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Tanaka Y. What is rheumatoid factor? From screening to personalized management. Rheumatology (Oxford) 2025; 64:ii9-ii14. [PMID: 39792161 PMCID: PMC11981331 DOI: 10.1093/rheumatology/keaf003] [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: 06/01/2024] [Revised: 10/06/2024] [Accepted: 10/22/2024] [Indexed: 01/12/2025] Open
Abstract
The RF is a representative autoantibody against the crystallizable fragment (Fc) of denatured IgG that is primarily detected in patients with RA. Although five types of TNF inhibitors can be used to treat RA, no guidelines are available for selecting the appropriate inhibitor for treatment. High serum RF levels are associated with high disease activity, progressive joint destruction, life prognosis associated with organ damage, decreased treatment responsiveness to TNF inhibitors and other drugs and low treatment retention rates. Meanwhile, certolizumab pegol (CZP), a TNF inhibitor without the Fc region, remains at high concentrations in the blood. Unlike other antibody drugs with the Fc region, CZP maintains efficacy in patients with high serum RF levels. When serum IgM-RF levels are high, antibody drugs with the Fc region are more likely to bind to IgM-RF and be degraded. Thus, CZP without the Fc region may be more favourable for patients with high serum RF levels.
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
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Heckert SL, Maassen JM, Nevins I, Baudoin P, Steup-Beekman GM, Huizinga TWJ, Bergstra SA, Allaart CF. Long-term clinical outcomes in early rheumatoid arthritis that was treated-to-target in the BeSt and IMPROVED studies. Rheumatology (Oxford) 2025; 64:1052-1059. [PMID: 38561181 PMCID: PMC11879312 DOI: 10.1093/rheumatology/keae212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/07/2024] [Accepted: 03/19/2024] [Indexed: 04/04/2024] Open
Abstract
OBJECTIVES To assess disease outcomes after 20 and 12 years of patients with RA or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials. METHODS In BeSt (inclusion 2000-02, duration 10 years), 508 patients with early RA were randomized to: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial csDMARD combination therapy, 4. initial bDMARD/csDMARD combination therapy. The treatment target was low disease activity (DAS ≤ 2.4).In IMPROVED (inclusion 2007-10, duration 5 years), 610 patients with early RA/UA started MTX with prednisone bridging. The treatment target was remission (DAS < 1.6). Patients not in early remission were randomized to 1. csDMARD combination therapy or 2. bDMARD/csDMARD combination therapy.Between 2019 and 22, these patients were invited for long-term follow-up. RESULTS One-hundred-fifty-three ex-Best and 282 ex-IMPROVED patients participated in the follow-up study after a median of 12 and 20 years since the study started.In ex-BeSt and ex-IMPROVED patients, the rate of low disease activity was 91%, and 68% were in DAS remission. Median SHS was 14.0 in ex-BeSt (IQR 6.0-32.5; progression since end BeSt 6.0, IQR 2.0-12.5) and 8 in ex-IMPROVED participants (IQR 3-16; progression since end IMPROVED 4, IQR 2-9). Mean HAQ was 0.8 ± 0.6 in ex-BeSt (change since end BeSt: 0.3 ± 0.5) and 0.6 ± 0.6 in ex-IMPROVED participants (change since end IMPROVED: 0.06 ± 0.5). CONCLUSION At 12/20 years after treatment started, the majority of RA and UA patients who had been treated to target low DAS or DAS remission were in DAS remission and had limited functional disability. Radiographic damage progression was mild although not completely suppressed.
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Affiliation(s)
- Sascha Louise Heckert
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Johanna M Maassen
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Isabell Nevins
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Paul Baudoin
- Rheumatology, Reumazorg Zuid West Nederland, Roosendaal, The Netherlands
| | - Gerda M Steup-Beekman
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
- Rheumatology, Haaglanden Medical Center, The Hague, The Netherlands
| | - Tom W J Huizinga
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Sytske Anne Bergstra
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | - Cornelia F Allaart
- Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
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Tanaka Y, Atsumi T, Aletaha D, Schulze-Koops H, Fukada H, Watson C, Takeuchi T. The Uncoupling of Disease Activity from Joint Structural Progression in Patients with Rheumatoid Arthritis Treated with Filgotinib. Rheumatol Ther 2025; 12:53-66. [PMID: 39592547 PMCID: PMC11751281 DOI: 10.1007/s40744-024-00725-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
INTRODUCTION While modern treatments can prevent progressive bone destruction in patients with rheumatoid arthritis (RA) achieving clinical remission, it is unclear whether residual clinical activity may cause or be associated with progressive joint damage. This post hoc analysis evaluated the association between clinical disease activity and structural progression in patients with RA treated with filgotinib (FIL) in FINCH 1 (NCT02889796). METHODS Patients with RA and inadequate response to methotrexate (MTX) use were randomized 3:3:2:3 to FIL 200 mg (FIL200) or FIL 100 mg (FIL100) once daily, adalimumab 40 mg biweekly, or placebo, all with background MTX. We evaluated the change from baseline (CFB) in modified total Sharp score (mTSS), erosion score, and joint space narrowing score among patients achieving Clinical Disease Activity Index (CDAI) remission (CDAI ≤ 2.8), low disease activity (LDA; 2.8 < CDAI ≤ 10), medium disease activity (MDA; 10 < CDAI ≤ 22), and high disease activity (HDA; CDAI > 22) at 24 weeks. RESULTS At week 24, the least squares (LS) mean CFB in mTSS was similarly low across treatments among patients who achieved CDAI remission (range 0.00-0.11) or LDA (n = 285 and 575, respectively). In patients with MDA and HDA (n = 471 and 157, respectively), smaller LS mean CFB in mTSS was seen in the FIL200 group vs. the placebo group (P < 0.05 for both). CONCLUSIONS RA clinical remission and LDA achievement were associated with suppressed progression of joint destruction over 24 weeks in all treatment groups. Only FIL200 significantly inhibited joint damage compared with placebo in patients with MDA or HDA, indicating an uncoupling of clinical disease activity and structural progression in patients receiving FIL200. TRIAL REGISTRATION NCT02889796.
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Affiliation(s)
- Yoshiya Tanaka
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan.
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Daniel Aletaha
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Vienna, Austria
| | - Hendrik Schulze-Koops
- Division of Rheumatology and Clinical Immunology, Department of Medicine IV, Ludwig Maximilian University, Munich, Germany
| | | | | | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Saitama Medical University, Saitama, Japan
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Komatsu R, Fujii R, Ogasawara T, Suzuki-Takahashi Y, Chen S, Sugishita Y, Niki H, Yudoh K. CDK6-Dependent, CDK4-Independent Synovial Hyperplasia in Arthritic Mice and Tumor Necrosis Factor-α-Induced Proliferation of Synovial Fibroblasts. Int J Mol Sci 2025; 26:1151. [PMID: 39940918 PMCID: PMC11817658 DOI: 10.3390/ijms26031151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/24/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Palbociclib, a dual CDK4/6 kinase inhibitor used for breast cancer, has been explored as a treatment option for rheumatoid arthritis (RA). Preclinical studies have reported palbociclib-induced myelosuppression, but no such effects have been observed in Cdk4 or Cdk6 single-deficient mice. Synoviocyte proliferation-associated in collagen-induced arthritis 1/serum amyloid A-like 1 (SPACIA1/SAAL1) is involved in G1 phase progression. Given that SPACIA1/SAAL1 upregulates CDK6 (but not CDK4) expression, we aimed to determine whether suppressing CDK6 expression alone could prevent synovial hyperplasia without myelosuppression. The effects of CDK6 expression on TNF-α-induced rheumatoid arthritis synovial fibroblast (RASF) proliferation and synovial hyperplasia in collagen-induced arthritis (CIA) mice were investigated by modulating the transcriptional level with a CDK6 expression inhibitor (indole-3-carbinol), CDK6 small interfering RNA (siRNA), and Cdk6-deficient mice. Indole-3-carbinol or CDK6 siRNA inhibited TNF-α-induced RASF proliferation without suppressing CDK4 expression and reduced retinoblastoma protein phosphorylation. In CIA mice, indole-3-carbinol did not cause myelosuppression, considerably delayed CIA onset and progression, and reduced arthritis severity. Cdk6-deficient mice showed similar improvements in CIA pathogenesis but had lower serum anti-type II collagen IgG levels. Notably, synovial hyperplasia was not observed in Cdk6-deficient mice. CIA-synovial hyperplasia depends on CDK6, but not CDK4, expression.
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Affiliation(s)
- Rie Komatsu
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Ryoji Fujii
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Toru Ogasawara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;
| | - Yuki Suzuki-Takahashi
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Sandy Chen
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Yodo Sugishita
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Hisateru Niki
- Department of Orthopedic Surgery, St. Marianna University School of Medicine, Kawasaki 216-8511, Kanagawa, Japan;
| | - Kazuo Yudoh
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
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Konzett V, Aletaha D. Management strategies in rheumatoid arthritis. Nat Rev Rheumatol 2024; 20:760-769. [PMID: 39448800 DOI: 10.1038/s41584-024-01169-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2024] [Indexed: 10/26/2024]
Abstract
Management of rheumatoid arthritis (RA) has evolved from simply the direct translation of drug efficacy results from clinical trials to patient care, to a more complex longitudinal process that considers not only drug efficacy but also the safety gestalt of a treatment and patient profiles and preferences, as well as health-economic factors. With numerous DMARDs available to treat RA, knowledge about trial efficacy becomes less important than data that inform an appropriate clinical strategy for their optimal selection and use. Overly ambitious approaches targeting the 'maximum' level of success could, for example, be prone to failure and create frustration, and lead to a large number of patients then being considered as 'difficult to treat'. Safety profiles might be more informative than efficacy profiles for precision medicine approaches. Contemporary RA management strategies might therefore take a more holistic approach, beyond merely efficacy, to the setting of targets that lead to improved compliance rather than aspirational successes, with consideration of each patient's multimorbidity profile and preferences, as well as the safety profile of each treatment. Ultimately, the goal remains unchanged: maximizing health-related quality of life; however, with a focus on optimal balance rather than superlatives.
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Affiliation(s)
- Victoria Konzett
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Daniel Aletaha
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
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Wisłowska M. Comparison of treatment of severe rheumatoid arthritis patients with biological agents and JAK-STAT inhibitors. An extension study. Reumatologia 2024; 62:322-329. [PMID: 39677878 PMCID: PMC11635626 DOI: 10.5114/reum/194686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/16/2024] [Indexed: 12/17/2024] Open
Abstract
Introduction This study compared treatment with biologic agents and Janus kinase inhibitors (JAKi) in combination with methotrexate (MTX) for rheumatoid arthritis (RA) in a real-world setting at a large center in Poland. There is a persistent shortage of such studies, and illustrating the switching of medications in search of a suitable way of treatment for a given patient is a crucial step towards future personalized therapy. Aim of the study This study is an extension of the initial work published in 2022 in Reumatologia, with the addition of an analysis of patients treated with upadacitinib. The study compared the effectiveness and side effects after treatment of biological disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) in combination with MTX. Materials and methods A total of 130 patients with active severe RA (Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate [DAS28(ESR)] value > 5.1) were treated at the Rheumatologic Outpatients Department of the Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland between January 2010 and September 2021. All patients were treated with MTX 25 mg per week. They were divided into two groups: group I (80 patients) treated with biologic agents, and group II (50 patients) treated with JAKi. Assessment of DAS28(ESR) and Simplified Disease Activity Index (SDAI) and analysis of Boolean criteria for remission were performed. Remission or low disease activity, switching between drugs and adverse events were assessed and compared between studied groups. Results Patients treated with tsDMARDs had previously used a higher number of conventional synthetic DMARDs (csDMARDs) and bDMARDs compared to those treated with bDMARDs. However, they achieved lower SDAI and assessment of disease activity using Visual Analogue Scale (VAS) values, and a higher proportion of patients achieved Boolean criteria for remission after treatment. Conclusions The results of treatment with JAKi were successful, but the potential side effects indicate that this treatment may not be equally suitable for all RA patients.
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Affiliation(s)
- Małgorzata Wisłowska
- Rheumatology Clinic of the National Institute of Geriatric, Rheumatology and Rehabilitation in Warsaw, Poland
- Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
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Venetsanopoulou AI, Voulgari PV, Drosos AA. Optimizing withdrawal strategies for anti-TNF-α therapies in rheumatoid arthritis. Expert Opin Biol Ther 2024; 24:815-825. [PMID: 39051615 DOI: 10.1080/14712598.2024.2384000] [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: 02/27/2024] [Accepted: 07/20/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease that significantly impacts patients' quality of life. While treatment options have expanded over the years, including the introduction of tumor necrosis factor-alpha (TNFα) inhibitors (TNFi), optimizing withdrawal strategies for these agents remains a challenge. AREAS COVERED This review examines the current evidence on TNFi withdrawal strategies in RA, focusing on factors influencing withdrawal decisions such as disease activity monitoring, treatment response, patient characteristics, and biomarkers. A comprehensive literature search was conducted, including randomized controlled trials, observational studies, and expert guidelines. The pathophysiology of RA, current pharmacological agents, and the treat-to-target strategy are discussed to provide a holistic understanding of RA management. EXPERT OPINION Withdrawal strategies could be suitable for certain patients, keeping in mind that several factors influence withdrawal decisions, including treatment response, disease activity and monitoring, and patient characteristics. The decision to withdraw TNFi must balance the benefits against the potential risks of disease flare and long-term treatment-related adverse effects. Combining DMARDs and TNFi early improves outcomes, supporting tapering strategies for cost-effectiveness and flare prevention. Future directions, including precision medicine approaches, patient-centered care models, and health economics analyses, are proposed to further optimize RA management and improve patient outcomes.
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Affiliation(s)
- Aliki I Venetsanopoulou
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paraskevi V Voulgari
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
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Schreiner MM, Straub J, Apprich S, Staats K, Windhager R, Aletaha D, Böhler C. The influence of biological DMARDs on aseptic arthroplasty loosening: a retrospective cohort study. Rheumatology (Oxford) 2024; 63:970-976. [PMID: 37402609 PMCID: PMC10986799 DOI: 10.1093/rheumatology/kead304] [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: 02/11/2023] [Revised: 05/21/2023] [Accepted: 06/08/2023] [Indexed: 07/06/2023] Open
Abstract
OBJECTIVE To investigate whether biological DMARDs affect the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA) in patients with RA. METHODS We retrospectively identified all patients suffering from RA who underwent THA/TKA at our academic centre between 2002 and 2015 and linked them with an existing prospective observational RA database at our institution. The risk of aseptic loosening was estimated using radiological signs of component loosening (RCL). A time-dependent Cox regression analysis was used to compare the risk of implant loosening between patients treated with traditional DMARDS and biological DMARDs, or alternately both over time. RESULTS A total of 155 consecutive total joint arthroplasties (TJAs) (103 TKA vs 52 THA) was retrospectively included in the study. Mean age at implantation was 59 ± 13 years. Mean follow-up time was 69 ± 43 months. Overall, 48 (31%) TJAs showed signs of RCL, with 28 (27.2%) RCLs occurring after TKA compared with 20 after THA (38.5%). A significant difference regarding the incidence of RCL between the traditional DMARDs group (39 cases of RCL, 35%) and the biological DMARDs group (nine cases of RCL, 21%) (P = 0.026) was observed using the log-rank test. This was also true when using a time-dependent Cox regression with therapy as well as arthroplasty location (hip vs knee) as variables (P = 0.0447). CONCLUSION Biological DMARDs may reduce the incidence of aseptic loosening after TJA in patients with RA compared with traditional DMARDs. This effect seems to be more pronounced after TKA than THA.
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Affiliation(s)
- Markus M Schreiner
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Jennifer Straub
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Sebastian Apprich
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Kevin Staats
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Reinhard Windhager
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Daniel Aletaha
- Department of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Christoph Böhler
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
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Yokota K. Osteoclast differentiation in rheumatoid arthritis. Immunol Med 2024; 47:6-11. [PMID: 37309864 DOI: 10.1080/25785826.2023.2220931] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 05/30/2023] [Indexed: 06/14/2023] Open
Abstract
Osteoclasts, derived from the monocyte/macrophage line of bone marrow hematopoietic stem cell progenitors, are the sole bone-resorbing cells of the body. Conventional osteoclast differentiation requires macrophage colony-stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. Rheumatoid arthritis (RA) is the most prevalent systemic autoimmune disease and inflammatory arthritis characterized by bone destruction. Increased levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in the serum and joints, cause excessive bone destruction. We have recently reported that stimulation of human peripheral blood monocytes with TNF-α and IL-6 induces the differentiation of osteoclasts with bone resorption activity. This review presents the functional differences between representative osteoclasts, conventional RANKL-induced osteoclasts, and recently identified proinflammatory cytokine (TNF-α and IL-6)-induced osteoclasts in RA patients. We believe novel pathological osteoclasts associated with RA will be identified, and new therapeutic strategies will be developed to target these osteoclasts and prevent the progression of bone destruction.
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Affiliation(s)
- Kazuhiro Yokota
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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10
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Merola JF, Chakravarty SD, Choi O, Chan D, Gottlieb AB. A clinical review of structural damage in psoriatic arthritis for dermatologists: From pathogenesis to ongoing controversies. J Am Acad Dermatol 2024; 90:349-357. [PMID: 37852305 DOI: 10.1016/j.jaad.2023.10.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/29/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023]
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory disease that often goes unrecognized in patients with psoriasis. As a result, patients may develop significant structural damage before diagnosis and initiation of adequate treatment. Dermatologists are in an unique position to identify early signs and symptoms of PsA. Here, we briefly review the pathogenesis of PsA, differences in PsA presentation within real-world dermatology practice versus rheumatology clinical trials, and imaging modalities that can be used to assess structural damage. We then discuss several ongoing controversies related to prediction, assessment, and treatment of PsA-related structural damage. Debated questions include the following: (1) Does subclinical enthesitis predict progression from psoriasis to PsA?, (2) Does methotrexate inhibit progression of structural damage?, (3) Does structural damage correlate with clinical disease activity?, and (4) Can progression from psoriasis to PsA be prevented? Evidence presented herein suggests that dermatologists, together with rheumatologists, can play important roles in the early diagnosis and treatment of PsA, thereby potentially preventing irreversible structural damage.
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Affiliation(s)
- Joseph F Merola
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Soumya D Chakravarty
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania; Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Olivia Choi
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania
| | - Daphne Chan
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania
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Konzett V, Kerschbaumer A, Smolen JS, Kristianslund EK, Provan SA, Kvien TK, Aletaha D. Definition of rheumatoid arthritis flare based on SDAI and CDAI. Ann Rheum Dis 2024; 83:169-176. [PMID: 37890977 DOI: 10.1136/ard-2023-224742] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023]
Abstract
OBJECTIVE To develop and validate definitions for disease flares in rheumatoid arthritis (RA) based on the quantitative Simplified and Clinical Disease Activity Indices (SDAI, CDAI). METHODS We analysed RA treatment courses from the Norwegian disease-modifying antirheumatic drug registry (NOR-DMARD) and the Vienna RA cohort. In a receiver operating curve analysis, we determined flare definitions for absolute changes in SDAI and CDAI based on a semiquantitative patient anchor. NOR-DMARD was sampled into an 80%-training cohort for cut point derivation and a 20%-test cohort for internal validation. The definitions were then externally validated in the independent Vienna RA cohort and tested regarding their performance on longitudinal, content, face, and construct validity. RESULTS We analysed 4256 treatment courses from NOR-DMARD and 2557 from the Vienna RA cohort. The preliminary definitions for absolute changes in SDAI and CDAI for flare are an increase of 4.7 and 4.5, respectively. The definitions performed well in the test and external validation cohorts, and showed clinical face and construct validity, as flares significantly impact both functional ( ∆ Health Assessment Questionnaire flare vs no-flare +0.43; p<0.001) and structural ( ∆ modified Sharp Score 43% higher after flare; p<0.001) disease outcomes, and reflect consistent worsening across all disease core sets, both patient reported and objective. CONCLUSION We here provide novel definitions for flare in RA based on SDAI and CDAI, validated in two large independent real-world cohorts. In times of highly effective medications for RA, and consideration of their tapering, these definitions will be useful for guiding decision making in clinical practice and designing clinical trials.
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Affiliation(s)
- Victoria Konzett
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Andreas Kerschbaumer
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Josef S Smolen
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Eirik Klami Kristianslund
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Sella A Provan
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Tore K Kvien
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Daniel Aletaha
- Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
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Hagiwara S, Tsuboi H, Kuroda Y, Sawabe T, Uematsu N, Kawashima F, Sugita T, Terasaki M, Honda F, Yagishita M, Kondo Y, Sumida T, Matsumoto I. Comparative analysis of low-field magnetic resonance imaging in patients with rheumatoid arthritis treated with certolizumab pegol or infliximab. Mod Rheumatol 2023; 33:1097-1103. [PMID: 36440707 DOI: 10.1093/mr/roac138] [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: 06/03/2022] [Accepted: 11/04/2022] [Indexed: 11/08/2023]
Abstract
OBJECTIVES The aim is to clarify the differences in magnetic resonance imaging (MRI) findings between rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP) and infliximab (IFX). METHODS The study included RA patients who received CZP or IFX and were examined with low-field MRI (compacTscan; compact magnetic resonance imaging) at the beginning and again within 6 months of treatment initiation. Comparisons were made regarding background, clinical course, and differences in MRI findings following initiation of tumour necrosis factor inhibitors between the CZP and IFX treatment groups. MRI findings were evaluated by scoring erosion, bone marrow oedema (BME), and synovitis. RESULTS Ten cases in CZP and 18 cases in IFX group were compared. The biologic disease-modifying antirheumatic drug-naïve rate in the IFX group was significantly higher than that in the CZP group. After 6 months, disease activities were significantly decreased from baseline in both groups. Erosion score did not change significantly in both groups after 6 months. BME score was significantly decreased in the CZP group after 6 months, whereas in the IFX group, there was no significant change. Synovitis score was significantly decreased in both groups after 6 months. CONCLUSIONS The findings of our study suggest that, in patients with RA, CZP might improve BME more effectively than IFX.
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Affiliation(s)
- Shinya Hagiwara
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hiroto Tsuboi
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuki Kuroda
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tomonori Sawabe
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Nana Uematsu
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Fumina Kawashima
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Toshiki Sugita
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Mayu Terasaki
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Fumika Honda
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Mizuki Yagishita
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuya Kondo
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takayuki Sumida
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Isao Matsumoto
- Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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13
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Wu CY, Yang HY, Lai JH. Potential therapeutic targets beyond cytokines and Janus kinases for autoimmune arthritis. Biochem Pharmacol 2023; 213:115622. [PMID: 37230194 DOI: 10.1016/j.bcp.2023.115622] [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: 03/14/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Synovial inflammation and destruction of articular cartilage and bone are hallmarks of autoimmune arthritis. Although current efforts to inhibit proinflammatory cytokines (biologics) or block Janus kinases (JAK) appear to be promising in many patients with autoimmune arthritis, adequate disease control is still lacking in a significant proportion of autoimmune arthritis patients. The possible adverse events from taking biologics and JAK inhibitors, such as infection, remain a major concern. Recent advances showing the effects of a loss of balance between regulatory T cells and T helper-17 cells as well as how the imbalance between osteoblastic and osteoclastic activities of bone cells exaggerates joint inflammation, bony destruction and systemic osteoporosis highlight an interesting area to explore in the search for better therapeutics. The recognition of the heterogenicity of synovial fibroblasts in osteoclastogenesis and their crosstalk with immune and bone cells provides an opportunity for identifying novel therapeutic targets for autoimmune arthritis. In this commentary, we comprehensively review the current knowledge regarding the interactions among heterogenic synovial fibroblasts, bone cells and immune cells and how they contribute to the immunopathogenesis of autoimmune arthritis, as well as the search for novel therapeutic targets not targeted by current biologics and JAK inhibitors.
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Affiliation(s)
- Chao-Yi Wu
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Huang-Yu Yang
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Jenn-Haung Lai
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei 114, Taiwan.
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14
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Matsuda K, Shiba N, Hiraoka K. New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis. Int J Mol Sci 2023; 24:ijms24065173. [PMID: 36982247 PMCID: PMC10049180 DOI: 10.3390/ijms24065173] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.
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Affiliation(s)
- Kotaro Matsuda
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Naoto Shiba
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Koji Hiraoka
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
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15
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Heckert SL, Bergstra SA, Goekoop-Ruiterman YPM, Güler-Yüksel M, Lems WF, Matthijssen XME, van Oosterhout M, Huizinga TWJ, Allaart CF. Frequency of joint inflammation is associated with local joint damage progression in rheumatoid arthritis despite long-term targeted treatment. RMD Open 2023; 9:rmdopen-2022-002552. [PMID: 36609354 PMCID: PMC9827264 DOI: 10.1136/rmdopen-2022-002552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/07/2022] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVES To investigate whether in rheumatoid arthritis (RA) frequency of local joint inflammation is associated with radiographic joint damage progression in that joint. METHODS Data from 473 patients with RA and available radiographs from the BeSt study were used. Patients were treated to target (Disease Activity Score of ≤2.4) for a median of 10 years. At each study visit every 3 months, joints were assessed for swelling and tenderness. Radiographs of hands and feet were made yearly. A generalised linear mixed model was used to assess the association between the percentage of study visits at which clinical inflammation was observed in a joint (cumulative inflammation) and radiographic joint damage in that same joint. Clinical inflammation was primarily defined as joint swelling (with or without joint tenderness). For secondary analyses, we also investigated joint tenderness without joint swelling. Damage was measured as the percentage of the maximum possible Sharp-Van der Heijde score in a particular joint. RESULTS Cumulative local joint swelling was associated with local progression of radiographic damage in the same joint (β=0.14, 95% CI 0.13 to 0.15). This association was also found in a subset of joints that were swollen at least once. Cumulative local joint tenderness without concurrent local joint swelling was less strongly associated with local radiographic joint damage progression (β=0.04, 95% CI 0.03 to 0.05). CONCLUSIONS In RA, long-term cumulative local joint inflammation is associated with joint damage progression in the same joint.
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Affiliation(s)
- Sascha L Heckert
- Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | - Melek Güler-Yüksel
- Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, The Netherlands
| | - Willem F Lems
- Rheumatology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | | | | | - Tom W J Huizinga
- Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
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16
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Wang T, Wang Z, Qi W, Jiang G, Wang G. Possible Future Avenues for Rheumatoid Arthritis Therapeutics: Hippo Pathway. J Inflamm Res 2023; 16:1283-1296. [PMID: 36998323 PMCID: PMC10045326 DOI: 10.2147/jir.s403925] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/14/2023] [Indexed: 04/01/2023] Open
Abstract
Rheumatoid arthritis (RA) is a persistent systemic autoimmune disease with the hallmarks of swelling of the joint, joint tenderness, and progressive joint destruction, which may cause synovial inflammation and pannus as a basic pathological change, resulting in joint malformations and serious disorders. At present, the precise etiology and mechanism of pathogenesis of RA are unknown. The imbalance of immune homeostasis is the origin of RA. Hippo pathway is widely expressed in a range of cell lineages and plays a fundamental role in maintaining the immune steady state and may be involved in the pathogenic mechanism of RA. This study reviews the progress of Hippo pathway and its main members in the pathogenesis of RA from three aspects: regulating the maintenance of autoimmune homeostasis, promoting the pathogenicity of synovial fibroblasts and regulating the differentiation of osteoclasts. The study also presents a new way to recognize the pathogenesis of rheumatoid arthritis, which is favorable for finding a new way for treating the rheumatoid arthritis.
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Affiliation(s)
- Tao Wang
- Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
| | - Zhandong Wang
- Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
| | - Wenxia Qi
- Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
| | - Ganggang Jiang
- Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
| | - Gang Wang
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China
- Correspondence: Gang Wang, Email
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17
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Therapeutic Utility and Adverse Effects of Biologic Disease-Modifying Anti-Rheumatic Drugs in Inflammatory Arthritis. Int J Mol Sci 2022; 23:ijms232213913. [PMID: 36430392 PMCID: PMC9692587 DOI: 10.3390/ijms232213913] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/03/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Targeting specific pathologic pro-inflammatory cytokines or related molecules leads to excellent therapeutic effects in inflammatory arthritis, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Most of these agents, known as biologic disease-modifying anti-rheumatic drugs (bDMARDs), are produced in live cell lines and are usually monoclonal antibodies. Several types of monoclonal antibodies target different pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-6, and IL-23/12. Some bDMARDs, such as rituximab and abatacept, target specific cell-surface molecules to control the inflammatory response. The therapeutic effects of these bDMARDs differ in different forms of inflammatory arthritis and are associated with different adverse events. In this article, we summarize the therapeutic utility and adverse effects of bDMARDs and suggest future research directions for developing bDMARDs.
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18
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Iwamoto N, Kawakami A. The monocyte-to-osteoclast transition in rheumatoid arthritis: Recent findings. Front Immunol 2022; 13:998554. [PMID: 36172385 PMCID: PMC9510592 DOI: 10.3389/fimmu.2022.998554] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
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19
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Podewski AF, Glimm AM, Fischer I, Bruyn GAW, Hanova P, Hammer HB, Aga AB, Haavardsholm EA, Ramiro S, Burmester GR, Backhaus M, Ohrndorf S. The MCP2 and the wrist plus two extensor compartments are the most affected and responsive joints/tendons out of the US7 score in patients with rheumatoid arthritis-an observational study. Arthritis Res Ther 2022; 24:183. [PMID: 35932087 PMCID: PMC9354335 DOI: 10.1186/s13075-022-02874-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/18/2022] [Indexed: 11/25/2022] Open
Abstract
Background There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. Methods RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. Results A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p < 0.001) and the palmar side of the finger joints by PD (p < 0.001) were more frequently pathologic. The reduced US7 score (GS/PD: palmar MCP2, dorsal wrist, EDC and ECU, only PD: dorsal MCP2) showed therapy response (SRM 0.433) after 6 months and retained 76% of the full US7 score’s information. No major differences between the groups of early and established RA could be detected. Conclusions The wrist, MCP2, EDC, and ECU tendons were most frequently pathologic and responsive to therapy in both early and established RA and should therefore be included in a comprehensive score for monitoring RA patients on patient-level. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02874-y.
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Affiliation(s)
- A F Podewski
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany. .,Department of Internal Medicine - Rheumatology and Clinical Immunology, Park-Klinik Weißensee, Berlin, Germany.
| | - A M Glimm
- Department of Endocrinology, Nephrology, Rheumatology, Division Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany
| | - I Fischer
- Biostatistics Tubingen, Tubingen, Germany
| | - G A W Bruyn
- Department of Rheumatology, MC Groep Hospitals, Lelystad, Netherlands
| | - P Hanova
- Department of Rheumatology, First Faculty of Medicine, Charles University of Prague, Prague, Czech Republic
| | - H B Hammer
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - A B Aga
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - E A Haavardsholm
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - S Ramiro
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.,Zuyderland Medical Center, Heerlen, The Netherlands
| | - G R Burmester
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - M Backhaus
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Department of Internal Medicine - Rheumatology and Clinical Immunology, Park-Klinik Weißensee, Berlin, Germany
| | - S Ohrndorf
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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20
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Komatsu N, Takayanagi H. Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol 2022; 18:415-429. [PMID: 35705856 DOI: 10.1038/s41584-022-00793-5] [Citation(s) in RCA: 245] [Impact Index Per Article: 81.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.
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Affiliation(s)
- Noriko Komatsu
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
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21
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Wisłowska M. Comparison of treatment of severe rheumatoid arthritis patients with biological agents and JAK-STAT inhibitors. An observational study. Reumatologia 2022; 60:81-91. [PMID: 35782030 PMCID: PMC9238315 DOI: 10.5114/reum.2022.115987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/15/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Treatment of severe rheumatoid arthritis (RA) is currently based either on biological agents or Janus kinase/signal transducer and activator of transcription inhibitors, most often in combination with methotrexate (MTX). Aim of the study The aim of the study was to compare the effectiveness and side effects of bio- logic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs treatment. Material and methods The analysis included 108 RA patients with active disease treated with MTX 25 mg per week. Eighty patients (group I) were treated with bDMARDs and 28 patients (group II) with JAK-STAT inhibitors. The duration of morning stiffness, pain on Visual Analogue Scale (VAS), 28-joints Disease Activity Score (DAS28) and Simplified Disease Activity Score (SDAI) were assessed. Classical radiographic images of patients' hands and feet using the Larsen and Dale's criteria were evaluated. The effects of treatment with bDMARDs and tsDMARDs were analyzed. Results All studied patients presented at least Larsen and Dale's stage 3 of X-ray changes typical for RA. There were no statistically significant differences in disease duration, ESR, CRP, DAS28 and SDAI values between studied groups. Patients from group II previously used higher numbers of bDMARDs than group I treated with bDMARDs. Low disease activity after treatment was achieved by all patients; therefore patients from group II (treated with tsDMARDs) achieved lower values of patients' global assessment on VAS. Conclusions The results of the present observational study indicated that treatment with JAK inhibitors is very promising. These drugs are not inferior in effectiveness to bDMARDs. It is important to monitor patients for thromboembolic events before and during JAK treatment.
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Affiliation(s)
- Małgorzata Wisłowska
- Central Clinical Hospital of the Ministry of Interior and Administration in Warsaw, Poland
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22
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Tominaga A, Ikari K, Yano K, Tanaka E, Inoue E, Harigai M, Okazaki K. Surgical Intervention for Patients With Rheumatoid Arthritis is Declining Except for Foot and Ankle Surgery: A Single-Center, 20-Year Observational Cohort Study. Mod Rheumatol 2022; 33:509-516. [PMID: 35536604 DOI: 10.1093/mr/roac042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/07/2022] [Accepted: 04/24/2022] [Indexed: 11/12/2022]
Abstract
OBJECTIVE A global downward trend in the number of rheumatoid arthritis (RA)-related surgeries has been reported. The purpose of our study was to investigate the latest trends in RA-related surgeries in a single-center Japanese RA cohort. METHODS This study was a retrospective analysis of RA-related surgeries between 2001 and 2020 in the Institute of Rheumatology Rheumatoid Arthritis cohort. An average of 4,944 patients per semiannual survey was included in the study. The primary goal was to analyze the half-year period prevalence proportion (HPP) of RA-related surgeries in a 20-year period, and the secondary goal was to analyze the HPP of surgeries by site or by categories of disease activity. RESULTS There has been a downward trend in the HPP of RA-related surgeries in the 20-year study period. The total HPP of RA-related surgeries decreased by 50.3% during the 20-year study period. There was a significant decrease in knee, hip, shoulder/elbow, and hand procedures. Only foot/ankle joint surgeries significantly increased in volume during this period (p=0.001). The HPP of RA-related surgeries remained unchanged in patients with remission or low disease activity. CONCLUSION The number of RA-related surgeries decreased over a 20-year period, but foot/ankle joint surgeries increased in the site-specific evaluation.
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Affiliation(s)
- Ayako Tominaga
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsunori Ikari
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.,Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan.,Division of Multidisciplinary Management of Rheumatic Diseases, Tokyo Women's Medical University, Tokyo, Japan
| | - Koichiro Yano
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.,Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Eiichi Tanaka
- Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan.,Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Eisuke Inoue
- Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan.,Showa University Research Administration Center, Showa University, Tokyo, Japan
| | - Masayoshi Harigai
- Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan.,Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Ken Okazaki
- Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
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23
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Hasegawa T, Ishii M. Pathological Osteoclasts and Precursor Macrophages in Inflammatory Arthritis. Front Immunol 2022; 13:867368. [PMID: 35464401 PMCID: PMC9024112 DOI: 10.3389/fimmu.2022.867368] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023] Open
Abstract
Macrophages comprise a variety of subsets with diverse biological functions, including inflammation, tissue repair, regeneration, and fibrosis. In the bone marrow, macrophages differentiate into multinucleated osteoclasts, which have a unique bone-destroying capacity and play key roles in physiological bone remodelling. In contrast, osteoclasts are also involved in inflammatory bone erosion in arthritis and it has been unclear whether the osteoclasts in different tissue settings arise from similar monocytoid precursors and share similar phenotypes. Rapid progresses in the sequencing technologies have provided many important insights regarding the heterogeneity of different types of osteoclasts. The application of single-cell RNA sequencing (scRNA-seq) to the osteoclast precursor-containing macrophages enabled to identify the specific subpopulation differentiating into pathological mature osteoclasts in joints. Furthermore, an intravital imaging technology using two-photon microscopy has succeeded in visualizing the real-time dynamics of immune cells in the synovial microenvironment. These technologies together contributed to characterize the unique macrophages in the inflamed synovium, termed “arthritis-associated osteoclastogenic macrophages (AtoMs)”, causing the pathological bone destruction in inflammatory arthritis. Here, we review and discuss how novel technologies help to better understand the role of macrophages in inflammatory arthritis, especially focusing of osteoclastogenesis at the pannus-bone interface.
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Affiliation(s)
- Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan
- World Premier International Research Center Initiative (WPI)-Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- *Correspondence: Masaru Ishii,
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Huang W, Li X, Huang C, Tang Y, Zhou Q, Chen W. LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation. Front Immunol 2022; 12:807738. [PMID: 35087527 PMCID: PMC8786719 DOI: 10.3389/fimmu.2021.807738] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.
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Affiliation(s)
- Wentao Huang
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Xue Li
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Chen Huang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central, Hospital, Guangzhou, China
| | - Yukuan Tang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central, Hospital, Guangzhou, China
| | - Quan Zhou
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Wenli Chen
- Ministry of Education (MOE) Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.,Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
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25
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Lopez-Romero P, de la Torre I, Haladyj E, Aletaha D, Smolen JS. Baricitinib further enhances disease-modifying effects by uncoupling the link between disease activity and joint structural progression in patients with rheumatoid arthritis. Ann Rheum Dis 2022; 81:622-631. [PMID: 35193872 PMCID: PMC8995831 DOI: 10.1136/annrheumdis-2021-221323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 02/01/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVES To evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials. METHODS In RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN). RESULTS For MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p<0.001). For csDMARD-naïve patients, progression was lower in REM/LDA versus MDA/HDA within the MTX group (p<0.001). However, for baricitinib+MTX (p=0.5) or baricitinib monotherapy (p=0.07), progression was similar regardless of disease activity. In MDA/HDA groups, progression was lower with baricitinib+MTX (p<0.001) and numerically lower with baricitinib monotherapy (p=0.07) versus MTX. C reactive protein (≤5 mg/L and >5 mg/L) sensitivity analyses supported the primary findings. CONCLUSIONS Baricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states.
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Affiliation(s)
| | | | - Ewa Haladyj
- Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Daniel Aletaha
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Josef S Smolen
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
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26
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Platzer A, Alasti F, Smolen JS, Aletaha D, Radner H, Blüml S. Trajectory clusters of radiographic progression in patients with rheumatoid arthritis: associations with clinical variables. Ann Rheum Dis 2022; 81:175-183. [PMID: 34376384 DOI: 10.1136/annrheumdis-2021-220331] [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: 03/10/2021] [Accepted: 07/29/2021] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Identification of trajectories of radiographic damage in rheumatoid arthritis (RA) by clustering patients according to the shape of their curve of Sharp-van der Heijde scores (SHSs) over time. Developing models to predict their progression cluster from baseline characteristics. METHODS Patient-level data over a 2-year period from five large randomised controlled trials on tumour necrosis factor inhibitors in RA were used. SHSs were clustered in a shape-respecting manner to identify distinct clusters of radiographic progression. Characteristics of patients within different progression clusters were compared at baseline and over time. Logistic regression models were developed to predict trajectory of radiographic progression using information at baseline. RESULTS In total, 1887 patients with 7738 X-rays were used for cluster analyses. We identified four distinct clusters with characteristic shapes of radiographic progression: one with a stable SHS over the whole 2-year period (C0/lowChange; 86%); one with relentless progression (C1/rise; 5.8%); one with decreasing SHS (C2/improvement; 6.9%); one going up and down (C3/bothWays; 1.4%) of the SHS. Robustness of clusters were confirmed using different clustering methods. Regression models identified disease duration, baseline C-reactive protein (CRP) and SHS and treatment status as predictors for cluster assignment. CONCLUSIONS We were able to identify and partly characterise four different clusters of radiographic progression over time in patients with RA, most remarkably one with relentless progression and another one with amelioration of joint damage over time, suggesting the existence of distinct patterns of joint damage accrual in RA.
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Affiliation(s)
- Alexander Platzer
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
| | - Farideh Alasti
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
| | - Josef S Smolen
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
| | - Daniel Aletaha
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
| | - Helga Radner
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
| | - Stephan Blüml
- Department of Rheumatology, Medical University of Vienna, Wien, Vienna, Austria
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27
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Ozaki Y, Nomura S. Treatment of Connective Tissue Disease-Related Intractable Disease with Biological Therapeutics. Open Access Rheumatol 2021; 13:293-303. [PMID: 34611450 PMCID: PMC8487282 DOI: 10.2147/oarrr.s328211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
Abstract
The treatment of connective tissue disease (CTD) and CTD-related intractable diseases (CTD-IDs) currently depends on the use of steroid therapy. Approximately 20 years have passed since the approval of infliximab for rheumatoid arthritis in 2003. Since then, several biological therapeutics have been marketed and adapted for many CTDs and CTD-IDs other than rheumatoid arthritis. Although conventional treatment for patients with these diseases is rarely used because of their poor prognosis, these cases may benefit from biological therapeutics. However, choosing biological therapeutics is difficult because they have different target molecules compared with conventional therapeutics. In this review, we address the current situation of biological therapeutics for CTD-IDs including Behcet's disease, psoriatic arthritis, ankylosing spondylitis, anti-neutrophil cytoplasmic antibody-related arthritis, and adult Still's disease, as well as the choice of biological therapeutics in clinical practice.
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Affiliation(s)
- Yoshio Ozaki
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
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28
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Hasegawa T, Kikuta J, Ishii M. Imaging of bone and joints in vivo: pathological osteoclastogenesis in arthritis. Int Immunol 2021; 33:679-686. [PMID: 34324641 DOI: 10.1093/intimm/dxab047] [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: 05/15/2021] [Accepted: 07/28/2021] [Indexed: 11/12/2022] Open
Abstract
Osteoimmunology highlights the reciprocal interactions between the skeletal and immune systems. Over the past two decades, many molecules that link the two have been identified, including cytokines, receptors and transcription factors, leading to successful translation of research into therapeutic approaches to autoimmune diseases such as rheumatoid arthritis. The development of an intravital imaging system using multi-photon microscopy, combined with a variety of fluorescent probes and reporter mouse strains, has provided valuable insights into the real-time dynamics of osteoclasts and immune cells in the bone marrow. This technique is now applied to the synovial tissue of arthritic mice to investigate the pathogenesis of osteoimmune diseases and enables direct observation of complex biological phenomena in vivo. In addition, rapid progress in the next-generation sequencing technologies has provided important insights into the field of osteoimmunology through characterizing individual cells in the synovial microenvironment. Single-cell RNA sequencing (scRNA-seq) dissects cellular heterogeneity within a biological system and enables the identification of specific cells differentiating into mature osteoclasts within the previously defined "osteoclast precursor (OP)-containing population". In this review, we will explain the cellular interactions and cytokine milieu involved in inflammatory bone destruction and update how the novel technologies, such as scRNA-seq and intravital imaging, have contributed to better understand the pathogenesis of bone destruction in arthritis.
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Affiliation(s)
- Tetsuo Hasegawa
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Yamada-oka, Suita, Osaka, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka, Japan.,Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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29
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Gaudiani MA, Winkelman RD, Ravishankar P, Rabah NM, Mroz TE, Coughlin DJ. The association of preoperative TNF-alpha inhibitor use and reoperation rates in spinal fusion surgery. Spine J 2021; 21:972-979. [PMID: 33545374 DOI: 10.1016/j.spinee.2021.01.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/07/2021] [Accepted: 01/28/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Preoperative TNF-AI use has been associated with increased rate of postoperative infections and complications in a variety of orthopedic procedures. However, the association between TNF-AI use and complications following spine surgery has not yet been studied. PURPOSE The purpose of the present study was to assess the risk of reoperation in patients prescribed TNF-AI undergoing spinal fusion surgery. STUDY DESIGN This is a retrospective review. PATIENT SAMPLE A total of 427 patients who underwent spinal fusion surgery at a large healthcare system from 1/1/2009 to 12/31/2018. OUTCOME MEASURE Reoperation within 1 year. METHODS We retrospectively reviewed the records of patients who underwent spinal fusion surgery at a large healthcare system from 1/1/2009 to 12/31/2018. There were three distinct cohorts of spine surgery patients under study: patients with TNF-AI use in 90 days before surgery, patients with non-TNF-AI DMARD medications use in the 90 days before surgery, and patients taking neither TNF-AI nor other DMARD medications in 90 days before surgery. The primary outcome of interest was reoperation for any reason within 1 year following surgery. RESULTS Our study included 90 TNF-AI, 90 DMARD, and 123 control patients. Reoperation up to 1-year postsurgery occurred in 19% (n=17) of the TNF-AI group, 11% (n=10) of the DMARD group, and 6% (n=7) of the control group. The reasons for reoperation for TNF-AI group were 47% (n=8) infection and 53% (n=9) other causes which included failure to fuse and adjacent segment disease. Reasons for reoperation at 1 year were 40% (n=4) infection and 60% (n=6) other causes for DMARD patients and 14% (n=1) infection with 86% (n=6) other causes for control patients. The cox-proportional hazard model of reoperation within 1 year indicated that the odds of reoperation were 3.1 (95% CI:1.4-7.0) and 2.2 (95% CI 0.96-5.3) times higher in the TNF-AI and DMARD groups, respectively, compared to the control group. CONCLUSIONS Patients taking TNF-AIs before surgery were found to have a significantly higher rate of reoperation in the 1 year following surgery compared to controls. The higher rate of reoperation associated with TNF-AI use before spinal fusion surgery represents the potential for higher morbidity and costs for patient which is important to consider for both surgeon and patient in preoperative decision making.
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Affiliation(s)
- Michael A Gaudiani
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Robert D Winkelman
- Center for Spine Health, Cleveland Clinic, Desk S40, 9500 Euclid Ave, Cleveland, OH 44195, USA
| | - Pavitra Ravishankar
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Nicholas M Rabah
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Thomas E Mroz
- Center for Spine Health, Cleveland Clinic, Desk S40, 9500 Euclid Ave, Cleveland, OH 44195, USA.
| | - Daniel J Coughlin
- Center for Spine Health, Cleveland Clinic, Desk S40, 9500 Euclid Ave, Cleveland, OH 44195, USA
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30
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Yokota K, Sato K, Miyazaki T, Aizaki Y, Tanaka S, Sekikawa M, Kozu N, Kadono Y, Oda H, Mimura T. Characterization and Function of Tumor Necrosis Factor and Interleukin-6-Induced Osteoclasts in Rheumatoid Arthritis. Arthritis Rheumatol 2021; 73:1145-1154. [PMID: 33512089 PMCID: PMC8361923 DOI: 10.1002/art.41666] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 01/21/2021] [Indexed: 12/18/2022]
Abstract
Objective We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. Methods Peripheral blood monocytes were cultured with a combination of TNF and IL‐6, TNF alone, IL‐6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL‐6–induced osteoclasts or RANKL‐induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole‐body bone mineral density (BMD) was examined. Results Peripheral blood monocytes stimulated with a TNF and IL‐6–induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL‐6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL‐6–induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL‐6–induced osteoclasts, but not in RANKL‐induced osteoclasts. The number of TNF and IL‐6–induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL‐induced osteoclast numbers negatively correlated with the whole‐body BMD of the same patients. Conclusion Our results demonstrate that TNF and IL‐6–induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.
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Affiliation(s)
- Kazuhiro Yokota
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama Medical University, Saitama, Japan
| | - Kojiro Sato
- Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | | | - Yoshimi Aizaki
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama Medical University, Saitama, Japan
| | - Shinya Tanaka
- Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan
| | - Miyoko Sekikawa
- Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan
| | | | - Yuho Kadono
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama Medical University, Saitama, Japan
| | - Hiromi Oda
- Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan
| | - Toshihide Mimura
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama Medical University, Saitama, Japan
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31
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Smolen JS, Choe JY, Weinblatt ME, Emery P, Keystone E, Genovese MC, Myung G, Hong E, Baek I, Ghil J. Pooled analysis of TNF inhibitor biosimilar studies comparing radiographic progression by disease activity states in rheumatoid arthritis. RMD Open 2021; 6:rmdopen-2019-001096. [PMID: 31958281 PMCID: PMC6999676 DOI: 10.1136/rmdopen-2019-001096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/24/2019] [Accepted: 12/26/2019] [Indexed: 12/18/2022] Open
Abstract
Objective To evaluate the relationship between disease activity and radiographic progression in rheumatoid arthritis, three phase III studies of SB4, SB2 and SB5 (biosimilars of etanercept, infliximab and adalimumab) were pooled to assess radiographic progression by disease activity status. Methods Patients from each study with radiographic data were pooled and grouped based on disease activity state (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)), determined by disease activity score based on 28-joint count (DAS28) per erythrocyte sedimentation rate, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at different time points. Mean change in modified Total Sharp Score (mTSS) and the proportion of radiographic non-progressors of higher disease activity groups (LDA, MDA and HDA) in reference to remission were summarised descriptively, with comparison of ORs using logistic models. Results 1265 patients were included. In all treatments combined, the 1 year mean change in mTSS was 0.03, 0.4, 0.3 and 1.3 and proportion of radiographic non-progressors was 79.8%, 78.1%, 74.1% and 58.4% in the week 24/30 DAS28-determined remission, LDA, MDA and HDA groups, respectively. ORs (95% CIs) of the proportion of non-progressors were lowest in the HDA group in reference to remission (0.35 (0.23 to 0.54)), followed by MDA (0.72 (0.50 to 1.05)) and LDA (0.90 (0.55 to 1.48)) groups. Similar trends were observed when disease activity was assessed using SDAI or CDAI. Conclusion A pooled analysis of radiographic assessment data from three biosimilar studies showed that radiographic progression is small overall but increases with worse disease activity. Trial registration numbers NCT01895309, NCT01936181 and NCT02167139
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Affiliation(s)
- Josef S Smolen
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Vienna, Austria
| | - Jung-Yoon Choe
- Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Michael E Weinblatt
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paul Emery
- University of Leeds, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK
| | - Edward Keystone
- Divison of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mark C Genovese
- Division of Immunology and Rheumatology, Stanford University Medical Center, Stanford, California, USA
| | - Gihyun Myung
- Samsung Bioepis Co Ltd, Incheon, Republic of Korea
| | - Evelyn Hong
- Samsung Bioepis Co Ltd, Incheon, Republic of Korea
| | - Inyoung Baek
- Samsung Bioepis Co Ltd, Incheon, Republic of Korea
| | - Jeehoon Ghil
- Samsung Bioepis Co Ltd, Incheon, Republic of Korea
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32
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Shu H, Zhao H, Shi Y, Lu C, Li L, Zhao N, Lu A, He X. Transcriptomics-based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen-induced arthritis. Chin Med 2021; 16:31. [PMID: 33845855 PMCID: PMC8042720 DOI: 10.1186/s13020-021-00439-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/14/2021] [Accepted: 03/25/2021] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied with joint destruction that often leads to disability. Wang-Bi capsule (WB), a traditional Chinese medicine-based herbs formula, has exhibited inhibition effect on joint destruction of collagen-induced arthritis (CIA) animal model in our previous study. But its molecular mechanisms are still obscure. METHODS CIA rats were treated intragastrical with WB for eight weeks, and the effect of joints protection were evaluated by hematoxylin and eosin (H&E) staining, safranin O fast green staining, tartrate-resistant acid phosphatase (TRAP) staining and micro‑CT scanning analysis. The transcriptomic of tarsal joints were used to investigate how WB alleviated joint destruction. RESULTS The histological examination of ankle joints showed WB alleviated both cartilage damage and bone destruction of CIA rats. This protective effect on joints were further evidenced by micro-CT analysis. The transcriptomic analysis showed that WB prominently changed 12 KEGG signaling pathways ("calcium signaling pathway", "cAMP signaling pathway", "cell adhesion molecules", "chemokine signaling pathway", "complement and coagulation cascades", "MAPK signaling pathway", "NF-kappa B signaling pathway", "osteoclast differentiation", "PI3K-Akt signaling pathway", "focal adhesion", "Gap junction" and "Rap1 signaling pathway") associated with bone or cartilage. Several genes (including Il6, Tnfsf11, Ffar2, Plg, Tnfrsf11b, Fgf4, Fpr1, Siglec1, Vegfd, Cldn1, Cxcl13, Chad, Arrb2, Fgf9, Egfr) regulating bone resorption, bone formation and cartilage development were identified by further analysis. Meanwhile, these differentially expressed genes were validated by real-time quantitative PCR. CONCLUSIONS Overall, the protective effect of WB treatment on joint were confirmed in CIA rats, and its basic molecular mechanisms may be associated with regulating some genes (including Il6, Tnfsf11, Ffar2 and Plg etc.) involved in bone resorption, bone formation and cartilage development.
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Affiliation(s)
- Haiyang Shu
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Hanxiao Zhao
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yingjie Shi
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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Ferreira RJO, Welsing PMJ, Jacobs JWG, Gossec L, Ndosi M, Machado PM, van der Heijde D, Da Silva JAP. Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients. Ann Rheum Dis 2021; 80:293-303. [PMID: 33023964 DOI: 10.1136/annrheumdis-2020-217171] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 08/29/2020] [Accepted: 09/03/2020] [Indexed: 01/01/2023]
Abstract
OBJECTIVES To determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA). METHODS Meta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0-10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire-Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared. RESULTS Individual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%). CONCLUSION 4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets.
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Affiliation(s)
- Ricardo J O Ferreira
- Rheumatology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
- Health Sciences Research Unit: Nursing (UICISA: E), Escola Superior de Enfermagem de Coimbra, Coimbra, Portugal
| | - Paco M J Welsing
- Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands
| | | | - Laure Gossec
- Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, Sorbonne Université, Paris, France
- Rheumatology, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Mwidimi Ndosi
- Faculty of Health and Applied Sciences, University of the West of England Bristol, Bristol, UK
| | - Pedro M Machado
- Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK
- Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK
- Rheumatology, Northwick Park Hospital, London North west UniversityHealthcare NHS Trust, London, UK
| | | | - Jose A P Da Silva
- Rheumatology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
- Clínica Universitária de Reumatologia, and i-CBR Coimbra Institute for Clinical and Biological Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Buch MH, Eyre S, McGonagle D. Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol 2020; 17:17-33. [PMID: 33293696 DOI: 10.1038/s41584-020-00541-7] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2020] [Indexed: 12/13/2022]
Abstract
Despite nearly three decades of advances in the management of rheumatoid arthritis (RA), a substantial minority of patients are exposed to multiple DMARDs without necessarily benefitting from them; a group of patients variously designated as having 'difficult to treat', 'treatment-resistant' or 'refractory' RA. This Review of refractory RA focuses on two types of patients: those for whom multiple targeted therapies lack efficacy and who have persistent inflammatory pathology, which we designate as persistent inflammatory refractory RA (PIRRA); and those with supposed refractory RA who have continued disease activity that is predominantly independent of objective evidence of inflammation, which we designate as non-inflammatory refractory RA (NIRRA). These two types of disease are not mutually exclusive, but identifying those individuals with predominant PIRRA or NIRRA is important, as it informs distinct treatment and management approaches. This Review outlines the clinical differences between PIRRA and NIRRA, the genetic and epigenetic mechanisms and immune pathways that might contribute to the immunopathogenesis of recalcitrant synovitis in PIRRA, and a possible basis for non-inflammatory symptomatology in NIRRA. Future approaches towards the definition of refractory RA and the application of single-cell and integrated omics technologies to the identification of refractory RA endotypes are also discussed.
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Affiliation(s)
- Maya H Buch
- Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK. .,NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University Foundation Trust, Manchester, UK. .,Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
| | - Stephen Eyre
- Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK.,NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University Foundation Trust, Manchester, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Rocha FAC, Pinto ACMD, Lopes JR, Deodhar A. Tumor necrosis factor inhibitors prevent structural damage in hips in ankylosing spondylitis-time to reconsider treatment guidelines? A case series and review of literature. Clin Rheumatol 2020; 40:1881-1887. [PMID: 33230684 DOI: 10.1007/s10067-020-05519-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 11/28/2022]
Abstract
Tumor necrosis factor inhibitors (TNFi) are indicated to treat ankylosing spondylitis (AS), also termed radiographic axial spondyloarthritis (axSpA). The main indication for TNFi is symptom relief, and whether they retard spinal structural damage as assessed by radiography is debated. Hips are the most common "non-spinal" joints involved in AS patients leading to major incapacitation. No major treatment guidelines mention measures to prevent peripheral joint damage, especially hips, in individuals with AS. We present our experience of prevention of structural damage in hips by TNFi in 4 AS patients from our practice. We conducted a literature review looking for articles describing prevention of structural damage progression in hips by TNFi. Over a 10-year period, three out of four patients were treated with TNFi and had no progression in hip damage as assessed by imaging. Only one patient that withdrew the TNFi due to infectious complications developed rapid worsening and required hip arthroplasty. Our literature review showed multiple case series with similar results suggesting that use of TNFi in patients with AS may prevent structural damage and at least postpone a hip replacement at a young age. Based on our experience, as well as from the literature review, we believe that treatment guidelines in axSpA should recommend prompt institution of TNFi following identification of hip involvement in patients to prevent a major source of disability. Whether interleukin (IL)-17 inhibitors or targeted synthetic anti-rheumatic drugs have hip sparing effects in patients with AS should also be investigated. Key Points • Hip involvement in ankylosing spondylitis is a major source of disability. • TNFi prevent hip damage in ankylosing spondylitis. • Prompt institution of TNFi should follow suspicion of hip involvement in ankylosing spondylitis.
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Affiliation(s)
- Francisco Airton Castro Rocha
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil. .,Instituto de Biomedicina - Laboratório de Investigação em Osteoartropatias, Rua Cel. Nunes de Melo, 1315 - 1°. Andar, Rodolfo Teófilo, Fortaleza, CE, 60430-270, Brazil.
| | | | | | - Atul Deodhar
- Oregon Health & Science University, Portland, OR, USA
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Hayashi S, Matsubara T, Fukuda K, Funahashi K, Hashimoto M, Maeda T, Kamenaga T, Takashima Y, Matsumoto T, Niikura T, Kuroda R. Predictive factors for effective selection of Interleukin-6 inhibitor and tumor necrosis factor inhibitor in the treatment of rheumatoid arthritis. Sci Rep 2020; 10:16645. [PMID: 33024253 PMCID: PMC7538428 DOI: 10.1038/s41598-020-73968-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 09/15/2020] [Indexed: 12/27/2022] Open
Abstract
Treatment of rheumatoid arthritis (RA) is aimed at long-term remission and inhibition of joint destruction by different biologic drugs. However, the choice of a particular biologic agent based on individual cases of RA remains unestablished. Interleukin-6 (IL-6) inhibitor and tumor necrosis factor (TNF) inhibitor are common biologics used for the treatment of RA. This study aimed to investigate predictive factors for effective selection of tocilizumab (IL-6 inhibitor) and etanercept (TNF inhibitor) in patients with RA. This is a retrospective cohort study. The 196 patients analyzed in this study were divided into four groups: tocilizumab treatment as the first biologic group (TCZ first, 42 patients), tocilizumab as second/ third biologic group (TCZ second, 34 patients), etanercept as the first biologic group (ETN first, 103 patients) and etanercept as second/third group (ETN second, 17 patients). Visual analog scale (VAS), clinical disease activity index (CDAI), and modified health assessment questionnaire (mHAQ) scores at the initiation of biologic treatment and after 6 months of tocilizumab and etanercept therapy were measured and compared to clinical parameters and radiographical parameters among the four groups. CRP, MMP-3, VAS, CDAI, and HAQ were improved after 6 months of treatment in all groups. Improvement of clinical outcomes was correlated with CRP value, duration of RA, and Sharp scores at the initiation of treatment. Multivariate analysis demonstrated improvement in CDAI was significantly associated with the yearly progression of erosion according to the Sharp score in TCZ first group (OR, 1.5; 95% CI, 1.03–2.07) and was negatively associated with the duration of RA (OR, 0.49; 95% CI, 0.29–0.86) at the initiation of treatment with ETN first group. We identified the predictive factors for effective selection of tocilizumab and etanercept treatment and established the effectiveness of tocilizumab for the patients with rapid progressive joint erosion and etanercept for the early administration from diagnosis of RA.
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Affiliation(s)
- Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Tsukasa Matsubara
- Department of Orthopaedic Surgery, Matsubara Mayflower Hospital, Kato, Japan
| | - Koji Fukuda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | | | | | - Toshihisa Maeda
- Department of Orthopaedic Surgery, Matsubara Mayflower Hospital, Kato, Japan
| | - Tomoyuki Kamenaga
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoshinori Takashima
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Möller B, Aletaha D, Andor M, Atkinson A, Aubry-Rozier B, Brulhart L, Dan D, Finckh A, Grobéty V, Mandl P, Micheroli R, Nissen MJ, Nydegger AM, Scherer A, Tamborrini G, Ziswiler HR, Zufferey P. Synovitis in rheumatoid arthritis detected by grey scale ultrasound predicts the development of erosions over the next three years. Rheumatology (Oxford) 2020; 59:1556-1565. [PMID: 31630207 PMCID: PMC7310093 DOI: 10.1093/rheumatology/kez460] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/30/2019] [Indexed: 01/20/2023] Open
Abstract
Objectives To evaluate grey scale US (GSUS) and power Doppler US synovitis (PDUS), separately or in combination (CombUS), to predict joint damage progression in RA. Methods In this cohort study nested in the Swiss RA register, all patients with sequential hand radiographs at their first US assessment were included. We analysed the summations of semi-quantitative GSUS, PDUS and CombUS assessments of both wrists and 16 finger joints (maximum 54 points) at their upper limit of normal, their 50th, 75th or 87.5th percentiles for the progression of joint damage (ΔXray). We adjusted for clinical disease activity measures at baseline, the use of biological DMARDs and other confounders. Results After a median of 35 months, 69 of 250 patients with CombUS (28%), 73 of 259 patients with PDUS (28%) and 75 of 287 patients with available GSUS data (26%) demonstrated joint damage progression. PDUS beyond upper limit of normal (1/54), GSUS and CombUS each at their 50th (9/54 and 10/54) and their 75th percentiles (14/54 and 15/54) were significantly associated with ΔXray in crude and adjusted models. In subgroup analyses, GSUS beyond 14/54 and CombUS higher than 15/54 remained significantly associated with ΔXray in patients on biological DMARDs, while clinical disease activity measures had no significant prognostic power in this subgroup. Conclusion Higher levels of GSUS and CombUS are associated with the development of erosions. GSUS appears to be an essential component of synovitis assessment and an independent predictor of joint damage progression in patients on biological DMARDs.
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Affiliation(s)
- Burkhard Möller
- Rheumatology, Immunology and Allergy, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Daniel Aletaha
- Medical Department III, Rheumatology, Medical University Vienna, Vienna, Austria
| | | | - Andrew Atkinson
- Rheumatology, Immunology and Allergy, Inselspital, University Hospital of Bern, Bern, Switzerland.,SCQM statistics group, Zurich
| | | | | | - Diana Dan
- Rheumatology, Lausanne University Hospital, Lausanne
| | - Axel Finckh
- Rheumatology, University Hospitals of Geneva, Geneva
| | | | - Peter Mandl
- Medical Department III, Rheumatology, Medical University Vienna, Vienna, Austria
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Rheumatoid arthritis patients on persistent moderate disease activity on biologics have adverse 5-year outcome compared to persistent low-remission status and represent a heterogeneous group. Arthritis Res Ther 2020; 22:226. [PMID: 32993800 PMCID: PMC7523072 DOI: 10.1186/s13075-020-02313-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background The long-term outcome of rheumatoid arthritis (RA) patients who in clinical practice exhibit persistent moderate disease activity (pMDA) despite treatment with biologics has not been adequately studied. Herein, we analyzed the 5-year outcome of the pMDA group and assessed for within-group heterogeneity. Methods We included longitudinally monitored RA patients from the Hellenic Registry of Biologic Therapies with persistent (cumulative time ≥ 50% of a 5-year period) moderate (pMDA, 3.2 < DAS28 ≤ 5.1) or remission/low (pRLDA, DAS28 ≤ 3.2) disease activity. The former was further classified into persistent lower-moderate (plMDA, DAS28 < 4.2) and higher-moderate (phMDA, DAS28 ≥ 4.2) subgroups. Five-year trajectories of functionality (HAQ) were the primary outcome in comparing pRLDA versus pMDA and assessing heterogeneity within the pMDA subgroups through multivariable mixed-effect regression. We further compared serious adverse events (SAEs) occurrence between the two groups. Results We identified 295 patients with pMDA and 90 patients with pRLDA, the former group comprising of plMDA (n = 133, 45%) and phMDA (n = 162, 55%). pMDA was associated with worse 5-year functionality trajectory than pRLDA (+ 0.27 HAQ units, CI 95% + 0.22 to + 0.33; p < 0.0001), while the phMDA subgroup had worse 5-year functionality than plMDA (+ 0.26 HAQ units, CI 95% 0.18 to 0.36; p < 0.0001). Importantly, higher persistent disease activity was associated with more SAEs [pRLDA: 0.2 ± 0.48 vs pMDA: 0.5 ± 0.96, p = 0.006; plMDA: 0.32 ± 0.6 vs phMDA: 0.64 ± 1.16, p = 0.038]. Male gender (p = 0.017), lower baseline DAS28 (p < 0.001), HAQ improvement > 0.22 (p = 0.029), and lower average DAS28 during the first trimester since treatment initiation (p = 0.001) independently predicted grouping into pRLDA. Conclusions In clinical practice, RA patients with pMDA while on bDMARDs have adverse long-term outcomes compared to lower disease activity status, while heterogeneity exists within the pMDA group in terms of 5-year functionality and SAEs. Targeted studies to better characterize pMDA subgroups are needed, in order to assist clinicians in tailoring treatments.
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Liu Y, Qi G, Bellanti JA, Moser R, Ryffel B, Zheng SG. Regulatory T cells: A potential weapon to combat COVID-19? MedComm (Beijing) 2020; 1:157-164. [PMID: 32838397 PMCID: PMC7436572 DOI: 10.1002/mco2.12] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Since the end of December 2019, a novel coronavirus SARS-CoV-2 began to spread, an infection disease termed COVID-19. The virus has spread throughout the world in a short period of time, resulting in a pandemic. The number of reported cases in global reached 5 695 596 including 352 460 deaths, as of May 27, 2020. Due to the lack of effective treatment options for COVID-19, various strategies are being tested. Recently, pathologic studies conducted by two teams in China revealed immunopathologic abnormalities in lung tissue. These results have implications for immunotherapy that could offer a novel therapy strategy for combating lethal viral pneumonia. This review discusses the clinical and pathological features of COVID-19, the roles of immune cells in pathological processes, and the possible avenues for induction of immunosuppressive T regulatory cells attenuating lung inflammation due to viral infection. It is our hope that these proposals may both be helpful in understanding the novel features of SARS-CoV-2 pneumonia as well as providing new immunological strategies for treating the severe sequelae of disease manifestations seen in people infected with SARS-CoV-2.
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Affiliation(s)
- Yu Liu
- Department of Clinical ImmunologySun Yat‐sen University Third Affiliated HospitalGuangzhouP. R. China
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental RegulationGuilin Medical UniversityGuilinP. R. China
| | - Guangying Qi
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental RegulationGuilin Medical UniversityGuilinP. R. China
| | - Joseph A. Bellanti
- Department of Pediatrics and Microbiology‐ImmunologyGeorgetown University Medical CenterWashingtonDistrict of Columbia
| | - René Moser
- Institute for Biopharmaceutical ResearchMatzingenSwitzerland
| | - Bernhard Ryffel
- Experimental and Molecular Immunology and Neurogenetics (INEM)UMR 7355 INEMCNRS‐University of OrleansOrleansFrance
| | - Song Guo Zheng
- Department of Internal MedicineOhio State University College of Medicine and Wexner Medical Center, Medical CenterColumbusOhio
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Smolen JS, Kang YM, Yoo WH, Emery P, Weinblatt ME, Keystone EC, Genovese MC, Myung G, Baek I, Ghil J. Radiographic progression based on baseline characteristics from TNF inhibitor biosimilar studies in patients with rheumatoid arthritis. Arthritis Res Ther 2020; 22:188. [PMID: 32795341 PMCID: PMC7427775 DOI: 10.1186/s13075-020-02267-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
Objective Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction. Methods Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson’s correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression. Results A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson’s correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001). Conclusions In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach. Clinical trial registration numbers EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results
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Affiliation(s)
- Josef S Smolen
- Division of Rheumatology, Department of Medicine, Medical University of Vienna, Waehinger Guertel 18-20, A-1090, Vienna, Austria.
| | - Young Mo Kang
- Division of Rheumatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Wan-Hee Yoo
- Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Hospital, Jeonju, Republic of Korea
| | - Paul Emery
- University of Leeds, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK
| | - Michael E Weinblatt
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Edward C Keystone
- Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mark C Genovese
- Division of Immunology and Rheumatology, Stanford University Medical Center, Stanford, CA, USA
| | - Gihyun Myung
- Samsung Bioepis Co., Ltd., Incheon, Republic of Korea
| | - Inyoung Baek
- Samsung Bioepis Co., Ltd., Incheon, Republic of Korea
| | - Jeehoon Ghil
- Samsung Bioepis Co., Ltd., Incheon, Republic of Korea
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Vaidya J, Shende P. Potential of Sonophoresis as a Skin Penetration Technique in the Treatment of Rheumatoid Arthritis with Transdermal Patch. AAPS PharmSciTech 2020; 21:180. [PMID: 32601758 DOI: 10.1208/s12249-020-01725-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 06/02/2020] [Indexed: 01/17/2023] Open
Abstract
Rheumatoid arthritis, a chronic disorder, limits the use of chemical penetration enhancers for a prolonged period of time. Moreover, systemic routes of administration of the first-line drug, methotrexate, have shown undesirable systemic as well as local side effects. The objective of this research was to overcome the limitations associated with treatment of rheumatoid arthritis by utilizing three physical transdermal penetration enhancement techniques namely cold-laser, electroporation, and sonophoresis to deliver methotrexate. Methotrexate patch was prepared using solvent casting method and the ex-vivo release of methotrexate in combination with three physical penetration enhancers (sonophoresis, electroporation, and cold laser) were studied. The best technique was employed in pre-clinical testing in arthritic and control groups of male Wistar rats excluding remaining two techniques. The comparative ex-vivo studies showed that the penetration enhancement of methotrexate is maximum by sonophoresis followed by electroporation and cold laser (sonophoresis > electroporation > cold laser). In pharmacodynamic studies, the reduction in diameter of injected and non-injected paw on day 5 and day 21 for group 4 (ultrasound pre-treated group) was higher as compared to group 3 (group receiving only methotrexate patch). The motility score and the reduction in pain were significantly improved for group 4 than group 3 on both day 5 and day 21 (P ˂ 0.05) which confirmed the faster recovery of animals of group 4 due to penetration enhancement of methotrexate patch by ultrasound treatment. From the results, it can be concluded that sonophoresis along with methotrexate patch has shown a significant effect in the treatment of rheumatoid arthritis.
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A Three Year Retrospective Analysis Of Anti-Tnf Treatment Outcomes In Rheumatoid Arthritis And Ankylosing Spondylitis Patients. JOURNAL OF CONTEMPORARY MEDICINE 2020. [DOI: 10.16899/jcm.645326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Song YJ, Choi IA, Meylan F, Demoruelle MK, Farley T, Richard AC, Hawley E, Botson J, Hong YJ, Lee EY, Mian SR, Hamilton BC, Thiele GM, Mikuls TR, Gara N, Ward CD, Lamberth S, Deane KD, Heller T, Ward MM, Lee DM, Migone TS, Stohl W, O'Dell JR, Norris JM, Holers VM, Gregersen P, Song YW, Siegel RM. Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF. Arthritis Res Ther 2020; 22:106. [PMID: 32381123 PMCID: PMC7204024 DOI: 10.1186/s13075-020-02198-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 04/23/2020] [Indexed: 02/08/2023] Open
Abstract
Background The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. Methods We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. Results Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. Conclusions TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.
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Affiliation(s)
- Yun-Jeong Song
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - In Ah Choi
- Division of Rheumatology, Department of Internal Medicine, MMBS, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Françoise Meylan
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - M Kristen Demoruelle
- Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 80207, USA
| | - Taylor Farley
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - Arianne C Richard
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - Eric Hawley
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - John Botson
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
| | - Yoo Jin Hong
- Division of Rheumatology, Department of Internal Medicine, MMBS, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, MMBS, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Sabina R Mian
- Division of Rheumatology, Department of Medicine, Los Angeles County University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Bartlett C Hamilton
- Rheumatology Division, Department of Medicine, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Geoffrey M Thiele
- Rheumatology Division, Department of Medicine, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Ted R Mikuls
- Rheumatology Division, Department of Medicine, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Naveen Gara
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | | | - Sarah Lamberth
- Immunology Biomarkers group, Pharmaceutical Companies of J&J, LLC, Spring House, PA, USA
| | - Kevin D Deane
- Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 80207, USA
| | - Theo Heller
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Michael M Ward
- Clinical Trials and Outcomes Branch, NIAMS, NIH, Bethesda, MD, USA
| | - David M Lee
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Present address: Janssen Research and Development, Spring House, PA, USA
| | | | - William Stohl
- Division of Rheumatology, Department of Medicine, Los Angeles County University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - James R O'Dell
- Rheumatology Division, Department of Medicine, University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | | | - V Michael Holers
- Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 80207, USA
| | - Peter Gregersen
- Center for Genomics & Human Genetics, The Feinstein Institute for Medical Research, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA
| | - Yeong-Wook Song
- Division of Rheumatology, Department of Internal Medicine, MMBS, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Richard M Siegel
- Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA.
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Nakabo S, Tsuji Y, Inagaki M, Tsuji H, Nakajima T, Murakami K, Terao C, Hashimoto M, Furu M, Tanaka M, Ito H, Fujii T, Mimori T, Fujii Y. Severe joint deformity and patient global assessment of disease are associated with discrepancies between sonographic and clinical remission: A cross-sectional study of rheumatoid arthritis patients. Mod Rheumatol 2020; 31:334-342. [PMID: 32243209 DOI: 10.1080/14397595.2020.1751922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Although recent clinical trials showed that ultrasound (US) remission is not required to achieve good outcomes at the group level, it currently remains unclear whether the prognosis of individual patients in clinical remission, but not US remission, i.e. those with subclinical sonographic synovitis (SSS), is favorable. However, it is no longer acceptable to perform US on all patients in order to identify those with SSS. Therefore, the present study was initiated to elucidate the conditions under which SSS is frequently detected. METHODS In total, 563 consecutive RA patients were recruited. Bilateral 2-5 MCP, wrist, ankle, and 2-5 MTP joints were scanned by US, and Gray scale and Power Doppler (PD) images were scored semi-quantitatively. Clinical data were obtained by physicians who were blind to US results. Changes in the modified Total Sharp Score (mTSS) of tocilizumab (TCZ) users were calculated. RESULTS A total of 402 patients were included. SSS was more frequently detected in patients with more severe joint deformity, even if they were in remission. In contrast, a high Patient Global Assessment of Disease (PtGA) did not reflect SSS. Furthermore, the relationship between PtGA and PD scores was weak. Although the frequency of SSS was high in TCZ user, the presence of SSS in TCZ users not always results in the progression of mTSS. CONCLUSIONS While remission is overestimated in patients with severe joint deformity, underestimations may occur in those who do not fulfill remission criteria because of a high PtGA.
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Affiliation(s)
- Shuichiro Nakabo
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuko Tsuji
- Department of Human Health Sciences, Clinical Ultrasound Laboratory, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Maiko Inagaki
- Department of Human Health Sciences, Clinical Ultrasound Laboratory, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideaki Tsuji
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshiki Nakajima
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosaku Murakami
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.,Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.,The Department of Applied Genetics, the School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Motomu Hashimoto
- Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Moritoshi Furu
- Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masao Tanaka
- Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiromu Ito
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takao Fujii
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Wakayama, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Ijinkai Takeda General Hospital, Kyoto, Japan
| | - Yasutomo Fujii
- Department of Human Health Sciences, Clinical Ultrasound Laboratory, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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45
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Mease P, Husni ME, Kafka S, Chakravarty SD, Harrison DD, Lo KH, Xu S, Hsia EC, Kavanaugh A. Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial. Arthritis Res Ther 2020; 22:43. [PMID: 32143685 PMCID: PMC7059340 DOI: 10.1186/s13075-020-2126-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 02/06/2020] [Indexed: 11/10/2022] Open
Abstract
Background In the GO-VIBRANT trial of intravenous golimumab in psoriatic arthritis (PsA), golimumab significantly inhibited radiographic progression. In post hoc analyses, we evaluated changes in total PsA-modified Sharp/van der Heijde scores (SHS) across levels of composite index-defined disease activity following treatment. Methods In this phase-3, double-blind, placebo-controlled trial, 480 bio-naïve patients with active PsA randomly received intravenous golimumab 2 mg/kg (N = 241; week 0, week 4, every 8 weeks [q8w]) or placebo (N = 239; week 0, week 4, week 12, week 20) followed by golimumab (week 24, week 28, q8w) through week 52. Week 24 and week 52 SHS changes in patient subgroups, defined by levels of disease activity as assessed by several composite measures (minimal disease activity [MDA], very low disease activity [VLDA], Psoriatic ArthritiS Disease Activity Score [PASDAS], Disease Activity in Psoriatic Arthritis [DAPsA], Clinical Disease Activity Index [CDAI]), were evaluated post hoc in 474 patients with evaluable radiographic data. Partially (last-observation-carried-forward methodology) and completely (nonresponder methodology) missing data were imputed. Results Across indices, golimumab-treated patients demonstrated less radiographic progression than placebo-treated patients, regardless of disease activity state achieved via golimumab, from week 0 to 24 (e.g., mean changes in PsA-modified SHS were − 0.83 vs. 0.91, respectively, in patients achieving MDA and − 0.05 vs. 1.49, respectively, in those not achieving MDA). Treatment differences observed at week 24 persisted through week 52, despite placebo-randomized patients crossing over to golimumab at week 24 (e.g., mean changes in PsA-modified SHS from week 0 to 52 for golimumab- vs. placebo→golimumab-treated patients achieving MDA were − 1.16 vs. 1.19, respectively) and regardless of whether low disease activity was achieved (0.03 vs. 1.50, respectively, in those not achieving MDA). Consistent patterns were observed for disease activity assessed using VLDA, PASDAS, DAPsA, and CDAI composite endpoints. Conclusions The extent of structural damage inhibition afforded by up to 1 year of intravenous golimumab treatment paralleled levels of PsA activity, with greater progression of structural damage observed in patients with sustained higher disease activity. Among patients not achieving low levels of disease activity across several composite indices, golimumab-randomized patients appeared to exhibit far less progression of structural damage than placebo-randomized PsA patients, illustrating a potential disconnect between responses, wherein golimumab can inhibit structural damage independent of clinical effect. Trial registration ClinicalTrials.gov. NCT02181673. Registered 04 July 2014.
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Affiliation(s)
- Philip Mease
- Seattle Rheumatology Associates, Swedish Medical Center/Providence St. Joseph Health and University of Washington School of Medicine, 601 Broadway, Suite 600, Seattle, WA, 98122, USA.
| | | | - Shelly Kafka
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Soumya D Chakravarty
- Janssen Scientific Affairs, LLC, Horsham, PA, USA.,Drexel University College of Medicine, Philadelphia, PA, USA
| | | | - Kim Hung Lo
- Janssen Research & Development, LLC, Spring House, PA, USA
| | - Stephen Xu
- Janssen Research & Development, LLC, Spring House, PA, USA
| | - Elizabeth C Hsia
- Janssen Research & Development, LLC, Spring House, PA, USA.,University of Pennsylvania, Philadelphia, PA, USA
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Landewé R, Ritchlin CT, Aletaha D, Zhang Y, Ganz F, Hojnik M, Coates LC. Inhibition of radiographic progression in psoriatic arthritis by adalimumab independent of the control of clinical disease activity. Rheumatology (Oxford) 2020; 58:1025-1033. [PMID: 30608620 PMCID: PMC6532443 DOI: 10.1093/rheumatology/key417] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/03/2018] [Indexed: 12/15/2022] Open
Abstract
Objectives To evaluate the relationship between radiographic progression and disease activity in subjects with PsA treated with adalimumab (ADA) or placebo (PBO) and the impact of concomitant MTX. Methods This was a post hoc analysis of the randomized, double-blind, PBO-controlled ADEPT trial. Subjects were categorized according to time-averaged (TA) disease activity (remission, low, moderate or high) based on Disease Activity Score of 28 joints with CRP [DAS28(CRP)], Disease Activity Index for Psoriatic Arthritis (DAPSA) or Psoriatic Arthritis Disease Activity Score (PASDAS), and achievement of minimal disease activity (MDA) at week 24. Radiographic progression was assessed as change in modified total Sharp score (ΔmTSS) from baseline to week 24. The analyses included interaction terms between disease activity and treatment on radiographic progression, comparison of radiographic progression in subjects categorized by disease activity and treatment, and correlation between disease activity and radiographic progression by treatment. Results The interaction terms for TA disease activity and treatment on ΔmTSS were significant (P = 0.002–0.008). Irrespective of concomitant MTX, ΔmTSS was lower with ADA vs PBO in all disease activity categories. Importantly, even in subjects having moderate or high disease activity or not achieving MDA, ΔmTSS was significantly lower on ADA than PBO (P = 0.05–0.001 for TA-DAPSA, TA-PASDAS and MDA). Correlations between TA disease activity scores and ΔmTSS were moderately positive and significant (P < 0.001) with PBO but non-significant with ADA. Conclusion Among subjects with PsA treated with ADA, there was evidence of a ‘disconnect’ between disease activity and radiographic progression: inhibition of radiographic progression was greater than expected based on control of clinical disease activity alone. MTX had no added effect. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT00646386.
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Affiliation(s)
- Robert Landewé
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Centre, Amsterdam, The Netherlands
| | - Christopher T Ritchlin
- Allergy, Immunology & Rheumatology Division, University of Rochester Medical Center, Rochester, NY, USA
| | - Daniel Aletaha
- Division of Rheumatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | | | | | | | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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47
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Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. Impact of Cumulative Inflammation, Cardiac Risk Factors, and Medication Exposure on Coronary Atherosclerosis Progression in Rheumatoid Arthritis. Arthritis Rheumatol 2020; 72:400-408. [PMID: 31532064 DOI: 10.1002/art.41122] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 09/12/2019] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To explore incidence and progression of coronary atherosclerosis and identify determinants in patients with rheumatoid arthritis (RA). We specifically evaluated the impact of inflammation, cardiac risk factors, duration of medication exposure, and their interactions on coronary plaque progression. METHODS One hundred one participants with baseline coronary computed tomography angiography findings underwent follow-up assessment a mean ± SD of 83 ± 3.6 months after baseline. Plaque burden was reported as the segment involvement score (describing the number of coronary segments with plaque) and the segment stenosis score (characterizing the cumulative plaque stenosis over all evaluable segments). Plaque composition was classified as noncalcified, mixed, or calcified. Coronary artery calcium (CAC) was quantified using the Agatston method. RESULTS Total plaque increased in 48% of patients, and progression was predicted by older age, higher cumulative inflammation, and total prednisone dose (P < 0.05). CAC progressors were older, more obese, hypertensive, and had higher cumulative inflammation compared to nonprogressors (P < 0.05). Longer exposure to biologics was associated with lower likelihood of noncalcified plaque progression, lesion remodeling, and constrained CAC change in patients without baseline calcification, independent of inflammation, prednisone dose, or statin exposure (all P < 0.05). Longer statin treatment further restricted noncalcified plaque progression and attenuated the effect of inflammation on increased plaque and CAC (P < 0.05). Stringent systolic blood pressure (BP) control further weakened the effect of inflammation on total plaque progression. CONCLUSION Inflammation was a consistent and independent predictor of coronary atherosclerosis progression in RA. It should therefore be specifically targeted toward mitigating cardiovascular risk. Biologic disease-modifying antirheumatic drugs, statins, and BP control may further constrain plaque progression directly or indirectly.
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Ten Klooster PM, Versteeg LGA, Oude Voshaar MAH, de la Torre I, De Leonardis F, Fakhouri W, Zaremba-Pechmann L, van de Laar M. Radiographic progression can still occur in individual patients with low or moderate disease activity in the current treat-to-target paradigm: real-world data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Arthritis Res Ther 2019; 21:237. [PMID: 31718678 PMCID: PMC6852758 DOI: 10.1186/s13075-019-2030-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 10/09/2019] [Indexed: 11/26/2022] Open
Abstract
Background The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset < 1 year) treated according to treat-to-target (T2T) therapy. Methods Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined. Results A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson’s correlation coefficient r = 0.17, P < 0.05) and 3-year follow-up (r = 0.21, P < 0.05). Individual slopes of the relationship between DAS28-ESR and progression scores in each time interval were significantly correlated over time and the slope of the first 6 months was moderately associated with this slope at later time points (r between 0.39 and 0.59; P values < 0.001). Between 15.9 to 22.7% and 16.7 to 38.5% of patients with low and moderate time-integrated disease activity, respectively, experienced relevant (ΔSHS ≥ 3) radiographic progression at the different time intervals. Analyses using CRP showed similar results. Conclusions In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years. Trial registration Netherlands Trial Register NTR578, 12 January 2006.
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Affiliation(s)
- Peter M Ten Klooster
- Transparency in Healthcare, Hengelo, the Netherlands. .,Arthritis Centre Twente, University of Twente, Enschede, the Netherlands. .,Department of Psychology, Health & Technology, University of Twente, PO BOX 217, 7500 AE, Enschede, the Netherlands.
| | - Letty G A Versteeg
- Arthritis Centre Twente, University of Twente, Enschede, the Netherlands.,Arthritis Centre Twente, Medisch Spectrum Twente, Enschede, the Netherlands
| | - Martijn A H Oude Voshaar
- Transparency in Healthcare, Hengelo, the Netherlands.,Arthritis Centre Twente, University of Twente, Enschede, the Netherlands
| | | | | | | | | | - Mart van de Laar
- Transparency in Healthcare, Hengelo, the Netherlands.,Arthritis Centre Twente, University of Twente, Enschede, the Netherlands.,Arthritis Centre Twente, Medisch Spectrum Twente, Enschede, the Netherlands
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Finzel S, Kraus S, Figueiredo CP, Regensburger A, Kocijan R, Rech J, Schett G. Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis. Ann Rheum Dis 2019; 78:1186-1191. [PMID: 31142474 DOI: 10.1136/annrheumdis-2018-214894] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To compare the effects of interleukin-6 (IL-6) receptor and tumour necrosis factor inhibition on inducing repair of existing bone erosions in patients with very early rheumatoid arthritis (RA). METHODS Prospective non-randomised observational study in patients with active erosive RA with inadequate response to methotrexate (MTX) receiving either tocilizumab (TOC) monotherapy or adalimumab (ADA) with MTX for 52 weeks. Erosion volumes were assessed in metacarpal heads (MCH) and the radius by high-resolution peripheral quantitative CT at baseline and after 52 weeks. Clinical response was monitored using Clinical Disease Activity Index, Simple Disease Activity Index and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) scores every 12 weeks. RESULTS TOC (N=33) and ADA/MTX (N=33) treatment groups were balanced for age, sex, body mass index, comorbidities, disease and activity, functional state, autoantibody status, baseline bone damage and baseline bone biomarkers. Both TOC (DAS28-ESR: baseline: 6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6; 2.8±1.2) significantly reduced disease activity. Erosion volumes significantly decreased in the MCH and radius of patients with RA treated with TOC (p<0.001) but not in patients treated with ADA/MTX (p=0.77), where they remained stable in size. Mean decrease in erosion volume in TOC-treated patients was -1.0±1.1 mm3 and -3.3±5.9 mm3 in the MCH and radius of TOC-treated patients, respectively, and -0.05±0.9 mm3 and -0.08±4.1 mm3 in patients treated with ADA/MTX. CONCLUSIONS The REBONE study shows that TOC monotherapy achieves more pronounced repair of existing bone erosions than ADA/MTX. Hence, IL-6 is a central factor for the disturbed bone homeostasis in the joints of patients with RA.
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Affiliation(s)
- Stephanie Finzel
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
- Department of Rheumatology, University of Freiburg, Freiburg, Germany
| | - Sebastian Kraus
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
| | - Camille Pinto Figueiredo
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
- Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Adrian Regensburger
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
| | - Roland Kocijan
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
| | - Juergen Rech
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitaetsklinikum Erlangen, Erlangen, Germany
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50
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Rheumatoid arthritis disease activity and the risk of aseptic arthroplasty loosening. Semin Arthritis Rheum 2019; 50:245-251. [PMID: 31471012 DOI: 10.1016/j.semarthrit.2019.07.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/20/2019] [Accepted: 07/31/2019] [Indexed: 11/21/2022]
Abstract
OBJECTIVES To assess the influence of rheumatoid arthritis (RA) disease activity (DA) on the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA). METHODS We identified RA patients who underwent THA/TKA and determined their DA using the simplified disease activity index (SDAI). The risk of aseptic loosening was estimated using radiographic signs of component loosening (RCL). We performed Cox regression to estimate RCL based on SDAI, adjusting for therapy. We also investigated a cohort of 2:1 matched osteoarthritis (OA) patients as a control group without systemic inflammation. RESULTS We identified 49 RA patients with a history of THA/TKA, of whom 18 (36.7%) showed RCL. SDAI over time was significantly higher in patients with RCL (median; 25th and 75th percentile: 10.8 months; 8.6 and 15.8; vs 7.0 months; 2.7 and 15.5;p = 0.043). In the regression model, each unit of mean SDAI over time significantly increased the risk of RCL (HR 1.125, 95% CI 1.021-1.241;p = 0.018). Patients treated with biological had a lower risk of RCL than those treated with traditional DMARDs (HR 0.192, 95% CI 0.042-0.891;p = 0.035). In the 88 matched OA patients, the RCL rate was significantly lower than in the RA group (13.6%;p = 0.002). CONCLUSION Higher inflammatory DA increases the risk for radiographic loosening after THA/TKA in patients with RA. The significantly lower risk in patients with OA further underlines the potential role of inflammatory DA. In the context of treating RA to target, the presence of an arthroplasty might be considered as an indication for more stringent control of DA.
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