inhibitors in axial spondyloarthritis. Rheumatol Adv Pract 2024; 8:rkae141. [PMID: 39660106 PMCID: PMC11630911 DOI: 10.1093/rap/rkae141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/03/2024] [Indexed: 12/12/2024] Open
Abstract
Axial spondyloarthritis (axSpA) is a chronic illness with limited treatment options. The role of Janus kinase (JAK) inhibition as a therapeutic option has increasingly become a focus of research in recent years as they have brought a new mode of action to the clinical armamentarium. This review assesses the efficacy and safety profile of these drugs in axSpA. The current phase 2 and 3 clinical trials data are summarized across tofacitinib, upadacitinib and filgotinib. Moreover, the safety profiles of these drugs, in the context of emerging safety signals such as during the ORAL surveillance study, are reviewed. In summary, JAK inhibitors offer a novel therapeutic target for axSpA and appear to address some of the unmet needs for patients who have either failed to respond to current treatment options or in whom they are contraindicated. There is a relative lack of evidence in non-radiographic axSpA and longer-term trials are needed to establish true efficacy and safety profile in radiographic axSpA.
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Affiliation(s)
- Saad Ahmed
- General Medicine, Colchester Hospital, Colchester, UK
| | - Rohan Yesudian
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Hassan Ubaide
- General Medicine, Colchester Hospital, Colchester, UK
| | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
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Ma C, Jairath V, Feagan BG, Peyrin-Biroulet L, Danese S, Sands BE, Panaccione R. Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2024; 21:792-808. [PMID: 39379665 DOI: 10.1038/s41575-024-00989-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/03/2024] [Indexed: 10/10/2024]
Abstract
Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.
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Affiliation(s)
- Christopher Ma
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
- Alimentiv Inc., London, Ontario, Canada.
| | - Vipul Jairath
- Alimentiv Inc., London, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Brian G Feagan
- Alimentiv Inc., London, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Bruce E Sands
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Remo Panaccione
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
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Wang L, Xin L, Cao Y, Xu Q, Dong J, Fan P, Hou W, Wang Q, Meng J, Zhang R, Gao J. Development of a Controllable Intelligent Drug Delivery System for Efficient Treatment of Rheumatoid Arthritis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:51970-51980. [PMID: 39288084 DOI: 10.1021/acsami.4c09087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Rheumatoid arthritis (RA) is a complex inflammatory disease of the joints, which is often accompanied by degeneration of articular cartilage and bone erosion, seriously affecting the quality of life and psychological state of patients. RA is difficult to be cured completely, and currently the main purpose of relief is through the use of anti-inflammatory and antirheumatic drugs, hormones, and biological agents. Tofacitib is a new type of small molecule inhibitor, which has a good effect in the treatment of RA. The current direct drug delivery method has serious side effects caused by the systemic distribution of the drug, so there is a need to develop an intelligent drug delivery system to realize precise treatment. In this work, tofacitib, gallic acid, targeted molecule folic acid, and Fe(III) were selected to assemble a novel type of artificial controllable nanodrug GF-TF. The self-photoacoustic/magnetic resonance imaging (self-PA/MRI) monitored the enrichment of GF-TF in the lesion in real-time, and artificially regulated the addition of deferoxamine (DFO) at the optimal enrichment. DFO strongly chelates Fe(III) in GF-TF and causes its structure to disintegrate gradually, and the self-PA/MRI signal of GF-TF became weaker while tofacitib began to be released, thus realizing the precise and artificially controlled release of the drug under the guidance of imaging. This nanodrug not only achieves efficient aggregation of drugs in inflamed joints, but also achieves real-time monitoring and precise control of drug release through self-PA/MRI, providing a new strategy for the precise treatment of RA.
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Affiliation(s)
- Lei Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Lei Xin
- Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China
| | - Yuchen Cao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Qi Xu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | | | - Peixin Fan
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Wenrun Hou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | | | - Jian Meng
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
- Shanxi Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China
| | | | - Jinfang Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
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Yoon H, Ye BD, Kang SB, Lee KM, Choi CH, Jo JY, Woo J, Cheon JH. Safety and effectiveness of tofacitinib in Korean adult patients with ulcerative colitis: post-marketing surveillance study. BMC Gastroenterol 2024; 24:273. [PMID: 39160459 PMCID: PMC11331763 DOI: 10.1186/s12876-024-03336-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/23/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea. METHODS This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks. RESULTS A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks. CONCLUSION Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings. TRIAL REGISTRATION This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.
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Affiliation(s)
- Hyuk Yoon
- Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Byong Duk Ye
- University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sang-Bum Kang
- The Catholic University of Korea, Daejeon ST. Mary's Hospital, Daejeon, Korea
| | - Kang-Moon Lee
- The Catholic University of Korea, ST. Vincent's Hospital, Suwon, Gyeonggi-do, Korea
| | | | | | - Juwon Woo
- Pfizer Pharmaceutical Korea Ltd, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, College of Medicine, Yonsei University, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
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Xu H, Zhang X, Wang X, Li B, Yu H, Quan Y, Jiang Y, You Y, Wang Y, Wen M, Liu J, Wang M, Zhang B, Li Y, Zhang X, Lu Q, Yu CY, Cao X. Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity. Immunity 2024; 57:1796-1811.e8. [PMID: 38908373 DOI: 10.1016/j.immuni.2024.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 10/06/2023] [Accepted: 05/30/2024] [Indexed: 06/24/2024]
Abstract
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.
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Affiliation(s)
- Henan Xu
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Xiao Zhang
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xin Wang
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Bo Li
- Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Hang Yu
- Institute of Materia Medical, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Yuan Quan
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yan Jiang
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yuling You
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yan Wang
- Institute of Materia Medical, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Mingyue Wen
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Juan Liu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, Beijing 100730, China
| | - Bo Zhang
- Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yixian Li
- CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, Beijing 100730, China
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Chu-Yi Yu
- CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xuetao Cao
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Frontiers Research Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China; National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Navy Medical University, Shanghai 200433, China.
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Favalli EG, Maioli G, Caporali R. Biologics or Janus Kinase Inhibitors in Rheumatoid Arthritis Patients Who are Insufficient Responders to Conventional Anti-Rheumatic Drugs. Drugs 2024; 84:877-894. [PMID: 38949688 PMCID: PMC11343917 DOI: 10.1007/s40265-024-02059-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/02/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.
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Affiliation(s)
- Ennio Giulio Favalli
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono, 7, 20122, Milan, Italy
- Department of Rheumatology and Medical Sciences, Gaetano Pini-CTO Hospital, P.zza Cardinal Ferrari 1, 20122, Milan, Italy
| | - Gabriella Maioli
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono, 7, 20122, Milan, Italy.
- Department of Rheumatology and Medical Sciences, Gaetano Pini-CTO Hospital, P.zza Cardinal Ferrari 1, 20122, Milan, Italy.
| | - Roberto Caporali
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono, 7, 20122, Milan, Italy
- Department of Rheumatology and Medical Sciences, Gaetano Pini-CTO Hospital, P.zza Cardinal Ferrari 1, 20122, Milan, Italy
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11
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Raychaudhuri SP, Shah RJ, Banerjee S, Raychaudhuri SK. JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis and Their Clinical Significance. Curr Rheumatol Rep 2024; 26:204-213. [PMID: 38492148 PMCID: PMC11116266 DOI: 10.1007/s11926-024-01144-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 03/18/2024]
Abstract
PURPOSE OF REVIEW Janus kinase-signal transducers and activators of transcription cell signaling proteins (JAK-STATs) play a key regulatory role in functioning of several inflammatory cytokines. JAK-STAT signaling proteins are the key regulators of the cytokine/cytokine receptor system involved in the pathogenesis of various autoimmune disease including spondyloarthritis (SpA). This article mainly highlights the JAK-STAT signaling system, its association with the relevant cytokine/cytokine-receptor system, and its regulatory role in pathogenesis of SpA. Also, we have briefly addressed the principle for the use JAKi in SpA and the current status of use of JAK inhibitors (JAKi) in SpA. RECENT FINDINGS Recent developments with newer JAK molecules as well as other molecules beyond JAK inhibitors are now an exciting field for the development of novel therapies for autoimmune diseases and various malignant conditions. In this article, we have provided a special emphasis on how various cell signaling systems beyond JAK/STAT pathway are relevant to SpA and have provided a comprehensive review on this upcoming field in respect to the novel TYK2 inhibitors, RORγT inhibitors, mTOR inhibitors, NGF inhibitors, and various STAT kinase inhibitors. SpA are a group of autoimmune diseases with multifactorial etiologies. SpA is linked with genetic predisposition, environmental risk factors, and the immune system-mediated systemic inflammation. Here, we have provided the regulatory role of JAK/STAT pathway and other intracellular signaling system in the pathogenesis of SpA and its therapeutic relevance.
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Affiliation(s)
- Siba P Raychaudhuri
- Department of Rheumatology, UC Davis Medical Center, Sacramento, CA, USA.
- VA Sacramento Medical Center, Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA.
- UC Davis School of Medicine, Davis, CA, USA.
| | - Ruchi J Shah
- Department of Rheumatology, UC Davis Medical Center, Sacramento, CA, USA
| | - Sneha Banerjee
- VA Sacramento Medical Center, Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA
| | - Smriti K Raychaudhuri
- VA Sacramento Medical Center, Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA
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12
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Akiyama S, Yokoyama K, Yagi S, Shinzaki S, Tsuruta K, Yoshioka S, Sako M, Shimizu H, Kobayashi M, Sakurai T, Nomura K, Shibuya T, Takahara M, Hiraoka S, Sugai K, Yanai S, Yoshida A, Koroku M, Omori T, Saruta M, Matsumoto T, Okamoto R, Tsuchiya K, Fujii T. Efficacy and safety of filgotinib for ulcerative colitis: A real-world multicenter retrospective study in Japan. Aliment Pharmacol Ther 2024; 59:1413-1424. [PMID: 38494867 DOI: 10.1111/apt.17961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/03/2024] [Accepted: 03/08/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND AND AIMS While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited. METHODS This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated. RESULTS We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported. CONCLUSIONS Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.
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Affiliation(s)
- Shintaro Akiyama
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kaoru Yokoyama
- Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Soichi Yagi
- Department of Gastroenterology, Faculty of Medicine, Hyogo Medical University, Hyogo, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology, Faculty of Medicine, Hyogo Medical University, Hyogo, Japan
| | - Kozo Tsuruta
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Shinichiro Yoshioka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Minako Sako
- Center for Inflammatory Bowel Disease, Tokyo Yamate Medical Center, Japan Community Healthcare Organization, Tokyo, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mariko Kobayashi
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Toshiyuki Sakurai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kei Nomura
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kyohei Sugai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Shunichi Yanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Atsushi Yoshida
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kanagawa, Japan
| | - Miki Koroku
- Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Teppei Omori
- Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Kotake K, Mitsuboshi S. Association Between the Dose of Tofacitinib and Risk of Herpes Zoster in Patients With Rheumatoid Arthritis: Analysis of Japanese Adverse Drug Event Report Data. Cureus 2024; 16:e62372. [PMID: 39006739 PMCID: PMC11246770 DOI: 10.7759/cureus.62372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Tofacitinib is one of the Janus kinase inhibitors approved for the treatment of rheumatoid arthritis. The major adverse event of this drug is herpes zoster, which can lead to death in severe cases. The risk of herpes zoster has been studied at 10 mg/day of tofacitinib; however, 5 mg/day, which is recommended in patients with chronic kidney disease, is unclear. OBJECTIVE To investigate whether 5 mg/day of tofacitinib reduced the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients. METHODS We analyzed the Japanese Adverse Drug Event Report Data (JADER) database and compared the frequency of herpes zoster in rheumatoid arthritis patients treated with tofacitinib 5 mg/day and 10 mg/day. Multivariable logistic regression analysis was performed to identify the risk factors for herpes zoster in tofacitinib users. RESULTS A total of 812 tofacitinib users with rheumatoid arthritis were identified, including 131 with herpes zoster. Disproportionality for herpes zoster was observed between 5 mg/day and 10 mg/day (reporting odds ratio (OR): 0.68, 95% confidence interval (CI): 0.47-0.98, P = 0.045). Multivariable logistic regression analysis showed that the risk of herpes zoster was significantly increased in female patients (OR: 1.87, 95% CI: 1.12-3.12, P = 0.016) and methotrexate users (OR: 1.69, 95% CI: 1.12-2.54, P = 0.013) and significantly decreased with tofacitinib 5 mg/day compared with 10 mg/day (OR: 0.62, 95% CI: 0.40-0.96, P = 0.032). CONCLUSION We suggest that tofacitinib 5 mg/day may decrease the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients.
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Affiliation(s)
- Kazumasa Kotake
- Pharmacy Department, Zikei Hospital/Zikei Institute of Psychiatry, Okayama, JPN
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Ayoub M, Mattay S, Yarur AJ, Deepak P. Managing Risks with Newer Oral Small Molecules in Patients with Inflammatory Bowel Diseases. Curr Gastroenterol Rep 2024; 26:145-156. [PMID: 38353899 DOI: 10.1007/s11894-024-00923-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2024] [Indexed: 05/12/2024]
Abstract
PURPOSE OF REVIEW Treatment of Inflammatory Bowel Diseases (IBD) is challenging; thus, the need for newer therapeutic options with an oral route of administration has led to the development of novel small molecules drugs (SMDs). We aim to highlight the most common Adverse events (AEs) associated with SMDs and recommendations on monitoring for AEs before and during treatment. RECENT FINDINGS SMDs, such as Tofacitinib, a JAK inhibitor, have been associated with laboratory abnormalities, infections, and risk of thromboembolic events. Therefore, oral agents with greater selectivity in JAK inhibition, such as tofacitinib and upadacitinib, were later developed. Ozanimod and etrasimod, S1PR agonists, require closer safety profile monitoring by clinicians. Multiple therapies have been recently developed with variable efficacy. However, they have been associated with AEs, and some require close monitoring prior to and during therapy. Clinicians should highlight these adverse events to patients while reassuring the safety profile of these novel SMDs for IBD is favorable.
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Affiliation(s)
- Malek Ayoub
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Shivani Mattay
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Andres J Yarur
- Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Inflammatory Bowel Disease Institute, Los Angeles, CA, USA
| | - Parakkal Deepak
- Division of Gastroenterology, John T. Milliken Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus, Box 8124, St. Louis, MO, 63110, USA.
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Liu H, Wang Y, Le Q, Tong J, Wang H. The IFN-γ-CXCL9/CXCL10-CXCR3 axis in vitiligo: Pathological mechanism and treatment. Eur J Immunol 2024; 54:e2250281. [PMID: 37937817 DOI: 10.1002/eji.202250281] [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: 03/30/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/09/2023]
Abstract
Vitiligo is a disease featuring distinct white patches that result from melanocyte destruction. The overall pathogenesis of vitiligo remains to be elucidated. Nevertheless, considerable research indicates that adaptive immune activation plays a key role in this process. Specifically, the interferon-gamma (IFN-γ), C-X-C motif chemokine ligands (CXCL9/10), and C-X-C motif chemokine receptor (CXCR3) signaling axis, collectively referred to as IFN-γ-CXCL9/10-CXCR3 or ICC axis, has emerged as a key mediator responsible for the recruitment of autoimmune CXCR3+ CD8+ T cells. These cells serve as executioners of melanocytes by promoting their detachment and apoptosis. Moreover, IFN-γ is generated by activated T cells to create a positive feedback loop, exacerbating the autoimmune response. This review not only delves into the mechanistic insights of the ICC axis but also explores the significant immunological effects of associated cytokines and their receptors. Additionally, the review provides a thorough comparison of existing and emerging treatment options that target the ICC axis for managing vitiligo. This review aims to foster further advancements in basic research within related fields and facilitate a deeper understanding of alternative treatment strategies targeting different elements of the axis.
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Affiliation(s)
- Hanqing Liu
- Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Yihui Wang
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Qianqian Le
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Jiajia Tong
- Shanghai Institute of Immunology, Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Honglin Wang
- Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
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Kim YE, Kim YJ, Jeong DH, Kim S, Kim MJ, Kim HH, Jo KW, Park SH, Hong S. Continued JAK inhibitor treatment on the risk of recurrent herpes zoster reactivation in patients with immune-mediated inflammatory diseases: A nationwide population-based study in South Korea. Semin Arthritis Rheum 2024; 65:152362. [PMID: 38281468 DOI: 10.1016/j.semarthrit.2024.152362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/18/2023] [Accepted: 12/27/2023] [Indexed: 01/30/2024]
Abstract
BACKGROUND To investigate the risk of recurrent herpes zoster (HZ) reactivation under continued Janus kinase inhibitor (JAKi) therapy in patients with immune-mediated inflammatory diseases (IMID) who developed HZ reactivation. METHODS Data from the Korean Health Insurance Review and Assessment Service (HIRA) of patients with rheumatoid arthritis (RA) or ulcerative colitis (UC) gathered from 2007 to 2021 were analyzed. RESULTS A total of 3947 (RA 3540, UC 407) receiving JAKi were included. After median 0.95 years (IQR, 0.93-2.58) of therapy, 611 (15.5%) patients developed HZ reactivation (incidence rate: 8.38/100 person-years [PY]). After excluding 151 patients with lack of data after HZ reactivation, 460 patients (JAKi continuation group, n = 386 [83.9%]; JAKi discontinuation group, n = 74 [16.1%]) were analyzed for the risk of subsequent recurrent HZ reactivation. During further follow-up of median 1.11 years (IQR, 0.53-1.91), 36 (9.3%) and 6 (8.1%) patients in the JAKi continuation group and JAKi discontinuation group experienced a recurrence of HZ, respectively. The incidence rate of subsequent recurrent HZ reactivation was not significantly different between the two groups (5.3/100 vs. 5.9/100 PY; P = 0.52). After adjusting for age, sex, usage of corticosteroids, and antiviral agents, continued use of JAKi was not a significant risk factor for subsequent HZ reactivation (adjusted hazard ratio, 0.71 [CI, 0.29-1.72], P = 0.45). CONCLUSION In this nationwide population-based study on patients with RA or UC, continued use of JAKi was not associated with a significant risk of subsequent recurrent HZ reactivation. JAKi therapy may be maintained in patients with IMID even after HZ reactivation.
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Affiliation(s)
- Young-Eun Kim
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Ye-Jee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae Hyun Jeong
- Department of Pulmonology, Sahmyook Medical Center, Seoul, Republic of Korea
| | - Seonok Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min Jee Kim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Hyeon Hwa Kim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Kyung-Wook Jo
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
| | - Sang Hyoung Park
- Division of Gastroenterology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
| | - Seokchan Hong
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
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17
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Kuwana M, Sugiyama N, Momohara S, Atsumi T, Takei S, Tamura N, Harigai M, Fujii T, Matsuno H, Takeuchi T, Yamamoto K, Takasaki Y, Tanigawa M, Endo Y, Hirose T, Morishima Y, Yoshii N, Mimori T, Takagi M. Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance. Mod Rheumatol 2024; 34:272-286. [PMID: 37405710 DOI: 10.1093/mr/road063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/17/2023] [Indexed: 07/06/2023]
Abstract
OBJECTIVES We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER NCT01932372.
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Affiliation(s)
- Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
| | - Naonobu Sugiyama
- Inflammation and Immunology Medical Affairs, Pfizer Japan Inc., Tokyo, Japan
| | - Shigeki Momohara
- Kusanagi Orthopedic Rheumatology Clinic, Shizuoka, Japan
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Syuji Takei
- Pediatric Rheumatology, Medical Center for Children, Kagoshima University Hospital, Kagoshima, Japan
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Masayoshi Harigai
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan
| | | | - Tsutomu Takeuchi
- Department of Rheumatology, Keio University School of Medicine, Tokyo, Japan
- Saitama Medical University, Saitama, Japan
| | | | - Yoshinari Takasaki
- Juntendo Koshigaya Hospital, Juntendo University Faculty of Medicine, Saitama, Japan
| | | | | | - Tomohiro Hirose
- Inflammation and Immunology Medical Affairs, Pfizer Japan Inc., Tokyo, Japan
| | - Yosuke Morishima
- Inflammation and Immunology Medical Affairs, Pfizer Japan Inc., Tokyo, Japan
| | - Noritoshi Yoshii
- Inflammation and Immunology Medical Affairs, Pfizer Japan Inc., Tokyo, Japan
| | | | - Michiaki Takagi
- Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
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Kojima S, Iwamoto T, Kobayashi Y, Kato M, Takizawa F, Ida T, Suzuki J, Toda Y, Miyachi K, Iwata A, Furuta S, Ikeda K, Nakajima H. Immunogenicity and influence on disease activity of recombinant zoster vaccine in patients with rheumatoid arthritis treated with DMARDs. RMD Open 2024; 10:e003902. [PMID: 38388170 PMCID: PMC10882334 DOI: 10.1136/rmdopen-2023-003902] [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: 11/13/2023] [Accepted: 02/01/2024] [Indexed: 02/24/2024] Open
Abstract
OBJECTIVES This study aimed to determine the immunogenicity and the influence on disease activity of an adjuvanted recombinant varicella-zoster virus (VZV) subunit vaccine (RZV) in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs). METHODS This prospective longitudinal study enrolled 53 patients with RA (aged ≥50 years) treated with DMARDs (conventional synthetic (cs)DMARDs 20, biological (b)DMARDs 23 and targeted synthetic (ts)DMARDs 10) and 10 control individuals. The participants received two intramuscular RZV 2 months apart. VZV-specific CD4+ T cell responses (cell-mediated immunity; CMI) and IgG antibody responses (humoral immunity; HI) were assessed at 0 and 3 months after the first RZV administration using flow cytometry and enzyme immunoassay, respectively. Disease activity (Disease Activity Score 28-C reactive protein and Clinical Disease Activity Index), flares and adverse events were monitored for 6 months after the first vaccination. RESULTS VZV-specific CMI and HI significantly increased in the three DMARDs-treated patients with RA after RZV administration compared with the corresponding prevaccination values (p<0.001-0.014), and the magnitudes and fold-increases of those responses were not significantly different among the three DMARDs-treated patients with RA. Furthermore, the vaccine response rates of CMI and HI were not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients. Meanwhile, no significant increases in disease activity indices or adverse events were observed in these patients during the 6-month follow-up period after the first vaccination. RZV-induced RA flares occurred in two patients (3.8%) but were mild and controllable. CONCLUSION RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving DMARDs.
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Affiliation(s)
- Shotaro Kojima
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Taro Iwamoto
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Yoshihisa Kobayashi
- Department of Internal Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Manami Kato
- Department of Internal Medicine, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Fumiyoshi Takizawa
- Department of Internal Medicine, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Tomoaki Ida
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Junya Suzuki
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Yosuke Toda
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Kazusa Miyachi
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Arifumi Iwata
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Shunsuke Furuta
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Kei Ikeda
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
- Department of Rheumatology, Dokkyo Medical University, Mibu, Japan
| | - Hiroshi Nakajima
- Department of Allergy and Clinical Immunology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
- Chiba University Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba, Japan
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Yang Y, Li J, Liu J, Liu L, Wang Y, Hu J, Li Z, Gu J, Zhang X, Xiao Z, Zheng J, Liu L, Li Z, Wei JCC. Safety and efficacy of peficitinib in Asian patients with rheumatoid arthritis who had an inadequate response or intolerance to methotrexate: results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2024; 42:100925. [PMID: 38357391 PMCID: PMC10865021 DOI: 10.1016/j.lanwpc.2023.100925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/28/2023] [Accepted: 09/17/2023] [Indexed: 02/16/2024]
Abstract
Background The efficacy and safety of the oral Janus kinase inhibitor peficitinib were investigated in Asian patients with rheumatoid arthritis (RA). Methods In this double-blind, phase 3 study, patients from mainland China, Korea, and Taiwan with RA and an inadequate response/intolerance to methotrexate were randomized (1:1:1) to once-daily placebo (N = 128), peficitinib 100 mg (N = 129), or 150 mg (N = 128) in combination with non-biologic DMARDs. At Week 24, patients receiving placebo switched to peficitinib 100 mg or 150 mg. American College of Rheumatology (ACR) 20 response at Week 24/early termination (ET) was the primary endpoint. Adverse events (AEs) were assessed. The study was registered at ClinicalTrials (NCT03660059). Findings 385 patients were included in the analysis. ACR20 responses were statistically significantly higher in both peficitinib 100 mg (56.6%) and 150 mg (56.3%) groups versus placebo (24.2%); Odds Ratio (95% confidence interval, CI) 4.14 (2.42, 7.08) and 4.07 (2.38, 6.96), respectively (both P < 0.001) at Week 24/ET. The incidence rate of herpes zoster related disease (herpes zoster and varicella) was higher in patients who received peficitinib versus placebo, but no dose dependency was observed (incidence rate/100 patient-years (95% CI): peficitinib 6.7 (4.32, 10.37); placebo 3.7 (0.93, 14.88). Interpretation In Asian patients with RA and an inadequate response/intolerance to methotrexate, peficitinib 100 mg and 150 mg demonstrated superiority to placebo in the reduction of RA symptoms and was well tolerated. No additional benefit was observed with use of the higher peficitinib dose in this study population of predominantly Chinese patients. Funding Astellas Pharma.
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Affiliation(s)
- Yue Yang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Jingyang Li
- Department of Rheumatology and Immunology, Xiangya Hospital Zhuzhou Central South University, Hunan, China
| | - Ju Liu
- Department of Rheumatology, Jiu Jiang No. 1 People's Hospital, Jiangxi, China
| | - Lin Liu
- Department of Rheumatology, Xuzhou Central Hospital, Jiangsu, China
| | - Yongfu Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital Baotou Medical College, Inner Mongolia University of Science and Technology, Inner Mongolia, China
| | - Jiankang Hu
- Department of Rheumatology and Immunology, Pingxiang People's Hospital, Jiangxi, China
| | - Zhijun Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Jieruo Gu
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Sunyat Sen University, Guangdong, China
| | - Xiao Zhang
- Department of Rheumatology and Immunology, Guangdong Province People's Hospital, Guangdong, China
| | - Zhengyu Xiao
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Shantou University Medical College, Guangdong, China
| | | | - Lin Liu
- Astellas (China) Investment Co., Ltd, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - James Cheng-Chung Wei
- Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Department of Nursing, Chung Shan Medical University, Taichung, Taiwan
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20
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Karpouzas GA, Szekanecz Z, Baecklund E, Mikuls TR, Bhatt DL, Wang C, Sawyerr GA, Chen Y, Menon S, Connell CA, Ytterberg SR, Mortezavi M. Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance. Ther Adv Musculoskelet Dis 2023; 15:1759720X231201047. [PMID: 37942277 PMCID: PMC10629315 DOI: 10.1177/1759720x231201047] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/25/2023] [Indexed: 11/10/2023] Open
Abstract
Background In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). Objectives To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). Design This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. Methods In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Results Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. Conclusion In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. Registration NCT02092467.
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Affiliation(s)
- George A. Karpouzas
- Division of Rheumatology, Harbor-UCLA Medical Center, and the Lundquist Institute, Torrance, CA, USA
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Eva Baecklund
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Ted R. Mikuls
- Division of Rheumatology, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Deepak L. Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York, NY, USA
| | - Cunshan Wang
- Inflammation and Immunology, Pfizer Inc, Groton, CT, USA
| | | | - Yan Chen
- Inflammation and Immunology, Pfizer Inc, Collegeville, PA, USA
| | - Sujatha Menon
- Inflammation and Immunology, Pfizer Inc, Groton, CT, USA
| | | | | | - Mahta Mortezavi
- Inflammation and Immunology, Pfizer Inc, 66 Hudson Boulevard, New York, NY 10001, USA
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21
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Temby M, Boye TL, Hoang J, Nielsen OH, Gubatan J. Kinase Signaling in Colitis-Associated Colon Cancer and Inflammatory Bowel Disease. Biomolecules 2023; 13:1620. [PMID: 38002302 PMCID: PMC10669043 DOI: 10.3390/biom13111620] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Colorectal cancer is a known complication of chronic inflammation of the colon ("colitis-associated colon cancer"). Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Patients with IBD are at increased risk of colon cancer compared to the general population. Kinase signaling pathways play critical roles in both the inflammation and regulating cellular processes such as proliferation and survival that contribute to cancer development. Here we review the interplay of kinase signaling pathways (mitogen-activated protein kinases, cyclin-dependent kinases, autophagy-activated kinases, JAK-STAT, and other kinases) and their effects on colitis-associated colon cancer. We also discuss the role of JAK-STAT signaling in the pathogenesis of IBD and the therapeutic landscape of JAK inhibitors for the treatment of IBD.
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Affiliation(s)
- Michelle Temby
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA; (M.T.); (J.H.)
| | - Theresa L. Boye
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark; (T.L.B.); (O.H.N.)
| | - Jacqueline Hoang
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA; (M.T.); (J.H.)
| | - Ole H. Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark; (T.L.B.); (O.H.N.)
| | - John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305-5101, USA; (M.T.); (J.H.)
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22
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Dahabreh D, Jung S, Renert-Yuval Y, Bar J, Del Duca E, Guttman-Yassky E. Alopecia Areata: Current Treatments and New Directions. Am J Clin Dermatol 2023; 24:895-912. [PMID: 37606849 DOI: 10.1007/s40257-023-00808-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2023] [Indexed: 08/23/2023]
Abstract
Alopecia areata is an autoimmune hair loss disease that is non-scarring and is characterized by chronic inflammation at the hair follicle level. Clinically, patients' presentation varies from patchy, circumscribed scalp involvement to total body and scalp hair loss. Current management is guided by the degree of scalp and body involvement, with topical and intralesional steroid injections as primarily first-line for mild cases and broad immunosuppressants as the mainstay for more severe cases. Until recently, the limited number of blinded, randomized, placebo-controlled clinical trials for this disease had made establishing an evidence-based treatment paradigm challenging. However, growing insights into the pathogenesis of alopecia areata through blood and tissue analysis of human lesions have identified several promising targets for therapy. T-helper (Th) 1/interferon skewing has traditionally been described as the driver of disease; however, recent investigations suggest activation of additional immune mediators, including the Th2 pathway, interleukin (IL)-9, IL-23, and IL-32, as contributors to alopecia areata pathogenesis. The landscape of alopecia areata treatment has the potential to be transformed, as several novel targeted drugs are currently undergoing clinical trials. Given the recent US FDA approval of baricitinib and ritlecitinib, Janus kinase (JAK) inhibitors are a promising drug class for treating severe alopecia areata cases. This article will review the efficacy, safety, and tolerability of current treatments for alopecia areata, and will provide an overview of the emerging therapies that are leading the revolution in the management of this challenging disease.
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Affiliation(s)
- Dante Dahabreh
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E. 98th Street, New York, NY, 10029, USA
| | - Seungyeon Jung
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E. 98th Street, New York, NY, 10029, USA
- School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Yael Renert-Yuval
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA
| | - Jonathan Bar
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E. 98th Street, New York, NY, 10029, USA
| | - Ester Del Duca
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E. 98th Street, New York, NY, 10029, USA
| | - Emma Guttman-Yassky
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E. 98th Street, New York, NY, 10029, USA.
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23
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Harrington R, Harkins P, Conway R. Janus Kinase Inhibitors in Rheumatoid Arthritis: An Update on the Efficacy and Safety of Tofacitinib, Baricitinib and Upadacitinib. J Clin Med 2023; 12:6690. [PMID: 37892827 PMCID: PMC10607454 DOI: 10.3390/jcm12206690] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/14/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Janus kinase inhibitors (JAKis) are the most recent new drug class to arrive to the market for rheumatoid arthritis (RA) treatment. While they have proven to be a very effective treatment option, there remains significant concern regarding the risk of cardiovascular events, thrombosis and malignancy, particularly given the findings of the post-marketing ORAL Surveillance study and FDA black box warnings. This article reviews the key findings of the most impactful cohort of studies and registry data since ORAL Surveillance. It also evaluates the role of JAKis in practice and offers guidance on risk stratifying patients and determining their suitability for a JAKi.
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Affiliation(s)
- Robert Harrington
- Department of Rheumatology, St. James’s Hospital, James Street, Dublin 8, D08 NHY1 Dublin, Ireland;
| | | | - Richard Conway
- Department of Rheumatology, St. James’s Hospital, James Street, Dublin 8, D08 NHY1 Dublin, Ireland;
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24
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Kinast V, Andreica I, Ahrenstorf G, Gömer A, Elsner C, Schlienkamp S, Schrader JA, Klöhn M, Ulrich RG, Broering R, Vondran FWR, Todt D, Behrendt P, Dittmer U, Hamprecht A, Witte T, Baraliakos X, Steinmann E. Janus kinase-inhibition modulates hepatitis E virus infection. Antiviral Res 2023; 217:105690. [PMID: 37517633 DOI: 10.1016/j.antiviral.2023.105690] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/24/2023] [Accepted: 07/27/2023] [Indexed: 08/01/2023]
Abstract
Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication. To this end, we evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E. Further, experiments with HEV (Kernow-C1 p6) were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. Upregulation of interferon-stimulated genes (ISG) was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. The obtained results suggest that therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, JAKi treatment and the occurrence of elevated liver enzymes requires a monitoring of potential HEV infections.
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Affiliation(s)
- Volker Kinast
- Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany; Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.
| | - Ioana Andreica
- Rheumazentrum Ruhrgebiet, Ruhr University Bochum, Herne, Germany
| | - Gerrit Ahrenstorf
- Klinik für Immunologie und Rheumatologie, Medical University Hannover, Hannover, Germany
| | - André Gömer
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Carina Elsner
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sarah Schlienkamp
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Jil Alexandra Schrader
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Rainer G Ulrich
- Institute of Novel and Emerging Infectious Disease, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493, Greifswald, Insel Riems, Germany; German Centre for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, 17493, Greifswald, Insel Riems, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Florian W R Vondran
- ReMediES, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany
| | - Patrick Behrendt
- Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Axel Hamprecht
- Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Torsten Witte
- Klinik für Immunologie und Rheumatologie, Medical University Hannover, Hannover, Germany
| | | | - Eike Steinmann
- Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research, External Partner Site, 44801, Bochum, Germany.
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25
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Shah RJ, Banerjee S, Raychaudhuri S, Raychaudhuri SP. JAK-STAT inhibitors in Immune mediated diseases: An Overview. Indian J Dermatol Venereol Leprol 2023; 89:691-699. [PMID: 37609730 DOI: 10.25259/ijdvl_1152_2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 05/28/2023] [Indexed: 08/24/2023]
Abstract
For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases.
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Affiliation(s)
- Ruchi Jayesh Shah
- Department of Medicine, School of Medicine, University of California Davis, USA
| | - Sneha Banerjee
- Department of Veterans Affairs, VA Sacramento Medical Center, Northern California Health Care, California, CA, USA
| | - Smriti Raychaudhuri
- Department of Veterans Affairs, VA Sacramento Medical Center, Northern California Health Care, California, CA, USA
| | - Siba P Raychaudhuri
- Department of Medicine, School of Medicine, University of California Davis, USA
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26
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Tanaka Y. Making a prescribing choice for rheumatoid arthritis: a focus on small molecule drugs vs. biologics for the most favourable patient outcome. Expert Opin Pharmacother 2023; 24:1791-1798. [PMID: 37563102 DOI: 10.1080/14656566.2023.2247325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/12/2023]
Abstract
INTRODUCTION The molecular targeted therapies available for rheumatoid arthritis include 10 types of biological disease-modifying antirheumatic drugs (bDMARDs) and five types of Janus kinase (JAK) inhibitors. This article reviews the differential and proper use of bDMARDs and JAK inhibitors, focusing on their efficacy and safety, based mainly on phase III clinical trials. AREA COVERED The JAK inhibitors approved for treating rheumatoid arthritis are compared with bDMARDs based on the evidence derived from global phase III trials. EXPERT OPINION In patients with inadequate responses to bDMARDs and JAK inhibitors, switching between these drugs is comparable in efficacy in both directions. Head-to-head comparison demonstrated that baricitinib and upadacitinib are more efficacious than tumor necrosis factor (TNF) inhibitors. However, the ORAL Surveillance study demonstrated that JAK inhibitors are associated with higher incidences of death, major adverse cardiovascular events, malignancies and thrombosis than TNF inhibitors in at-risk patients. The need for risk assessment by pre-treatment screening, regular monitoring during treatment, and appropriate systemic management in adverse events should be recognized. Meanwhile, some JAK-inhibitors were efficacious even for difficult-to-treat disease. These results suggest the need for establishing therapeutic strategies considering the balance between safety and efficacy in individual patients.
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Affiliation(s)
- Yoshiya Tanaka
- University of Occupational and Environmental Health Japan, Kitakyushu, Japan
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27
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Choi SR, Shin A, Ha YJ, Lee YJ, Lee EB, Kang EH. Comparative risk of infections between JAK inhibitors versus TNF inhibitors among patients with rheumatoid arthritis: a cohort study. Arthritis Res Ther 2023; 25:129. [PMID: 37495973 PMCID: PMC10369724 DOI: 10.1186/s13075-023-03111-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/10/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea. METHODS Using 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users. RESULTS We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI. CONCLUSIONS This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.
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Affiliation(s)
- Se Rim Choi
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Kyeongki-do, Seongnam-si, South Korea
| | - Anna Shin
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Kyeongki-do, Seongnam-si, South Korea
| | - You-Jung Ha
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Kyeongki-do, Seongnam-si, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Yun Jong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Kyeongki-do, Seongnam-si, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Eun Bong Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Eun Ha Kang
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Kyeongki-do, Seongnam-si, South Korea.
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
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Song YJ, Cho SK, Kim H, Kim HW, Nam E, Jeon JY, Yoo HJ, Choi CB, Kim TH, Jun JB, Bae SC, Yoo DH, Sung YK. Increased risk of herpes zoster with tofacitinib treatment in Korean patients with rheumatoid arthritis: a single-center prospective study. Sci Rep 2023; 13:7877. [PMID: 37188765 DOI: 10.1038/s41598-023-33718-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
We aimed to determine the risk of herpes zoster (HZ) in Korean rheumatoid arthritis (RA) patients on tofacitinib compared with tumor necrosis factor inhibitor (TNFi) treatment. From the prospective cohorts of RA patients who started tofacitinib or TNFi in an academic referral hospital in Korea, patients who started tofacitinib between March 2017 and May 2021 and those who started TNFi between July 2011 and May 2021 were included. Baseline characteristics of tofacitinib and TNFi users were balanced through inverse probability of treatment weighting (IPTW) using the propensity score including age, disease activity of RA and medication use. The incidence rate of HZ in each group and incidence rate ratio (IRR) were calculated. A total of 912 patients were included: 200 tofacitinib and 712 TNFi users. There were 20 cases of HZ among tofacitinib users and 36 among TNFi users during observation period of 331.4 person-years (PYs) and 1950.7 PYs, respectively. In IPTW analysis with a balanced sample, IRR of HZ was 8.33 (95% confidence interval 3.05-22.76). Tofacitinib use increased the risk of HZ compared with TNFi in Korean patients with RA, but the rate of serious HZ or permanent discontinuation of tofacitinib due to HZ event was low.
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Affiliation(s)
- Yeo-Jin Song
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Soo-Kyung Cho
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Hyoungyoung Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Hye Won Kim
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Eunwoo Nam
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Ja-Young Jeon
- Pfizer Pharmaceuticals Korea Ltd., Seoul, Republic of Korea
| | - Hyun-Jeong Yoo
- Pfizer Pharmaceuticals Korea Ltd., Seoul, Republic of Korea
| | - Chan-Bum Choi
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Tae-Hwan Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Jae-Bum Jun
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Dae Hyun Yoo
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Yoon-Kyoung Sung
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
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Atzeni F, Gozza F, Riva A, Alciati A, Galloway J. Conventional, biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors and varicella zoster virus. Expert Opin Pharmacother 2023; 24:679-689. [PMID: 36946287 DOI: 10.1080/14656566.2023.2195050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
INTRODUCTION The advent of biological disease-modifying anti-rheumatic drugs (bDMARDs), and more recently of Janus kinase inhibitors (JAKi), has had a major impact on the herpes zoster (HZ) reactivation, which represents an important clinical challenge in the treatment of inflammatory arthritis (IA) in patients with a complete pharmacological control of peripheral inflammation. AREAS COVERED In this review, we provide an overview on the effects of conventional DMARDs/ bDMARDs and JAKi on HZ reactivation. Furthermore, we underline the controversial findings and the potential management strategies. We searched PubMed, Medline, and the Cochrane Library for papers published between 1995 and February 2017. EXPERT OPINION The overall data showed a slightly higher risk of HZ in patients treated with bDMARDs, and more pronounced for those treated with JAKi. As management strategies, we suggest an effective vaccination campaign and a focus on early diagnosis.
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Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | - Francesco Gozza
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | - Agostino Riva
- Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy
- III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
| | - Alessandra Alciati
- Department of Clinical Neurosciences, Villa S. Benedetto Menni, Albese (Como), Italy
- Humanitas Clinical and Research Center, Rozzano, Italy
| | - James Galloway
- Centre for Rheumatic Diseases, King's College London, London, UK
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Imafuku S. Recent advance in management of herpes simplex in Japan. J Dermatol 2023; 50:299-304. [PMID: 36779390 DOI: 10.1111/1346-8138.16734] [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: 12/18/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 02/14/2023]
Abstract
Herpes simplex, a common infection caused by the herpes simplex virus (HSV), is transmitted through contact of the skin/mucous membrane and establishes latency in the sensory ganglia for the rest of the life of the host. HSV occasionally reactivates and forms blisters around the lips or genitalia in some patients. Repeated overt symptoms, and, much more frequent, subclinical reactivation in the mucosa, make the host retain anti-HSV immunity continuously, resulting in maintaining steadily elevated antibody titer at any point after infection. Clinical symptoms differ in primary infection and recurrence. Primary infections sometimes manifest as severe symptoms such as fever and lymphadenopathy in addition to blisters/erosions of the skin, gingiva, lips, and oral mucosa, while recurrent herpes is generally mild. Diagnosing typical herpes simplex is not difficult, but when the course and manifestations are typical, definitive tests to identify HSV infection are limited since serology is not useful except with primary infection. For treatment, safe and effective oral antiviral drugs are available. Patient-initiated therapy is a new method of administration labeled in Japan. Amenamevir, an inhibitor of viral helicase primase, is available in Japan and labeled in addition to herpes zoster. These new diagnostic and therapeutic tools should be used for better management of herpes simplex.
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Affiliation(s)
- Shinichi Imafuku
- Faculty of Medicine - Dermatology, Fukuoka University, Fukuoka, Japan
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Nielsen OH, Boye TL, Gubatan J, Chakravarti D, Jaquith JB, LaCasse EC. Selective JAK1 inhibitors for the treatment of inflammatory bowel disease. Pharmacol Ther 2023; 245:108402. [PMID: 37004800 DOI: 10.1016/j.pharmthera.2023.108402] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Janus kinase (JAK) inhibitors, also known as jakinibs, are third-generation oral small molecules that have expanded the therapeutic options for the management of chronic inflammatory diseases, including inflammatory bowel disease (IBD). Tofacitinib, a pan-JAK inhibitor, has spearheaded the new JAK class for IBD treatment. Unfortunately, serious adverse effects, including cardiovascular complications such as pulmonary embolism and venous thromboembolism or even death from any cause, have been reported for tofacitinib. However, it is anticipated that next-generation selective JAK inhibitors may limit the development of serious adverse events, leading to a safer treatment course with these novel targeted therapies. Nevertheless, although this drug class was recently introduced, following the launch of second-generation biologics in the late 1990s, it is breaking new ground and has been shown to efficiently modulate complex cytokine-driven inflammation in both preclinical models and human studies. Herein, we review the clinical opportunities for targeting JAK1 signaling in the pathophysiology of IBD, the biology and chemistry underpinning these target-selective compounds, and their mechanisms of actions. We also discuss the potential for these inhibitors in efforts to balance their benefits and harms.
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32
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Traboulsi C, Ayoub F, Silfen A, Rodriguez TG, Rubin DT. Upadacitinib Is Safe and Effective for Crohn's Disease: Real-World Data from a Tertiary Center. Dig Dis Sci 2023; 68:385-388. [PMID: 35695972 DOI: 10.1007/s10620-022-07582-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/23/2022] [Indexed: 12/30/2022]
Abstract
Upadacitinib is a selective JAK-1 inhibitor approved for the treatment of rheumatoid arthritis and more recently, ulcerative colitis. Phase II trials demonstrated that upadacitinib induces endoscopic remission in patients with moderate-to-severe Crohn's disease. However, real-world data are lacking. We present a short report on our experience with off-label upadacitinib in patients with CD at a tertiary center. In this cohort of medically refractory patients with CD, treatment with upadacitinib resulted in subjective and objective responses in 25 and 42% of patients, respectively. Even at doses that are considered lower than currently being studied for CD, upadacitinib was associated with a favorable benefit-to-risk profile.
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Affiliation(s)
- Cindy Traboulsi
- University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL, 60637, USA
| | - Fares Ayoub
- University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL, 60637, USA
| | - Alexa Silfen
- University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL, 60637, USA
| | - Tina G Rodriguez
- University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL, 60637, USA
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL, 60637, USA.
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Sepriano A, Kerschbaumer A, Bergstra SA, Smolen JS, van der Heijde D, Caporali R, Edwards CJ, Verschueren P, de Souza S, Pope J, Takeuchi T, Hyrich K, Winthrop KL, Aletaha D, Stamm T, Schoones JW, Landewé RBM. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2023; 82:107-118. [PMID: 36376026 DOI: 10.1136/ard-2022-223357] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/25/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). METHODS SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used. RESULTS Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi. CONCLUSION The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.
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Affiliation(s)
- Alexandre Sepriano
- CHRC Campus Nova Medical School, Lisboa, Portugal .,Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andreas Kerschbaumer
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Wien, Austria
| | | | - Josef S Smolen
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Wien, Austria.,2nd Department of Medicine, Hietzing Hospital, Wien, Austria
| | | | - Roberto Caporali
- Department of Clinical Sciences and Community Health, ASS G. Pini, University of Milan, Milano, Italy.,Department of Rheumatology, ASST PINI-CTO, Milan, Italy
| | - Christopher J Edwards
- NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Patrick Verschueren
- Rheumatology, KU Leuven University Hospitals, Leuven, Belgium.,Engineering Research Centre, Lueven, Belgium
| | - Savia de Souza
- Patient Research Partner Network, European Alliance of Associations for Rheumatology, Zurich, Switzerland
| | - Janet Pope
- Medicine, Division of Rheumatology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Japan.,Saitama Medical University, Iruma-gun, Japan
| | - Kimme Hyrich
- Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester, UK.,NIHR Manchester Biomedical Research Centre, Manchester, UK
| | - Kevin L Winthrop
- School of Public Health, Oregon Health & Science University, Portland, Oregon, USA
| | - Daniel Aletaha
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Wien, Austria
| | - Tanja Stamm
- Section for Outcomes Research, Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Wien, Austria.,Institute for Arthritis and Rehabilitation, Ludwig Boltzmann, Vienna, Austria
| | - Jan W Schoones
- Walaeus Library, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert B M Landewé
- Amsterdam Rheumatology Center, Amsterdam University Medical Centres, Amsterdam, The Netherlands.,Rheumatology, Zuyderland Medical Centre Heerlen, Heerlen, The Netherlands
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Upadacitinib Was Efficacious and Well-tolerated Over 30 Months in Patients With Crohn's Disease in the CELEST Extension Study. Clin Gastroenterol Hepatol 2022; 20:2337-2346.e3. [PMID: 34968730 DOI: 10.1016/j.cgh.2021.12.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The long-term efficacy and safety of upadacitinib was evaluated in an open-label extension (OLE) of a phase II, double-blind, randomized trial of patients with Crohn's disease. METHODS Patients who completed the 52-week study (CELEST) received upadacitinib in the CELEST OLE as follows: those who had received immediate-release upadacitinib 3, 6, or 12 mg twice daily or 24 mg once daily (QD) received extended-release upadacitinib 15 mg QD and those who had received immediate-release upadacitinib 12 or 24 mg twice daily as rescue therapy received extended-release upadacitinib 30 mg QD. If any patient initiating upadacitinib 15 mg QD in CELEST OLE lost response at or after week 4, the dose was escalated to upadacitinib 30 mg QD (dose-escalated group). Clinical, endoscopic, inflammatory and quality-of-life measures were assessed. RESULTS A total of 107 CELEST study completers entered CELEST OLE. The proportion of patients with clinical remission 2.8/1.0 was maintained between week 0 and month 30 in all groups (month 30: 15 mg, 61%; 30 mg, 54%; dose-escalation, 55%). Endoscopic response was maintained in all groups (month 24: 68%, 67%, and 40%, respectively). The rates of adverse events (AEs), serious AEs, AEs leading to discontinuation, infections, serious infections, herpes zoster, and creatine phosphokinase elevation were higher with upadacitinib 30 mg vs 15 mg. CONCLUSION Sustained long-term benefit at 30 months and further endoscopic improvements to month 24 were observed in patients with Crohn's disease receiving upadacitinib. Safety over 30 months was consistent with the known safety profile of upadacitinib. CLINICALTRIALS gov ID no: NCT02782663.
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35
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Matsuoka K, Hisamatsu T, Kim HJ, Ye BD, Arai S, Hoshi M, Yuasa H, Tabira J, Toyoizumi S, Shi N, Woo J, Hibi T. Safety and efficacy of long-term tofacitinib treatment in East Asian patients with ulcerative colitis in OCTAVE Open. J Gastroenterol Hepatol 2022; 37:1884-1892. [PMID: 35734858 PMCID: PMC9796539 DOI: 10.1111/jgh.15923] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/31/2022] [Accepted: 06/18/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIM Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present safety and efficacy data from patients from East Asia (Japan, Korea, and Taiwan) in OCTAVE Open, an open-label, long-term extension study. METHODS Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg twice daily (BID); all others received tofacitinib 10 mg BID. Proportions and IRs (unique patients with events/100 patient-years) were calculated for adverse events (AEs) of special interest. Efficacy endpoints were evaluated up to 36 months. RESULTS In OCTAVE Open, 105/944 patients were from East Asia (tofacitinib 5 mg BID, n = 22; tofacitinib 10 mg BID, n = 83). Overall, 87.6% and 24.8% of patients had AEs and serious AEs, respectively; IRs (95% CI) for AEs of special interest were herpes zoster (HZ; non-serious and serious), 6.07 (3.40-10.02); serious infections, 1.47 (0.40-3.76); opportunistic infections, 1.91 (0.62-4.45); major cardiovascular adverse events, 0.37 (0.01-2.04); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.37 (0.01-2.04); and NMSC, 0.00 (0.00-1.35). No deaths, venous thromboembolic events, or gastrointestinal perforations occurred. At month 36, 68.2% and 54.2% of patients had a clinical response, 68.2% and 53.0% had endoscopic improvement, and 63.6% and 49.4% were in remission with tofacitinib 5 and 10 mg BID, respectively. CONCLUSIONS The HZ IR in East Asian patients was numerically higher versus the global study population; excluding HZ, tofacitinib safety and efficacy were consistent with the global study population.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal MedicineToho University Sakura Medical CenterChibaJapan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and HepatologyKyorin University School of MedicineTokyoJapan
| | - Hyo Jong Kim
- Center for Crohn's and ColitisKyung Hee University College of MedicineSeoulKorea
| | - Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
| | | | | | | | | | | | | | | | - Toshifumi Hibi
- Center for Advanced IBD Research and TreatmentKitasato University Kitasato Institute HospitalTokyoJapan
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JAK-STAT Signaling Pathway in Non-Infectious Uveitis. Biochem Pharmacol 2022; 204:115236. [PMID: 36041544 DOI: 10.1016/j.bcp.2022.115236] [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: 07/20/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022]
Abstract
Non-infectious uveitis (NIU) refers to various intraocular inflammatory disorders responsible for severe visual loss. Cytokines participate in the regulation of ocular homeostasis and NIU pathological processes. Cytokine receptors transmit signals by activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. Increasing evidence from human NIU and experimental models reveals the involvement of the JAK-STAT signaling pathway in NIU pathogenesis. Several small-molecule drugs that potentially inhibit multiple cytokine-dependent pathways are under investigation for treating autoimmune diseases, implicating possible applications for NIU treatment. This review summarizes the current understanding of the diverse roles of the JAK-STAT signaling pathway in ocular homeostasis and NIU pathology, providing a rationale for targeting JAKs and STATs for NIU treatment. Moreover, available evidence for the safety and efficacy of JAK inhibitors for refractory uveitis and potential approaches for treatment optimization are discussed.
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Lin QX, Meng HJ, Pang YY, Qu Y. Recurrent herpes zoster in a rheumatoid arthritis patient treated with tofacitinib: A case report and review of the literature. World J Clin Cases 2022; 10:8703-8708. [PMID: 36157812 PMCID: PMC9453357 DOI: 10.12998/wjcc.v10.i24.8703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/16/2022] [Accepted: 07/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Tofacitinib is an oral Janus kinase (JAK) inhibitor that is currently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis (RA). Varicella zoster virus reactivation leading to herpes zoster (HZ) is an adverse effect of this drug; however, recurrent HZ at the same site is a rare clinical condition.
CASE SUMMARY A 70-year-old female RA patient had undergone 1-year of tofacitinib treatment (10 mg daily). About 1 mo after initiation of oral tofacitinib, she developed blisters on the left flank and abdomen and was diagnosed with HZ; antiviral therapy with acyclovir was resolutory. However, 5 d prior to presentation at our hospital, erythema and blisters with severe pain recurred at the same site. Small clustered blisters and bullous were visible on the left lumbar abdomen and perineum, with a pain score of 8 (visual analogue scale). Antiviral, nutritional supplement, analgesic and other treatments led to healing but over an atypically long period (approximately 26 d, vs approximately 1 wk). HZ is a common and serious adverse reaction of JAK inhibitors, but it rarely recurs. Our patient’s experience of HZ recurrence at the same site, with a wider affected area, more severe pain and longer healing period, is inconsistent with previous reports.
CONCLUSION Same-anatomical site HZ recurrence may occur during oral tofacitinib treatment, with more severe clinical manifestations than in the initial occurrence.
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Affiliation(s)
- Qing-Xia Lin
- Department of Dermatology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Hui-Juan Meng
- Department of Dermatology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Yun-Yan Pang
- Department of Dermatology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Yan Qu
- Department of Dermatology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
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Sedeh FB, Henning MAS, Jemec GBE, Ibler KS. Comparative Efficacy and Safety of Monoclonal Antibodies and Janus Kinase Inhibitors in Moderate-to-severe Atopic Dermatitis: A Systematic Review and Meta-analysis. Acta Derm Venereol 2022; 102:adv00764. [PMID: 35818735 PMCID: PMC9574696 DOI: 10.2340/actadv.v102.2075] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The aim of this study was to compare the efficacies of systemic treatments with dupilumab, tralokinumab and Janus kinase inhibitors for moderate-to-severe atopic dermatitis. A systematic review following Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines was performed using Medline, EMBASE and Cochrane library. All randomized controlled trials investigating the efficacy of systemic treatments for moderate-to-severe atopic dermatitis in adults were included. Primary outcomes were the proportion of patients with atopic dermatitis achieving 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI) score after dupilumab, tralokinumab or Janus kinase inhibitors. Nineteen studies totalling 6,444 patients were included. In monotherapy studies, upadacitinib 30 mg once daily had the numerically highest efficacy regarding EASI-50, EASI-75 and EASI-90. In combination therapy studies with topical corticosteroids, dupilumab 300 mg once every other week had highest efficacy regarding EASI-50, and abrocitinib 200 mg once daily had the highest score regarding EASI-75 and EASI-90. Analysis provided evidence that dupilumab, tralokinumab and Janus kinase inhibitors all had an acceptable efficacy profile and resulted in clinically relevant improvements in EASI score. Furthermore, upadacitinib and abrocitinib seem to have great potential to treat patients with atopic dermatitis. However, further studies are needed to determine the long-term efficacy of Janus kinase inhibitors in adults with moderate-to-severe atopic dermatitis.
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Affiliation(s)
- Farnam B Sedeh
- Department of Dermato-venereology, Zealand University Hospital, Roskilde, Denmark.
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Takagi M, Atsumi T, Matsuno H, Tamura N, Fujii T, Okamoto N, Takahashi N, Nakajima A, Nakajima A, Tsujimoto N, Nishikawa A, Ishii T, Takeuchi T, Kuwana M. Safety and Effectiveness of Baricitinib for Rheumatoid Arthritis in Japanese Clinical Practice: 24-Week Results of All-Case Post-Marketing Surveillance. Mod Rheumatol 2022:6657693. [PMID: 35932218 DOI: 10.1093/mr/roac089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/27/2022] [Accepted: 08/06/2022] [Indexed: 11/14/2022]
Abstract
OBJECTIVES To assess safety and effectiveness of baricitinib treatment for rheumatoid arthritis (RA) in real-world clinical practice. METHODS This ongoing all-case post-marketing surveillance study (starting September 2017) includes all patients with RA treated with baricitinib in Japan. Safety and effectiveness (disease activity) were assessed for 24 weeks. RESULTS Safety analyses to February 2021 included 4731 patients (initial baricitinib dose: 4 mg/day, n=3058; 2 mg/day, n=1661; other, n=12); 1059 (22.38%) were ≥75 years, and 3362 (71.06%) previously received biologic therapy. Overall observational period was 1863.14 patient-years; 1174 (24.82%) patients discontinued baricitinib before Week 24, mostly for lack of effectiveness (n=478; 10.10%). Adverse events occurred in 1271 (26.87%) patients (serious: 203 [4.29%]; death: 18 [0.38%]). The incidence of herpes zoster, hepatic function disorder, and serious infection was 3.09%, 2.77%, and 1.90%, respectively. Malignancy occurred in 17 patients (0.36%) and major adverse cardiovascular events in seven patients (0.15%). Among patients with effectiveness data, at least 26.57% (Boolean) achieved remission at Week 24. CONCLUSIONS This large nationwide surveillance study evaluated the safety and effectiveness of 24 weeks of baricitinib for RA in real-world clinical practice. Continued surveillance of long-term safety is ongoing.
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Affiliation(s)
- Michiaki Takagi
- Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | | | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan
| | - Nami Okamoto
- Department of Pediatrics, School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Nobunori Takahashi
- Department of Orthopaedics/Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Ayako Nakajima
- Center for Rheumatic Diseases, Mie University Hospital, Tsu, Japan
| | | | | | | | | | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
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Mishra S, Jena A, Kakadiya R, Sharma V, Ahuja V. Positioning of tofacitinib in treatment of ulcerative colitis: a global perspective. Expert Rev Gastroenterol Hepatol 2022; 16:737-752. [PMID: 35875997 DOI: 10.1080/17474124.2022.2106216] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/22/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Tofacitinib has emerged as a useful drug for the treatment of ulcerative colitis (UC). AREAS COVERED There is an unmet need for cost-effective, non-immunogenic drugs with a safe adverse effect profile to treat patients with ulcerative colitis. In the present review, we evaluate the available literature to inform the appropriate positioning of tofacitinib in the current drug landscape and identify subsets where its use should be done with caution. EXPERT OPINION Tofacitinib is helpful in the treatment of patients where the standard conventional or biological therapies have failed or were not tolerated. With lower costs of the generic drug than the biologicals (or biosimilars), it could be an important therapy in low- to middle-income countries. The risk of infections, especially Herpes Zoster and tuberculosis, needs to be addressed before initiation. Tofacitinib should be avoided in patients with venous thromboembolism and cardiovascular disease risk factors. Due to limited evidence, the use is not recommended in pregnancy, while it should be used with caution in elderly citizens. Future trials should look into the head-to-head comparison of tofacitinib with biologicals. The role of tofacitinib in acute severe colitis needs evaluation with comparative trials with current standards of care.
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Affiliation(s)
- Shubhra Mishra
- Department of Gastroenterology, Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | - Anuraag Jena
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rinkalben Kakadiya
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Education and Research, New Delhi, India
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Tanaka Y, Takeuchi T, Kato D, Kaneko Y, Fukuda M, Izutsu H, Rokuda M. A pooled analysis of serious infections and herpes zoster-related disease in Asian patients with rheumatoid arthritis treated with peficitinib (ASP015K) over a median of 3 years. Mod Rheumatol 2022; 32:708-717. [PMID: 34918131 DOI: 10.1093/mr/roab069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/09/2021] [Accepted: 08/18/2021] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To analyse serious infection (SI) and herpes zoster-related disease (HZD) during long-term treatment of rheumatoid arthritis with the oral Janus kinase inhibitor, peficitinib (ASP015K). METHODS This was a post hoc analysis of pooled data from one Phase 2b study and two Phase 3 studies and final data from a long-term extension study of peficitinib in Asian rheumatoid arthritis patients. Two pooled datasets were analysed (Phase 3 studies and Phase 2/3 studies). Univariate and multivariate Cox regression analyses explored relationships between exposure-adjusted incidence rate of SI and HZD, peficitinib dose, and baseline factors. RESULTS Total peficitinib exposure for 1052 patients receiving once-daily peficitinib in the pooled Phase 2/3 Asian studies was 2998.9 patient-years. Exposure-adjusted incidence rates (95% confidence interval) of SI and HZD were 2.7 (2.2, 3.4) and 6.9 (6.0, 8.0) per 100 patient-years, respectively, in pooled Phase 2/3 studies. Advanced age was prognostic for SI and HZD, while baseline prednisolone dose was prognostic for SI. There was no temporal relationship between either adverse event and prolonged peficitinib administration. CONCLUSIONS As expected in this peficitinib-treated population, older patients had increased risk of SI and HZD, and those receiving higher prednisolone doses had increased risk of SI.
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Haddad EB, Cyr SL, Arima K, McDonald RA, Levit NA, Nestle FO. Current and Emerging Strategies to Inhibit Type 2 Inflammation in Atopic Dermatitis. Dermatol Ther (Heidelb) 2022; 12:1501-1533. [PMID: 35596901 PMCID: PMC9276864 DOI: 10.1007/s13555-022-00737-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Indexed: 12/30/2022] Open
Abstract
Type 2 immunity evolved to combat helminth infections by orchestrating a combined protective response of innate and adaptive immune cells and promotion of parasitic worm destruction or expulsion, wound repair, and barrier function. Aberrant type 2 immune responses are associated with allergic conditions characterized by chronic tissue inflammation, including atopic dermatitis (AD) and asthma. Signature cytokines of type 2 immunity include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, mainly secreted from immune cells, as well as IL-25, IL-33, and thymic stromal lymphopoietin, mainly secreted from tissue cells, particularly epithelial cells. IL-4 and IL-13 are key players mediating the prototypical type 2 response; IL-4 initiates and promotes differentiation and proliferation of naïve T-helper (Th) cells toward a Th2 cell phenotype, whereas IL-13 has a pleiotropic effect on type 2 inflammation, including, together with IL-4, decreased barrier function. Both cytokines are implicated in B-cell isotype class switching to generate immunoglobulin E, tissue fibrosis, and pruritus. IL-5, a key regulator of eosinophils, is responsible for eosinophil growth, differentiation, survival, and mobilization. In AD, IL-4, IL-13, and IL-31 are associated with sensory nerve sensitization and itch, leading to scratching that further exacerbates inflammation and barrier dysfunction. Various strategies have emerged to suppress type 2 inflammation, including biologics targeting cytokines or their receptors, and Janus kinase inhibitors that block intracellular cytokine signaling pathways. Here we review type 2 inflammation, its role in inflammatory diseases, and current and future therapies targeting type 2 pathways, with a focus on AD. INFOGRAPHIC.
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Affiliation(s)
| | - Sonya L Cyr
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
| | | | | | - Noah A Levit
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
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Winthrop KL, Vermeire S, Long MD, Panés J, Ng SC, Kulisek N, Mundayat R, Lawendy N, Vranic I, Modesto I, Su C, Melmed GY. Long-term Risk of Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib. Inflamm Bowel Dis 2022; 29:85-96. [PMID: 35648151 PMCID: PMC9825290 DOI: 10.1093/ibd/izac063] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report herpes zoster (HZ) incidence and risk factors in the tofacitinib UC clinical program (up to 7.8 years). METHODS Proportions and incidence rates (IRs; unique patients with events/100 patient-years) of HZ were evaluated in 4 cohorts: Induction (phase 2 and 3 induction study data), Maintenance (phase 3 maintenance study data), Overall (data from all phase 2, 3, and open-label, long-term extension studies), and Overall plus interim 6-month phase 3b and 4 data. Herpes zoster risk factors were assessed by Cox regression analysis. RESULTS In the Induction and Maintenance Cohorts, IRs for HZ (nonserious and serious) were numerically higher with tofacitinib 10 mg twice daily (BID) vs placebo and tofacitinib 10 vs 5 mg BID, respectively. With all tofacitinib doses (5 or 10 mg BID), IRs (95% confidence intervals) for HZ in the Overall and Overall plus phase 3b/4 Cohorts (total exposure, 2814.4 and 2999.7 patient-years, respectively) were 3.38 (2.73-4.15) and 3.30 (2.67-4.04), respectively. In the Overall plus phase 3b/4 Cohort, >90% of HZ were nonserious; >90% were mild/moderate; >90% resolved without discontinuing tofacitinib; 0.6% of patients had multiple HZ events. Herpes zoster IRs were stable when analyzed by 6-month intervals up to >30 months. Herpes zoster risk factors included older age, lower weight, geographic region, and prior tumor necrosis factor inhibitor (TNFi) failure. CONCLUSIONS Most HZ events were mild/moderate. Herpes zoster IRs remained stable over 7.8 years of exposure. Older age, lower weight, geographic region, and prior TNFi failure were associated with increased HZ risk. CLINICALTRIALS.GOV NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304.
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Affiliation(s)
- Kevin L Winthrop
- Address correspondence to: Kevin L. Winthrop, MD, MPH; Professor of Public Health, Infectious Diseases and Ophthalmology, OHSU-PSU School of Public Health, 3181 SW Sam Jackson Road, Portland, OR 97239, USA()
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Millie D Long
- University of North Carolina, Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina, USA
| | - Julian Panés
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Siew C Ng
- Institute of Digestive Disease, Department of Medicine and Therapeutics, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong
| | | | | | | | | | | | - Chinyu Su
- Pfizer Inc, Collegeville, Pennsylvania, USA
| | - Gil Y Melmed
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Identification of novel off targets of baricitinib and tofacitinib by machine learning with a focus on thrombosis and viral infection. Sci Rep 2022; 12:7843. [PMID: 35551258 PMCID: PMC9096754 DOI: 10.1038/s41598-022-11879-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 03/22/2022] [Indexed: 12/03/2022] Open
Abstract
As there are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with JAK inhibitors, the observed elevated risk may be a result of an off-target effect. Computational approaches combined with in vitro studies can be used to predict and validate the potential for an approved drug to interact with additional (often unwanted) targets and identify potential safety-related concerns. Potential off-targets of the JAK inhibitors baricitinib and tofacitinib were identified using two established machine learning approaches based on ligand similarity. The identified targets related to thrombosis or viral infection/reactivation were subsequently validated using in vitro assays. Inhibitory activity was identified for four drug-target pairs (PDE10A [baricitinib], TRPM6 [tofacitinib], PKN2 [baricitinib, tofacitinib]). Previously unknown off-target interactions of the two JAK inhibitors were identified. As the proposed pharmacological effects of these interactions include attenuation of pulmonary vascular remodeling, modulation of HCV response, and hypomagnesemia, the newly identified off-target interactions cannot explain an increased risk of thrombosis or viral infection/reactivation. While further evidence is required to explain both the elevated thrombosis and viral infection/reactivation risk, our results add to the evidence that these JAK inhibitors are promiscuous binders and highlight the potential for repurposing.
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Hu L, Man S, Ji X, Wang Y, Liu X, Zhang J, Song C, Zhu J, Huang F. Risk of infections of biological and targeted drugs in patients with spondyloarthritis: meta-analysis of randomized clinical trials. Chin Med J (Engl) 2022; 135:911-919. [PMID: 35730370 PMCID: PMC9276457 DOI: 10.1097/cm9.0000000000001928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Concerns exist regarding the risk of infections in patients with spondyloarthritis (SpA) treated with biologics. We assessed the risk of infections of biological and targeted drugs in patients with SpA by performing a meta-analysis based on randomized controlled trials (RCTs). METHODS A systematic literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library, and China Biology Medicine Disc for RCTs evaluating the risk of infections of biological therapy in patients with SpA from inception through August 9, 2021. We calculated a pooled Peto odds ratio (OR) for infections in biologics-treated patients vs. placebo patients. The risk of bias on the included RCTs was assessed by using the Cochrane Risk of Bias Tool. RESULTS In total, 62 studies were included in this meta-analysis. Overall, the risk of infection (Peto OR: 1.16, 95% confidence interval [CI]: 1.07-1.26, P < 0.001), serious infection (Peto OR: 1.65, 95% CI: 1.26-2.17, P < 0.001), upper respiratory tract infection (URTI) (Peto OR: 1.17, 95% CI: 1.04-1.32, P = 0.008), nasopharyngitis (Peto OR: 1.25, 95% CI: 1.10-1.42, P < 0.001), and Candida infection (Peto OR: 2.64, 95% CI: 1.48-4.71, P = 0.001) were increased in SpA patients treated with biologics compared with placebo. Sensitivity analysis based on biologics classes was conducted, and results demonstrated that compared with placebo, there was a higher risk of infection for tumor necrosis factor (TNF)-a inhibitors (Peto OR: 1.38, 95% CI: 1.13-1.68, P = 0.001) and interleukin (IL)-17 inhibitors (Peto OR: 1.55, 95% CI: 1.08-2.22, P = 0.018) in axial SpA, and for Janus kinase inhibitors in peripheral SpA (Peto OR: 1.39, 95% CI: 1.14-1.69, P = 0.001); higher risk of serious infection for IL-17 inhibitors in peripheral SpA (Peto OR: 3.46, 95% CI: 1.26-9.55, P = 0.016) and axial SpA (Peto OR: 2.01, 95% CI: 1.38-2.91, P < 0.001); higher risk of URTI for TNF-a inhibitors in axial SpA (Peto OR: 1.37, 95% CI: 1.05-1.78, P = 0.019), and for apremilast in peripheral SpA (Peto OR: 1.60, 95% CI: 1.08-2.36, P = 0.018); higher risk of nasopharyngitis for TNF-a inhibitors in axial SpA (Peto OR: 1.41, 95% CI: 1.05-1.90, P = 0.022) and peripheral SpA (Peto OR: 1.49, 95% CI: 1.09-2.05, P = 0.013), and for IL-17 inhibitors in axial SpA (Peto OR: 1.35, 95% CI: 1.01-1.82, P = 0.044); higher risk of herpes zoster for Janus kinase inhibitors in peripheral SpA (Peto OR: 2.18, 95% CI: 1.03-4.62, P = 0.043); higher risk of Candida infection for IL-17 inhibitors in peripheral SpA (Peto OR: 2.52, 95% CI: 1.31-4.84, P = 0.006). CONCLUSIONS This meta-analysis shows that biological therapy in patients with SpA may increase the risk of infections, including serious infections, URTI, nasopharyngitis, and Candida infection, which should be paid attention to in our clinical practice.
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Affiliation(s)
- Lidong Hu
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Siliang Man
- Department of Rheumatology, Beijing Jishuitan Hospital, Beijing 100035, China
| | - Xiaojian Ji
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Yiwen Wang
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Xingkang Liu
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jiaxin Zhang
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Chuan Song
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jian Zhu
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Feng Huang
- Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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Aringer M, Alarcón-Riquelme ME, Clowse M, Pons-Estel GJ, Vital EM, Dall’Era M. A glimpse into the future of systemic lupus erythematosus. Ther Adv Musculoskelet Dis 2022; 14:1759720X221086719. [PMID: 35368371 PMCID: PMC8972918 DOI: 10.1177/1759720x221086719] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/23/2022] [Indexed: 12/17/2022] Open
Abstract
This viewpoint article on a forecast of clinically meaningful changes in the management of systemic lupus erythematosus (SLE) in the next 10 years is based on a review of the current state of the art. The groundwork has been laid by a robust series of classification criteria and treatment recommendations that have all been published since 2019. Building on this strong foundation, SLE management predictably will take significant steps forward. Assessment for lupus arthritis will presumably include musculoskeletal sonography. Large-scale polyomics studies are likely to unravel more of the central immune mechanisms of the disease. Biomarkers predictive of therapeutic success may enter the field; the type I interferon signature, as a companion for use of anifrolumab, an antibody against the common type I interferon receptor, is one serious candidate. Besides anifrolumab for nonrenal SLE and the new calcineurin inhibitor voclosporin in lupus nephritis, both of which are already approved in the United States and likely to become available in the European Union in 2022, several other approaches are in advanced clinical trials. These include advanced B cell depletion, inhibition of costimulation via CD40 and CD40 ligand (CD40L), and Janus kinase 1 (Jak1) and Tyrosine kinase 2 (Tyk2) inhibition. At the same time, essentially all of our conventional therapeutic armamentarium will continue to be used. The ability of patients to have successful SLE pregnancies, which has become much better in the last decades, should further improve, with approaches including tumor necrosis factor blockade and self-monitoring of fetal heart rates. While we hope that the COVID-19 pandemic will soon be controlled, it has highlighted the risk of severe viral infections in SLE, with increased risk tied to certain therapies. Although there are some data that a cure might be achievable, this likely will remain a challenge beyond 10 years from now.
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Affiliation(s)
- Martin Aringer
- Professor of Medicine (Rheumatology), Division of Rheumatology, Department of Medicine III, University Medical Center and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany
| | - Marta E. Alarcón-Riquelme
- Department of Medical Genomics, GENYO, Pfizer-University of Granada-Andalusian Government Center for Genomics and Oncological Research, Granada, Spain
| | - Megan Clowse
- Division of Rheumatology & Immunology, Duke University, Durham, NC, USA
| | - Guillermo J. Pons-Estel
- Department of Rheumatology, Grupo Oroño–Centro Regional de Enfermedades Autoinmunes y Reumáticas (GO-CREAR), Rosario, Argentina
| | - Edward M. Vital
- University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Maria Dall’Era
- Lupus Clinic and Rheumatology Clinical Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Ishikawa Y, Nakano K, Tokutsu K, Nakayamada S, Matsuda S, Fushimi K, Tanaka Y. Short-Term Prognostic Factors in Hospitalized Herpes Zoster Patients and Its Associated Cerebro-Cardiovascular Events: A Nationwide Retrospective Cohort in Japan. Front Med (Lausanne) 2022; 9:843809. [PMID: 35308501 PMCID: PMC8931312 DOI: 10.3389/fmed.2022.843809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/28/2022] [Indexed: 11/13/2022] Open
Abstract
Background Short-term mortality and incidence of cerebrovascular and cardiovascular events (C-CVE) during hospitalization of patients with severe herpes zoster (HZ) have not been sufficiently investigated. We aimed to investigate short-term prognosis and incidence of C-CVE associated with HZ in hospitalized patients. Methods This retrospective cohort study from April 2016 to March 2018 included HZ inpatient cases selected from the Diagnosis Procedure Combination database—a Japanese nationwide inpatient database. HZ and C-CVE were diagnosed based on the 10th revision of the International Classification of Diseases and Injuries codes. The definition of primary exposure was that treatments were initiated within 7 days of admission, and antivirals were administered for ≥7 days. Main Outcomes were in-hospital deaths and C-CVE onset after hospitalization. Results Among 16,811,501 in-hospital cases registered from 1,208 hospitals, 29,054 cases with HZ were enrolled. The median age was 71.0 years, 15,202 cases (52.3%) were female, and the HZ types were the central nervous system (n=9,034), disseminated (n=3,051), and ophthalmicus (n=1,069) types. There were 301 (1.0%) in-hospital deaths and 385 (1.3%) post-hospitalization onset of C-CVE. The 30-day in-hospital survival rates with or without underlying disease were 96.8% and 98.5%, respectively. Age ≥75 years (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.55–3.05), liver cirrhosis or hepatic failure (HR, 5.93; 95% CI, 2.16–16.27), chronic kidney disease (HR, 1.82; 95% CI, 1.24–2.68), heart failure (HR, 1.65; 95% CI, 1.22–2.24), and old cerebrovascular events (HR, 1.92; 95% CI, 1.10–3.34) were associated with poor short-term prognosis. Age ≥75 years (odds ratio [OR], 1.70; 95% CI, 1.29–2.24), diabetes (OR, 1.50; 95% CI, 1.19–1.89), dyslipidemia (OR, 1.95; 95% CI, 1.51–2.51), hyperuricemia (OR, 1.63; 95% CI, 1.18–2.27), hypertension (OR, 1.76; 95% CI, 1.40–2.20), heart failure (OR, 1.84; 95% CI, 1.32–2.55), and glucocorticoid administration (OR, 1.59; 95% CI, 1.25–2.01) were associated with increased risks for in-hospital C-CVE onset. Conclusions The underlying diseases that could influence the short-term mortality of severe HZ were identified. Glucocorticoid is a possible risk factor for the in-hospital onset of C-CVE after severe HZ development.
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Affiliation(s)
- Yuichi Ishikawa
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Sato Clinic, Ebisu, Shibuya-ku, Tokyo, Japan
| | - Kazuhisa Nakano
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
| | - Kei Tokutsu
- Department of Preventive Medicine and Community Health, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Shinya Matsuda
- Department of Preventive Medicine and Community Health, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kiyohide Fushimi
- Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- *Correspondence: Yoshiya Tanaka
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Spiewak TA, Patel A. User's guide to JAK inhibitors in inflammatory bowel disease. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100096. [PMID: 35300073 PMCID: PMC8920857 DOI: 10.1016/j.crphar.2022.100096] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 01/01/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), are remitting and relapsing disorders of the gastrointestinal tract, highlighted by the dysregulation of pro- and anti-inflammatory mediators, which lead to mucosal damage. These conditions cause a significant burden worldwide as primary and secondary treatment failure rates remain high even with our current therapeutic options. This emphasizes the need for continued advancement in treatment efficacy with improved safety profiles. Novel disease-targeting therapeutics have been developed, most recently being the Janus kinase inhibitors (JAKi). JAKi serve as a promising new class of non-immunogenic small molecule inhibitors that modulate inflammatory pathways by blocking the critical role that Janus kinase (JAK) proteins play in mediating the innate and adaptive immune responses. Tofacitinib has been shown to be therapeutically efficacious, to have a tolerable safety profile, and to be available for adult patients with moderate-to-severe UC. This review was designed to serve as an overview and as practical guidance for medical practitioners. Author recommendations and appraisals of the quality of evidence throughout this article are based solely on personal opinion and are not the outcome of a formal methodology followed by a consensus group.
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Affiliation(s)
- Ted A. Spiewak
- Division of Gastroenterology & Hepatology, Brooke Army Medical Center, USA
| | - Anish Patel
- Division of Gastroenterology & Hepatology, Brooke Army Medical Center, USA
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Nakamura Y, Honda D, Takizawa N, Fujita Y. Herpes zoster meningitis in a rheumatoid arthritis patient treated with tofacitinib. BMJ Case Rep 2022; 15:e247276. [PMID: 35236687 PMCID: PMC8895891 DOI: 10.1136/bcr-2021-247276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2022] [Indexed: 12/30/2022] Open
Abstract
A man in his 70s with rheumatoid arthritis presented with seizures and coma and was transferred to our emergency department. Two months prior to admission, he started to take tofacitinib 10 mg/day. On admission, we noted a rash with a blister on the forehead, and herpes zoster was diagnosed. Cerebrospinal fluid examination suggested meningitis. An MRI of the brain showed no abnormality. Based on these findings, he was suspected with herpes zoster meningitis. We discontinued tofacitinib and treated the patient with intravenous acyclovir for 2 weeks. He regained complete consciousness, but right forehead skin lesion, severe vision loss in the right eye and right facial nerve paralysis remained as sequelae. Six weeks after admission, we restarted tofacitinib with oral valaciclovir as antiviral prophylaxis. Two years after admission, we administered Shingrix, an adjuvant recombinant vaccine for herpes zoster, and discontinued oral valaciclovir.
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Affiliation(s)
| | - Daiyu Honda
- Department of Neurology, Nagoya Daiichi Sekijuji Byoin, Nagoya, Aichi, Japan
| | - Naoho Takizawa
- Department of Rheumatology, Chubu Rosai Hospital, Nagoya, Aichi, Japan
| | - Yoshiro Fujita
- Department of Rheumatology, Chubu Rosai Hospital, Nagoya, Aichi, Japan
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Gialouri CG, Evangelatos G, Fragoulis GE. Choosing the Appropriate Target for the Treatment of Psoriatic Arthritis: TNFα, IL-17, IL-23 or JAK Inhibitors? Mediterr J Rheumatol 2022; 33:150-161. [PMID: 36127928 PMCID: PMC9450184 DOI: 10.31138/mjr.33.1.150] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
Psoriatic arthritis (PsA) is a highly heterogenous disease. Apart from arthritis and psoriasis, other manifestations can also occur, including enthesitis, dactylitis, axial-, nail-, eye- and bowel- involvement. Comorbidities are also frequent in the setting of PsA, with cardiovascular disease and mental-health disorders being the most frequent. The Rheumatologist's arsenal has many different treatment options for treating PsA. Despite their effectiveness, there are some differences in terms of efficacy and safety that might affect clinician's decision for one or the other drug. Comparing biologic DMARDs and JAK-inhibitors, one could say that they have similar effectiveness in terms of musculoskeletal manifestations. However, anti-IL-17 and anti-IL-23 drugs seem to be more effective for skin manifestations. In contrast, JAK-inhibitors and etanercept might be less effective for these manifestations. Inflammatory bowel disease and uveitis are non-responsive to etanercept and anti-IL-17 drugs. As regards to comorbidities, data are scarce, but future studies will shed light on possible differential effect of bDMARDs or JAK-inhibitors. Safety is always an important drive for choosing the appropriate treatment. Infections are the most common adverse event of these drugs. Etanercept and anti-IL-17 drugs are safer for patients having latent tuberculosis, while herpes zoster is more common in individuals receiving JAK-inhibitors. Finally, venous thromboembolism risk, should be taken into account when JAK-inhibitors are used. In this review, we comparatively present, as outlined above, the various aspects that could affect the choice of the appropriate bDMARD or JAK-inhibitor for the treatment of a PsA patient.
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Affiliation(s)
- Chrysoula G. Gialouri
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens,“Laiko” General Hospital, Athens, Greece
| | - Gerasimos Evangelatos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens,“Laiko” General Hospital, Athens, Greece
| | - George E. Fragoulis
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens,“Laiko” General Hospital, Athens, Greece
- Corresponding Author: George E. Fragoulis, MD, PhD Rheumatology Unit, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens Laiko General Hospital, Mikras Asias 75 Str, 11527 Athens, Greece, Tel.: +30 210 746 2636, E-mail:
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