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Nakashima A, Fujii H, Kuroda M, Zoshima T, Mizushima I, Nomura H, Kawano M. Asymmetrical Damage of the Wrist Joint Induces Lateralized Cortical Bone Loss in the Metacarpal Diaphysis in Patients with Rheumatoid Arthritis. J Clin Med 2024; 13:7652. [PMID: 39768575 PMCID: PMC11676186 DOI: 10.3390/jcm13247652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/12/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Osteoporosis is common in rheumatoid arthritis (RA), occurring either systemically or locally around inflamed joints. Decreased metacarpal bone density is a known marker of RA progression and hand function impairment. Although RA is generally characterized by symmetrical arthritis, some patients exhibit asymmetrical joint involvement. This study investigates the frequency of unilateral metacarpal bone density reduction in RA patients and aims to identify associated factors. Methods: This study included 143 RA patients (107 females, mean age 62.4 yrs., mean disease duration 11.1 yrs.). Bilateral hand X-rays were used to measure the cortical thickness rate (CTR) of the 2nd to 4th metacarpals. Unilateral bone density reduction was defined as a thin-to-thick-side CTR ratio (CTRR) < 0.8. Associations between CTR reduction and unilateral wrist joint damage (WJD) were analyzed. Results: Unilateral CTR reduction (CTRR < 0.8) was observed in 16.8% of patients, significantly associated with unilateral WJD. Among patients with unilateral WJD, 50.0% showed CTRR lateral (+) compared to 10.1% without unilateral WJD (p < 0.01). ANCOVA revealed significant effects of WJD laterality on CTRR, with an interaction effect showing greater CTRR laterality when thin-side WJD was present without thick-side WJD. Post-biologic treatment, CTR values decreased in both hands, indicating no improvement in bone density reduction. Conclusions: Approximately 17% of RA patients exhibited unilateral relative metacarpal bone density reduction, closely associated with unilateral WJD. This first detailed report on bone density laterality in RA underscores the need for early intervention and rehabilitation strategies in RA patients with hand involvement.
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Affiliation(s)
- Akikatsu Nakashima
- Department of Internal Medicine, Asanagi Hospital, 1-8 Gofuku-machi, Takaoka 933-0906, Japan; (A.N.)
- Division of Nephrology and Rheumatology, Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihigashi, Kanazawa 920-8530, Japan
| | - Hiroshi Fujii
- Division of Nephrology and Rheumatology, Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihigashi, Kanazawa 920-8530, Japan
| | - Masahiro Kuroda
- Department of Internal Medicine, Asanagi Hospital, 1-8 Gofuku-machi, Takaoka 933-0906, Japan; (A.N.)
| | - Takeshi Zoshima
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-Machi, Kanazawa 920-8640, Japan
| | - Ichiro Mizushima
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-Machi, Kanazawa 920-8640, Japan
| | - Hideki Nomura
- Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa 920-8640, Japan
| | - Mitsuhiro Kawano
- Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun 920-0293, Japan
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Kim Y, Kim GT. Positive Effects of Biologics on Osteoporosis in Rheumatoid Arthritis. JOURNAL OF RHEUMATIC DISEASES 2023; 30:3-17. [PMID: 37476528 PMCID: PMC10351356 DOI: 10.4078/jrd.22.0046] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/10/2022] [Accepted: 12/10/2022] [Indexed: 07/22/2023]
Abstract
Osteoporosis is a systemic skeletal disorder that causes vulnerability of bones to fracture owing to reduction in bone density and deterioration of the bone tissue microstructure. The prevalence of osteoporosis is higher in patients with autoimmune inflammatory rheumatic diseases, including rheumatoid arthritis (RA), than in those of the general population. In this autoimmune inflammatory rheumatic disease, in addition to known risk factors for osteoporosis, various factors such as chronic inflammation, autoantibodies, metabolic disorders, drugs, and decreased physical activity contribute to additional risk. In RA, disease-related inflammation plays an important role in local or systemic bone loss, and active treatment for inflammation can help prevent osteoporosis. In addition to conventional synthetic disease-modifying anti-rheumatic drugs that have been traditionally used for treatment of RA, biologic DMARDs and targeted synthetic DMARDs have been widely used. These agents can be employed more selectively and precisely based on disease pathogenesis. It has been reported that these drugs can inhibit bone loss by not only reducing inflammation in RA, but also by inhibiting bone resorption and promoting bone formation. In this review, the pathogenesis and research results of the increase in osteoporosis in RA are reviewed, and the effects of biological agents on osteoporosis are discussed.
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Affiliation(s)
- Yunkyung Kim
- Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Geun-Tae Kim
- Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
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Abtahi S, Cordtz R, Dreyer L, Driessen JHM, Boonen A, Burden AM. Biological Disease-Modifying Antirheumatic Drugs and Osteoporotic Fracture Risk in Patients with Rheumatoid Arthritis: A Danish Cohort Study. Am J Med 2022; 135:879-888.e3. [PMID: 35134369 DOI: 10.1016/j.amjmed.2022.01.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/06/2022] [Accepted: 01/14/2022] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Clinical trials have shown a beneficial effect from biological disease-modifying antirheumatic drugs (bDMARDs) on hand or axial bone loss in patients with rheumatoid arthritis; however, it is unclear if this translates to a reduced fracture risk. We investigated the effect of bDMARDs on osteoporotic fracture risk compared to no biological treatment in rheumatoid arthritis. METHODS A cohort of patients with rheumatoid arthritis aged 18+ from DANBIO was linked to population-based health registries in Denmark (2006-2016). Adopting a prevalent new-user design, we matched bDMARD users to bDMARD-naïve patients using time-conditional propensity scores. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, and forearm) was estimated among the matched patients by Cox proportional hazards models. RESULTS Out of 24,678 patients with rheumatoid arthritis, 4265 bDMARD users were matched to the same number of bDMARD-naïve patients (mean age 56.2 years, 74% female). During follow-up, 229 osteoporotic fractures occurred among bDMARD users and 205 fractures among bDMARD-naïve patients (incidence rates 12.1 and 13.0 per 1000 person-years, respectively). The use of bDMARDs was not associated with a reduced risk of osteoporotic fractures among patients with rheumatoid arthritis (hazard ratio 0.97, 95% confidence interval 0.78-1.20), compared with no biological treatment. The risk estimates were similar for all osteoporotic fracture sites. CONCLUSION We found no independent beneficial effect from using bDMARDs on reducing the risk of osteoporotic fractures in patients with rheumatoid arthritis.
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Affiliation(s)
- Shahab Abtahi
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - René Cordtz
- Departments of Clinical Medicine and Rheumatology, Aalborg University and Aalborg University Hospital, Aalborg, Denmark; Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Gentofte, Copenhagen, Denmark
| | - Lene Dreyer
- Departments of Clinical Medicine and Rheumatology, Aalborg University and Aalborg University Hospital, Aalborg, Denmark; DANBIO - The Danish Rheumatologic Database, Copenhagen, Denmark
| | - Johanna H M Driessen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Annelies Boonen
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, the Netherlands; Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - Andrea M Burden
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
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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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Chruściak T, Wisłowska M. Assessment of Rheumatoid Hand Function as a Characteristic Feature of Rheumatoid Arthritis in Patients Treated with Methotrexate or Methotrexate with Biological Agents with and without Deformation of Hands. Curr Rheumatol Rev 2022; 18:212-223. [PMID: 35168508 DOI: 10.2174/1573397118666220215092045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/19/2021] [Accepted: 09/20/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The hand is an excellent work tool that provides the functional ability to mechanical work. The hand is affected in rheumatoid arthritis (RA) patients, it is a significant problem in the functional sphere as a result of deformities, the grasping function limitation and muscle strength. OBJECTIVES The aim of the study was the assessment of grip strength, endurance and manipulation abilities of rheumatoid hands with or without deformities treated with methotrexate (MTX) or MTX plus biologics (MTX+BIO). MATERIAL AND METHODS The study involved 80 RA women, (40 received MTX+BIO, 40 MTX), treated at the Rheumatology Department of the Central Clinical Hospital of Interior Affairs in Warsaw. VAS-pain, DAS28, SDAI, HAQ, HAQ hands, estimation of hand grip strength, endurance, manipulation ability were analyzed. RESULTS In group MTX+BIO values of DAS28 (3.7±1.3 vs 4.3±1.2, p=0.019), HAQ (0.72 ± 0.57 vs 1.08± 0.87, p=0.011) and HAQ-hand (0.85±0.65 vs. 1.19±0.68, p=0.024) were statistically lower than in MTX group. Hand deformations recorded in 35 (43.7%) cases, 16 (40%) in MTX group, 19 (47.5%) in MTX+BIO. Comparison of grip strength, endurance, manipulation ability showed better results in MTX+BIO group with deformities (significance level from 0.013 to 0.046) than in MTX group. Relative differences in hand function in MTX + BIO group ranged from 10.8% (maximal power grip strength) to 127.6% (minimal hand endurance), after disease duration adjustment - from 28.2% (maximal power grip strength) to 148.4% (minimal hand endurance). CONCLUSION Measuring grip strength, hand endurance, manipulation abilities are useful in RA patients with hand deformities.
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Affiliation(s)
- Tomasz Chruściak
- Rehabilitation Center, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
| | - Małgorzata Wisłowska
- Internal Disease Department, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
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Jura-Półtorak A, Szeremeta A, Olczyk K, Zoń-Giebel A, Komosińska-Vassev K. Bone Metabolism and RANKL/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-α Inhibitors. J Clin Med 2021; 10:jcm10132905. [PMID: 34209821 PMCID: PMC8267676 DOI: 10.3390/jcm10132905] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (anti-TNF-α) therapy in combination with methotrexate on bone remodeling and osteoclastogenesis in female patients with RA. Serum levels of bone turnover markers (i.e., C- and N-terminal propeptides of type I procollagen (PICP and PINP), C- and N-terminal cross-linking telopeptides of type I collagen (CTX-I and NTX-I), and soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG)) were determined by immunoassay at baseline and 15 months after initiation of treatment. Bone mineral density was measured by dual-energy x-ray absorptiometry. We found a significant decrease in serum PINP levels, a biomarker of bone formation, and higher levels of CTX-I and sRANKL indicative of increased bone resorption in RA patients prior to TNFαI treatment compared to the controls. Anti-TNF-α therapy was effective in improving bone metabolism in RA patients as reflected in a decrease in CTX-I (at least partially due to the RANKL/OPG reduction) and a concomitant increase in PINP levels. The bone metabolism changes were independent of the type of TNFαI used. PINP and CTX-I were found to be useful markers of bone metabolism, which may prove the effectiveness of TNF-α therapy earlier than the bone density assessment.
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Affiliation(s)
- Agnieszka Jura-Półtorak
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 41-200 Sosnowiec, Poland; (A.S.); (K.O.); (K.K.-V.)
- Correspondence: ; Tel.: +48-32-364-11-50
| | - Anna Szeremeta
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 41-200 Sosnowiec, Poland; (A.S.); (K.O.); (K.K.-V.)
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 41-200 Sosnowiec, Poland; (A.S.); (K.O.); (K.K.-V.)
| | - Aleksandra Zoń-Giebel
- Silesian Center of Rheumatology, Rehabilitation and Prevention of Disability of Gen. Jerzy Ziętek in Ustroń, 43-450 Ustroń, Poland;
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 41-200 Sosnowiec, Poland; (A.S.); (K.O.); (K.K.-V.)
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7
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Pfeil A, Oelzner P, Hoffmann T, Renz DM, Wolf G, Böttcher J. Sind röntgenologische Scoring-Methoden als Parameter zur
Verlaufsbeurteilung der rheumatoiden Arthritis noch
zeitgemäß? AKTUEL RHEUMATOL 2021. [DOI: 10.1055/a-1394-0299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
ZusammenfassungDie radiologische Progression beschreibt das Ausmaß der
Gelenkzerstörung im Verlauf einer rheumatoiden Arthritis. Zur
Quantifizierung der radiologischen Progression werden Scoring-Methoden
(z. B. van der Heijde Modifikation des Sharp-Score) eingesetzt. In
verschiedenen Studien zu biologischen- bzw. target-synthetischen Disease
Modifying Anti-Rheumatic Drugs gelang nur unzureichend eine Differenzierung
der radiologischen Progression. Zudem finden die Scores oft keinen
routinemäßigen Einsatz in der klinischen
Entscheidungsfindung. Durch die computerbasierte Analyse von
Handröntgenaufnahmen ist eine valide Quantifizierung der
radiologischen Progression und die zuverlässige Bewertung von
Therapieeffekten möglich. Somit stellen die computerbasierten
Methoden eine vielversprechende Alternative in der Quantifizierung der
radiologischen Progression dar.
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Affiliation(s)
- Alexander Pfeil
- Klinik für Innere Medizin III, Universitätsklinikum
Jena, Jena, Deutschland
| | - Peter Oelzner
- Klinik für Innere Medizin III, Universitätsklinikum
Jena, Jena, Deutschland
| | - Tobias Hoffmann
- Klinik für Innere Medizin III, Universitätsklinikum
Jena, Jena, Deutschland
| | - Diane M. Renz
- Institut für Diagnostische und Interventionelle Radiologie,
Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Gunter Wolf
- Klinik für Innere Medizin III, Universitätsklinikum
Jena, Jena, Deutschland
| | - Joachim Böttcher
- Medizinische Fakultät, Friedrich-Schiller-Universität
Jena, Jena, Deutschland
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8
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Alder KD, Lee I, Munger AM, Kwon HK, Morris MT, Cahill SV, Back J, Yu KE, Lee FY. Intracellular Staphylococcus aureus in bone and joint infections: A mechanism of disease recurrence, inflammation, and bone and cartilage destruction. Bone 2020; 141:115568. [PMID: 32745687 DOI: 10.1016/j.bone.2020.115568] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/19/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023]
Abstract
Bone and joint infections are devastating afflictions. Although medical interventions and advents have improved their care, bone and joint infections still portend dismal outcomes. Indeed, bone and joint infections are associated with extremely high mortality and morbidity rates and, generally, occur secondary to the aggressive pathogen Staphylococcus aureus. The consequences of bone and joint infections are further compounded by the fact that although they are aggressively treated, they frequently recur and result in massive bone and articular cartilage loss. Here, we review the literature and chronicle the fact that the fundamental cellular components of the musculoskeletal system can be internally infected with Staphylococcus aureus, which explains the ready recurrence of bone and joint infections even after extensive administration of antibiotic therapy and debridement and offer potential treatment solutions for further study. Moreover, we review the ramifications of intracellular infection and expound that the massive bone and articular cartilage loss is caused by the sustained proinflammatory state induced by infection and offer potential combination therapies for further study to protect bone and cartilage.
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Affiliation(s)
- Kareme D Alder
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Inkyu Lee
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Department of Life Science, Chung-Ang University, Seoul, Republic of Korea; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Alana M Munger
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Hyuk-Kwon Kwon
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Montana T Morris
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Sean V Cahill
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - JungHo Back
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Kristin E Yu
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
| | - Francis Y Lee
- Department of Orthopædics & Rehabilitation, Yale University, School of Medicine, New Haven, CT, USA; Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, 330 Cedar St, TMP 523, PO Box 208071, New Haven, CT 06520-8071, USA.
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9
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Jäger E, Murthy S, Schmidt C, Hahn M, Strobel S, Peters A, Stäubert C, Sungur P, Venus T, Geisler M, Radusheva V, Raps S, Rothe K, Scholz R, Jung S, Wagner S, Pierer M, Seifert O, Chang W, Estrela-Lopis I, Raulien N, Krohn K, Sträter N, Hoeppener S, Schöneberg T, Rossol M, Wagner U. Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis. Nat Commun 2020; 11:4243. [PMID: 32843625 PMCID: PMC7447633 DOI: 10.1038/s41467-020-17749-6] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 07/16/2020] [Indexed: 12/17/2022] Open
Abstract
Increased extracellular Ca2+ concentrations ([Ca2+]ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca2+]ex. Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1β release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1β release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca2+] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA.
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Affiliation(s)
- Elisabeth Jäger
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Supriya Murthy
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Caroline Schmidt
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Magdalena Hahn
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Sarah Strobel
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Anna Peters
- Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany
| | - Claudia Stäubert
- Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany
| | - Pelin Sungur
- Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743, Jena, Germany
| | - Tom Venus
- Institute for Medical Physics and Biophysics, Leipzig University, Härtelstraße 16-18, 04107, Leipzig, Germany
| | - Mandy Geisler
- Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany
| | - Veselina Radusheva
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Stefanie Raps
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Kathrin Rothe
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Roger Scholz
- Department of Orthopaedic, Trauma and Plastic Surgery, Leipzig University, Liebigstraße 20, Leipzig, Germany
| | - Sebastian Jung
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Sylke Wagner
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Matthias Pierer
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Olga Seifert
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Wenhan Chang
- UCSF Department of Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Irina Estrela-Lopis
- Institute for Medical Physics and Biophysics, Leipzig University, Härtelstraße 16-18, 04107, Leipzig, Germany
| | - Nora Raulien
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany
| | - Knut Krohn
- DNA Core Unit Leipzig, Liebigstraße 19, 04103, Leipzig, Germany
| | - Norbert Sträter
- Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany
| | - Stephanie Hoeppener
- Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743, Jena, Germany
| | - Torsten Schöneberg
- Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany
| | - Manuela Rossol
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany.
| | - Ulf Wagner
- Department of Internal Medicine, Division of Rheumatology, Leipzig University, Liebigstraße 19, 04103, Leipzig, Germany.
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10
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Clynes MA, Jameson K, Prieto-Alhambra D, Harvey NC, Cooper C, Dennison EM. Impact of Rheumatoid Arthritis and Its Management on Falls, Fracture and Bone Mineral Density in UK Biobank. Front Endocrinol (Lausanne) 2019; 10:817. [PMID: 31849841 PMCID: PMC6888088 DOI: 10.3389/fendo.2019.00817] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/08/2019] [Indexed: 01/10/2023] Open
Abstract
Objectives: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease which presents with polyarthritis in addition to extra-articular manifestations. Historically, studies have shown a link between RA and adverse musculoskeletal outcomes but these studies were reported before the widespread use of biologic therapies. The aim of this study was therefore to investigate associations between RA, RA medications and bone mineral density, falls and fractures, using UK Biobank data. Methods: Diagnosis of RA was made using Hospital Episode Statistics (HES) ICD-10 coding. We assessed RA relationships with estimated bone mineral density (eBMD) from heel quantitative ultrasound measurements, self-reported falls (in last year) and HES recorded fracture, adjusted for age, ethnicity, BMI, smoking status, and physical activity. Results: Of 502,543 participants, 3849 (1.4%) of women and 1643 (0.7%) of men had a diagnosis of RA. Median age of the participants was 57 years (IQR 50-63) in women and 58 (IQR 50-64) in men. RA was associated with lower eBMD (men: β -0.244, 95% CI -0.378, -0.110 p < 0.001; women: β -0.217, 95% CI -0.297, -0.138 p < 0.001) a reported fall in the last year (men: OR 1.54, 95% CI 1.26, 1.87 p < 0.001; women: OR 1.36, 95% CI 1.19, 1.56 p < 0.001) and fracture in women (OR 1.76, 95% CI 1.43, 2.16 p < 0.001). Corticosteroid therapy in men (β -0.934, 95% CI -1.565, -0.304 p = 0.004) and disease modifying anti-rheumatic drug (DMARD) use in both sexes (men: β -0.437, 95% CI -0.761, -0.112 p = 0.008; women: β -0.243, 95% CI -0.421, -0.065 p = 0.007), but not biologic therapy, were associated with a lower eBMD with RA. Conclusions: RA was associated with lower eBMD, increased falls and fracture. Corticosteroid and DMARD therapy, but not biologic therapy, were associated with lower eBMD.
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Affiliation(s)
- Michael A. Clynes
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
| | - Karen Jameson
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
| | | | - Nicholas C. Harvey
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
| | - Cyrus Cooper
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
- NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Elaine M. Dennison
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
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11
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Lee JS, Lim DH, Oh JS, Kim YG, Lee CK, Yoo B, Hong S. Effect of TNF inhibitors on bone mineral density in rheumatoid arthritis patients receiving bisphosphonate: a retrospective cohort study. Rheumatol Int 2019; 40:481-487. [PMID: 31414225 DOI: 10.1007/s00296-019-04418-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 08/08/2019] [Indexed: 12/13/2022]
Abstract
We aimed to determine whether tumor necrosis factor inhibitors (TNFi) have beneficial effects on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis receiving bisphosphonate. A total of 199 RA patients, who were newly diagnosed with osteoporosis and receiving bisphosphonate between January 2005 and March 2017, were reviewed. Changes in BMD after 1 year were compared between patients treated with and without TNFi. The inverse probability of treatment weighting (IPTW) method using the propensity score was performed to minimize confounding factors, and logistic regression analysis was applied to identify any factors associated with significant BMD improvement (≥ 3%) at the lumbar spine and femur neck. Among patients receiving bisphosphonate, 29 were exposed to TNFi, and 170 patients were not exposed. The percentage change in BMD and the proportion of significant improvements at the lumbar spine and femur neck were similar between patients treated with and without TNFi, before and after IPTW adjustment. In addition, the disease activity score 28 (DAS28) with three variables [adjusted odds ratio (OR) 0.741, 95% confidence interval (CI) 0.592-0.927, p = 0.009] and cumulative steroid dose (adjusted OR 0.639, 95% CI 0.480-0.851, p = 0.002) were inversely associated with an improvement in BMD. Conversely, TNFi use was not associated with any improvement in BMD after adjustment by IPTW using the propensity score. TNFi did not influence BMD improvement in RA patients with osteoporosis receiving bisphosphonate, suggesting that TNFi cannot be considered as a preferred therapeutic option for increasing BMD.
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Affiliation(s)
- Jung Sun Lee
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea
| | - Doo-Ho Lim
- Division of Rheumatology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Ji Seon Oh
- Department of Biomedical Informatics, Asan Medical Center, Seoul, Korea
| | - Yong-Gil Kim
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea
| | - Chang-Keun Lee
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea
| | - Bin Yoo
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea
| | - Seokchan Hong
- Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
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12
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Tomizawa T, Ito H, Murata K, Hashimoto M, Tanaka M, Murakami K, Nishitani K, Azukizawa M, Okahata A, Doi K, Saito M, Furu M, Hamaguchi M, Mimori T, Matsuda S. Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis. Arthritis Res Ther 2019; 21:174. [PMID: 31307521 PMCID: PMC6631871 DOI: 10.1186/s13075-019-1956-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 07/01/2019] [Indexed: 12/20/2022] Open
Abstract
Background Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. Methods We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. Results The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32–85), 21.3 (12.3–30.0), and 3.2 (0.1–5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. Conclusions Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.
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Affiliation(s)
- T Tomizawa
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
| | - H Ito
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan.
| | - K Murata
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan.,Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - M Hashimoto
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - M Tanaka
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - K Murakami
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - K Nishitani
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan.,Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - M Azukizawa
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
| | - A Okahata
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
| | - K Doi
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
| | - M Saito
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
| | - M Furu
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan.,Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - M Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - T Mimori
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - S Matsuda
- Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-Cho, Shogoin, Sakyo, Kyoto, 606-8507, Japan
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Abstract
INTRODUCTION Tofacitinib inhibits the Janus kinases, tyrosine kinases that are activated by cytokines involved in the pathophysiology of rheumatoid arthritis. Areas covered: Clinical trials have revealed an anti-rheumatic effect of monotherapy and combination therapy with methotrexate (MTX). Post-hoc analysis of those clinical trials and real-world experiences will be reviewed to explore efficacy and safety. Expert commentary: The efficacy of tofacitinib monotherapy has garnered much attention and has been initiated in large number of patients. However, combination therapy with MTX is necessary in order to achieve the maximum effect. Combination therapy can be transferred to monotherapy by tapering and/or discontinuing MTX. The discontinuation of tofacitinib should be avoided and tapering should be investigated. There has been no new safety signal although venous thrombotic events (VTEs) have been raised and would require long-term follow-up. Increased events of Herpes zoster were observed and the use of a subunit vaccination is expected to become an effective tool for prevention. Post-hoc analysis of the clinical trials and real-world experience is revealing further usefulness of tofacitinib not only in rheumatoid arthritis but also other diseases. Additional experience and data from the real world are required to help improve the use of tofacitinib..
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Affiliation(s)
- Kunihiro Yamaoka
- a Department of Rheumatology and Infectious Diseases , Kitasato University School of Medicine , Sagamihara , Japan
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14
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Inhibition of periarticular bone loss is associated with clinical remission and ACR70-Response in rheumatoid arthritis. Rheumatol Int 2018; 39:637-645. [PMID: 30569216 DOI: 10.1007/s00296-018-4226-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 12/11/2018] [Indexed: 12/29/2022]
Abstract
The aim of this study, based on a post hoc analysis of the data set used in the RAPID 1 trial, focuses on the associations between metacarpal bone mineral density, as estimated by digital X-ray radiogrammetry (DXR), and clinical remission as well as ACR70-Response in rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP). The trial evaluates a total of 345 RA patients treated with methotrexate versus CZP 200 mg versus CZP 400 mg. All patients underwent X-rays of the hand at baseline and week 52 as well as computerized calculations of bone mineral density (BMD) by DXR. Clinical remission was defined as DAS28 < 2.6. ACR70-Response was also evaluated. The radiological assessment of disease progression was estimated using the modified total Sharp Score. The mean difference for DAS28 was observed for patients treated with CZP 400 mg (median: - 3.53, minimum: - 6.77; maximum: + 0.48) and CZP 200 mg (median: - 3.13, minimum: - 6.37; maximum: - 0.52) compared to the methotrexate group (median - 2.41, minimum: - 4.76; maximum: + 0.31). The DXR-BMD showed a minor bone loss for the treatment groups undergoing therapy with CZP 200 mg (median: - 0.009 g/cm2, minimum: - 0.059 g/cm2; maximum: + 0.095 g/cm2) and CZP 400 mg (median: - 0.008 g/cm2, minimum: - 0.064 g/cm2; maximum: + 0.080 g/cm2). The methotrexate group presented an advanced periarticular metacarpal bone loss as measured by DXR-BMD (median: - 0.024 g/cm2, minimum: - 0.102 g/cm2; maximum: + 0.057 g/cm2). In the case of clinical remission and ACR70-Response, no significant change of the DXR-BMD was observed for both CZP groups. The study highlights that patients treated with CZP show a less accentuated periarticular bone loss as estimated by DXR in comparison to patients with methotrexate plus placebo. In addition, patients with clinical remission and ACR70-Response revealed no periarticular demineralisation.
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15
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Ahmad HA, Alemao E, Guo Z, Iannaccone CK, Frits ML, Weinblatt M, Shadick NA. Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort. Adv Ther 2018; 35:232-242. [PMID: 29368271 PMCID: PMC5818577 DOI: 10.1007/s12325-017-0657-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Indexed: 01/01/2023]
Abstract
Introduction To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA). Methods Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR–BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2–immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1–3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] < 2.6) and bone loss was also explored. Results A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [−], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2− group. DXR–BMD was lower in the anti-CCP2+ vs. the anti-CCP2− groups (Gp1–3 vs. anti-CCP2−: P < 0.0001 for left and right hands). DXR–BMD decreased with increasing anti-CCP2 titer (P < 0.001 for left and right hands). Patients with low DXR–BMD were less likely to have a DAS28 (CRP) < 2.6 (P = 0.0181). Conclusion Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity. Funding Bristol-Myers Squibb. Trial Registration Clinicaltrials.gov identifier, NCT01793103. Electronic supplementary material The online version of this article (10.1007/s12325-017-0657-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Evo Alemao
- Bristol-Myers Squibb, Princeton, NJ, USA
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16
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Tawaratsumida H, Setoguchi T, Arishima Y, Ohtsubo H, Akimoto M, Ishidou Y, Nagano S, Taketomi E, Sunahara N, Komiya S. Risk factors for bone loss in patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs. BMC Res Notes 2017; 10:765. [PMID: 29268799 PMCID: PMC5740597 DOI: 10.1186/s13104-017-3086-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 12/13/2017] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients' variables to identify risk factors for least significant reduction of bone mineral density. RESULTS Least significant reduction of lumbar spine bone mineral density (≤ - 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (≤ - 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high-dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease-modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss.
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Affiliation(s)
- Hiroki Tawaratsumida
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Takao Setoguchi
- The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520 Japan
| | - Yoshiya Arishima
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideo Ohtsubo
- Center for Rheumatic Diseases, Japanese Red Cross Kagoshima Hospital, Kagoshima, Japan
| | - Masaki Akimoto
- Department of Hematology and Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yasuhiro Ishidou
- Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Satoshi Nagano
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Eiji Taketomi
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Orthopaedic Surgery, Japanese Red Cross Kagoshima Hospital, Kagoshima, Japan
| | - Nobuhiko Sunahara
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Orthopaedic Surgery, Japanese Red Cross Kagoshima Hospital, Kagoshima, Japan
| | - Setsuro Komiya
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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17
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Pfeil A, Haugeberg G, Renz DM, Reinhardt L, Jung C, Franz M, Wolf G, Böttcher J. Digital X-ray radiogrammetry and its sensitivity and specificity for the identification of rheumatoid arthritis-related cortical hand bone loss. J Bone Miner Metab 2017; 35:192-198. [PMID: 26979320 DOI: 10.1007/s00774-016-0741-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 01/22/2016] [Indexed: 01/01/2023]
Abstract
Digital X-ray radiogrammetry (DXR) is a computer-assisted diagnosis technique for quantifying cortical hand bone mineral density (BMD) as well as the metacarpal index (MCI) in the metacarpal bones from radiographs. The objective was to compare DXR-BMD and DXR-MCI between healthy individuals and patients with rheumatoid arthritis (RA) and verify the sensitivity and specificity of this technique for the identification of cortical hand bone loss as an additional diagnostic approach in RA. 618 patients were enrolled and divided into two groups: those with RA (n = 309) and a healthy control group (n = 309) as a reference database. DXR-BMD and the DXR-MCI were measured by DXR using hand radiographs. The severity of RA was evaluated by the modified Larsen score. Mean values for DXR-BMD and DXR-MCI in RA patients were significantly lower compared to healthy subjects (-20.7 and -21.1 %, respectively). Depending on the severity of RA-related joint damage, DXR-BMD revealed a significant reduction of -28.1 % and DXR-MCI -28.2 %, comparing score 1 and score 5 of the modified Larsen score. Both DXR-BMD and DXR-MCI had a high sensitivity (DXR-BMD 91 %, DXR-MCI 87 %) and a moderate specificity (DXR-BMD 47 %, DXR-MCI 49 %) to identify RA-related cortical hand bone loss. The DXR technique seems to be able to quantify RA-related periarticular bone loss as a characteristic feature in the course of RA. Consequently, periarticular osteoporosis seems to function as a reliable diagnostic approach comparable to erosions and joint space narrowing in the diagnosis of RA and as a surrogate marker for the progression of bone loss in RA.
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Affiliation(s)
- Alexander Pfeil
- Department of Internal Medicine III, Jena University Hospital, Friedrich-Schiller-University Jena, Erlanger Allee 101, 07747, Jena, Germany.
| | - Glenn Haugeberg
- Norwegian University of Science and Technology, Trondheim, Norway
| | - Diane M Renz
- Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller-University Jena, Erlanger Allee 101, 07747, Jena, Germany
| | - Lisa Reinhardt
- Department of Internal Medicine III, Jena University Hospital, Friedrich-Schiller-University Jena, Erlanger Allee 101, 07747, Jena, Germany
| | - Christian Jung
- Department of Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Duesseldorf, Moorenstraße 5, 40225, Duesseldorf, Germany
| | - Marcus Franz
- Department of Internal Medicine I, Jena University Hospital, Friedrich-Schiller-University Jena, Erlanger Allee 101, 07747, Jena, Germany
| | - Gunter Wolf
- Department of Internal Medicine III, Jena University Hospital, Friedrich-Schiller-University Jena, Erlanger Allee 101, 07747, Jena, Germany
| | - Joachim Böttcher
- Institute of Diagnostic and Interventional Radiology, SRH Wald-Klinikum Gera, Straße des Friedens 122, 07548, Gera, Germany
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18
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Szentpétery Á, Horváth Á, Gulyás K, Pethö Z, Bhattoa HP, Szántó S, Szücs G, FitzGerald O, Schett G, Szekanecz Z. Effects of targeted therapies on the bone in arthritides. Autoimmun Rev 2017; 16:313-320. [DOI: 10.1016/j.autrev.2017.01.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 12/07/2016] [Indexed: 12/17/2022]
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19
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Ørnbjerg LM, Østergaard M, Jensen T, Hørslev-Petersen K, Stengaard-Pedersen K, Junker P, Ellingsen T, Ahlquist P, Lindegaard H, Linauskas A, Schlemmer A, Dam MY, Hansen I, Lottenburger T, Ammitzbøll CG, Jørgensen A, Krintel SB, Raun J, Hetland ML, Slot O, Nielsen LK, Skjødt H, Majgaard O, Lorenzen T, Horn HC, Kowalski M, Johansen IL, Pedersen PM, Manilo N, Bliddal H. Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target strategy with or without adalimumab-a substudy of the optimized treatment algorithm in early RA (OPERA) trial. Clin Rheumatol 2016; 36:781-789. [PMID: 27921185 DOI: 10.1007/s10067-016-3489-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/21/2016] [Accepted: 11/17/2016] [Indexed: 01/01/2023]
Abstract
This study aims to investigate 1-year hand bone loss (HBL1-year) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/- adalimumab and to determine if HBL6months is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL6months (0-6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/-radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p < 0.10 were included in multivariable models. In 70 patients with available HBL1-year data, HBL1-year was median (interquartile range (IQR)) -1.9 (-3.3; -0.26 mg/cm2) in the MTX + placebo group and -1.8 (-3.6; 0.06) mg/cm2 in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL6months data and 2-year radiographic data, HBL6months was independently associated with ∆TSS after 2 years (β = -0.086 (95% confidence interval = -0.15; -0.025) TSS unit/mg/cm2 increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92-1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL1-year, irrespective of adalimumab; HBL6months was independently associated with ∆TSS after 2 years.
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Affiliation(s)
- L M Ørnbjerg
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - M Østergaard
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - T Jensen
- Department of Endocrinology, Hvidovre Hospital, Copenhagen, Denmark
| | - K Hørslev-Petersen
- King Christian X Hospital for Rheumatic Diseases, South Jutland Hospital, Gråsten, Denmark
- Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
| | - K Stengaard-Pedersen
- Department of Rheumatology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - P Junker
- Department of Rheumatology C, Odense University Hospital, Odense, Denmark
| | - T Ellingsen
- Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - P Ahlquist
- Department of Medicine, Vejle Regional Hospital, Vejle, Denmark
| | - H Lindegaard
- Department of Rheumatology C, Odense University Hospital, Odense, Denmark
| | - A Linauskas
- Department of Rheumatology, Vendsyssel Hospital, Hjørring, Denmark
| | - A Schlemmer
- Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
| | - M Y Dam
- Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - I Hansen
- Department of Rheumatology, Viborg Regional Hospital, Viborg, Denmark
| | - T Lottenburger
- Department of Medicine, Vejle Regional Hospital, Vejle, Denmark
| | - C G Ammitzbøll
- Department of Rheumatology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - A Jørgensen
- Department of Rheumatology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - S B Krintel
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
| | - J Raun
- King Christian X Hospital for Rheumatic Diseases, South Jutland Hospital, Gråsten, Denmark
| | - M L Hetland
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ole Slot
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Lars Kjær Nielsen
- Department of Rheumatology, Odense University Hospital, Svendborg, Denmark
| | - Henrik Skjødt
- Copenhagen Center for Arthritis Research and the DANBIO registry, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Ole Majgaard
- Department of Rheumatology, Slagelse Hospital, Slagelse, Denmark
| | - Tove Lorenzen
- Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark
| | | | - Marcin Kowalski
- Department of Rheumatology, Viborg Regional Hospital, Viborg, Denmark
| | | | | | - Natalia Manilo
- Department of Rheumatology, Bispebjerg Hospital, Copenhagen, Denmark
| | - Henning Bliddal
- Department of Rheumatology, Parker Institute, Frederiksberg Hospital, Copenhagen, Denmark
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20
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Song J, Chen Y, Jiang S, Yang K, Li X, Zhao X, Ouyang Y, Fan C, Yuan W. Efficient and Non-Toxic Biological Response Carrier Delivering TNF-α shRNA for Gene Silencing in a Murine Model of Rheumatoid Arthritis. Front Immunol 2016; 7:305. [PMID: 27594856 PMCID: PMC4990551 DOI: 10.3389/fimmu.2016.00305] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 07/27/2016] [Indexed: 12/29/2022] Open
Abstract
Small interfering RNA (siRNA) is an effective and specific method for silencing genes. However, an efficient and non-toxic carrier is needed to deliver the siRNA into the target cells. Tumor necrosis factor α (TNF-α) plays a central role in the occurrence and progression of rheumatoid arthritis (RA). In this study, we pre-synthetized a degradable cationic polymer (PDAPEI) from 2,6-pyridinedicarboxaldehyde and low-molecular-weight polyethyleneimine (PEI, Mw = 1.8 kDa) as a gene vector for the delivery of TNF-α shRNA. The PDAPEI/pDNA complex showed a suitable particle size and stable zeta potential for transfection. In vitro study of the PDAPEI/pDNA complex revealed a lower cytotoxicity and higher transfection efficiency when transfecting TNF-α shRNA to macrophages by significantly down-regulating the expression of TNF-α. Moreover, the complex was extremely efficient in decreasing the severity of arthritis in mice with collagen-induced arthritis. PDAPEI delivered TNF-α shRNA has great potential in the treatment of RA.
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Affiliation(s)
- Jialin Song
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Yinghui Chen
- Department of Neurology, Jinshan Hospital, Fudan University , Shanghai , China
| | - Shichao Jiang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong , China
| | - Kejia Yang
- School of Pharmacy, Shanghai JiaoTong University , Shanghai , China
| | - Xiaoming Li
- School of Pharmacy, Shanghai JiaoTong University , Shanghai , China
| | - Xiaotian Zhao
- School of Pharmacy, Shanghai JiaoTong University , Shanghai , China
| | - Yuanming Ouyang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine and Health, Shanghai, China
| | - Cunyi Fan
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China
| | - Weien Yuan
- School of Pharmacy, Shanghai JiaoTong University , Shanghai , China
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Koga T, Okada A, Fukuda T, Hidaka T, Ishii T, Ueki Y, Kodera T, Nakashima M, Takahashi Y, Honda S, Horai Y, Watanabe R, Okuno H, Aramaki T, Izumiyama T, Takai O, Miyashita T, Sato S, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Origuchi T, Nakamura H, Aoyagi K, Eguchi K, Kawakami A. Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy. Medicine (Baltimore) 2016; 95:e3476. [PMID: 27124044 PMCID: PMC4998707 DOI: 10.1097/md.0000000000003476] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01-1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17-2.59), RA typical erosion at baseline (95%CI 1.56-21.1), and the introduction of bDMARDs (95%CI 0.06-0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients' disease durations.
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Affiliation(s)
- Tomohiro Koga
- From the Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences (TK,YH, S-YK, NI, KI, MT, HN, AK); Japanese Red Cross Nagasaki Genbaku Hospital, Department of Rheumatology, Nagasaki (AO, MN, TA); Department of Rheumatology, Kurume University Medical Center, Kurume (TF, MN); Zenjinkai Shimin-no-Mori Hospital, Miyazaki (TH); Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai (TI, RW); Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital, Sasebo (YU); Tohoku Pharmaceutical University Hospital, Sendai (TK); Yu Family Clinic, Miyagi (YT); Kurume University School of Medicine, Kurume (SH); Department of Orthopaedic Surgery, Tohoku University Hospital (HO); East Sendai Rheumatism and Internal Medicine Clinic, Sendai (TI); Osaki Citizen Hospital, Osaki (OT); NHO Nagasaki Medical Center, Omura (TM); Clinical Research Center, Nagasaki University Hospital (SS); Department of Public Health (S-YK, KA); Department of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (TO); and Sasebo City General Hospital, Sasebo (KE), Japan
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22
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Ørnbjerg LM, Østergaard M, Jensen T, Hyldstrup L, Bach-Mortensen P, Bøyesen P, Thormann A, Tarp U, Bøhme WP, Lindegaard H, Poulsen UE, Schlemmer A, Graudal N, Rødgaard A, Espesen J, Kollerup GB, Glintborg B, Madsen OR, Jensen DV, Hetland ML. Establishment of age- and sex-adjusted reference data for hand bone mass and investigation of hand bone loss in patients with rheumatoid arthritis treated in clinical practice: an observational study from the DANBIO registry and the Copenhagen Osteoarthritis Study. Arthritis Res Ther 2016; 18:53. [PMID: 26912229 PMCID: PMC4766711 DOI: 10.1186/s13075-016-0952-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/08/2016] [Indexed: 12/31/2022] Open
Abstract
Background Rheumatoid arthritis is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) has therefore been proposed as an outcome measure for treatment efficacy. A definition of increased HBL adjusted for age- and sex-related bone loss is lacking. In this study, we aimed to: 1) establish reference values for normal hand bone mass (bone mineral density measured by digital x-ray radiogrammetry (DXR-BMD)); and 2) examine whether HBL is normalised in rheumatoid arthritis patients during treatment with tumour necrosis factor alpha inhibitors (TNFI). Methods DXR-BMD was measured from hand x-rays in a reference cohort (1485 men/2541 women) without arthritis randomly selected from an urban Danish population. Sex- and age-related HBL/year was estimated. DXR-BMD was measured in rheumatoid arthritis patients (n = 350: at start of TNFI, and ~2 years after TNFI start), of which 135 patients had three x-rays (~2 years prior to TNFI, at start of TNFI, and ~2 years after TNFI start). Individual HBL/year prior to and during TNFI was calculated and compared to reference values. Results Estimated HBL/year varied strongly with age and sex. Compared to the reference values, 75 % of 135 patients had increased HBL prior to TNFI treatment and 59 % had increased HBL during TNFI treatment (p = 0.17, Chi-squared). In 38 % (38/101) of patients with increased HBL, HBL was normalised during TNFI treatment, whereas 47 % (16/34) of patients with normal HBL prior to TNFI had increased HBL during TNFI treatment. In the 350 patients, increased HBL during TNFI was associated with time-averaged 28-joint disease activity score (odds ratio 1.69 (95 % Confidence Interval 1.34-2.15)/unit increase, p < 0.001), and patients in time-averaged remission had lower HBL than patients without remission (0.0032 vs. 0.0058 g/cm2/year; p < 0.001, Mann-Whitney). Conclusions We established age- and sex-specific reference values for DXR-BMD in a large cohort without arthritis. HBL was increased in the majority of rheumatoid arthritis patients initiating TNFI in clinical practice, and only normalised in a minority during TNFI. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-0952-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lykke Midtbøll Ørnbjerg
- DANBIO registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Ndr. Ringvej 57, DK-2600, Glostrup, Denmark. .,Rigshospitalet, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Mikkel Østergaard
- DANBIO registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Ndr. Ringvej 57, DK-2600, Glostrup, Denmark. .,Rigshospitalet, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Trine Jensen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
| | - Lars Hyldstrup
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
| | | | - Pernille Bøyesen
- Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
| | - Anja Thormann
- DANBIO registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Ndr. Ringvej 57, DK-2600, Glostrup, Denmark.
| | - Ulrik Tarp
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
| | | | - Hanne Lindegaard
- Department of Rheumatology, Odense University Hospital, Odense, Denmark.
| | | | - Anette Schlemmer
- Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark.
| | - Niels Graudal
- Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen, Denmark.
| | - Anne Rødgaard
- Center for Rheumatology and Spine Diseases, Rigshospitalet Glostrup, Glostrup, Denmark.
| | - Jakob Espesen
- Department of Internal Medicine, Lillebælt Hospital, Vejle, Denmark.
| | - Gina Birgitte Kollerup
- Department of Rheumatology, Copenhagen University Hospital Bispebjerg and Frederiksberg, Copenhagen, Denmark.
| | - Bente Glintborg
- Department of Internal Medicine, Holbæk Hospital, Holbæk, Denmark.
| | - Ole Rintek Madsen
- Department of Medicine and Rheumatology, Copenhagen University Hospital Gentofte, Gentofte, Denmark.
| | | | - Merete Lund Hetland
- DANBIO registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Ndr. Ringvej 57, DK-2600, Glostrup, Denmark. .,Rigshospitalet, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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23
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Ma CH, Lv Q, Yu YX, Zhang Y, Kong D, Niu KR, Yi CQ. Protective effects of tumor necrosis factor-α blockade by adalimumab on articular cartilage and subchondral bone in a rat model of osteoarthritis. Braz J Med Biol Res 2015; 48:863-70. [PMID: 26445328 PMCID: PMC4617111 DOI: 10.1590/1414-431x20154407] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/02/2015] [Indexed: 01/03/2023] Open
Abstract
We aimed to investigate the effects of an anti-tumor necrosis factor-α antibody (ATNF) on cartilage and subchondral bone in a rat model of osteoarthritis. Twenty-four rats were randomly divided into three groups: sham-operated group (n=8); anterior cruciate ligament transection (ACLT)+normal saline (NS) group (n=8); and ACLT+ATNF group (n=8). The rats in the ACLT+ATNF group received subcutaneous injections of ATNF (20 μg/kg) for 12 weeks, while those in the ACLT+NS group received NS at the same dose for 12 weeks. All rats were euthanized at 12 weeks after surgery and specimens from the affected knees were harvested. Hematoxylin and eosin staining, Masson's trichrome staining, and Mankin score assessment were carried out to evaluate the cartilage status and cartilage matrix degradation. Matrix metalloproteinase (MMP)-13 immunohistochemistry was performed to assess the cartilage molecular metabolism. Bone histomorphometry was used to observe the subchondral trabecular microstructure. Compared with the rats in the ACLT+NS group, histological and Mankin score analyses showed that ATNF treatment reduced the severity of the cartilage lesions and led to a lower Mankin score. Immunohistochemical and histomorphometric analyses revealed that ATNF treatment reduced the ACLT-induced destruction of the subchondral trabecular microstructure, and decreased MMP-13 expression. ATNF treatment may delay degradation of the extracellular matrix via a decrease in MMP-13 expression. ATNF treatment probably protects articular cartilage by improving the structure of the subchondral bone and reducing the degradation of the cartilage matrix.
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Affiliation(s)
- C H Ma
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
| | - Q Lv
- Department of Radiology, Tong Ji Hospital, Tong Ji University, Shanghai, CN
| | - Y X Yu
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
| | - Y Zhang
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
| | - D Kong
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
| | - K R Niu
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
| | - C Q Yi
- Department of Orthopedic Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, CN
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24
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Manara M, Sinigaglia L. Bone and TNF in rheumatoid arthritis: clinical implications. RMD Open 2015; 1:e000065. [PMID: 26557382 PMCID: PMC4632149 DOI: 10.1136/rmdopen-2015-000065] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 07/13/2015] [Indexed: 12/30/2022] Open
Abstract
Experimental data have demonstrated that tumour necrosis factor (TNF) plays a significant role in systemic and local bone loss related to rheumatoid arthritis (RA). In clinical studies on patients with RA, treatment with TNF inhibitors was able to arrest systemic bone loss assessed by bone mineral density and bone turnover markers, but there is scarce evidence of a clinically meaningful effect of TNF inhibition in preventing fractures. TNF inhibitors showed a higher efficacy in reducing radiographic progression related to the disease compared to methotrexate in randomised clinical trials. Data from observational studies seem to confirm the effectiveness of anti-TNF therapy in reducing joint damage evolution.
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Affiliation(s)
- Maria Manara
- Department of Rheumatology , Gaetano Pini Institute , Milan , Italy
| | - Luigi Sinigaglia
- Department of Rheumatology , Gaetano Pini Institute , Milan , Italy
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25
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Is there a role for Digital X-ray Radiogrammetry as surrogate marker for radiological progression and imaging of structural integrity in rheumatoid arthritis? BMC Musculoskelet Disord 2015; 16:155. [PMID: 26099641 PMCID: PMC4477593 DOI: 10.1186/s12891-015-0577-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 05/08/2015] [Indexed: 01/01/2023] Open
Abstract
Introduction The established scoring techniques based on radiographs present limitations in the evaluation of structural integrity due to high effectiveness of innovative therapeutic strategies. The aim of this study was to evaluate the periarticular mineralisation as detected by Digital X-ray Radiogrammetry (DXR) as surrogate marker for structural integrity during the course of rheumatoid arthritis (RA). Methods 11 centers throughout Germany contributed data of 94 patients with verified RA. The patients were treated with leflunomide or methotrexate during a mean observation period of 22 months. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR using digitized hand radiographs. The radiological assessment of disease progression was estimated by the Sharp Score. Results The Sharp Score revealed no significant change during the study period. DXR-BMD revealed minimal decrease of −1.4 % (leflunomide group) versus a higher reduction of −4.3 % (methotrexate group). Regarding DXR-MCI, a reduction of −2.2 % (leflunomide group) and −4.9 % (methotrexate group) was observed. Conclusion Quantitative data of hand bone mass estimated by the presented DXR-technique may be a complementary precise tool in the identification of RA-related radiographic changes and in the assessment of structural integrity.
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Siu S, Haraoui B, Bissonnette R, Bessette L, Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Kraft J, Lynde C, Gulliver W, Keeling S, Dutz J, Pope JE. Meta-Analysis of Tumor Necrosis Factor Inhibitors and Glucocorticoids on Bone Density in Rheumatoid Arthritis and Ankylosing Spondylitis Trials. Arthritis Care Res (Hoboken) 2015; 67:754-64. [DOI: 10.1002/acr.22519] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 10/25/2014] [Accepted: 11/11/2014] [Indexed: 12/25/2022]
Affiliation(s)
| | - Boulos Haraoui
- Centre Hospitalier de l'Universite de Montreal and Institut de Rhumatologie de Montreal; Montreal Quebec Canada
| | | | - Louis Bessette
- Centre Hospitalier Universitaire de Quebec; Quebec City Quebec Canada
| | - Camille Roubille
- University of Montreal Hospital Research Center and Notre-Dame Hospital; Montreal Quebec Canada
| | | | - Tara Starnino
- Sacre-Coeur Hospital of Montreal and The University of Montreal; Montreal Quebec Canada
| | - Collette McCourt
- University of British Columbia; Vancouver British Columbia Canada
| | | | | | - John Kraft
- Lynde Dermatology; Markham Ontario Canada
| | | | | | | | - Jan Dutz
- University of British Columbia; Vancouver British Columbia Canada
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27
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Gao LX, Jin HT, Xue XM, Wang J, Liu DG. Osteoporosis in rheumatic diseases. World J Rheumatol 2015; 5:23-35. [DOI: 10.5499/wjr.v5.i1.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 09/19/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Rheumatic diseases, characterized by chronic inflammation and damage to various organs and systems, include systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis and other connective tissue diseases. Bone is a target in many inflammatory rheumatic diseases. In recent years, the survival of patients with rheumatic diseases has increased markedly and the relationship between rheumatic diseases and osteoporosis (OP) has become more prominent. OP and related fragility fractures increase the morbidity and mortality of rheumatic disease. The cause of OP in rheumatic diseases is complex. The pathogenesis of OP in rheumatic diseases is multifactorial, including disease and treatment-related factors. Osteoimmunology, a crosstalk between inflammatory and bone cells, provides some insight into the pathogenesis of bone loss in systematic inflammatory diseases. The aim of this article is to review different risk factors in rheumatic diseases. Several factors play a role, such as chronic inflammation, immunological factors, traditional factors, metabolism and drug factors. Chronic inflammation is the most important risk factor and drug treatment is complex in patients with OP and rheumatic disease. Attention should be paid to bone loss in rheumatic disease. Optimal treatment of the underlying rheumatic disease is the first step towards prevention of OP and fractures. Apart from that, a healthy lifestyle is important as well as calcium and vitamin D supplementation. Bisphosphonates or denosumab might be necessary for patients with a low T score.
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28
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The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis. Biomaterials 2015; 44:45-54. [DOI: 10.1016/j.biomaterials.2014.12.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 11/28/2014] [Accepted: 12/16/2014] [Indexed: 12/23/2022]
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Early metacarpal bone mineral density loss using digital x-ray radiogrammetry and 3-tesla wrist MRI in established rheumatoid arthritis: a longitudinal one-year observational study. ARTHRITIS 2015; 2015:852989. [PMID: 25785197 PMCID: PMC4346684 DOI: 10.1155/2015/852989] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 01/13/2015] [Accepted: 01/13/2015] [Indexed: 11/18/2022]
Abstract
Objectives. Early change in rheumatoid arthritis (RA) is characterised by periarticular osteopenia. We investigated the relationship of early metacarpal digital X-ray radiogrammetry bone mineral density (DXR-BMD) change rate (RC-BMD, mg/cm2/month) to longitudinal changes in hand and feet radiographic and wrist MRI scores over 1 year. Materials and Methods. 10 RA patients completed the study and had wrist 3T-MRI and hand and feet X-rays at various time points over 1 year. MRI was scored by RAMRIS, X-ray was done by van der Heijde modified Sharp scoring, and RC-BMD was analysed using dxr-online. Results. There was good correlation amongst the two scorers for MRI measures and ICC for erosions: 0.984, BME: 0.943, and synovitis: 0.657. Strong relationships were observed between RC-BMD at 12-week and 1-year change in wrist marrow oedema (BME) (r = 0.78, P = 0.035) but not with erosion, synovitis, or radiographic scores. Conclusion. Early RC-BMD correlates with 1-year wrist BME change, which is a known predictor of future erosion and joint damage. However, in our pilot study, early RC-BMD did not show relationships to MRI erosion or radiographic changes over 1 year. This may reflect a slower kinetic in the appearance of MRI/radiographic erosions, generating the hypothesis that RC-BMD may be a more sensitive and early structural prognostic marker in RA follow-up.
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Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med 2014; 127:1208-32. [PMID: 24950486 DOI: 10.1016/j.amjmed.2014.06.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 05/22/2014] [Accepted: 06/09/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The study objective was to evaluate and update the safety data from randomized controlled trials of tumor necrosis factor inhibitors in patients treated for rheumatoid arthritis. METHODS A systematic literature search was conducted from 1990 to May 2013. All studies included were randomized, double-blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs). RESULTS Forty-four randomized controlled trials involving 11,700 subjects receiving tumor necrosis factor inhibitors and 5901 subjects receiving placebo or traditional disease-modifying antirheumatic drugs were included. Tumor necrosis factor inhibitor treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% confidence interval [CI], 1.13-1.78) and treatment discontinuation due to adverse events (OR, 1.23; 95% CI, 1.06-1.43) compared with placebo and traditional disease-modifying antirheumatic drug treatments. Specifically, patients taking adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63, respectively) and showed an increased risk of discontinuation due to adverse events (OR, 1.38, 1.67, and 2.04, respectively). In contrast, patients taking etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for malignancy varied across the different tumor necrosis factor inhibitors, none reached statistical significance. CONCLUSIONS These meta-analysis updates of the comparative safety of tumor necrosis factor inhibitors suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis.
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Affiliation(s)
- Tzeyu L Michaud
- Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis
| | - Young Hee Rho
- Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Mass
| | - Tatyana Shamliyan
- Evidence-Based Medicine Quality Assurance Elsevier, Clinical Solutions, Philadelphia, PA
| | - Karen M Kuntz
- Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis
| | - Hyon K Choi
- Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Mass.
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Kim HR, Kim KW, Kim BM, Jung HG, Cho ML, Lee SH. Reciprocal activation of CD4+ T cells and synovial fibroblasts by stromal cell-derived factor 1 promotes RANKL expression and osteoclastogenesis in rheumatoid arthritis. Arthritis Rheumatol 2014; 66:538-48. [PMID: 24574213 DOI: 10.1002/art.38286] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 11/14/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Stromal cell-derived factor 1 (SDF-1) is a chemokine that is involved in the bone-destructive process in rheumatoid arthritis (RA) and bony metastasis in malignancy. This study was undertaken to determine the role and mechanism of SDF-1 in RA-associated osteoclastogenesis. METHODS The expression of SDF-1, tumor necrosis factor α (TNFα), and RANKL in RA synovial tissue was analyzed using confocal microscopy. After synovial fibroblasts and CD4+ T cells were treated with SDF-1, RANKL messenger RNA expression was determined by real-time and reverse transcription polymerase chain reaction. Osteoclastogenesis was assessed by counting tartrate-resistant acid phosphatase-positive multinucleated cells in CD14+ monocytes cultured with SDF-1 in the presence of anticytokine antibodies or signal inhibitors and in monocytes cocultured with SDF-1-pretreated synovial fibroblasts and CD4+ T cells. RESULTS RANKL, TNFα, and SDF-1 were coexpressed in the lining and sublining of RA synovium. SDF-1 stimulated RANKL expression in RA synovial fibroblasts and CD4+ T cells, and TNFα inhibition reduced this stimulation. When monocytes isolated from human peripheral blood were cultured with SDF-1, they were differentiated into osteoclasts in the absence of RANKL. Monocytes were also differentiated into osteoclasts when they were cocultured with SDF-1-pretreated synovial fibroblasts or CD4+T cells; however, this osteoclastogenesis was reduced by TNFα inhibition. CONCLUSION Our findings indicate that SDF-1 induces osteoclastogenesis directly and indirectly via up-regulating RANKL expression in RA synovial fibroblasts and CD4+ T cells, and that this is mediated by TNFα. The axis of SDF-1 and RANKL is a potential therapeutic target for RA-associated bone destruction.
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Affiliation(s)
- Hae-Rim Kim
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
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Pfeil A, Oelzner P, Renz DM, Lehmann G, Wolf G, Boettcher J. Visualisation of structural damage as a surrogate marker of radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis 2014; 73:e24. [PMID: 24218405 DOI: 10.1136/annrheumdis-2013-204786] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Alexander Pfeil
- Department of Internal Medicine III, Jena University Hospital-Friedrich Schiller University Jena, , Jena, Germany
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Kälvesten J, Brismar TB, Persson A. Potential sources of quantification error when retrospectively assessing metacarpal bone loss from historical radiographs by using digital X-ray radiogrammetry: an experimental study. J Clin Densitom 2014; 17:104-8. [PMID: 23664111 DOI: 10.1016/j.jocd.2013.04.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 03/25/2013] [Accepted: 04/09/2013] [Indexed: 12/29/2022]
Abstract
During the past 15 yr, digital X-ray radiogrammetry (DXR) has been used to measure metacarpal bone mineral density (BMD). BMD is often measured in existing cohorts where X-ray images were not acquired in accordance with the DXR imaging protocol (DIP). The purpose of the present study was to analyze how deviations from DIP in historical radiographs may affect the reproducibility of DXR-BMD measurements. Cadaver hand phantoms were used to conduct repeat measurements of deviations from DIP with respect to voltage, exposure, lateral displacement, supination, combination of lateral displacement and supination or rotation, extension of the wrist, and edge enhancement. Direct digital radiography (Aristos; Siemens Healthcare, Erlangen, Germany) was used for image acquisition and dxr-online (Sectra, Linköping, Sweden) for DXR-BMD measurements. The influence of the tested deviations from DIP ranged from 0 to 32.5 mg/cm(2) (0-6.8%). On repetition with the same specimen, none of the deviations resulted in a within-specimen reproducibility error greater than 2 mg/cm(2) (0.4%, equivalent to a T-score of 0.042). Among the tested deviations, all except tube voltage had a magnitude greater than the normal measurement noise for the technique and must therefore be considered when planning a study based on historical images.
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Affiliation(s)
- Johan Kälvesten
- Division of Radiology, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Östergötland County Council, University Hospital, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; Sectra Imtec AB, Linköping, Sweden.
| | - Torkel B Brismar
- Division of Radiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Persson
- Division of Radiology, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Östergötland County Council, University Hospital, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
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Chemokine and cytokine levels in osteoarthritis and rheumatoid arthritis synovial fluid. J Immunol Methods 2013; 396:134-9. [DOI: 10.1016/j.jim.2013.08.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 08/03/2013] [Accepted: 08/12/2013] [Indexed: 01/22/2023]
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Cutolo M, Kitas GD, van Riel PLCM. Burden of disease in treated rheumatoid arthritis patients: going beyond the joint. Semin Arthritis Rheum 2013; 43:479-88. [PMID: 24080116 DOI: 10.1016/j.semarthrit.2013.08.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 08/12/2013] [Accepted: 08/13/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The disease burden in rheumatoid arthritis (RA) extends beyond the joint. This article evaluates the physical and psychosocial extra-articular burden of treated RA and relationships among diverse disease manifestations. METHODS MEDLINE searches identified papers published in English from January 2003 to December 2012 that evaluated systemic complications and psychosocial aspects associated with RA. Preference was given to studies with randomized cohorts and large (>100) sample sizes. Of 378 articles identified in the initial search, 118 were selected for inclusion. RESULTS RA is associated with multiple comorbidities and psychosocial impairments, including cardiovascular disease, osteoporosis, interstitial lung disease, infection, malignancies, fatigue, depression, cognitive dysfunction, reduced work performance, work disability, and decreased health-related quality of life. The etiology of the extra-articular burden may reflect the systemic inflammation and immune system alteration associated with RA, metabolic imbalances and side effects related to treatment, or the influence of comorbidities. Strategies that may help to reduce the extra-articular disease burden include personalized medicine and the potential introduction of treatments with new mechanisms of action. CONCLUSION Despite improvements in treating joint disease, the extra-articular burden in RA remains substantial, encompassing multiple comorbidities and psychosocial impairments.
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Affiliation(s)
- Maurizio Cutolo
- Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, Genoa 16132, Italy.
| | - George D Kitas
- Clinical Rheumatology and R&D Director, Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, United Kingdom; and Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, UK
| | - Piet L C M van Riel
- Rheumatology, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Kawai VK, Grijalva CG, Arbogast PG, Curtis JR, Solomon DH, Delzell E, Chen L, Ouellet-Hellstrom R, Herrinton L, Liu L, Mitchell EF, Stein CM, Griffin MR. Initiation of tumor necrosis factor α antagonists and risk of fractures in patients with selected rheumatic and autoimmune diseases. Arthritis Care Res (Hoboken) 2013; 65:1085-94. [PMID: 23281339 DOI: 10.1002/acr.21937] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 12/11/2012] [Indexed: 12/16/2022]
Abstract
OBJECTIVE We tested the hypothesis that initiation of tumor necrosis factor α (TNFα) antagonists reduced the risk of fractures compared to nonbiologic comparators in patients with autoimmune diseases. METHODS Using 4 large administrative databases, we assembled retrospective cohorts of patients with autoimmune diseases who initiated either a TNFα antagonist or a nonbiologic medication. We identified 3 mutually exclusive disease groups: rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and a combined group: psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). We used baseline covariate data to calculate propensity scores (PS) for each disease group and used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). We compared the risk of combined hip, radius/ulna, humerus, or pelvic fractures between PS-matched cohorts of new users of TNFα antagonists and nonbiologic comparators. RESULTS We identified 9,020, 2,014, and 2,663 new PS-matched episodes of TNFα antagonist and nonbiologic comparator use in RA, IBD, and PsO-PsA-AS cohorts, respectively. The risk of combined fractures was similar between new users of TNFα antagonists and nonbiologic comparators for each disease (HR 1.17, 95% CI 0.91-1.51; HR 1.49, 95% CI 0.72-3.11; and HR 0.92, 95% CI 0.47-1.82 for RA, IBD, and PsO-PsA-AS, respectively). In RA, the risk of combined fractures was associated with an average daily dosage of prednisone equivalents >10 mg/day at baseline compared with no glucocorticoid (HR 1.54, 95% CI 1.03-2.30). CONCLUSION The risk of fractures did not differ between initiators of a biologic agent and a nonbiologic comparator for any disease studied. Among RA patients, use of >10 mg/day of prednisone equivalents at baseline increased the fracture risk.
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Affiliation(s)
- Vivian K Kawai
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Mendoza Pinto C, García Carrasco M, Etchegaray Morales I, Jiménez Hernández M, Méndez Martínez S, Jiménez Hernández C, Briones Rojas R, Ramos Alvarez G, Rodríguez Gallegos A, Montiel Jarquín A, López Colombo A, Cervera R. Bone mineral density in systemic lupus erythematosus women one year after rituximab therapy. Lupus 2013; 22:1128-34. [PMID: 23989736 DOI: 10.1177/0961203313502861] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The objective of this study was to assess the effects of rituximab on bone mineral density (BMD) in women with systemic lupus erythematosus (SLE) 1 year after treatment. Thirty active female SLE patients treated with rituximab were compared with 43 SLE women not treated with rituximab. BMD was measured using dual energy X-ray absorptiometry (DEXA) before initiating biologic therapy and after 1 year. The mean age was 38.5 ± 2.1 years; median disease duration was 7 years. In the rituximab group, after 1 year of follow-up, BMD at the femoral neck (FN) decreased from 0.980 ± 0.130 g/cm(2) to 0.809 ± 0.139 g/cm(2) (-17.4%; p=0.001). Similarly, BMD at the lumbar spine (LS) decreased from 1.062 ± 0.137 g/cm(2) to 0.893 ± 0.194 g/cm(2) (-15.8%; p=0.001). In control subjects, BMD at the FN decreased from 0.914 ± 0.193 g/cm(2) to 0.890 ± 0.135 g/cm(2) (-2.6%; p=0.001), and BMD at the LS decreased from 0.926 ± 0.128 g/cm(2) to 0.867 ± 0.139 g/cm(2) (-6.2%; p=0.09). After 1 year, SLE patients had lower BMD at both the FN and LS, but the loss was greater in postmenopausal patients who had received rituximab therapy.
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Affiliation(s)
- C Mendoza Pinto
- 1Systemic Autoimmune Diseases Research Unit, IMSS, Puebla, México; Department of Immunology and Rheumatology, BUAP, Puebla, México; Department of Epidemiology and Health Public, BUAP, Puebla, México; Department of Radiology, Laboratorios Clínicos de Puebla, México; Direction of Education and Research, IMSS, Puebla, México; State Research Department, Research Unit, IMSS, Puebla, México; and Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain
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Hoff M, Kavanaugh A, Haugeberg G. Hand Bone Loss in Patients with Psoriatic Arthritis: Posthoc Analysis of IMPACT II Data Comparing Infliximab and Placebo. J Rheumatol 2013; 40:1344-8. [DOI: 10.3899/jrheum.121376] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Objective.In rheumatoid arthritis (RA), anti-tumor necrosis factor (anti-TNF) treatment is shown to reduce but not to arrest the rate of hand bone loss. This has not been assessed in psoriatic arthritis (PsA). Our objective was to examine changes in cortical hand bone density in patients with PsA treated with placebo or infliximab (IFX).Methods.Patients in IMPACT II (Induction and Maintenance Psoriatic Arthritis Clinical Trial 2) were randomized to placebo or IFX. After Week 24, all received IFX. In a subset of 120 patients, cortical hand bone density was assessed at Weeks 0, 24, and 54 by digital X-ray radiogrammetry (dxr-BMD) on the same radiographs scored for joint damage.Results.Changes from baseline to 24 weeks in dxr-BMD were −0.30% (SD 1.1%) in the placebo group and −0.08% (SD 1.4%) in the IFX group (p = 0.63). Between baseline and 54 weeks the changes were −0.71% (SD 2.1%) in the placebo group and 0.15% (SD 1.7%) in the IFX group (p = 0.07), and between 24 and 54 weeks −0.41% (SD 1.4%) and 0.23% (SD 0.8%), respectively (p = 0.05). No significant correlation was found between change in dxr-BMD and radiographic damage.Conclusion.This pilot study indicates that hand bone loss in PsA patients treated with anti-TNF can be arrested. Assessment of hand bone density may thus be a potential outcome measure for bone involvement and a response variable to treatment in PsA.
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Dimitroulas T, Nikas SN, Trontzas P, Kitas GD. Biologic therapies and systemic bone loss in rheumatoid arthritis. Autoimmun Rev 2013; 12:958-66. [PMID: 23542506 DOI: 10.1016/j.autrev.2013.03.015] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 03/12/2013] [Indexed: 12/12/2022]
Abstract
Chronic inflammation affects bone metabolism leading to disequilibrium in the rates of bone resorption and repair and subsequently to local and generalized bone loss. Osteoporosis represents an important co-morbidity of rheumatoid arthritis (RA) patients, which exhibit increased fracture risk. Osteoclasts play a pivotal role in the development and progression of bone loss, while resident synovial cells such as T cells, monocytes and synovial fibroblasts have been identified as sources of osteoclast differentiation signals in RA. This process is mainly mediated through the receptor activator of nuclear-kappa B ligand (RANKL) signalling system, which is upregulated by numerous proinflammatory cytokines involved in the pathogenesis of RA. Improved knowledge of the association between cells and cytokines of the immune system and their relationship to bone remodeling has revealed several promising targets for the treatment of inflammatory bone loss in RA. In this respect, initiation of biologic therapies targeting inflammatory cytokines and/or lymphocyte activation has modified RA therapy not only by blocking local and systemic inflammatory cascades but also by providing beneficial effects against bone and joint degradation. In this article we briefly present the modern view of the mechanisms that govern inflammatory bone loss, highlighting the role of cytokine-induced molecular pathways, and discuss in detail the effects of different biologic treatment strategies on bone mass in RA patients.
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Affiliation(s)
- Theodoros Dimitroulas
- Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands, UK.
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Rezaei H, Saevarsdottir S, Geborek P, Petersson IF, van Vollenhoven RF, Forslind K. Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial. BMC Musculoskelet Disord 2013; 14:79. [PMID: 23497111 PMCID: PMC3599105 DOI: 10.1186/1471-2474-14-79] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 02/27/2013] [Indexed: 01/01/2023] Open
Abstract
Background To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months. Methods From the total SWEFOT trial population, 159 patients had hand radiographs correctly timed and taken with same modality to be analyzed with DXR. All patients started treatment with methotrexate. After 3–4 months, patients with DAS28 > 3.2 were randomized to add sulfasalazine and hydroxychloroquine (triple therapy) or infliximab (MTX + INF). Those with DAS28 ≤3.2 were followed in regular care. Radiographic progression over 24 months was scored according to the Sharp van der Heijde score (SHS) and defined as >5 increase in T-SHS over 24 months. Hand bone mineral density (BMD) was measured by DXR at inclusion and 12 months and a change ≥2.5 mg/cm2/month was used as a cut-off for HBL. Results In the MTX responders, triple therapy, and MTX + INF groups, the proportions with HBL were 4.1%, 22.2% and 16.4%, respectively (p = 0.01), and the mean (SD) radiological progression in these groups was 3.91 (6.72), 7.40 (14.63) and 2.72 (4.55) respectively (p = 0.06). Patients with HBL had significantly greater risk for radiographic progression, compared with patients without HBL (odds ratio 3.09, 95% CI =1.20–7.79, p = 0.02). Conclusions Non-responders to MTX had a significantly greater risk of HBL than MTX-responders, despite the add-on therapies. Patients with HBL during the 12 months had greater risk of radiographic progression after 24 months. Evaluation of HBL may help to identify patients who are at risk of radiographic progression.
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Affiliation(s)
- Hamed Rezaei
- Unit of Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, SE 171 76, Sweden.
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Moon SJ, Ahn IE, Kwok SK, Park KS, Min JK, Park SH, Kim HY, Ju JH. Periarticular osteoporosis is a prominent feature in early rheumatoid arthritis: estimation using shaft to periarticular bone mineral density ratio. J Korean Med Sci 2013; 28:287-94. [PMID: 23399828 PMCID: PMC3565142 DOI: 10.3346/jkms.2013.28.2.287] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 12/17/2012] [Indexed: 12/14/2022] Open
Abstract
We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (ĸ = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration ≤ 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.
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Affiliation(s)
- Su-Jin Moon
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Inhye E. Ahn
- Department of Internal Medicine, The Methodist Hospital, Houston, TX, USA
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyung-Su Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jun-Ki Min
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ho-Youn Kim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyeon Ju
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Abstract
PURPOSE OF REVIEW Tumor necrosis factor (TNF) inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. RECENT FINDINGS There are many studies of the effects of TNF inhibitors on markers of bone turnover; however, few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the antiresorptive effects of anti-TNF therapy are related to control of disease activity. SUMMARY The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional nonbiologic therapies in the prevention of bone loss and fractures.
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Forslind K, Kälvesten J, Hafström I, Svensson B. Does digital X-ray radiogrammetry have a role in identifying patients at increased risk for joint destruction in early rheumatoid arthritis? Arthritis Res Ther 2012; 14:R219. [PMID: 23068060 PMCID: PMC4060357 DOI: 10.1186/ar4058] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 09/25/2012] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION The aim of this study was to investigate the role of hand bone mineral density (BMD) loss analyzed with digital X-ray radiogrammetry (DXR) in early rheumatoid arthritis (RA) as a predictor for progression of joint damage. METHODS In 379 patients with early RA, baseline and one-year hand BMD was measured with DXR and the hand bone loss (HBL) was analyzed using the smallest detectable change (HBLsdc) and tertiles (HBLtertiles). Joint damage in hands and feet were scored according to the Sharp van der Heijde (SHS) method at baseline and at one, two, five and eight years. At the same time-points Disease Activity Score (DAS28) was calculated and functional disability assessed. Rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed at baseline. RESULTS Sixty-six percent of the patients had hand BMD loss in the first year of RA determined by HBLsdc and 65% by HBLtertiles. Radiographic progression after two, five and eight years was associated with hand bone loss defined by HBLsdc. By HBLtertiles there were significant associations at all time-points except at eight years. The change in DXR at one year (ChDXR1yr) correlated significantly and inversely with the change in SHS (ChSHS) at two, five and eight years. Multivariate analysis showed that only change in SHS during the first year and the presence of anti-CCP were independent predictors of long-term progressive joint damage. If radiographic scores were not included, DXR-BMD loss was an independent predictor. Patients with great bone loss by HBLtertiles had significantly more often high disease activity after two years. However, neither bone loss by HBLsdc or HBLtertiles nor by ChDXR1yr was an independent predictor of remission after two, five and eight years. CONCLUSIONS This study confirms previous reports of an association of decrease in DXR-BMD during the first disease year with progression of radiographic joint damage over an extended period of time. This association was independent in a regression model only when radiological findings were excluded suggesting a possible predictive role of DXR-BMD in clinical practice when radiographic evaluation is not available. However, further studies are required before this can be established.
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Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann Rheum Dis 2012; 71:891-8. [PMID: 22128078 PMCID: PMC3371224 DOI: 10.1136/ard.2011.149849] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 10/06/2011] [Indexed: 12/27/2022]
Abstract
BACKGROUND Adalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive hand osteoarthritis (HOA) were assessed. METHODS Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSSTM). RESULTS The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab. Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients. CONCLUSION Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo.
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Affiliation(s)
- Gust Verbruggen
- Rheumatology Department, Ghent University Hospital, Ghent, Belgium.
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Kim SY, Schneeweiss S, Liu J, Solomon DH. Effects of disease-modifying antirheumatic drugs on nonvertebral fracture risk in rheumatoid arthritis: a population-based cohort study. J Bone Miner Res 2012; 27:789-96. [PMID: 22162140 PMCID: PMC3725780 DOI: 10.1002/jbmr.1489] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Several prior investigations demonstrate an improvement in bone mineral density associated with use of tumor necrosis factor inhibitors (TNFi). We compared the risk of osteoporotic fractures among patients with rheumatoid arthritis (RA) initiating a disease-modifying antirheumatic drug (DMARD). A population-based cohort study was conducted using health care utilization data (1996-2008) from a Canadian province and a U.S. commercial insurance plan. Patients with at least two RA diagnoses were identified, and follow-up began with the first prescription for a DMARD. Drug regimens were categorized into three mutually exclusive hierarchical groups: (1) TNFi with or without nonbiologic DMARDs (nbDMARD), (2) methotrexate (MTX) without a TNFi, or (3) other nbDMARD without a TNFi or MTX. Main outcomes were hospitalizations for fractures of the hip, wrist, humerus, or pelvis based on diagnoses and procedure codes. The study cohort consisted of 16,412 RA patients with 25,988 new treatment episodes: 5856 TNFi, 12,554 MTX, and 7578 other nbDMARD. The incidence rate per 1000 person-years for osteoporotic fracture were 5.11 [95% confidence interval (CI) 3.50-7.45] for TNFi, 5.35 (95% CI 4.08-7.02) for MTX, and 6.38 (95% CI 3.78-10.77) for other nbDMARD. After multivariable adjustment for osteoporosis and fracture-related risk factors, the risk of nonvertebral osteoporotic fracture was not different in either TNFi [hazard ratio (HR) 1.07, 95% CI 0.57-1.98] or MTX (HR 1.18, 95% CI 0.60-2.34) compared with nbDMARD. Among subjects diagnosed with RA, the adjusted risk of nonvertebral fracture was similar across persons starting a TNFi, MTX, or other nbDMARD.
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Affiliation(s)
- Seo Young Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, MA 02120, USA.
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Paquet J, Goebel JC, Delaunay C, Pinzano A, Grossin L, Cournil-Henrionnet C, Gillet P, Netter P, Jouzeau JY, Moulin D. Cytokines profiling by multiplex analysis in experimental arthritis: which pathophysiological relevance for articular versus systemic mediators? Arthritis Res Ther 2012; 14:R60. [PMID: 22414623 PMCID: PMC3446427 DOI: 10.1186/ar3774] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 11/23/2011] [Accepted: 03/13/2012] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION We have taken advantage of the large screening capacity of a multiplex immunoassay to better define the respective contribution of articular versus systemic cytokines in experimental arthritis. METHODS We performed a follow up (from 7 hours to 14 days) multiplex analysis of 24 cytokines in synovial fluid and sera of rats developing Antigen-Induced Arthritis (AIA) and confronted their protein level changes with molecular, biochemical, histological and clinical events occurring in the course of the disease. RESULTS The time-scheduled findings in arthritic joints correlated with time-dependent changes of cytokine amounts in joint effusions but not with their blood levels. From seven hours after sensitization, high levels of chemokines (MCP-1, MIP1α, GRO/KC, RANTES, eotaxin) were found in synovial fluid of arthritic knees whereas perivascular infiltration occurred in the synovium; local release of inflammatory cytokines (IFNγ, IL-1β, IL-6) preceded the spreading of inflammation and resulted in progressive degradation of cartilage and bone. Finally a local overexpression of several cytokines/adipocytokines poorly described in arthritis (IL-13, IL-18, leptin) was observed. CONCLUSIONS Distinct panels of cytokines were found in arthritic fluid during AIA, and the expected effect of mediators correlated well with changes occurring in joint tissues. Moreover, multiplex analysis could be helpful to identify new pathogenic mediators and to elucidate the mechanisms supporting the efficacy of putative targeted therapies.
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Affiliation(s)
- Joseph Paquet
- Physiopathologie, Pharmacologie et Ingénierie Articulaire - PPIA-UMR 7561 CNRS UHP, Université de Lorraine, Faculté de Médecine, BP 184, 54505 Vandoeuvre Les Nancy, France
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Inhibitors of JAK for the treatment of rheumatoid arthritis: rationale and clinical data. ACTA ACUST UNITED AC 2012. [DOI: 10.4155/cli.11.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Dhainaut A, Hoff M, Kälvesten J, Lydersen S, Forslind K, Haugeberg G. Long-term in-vitro precision of direct digital X-ray radiogrammetry. Skeletal Radiol 2011; 40:1575-9. [PMID: 21560007 PMCID: PMC3198192 DOI: 10.1007/s00256-011-1187-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 03/01/2011] [Accepted: 04/25/2011] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Digital X-ray radiogrammetry (DXR) calculates peripheral bone mineral density (BMD) from hand radiographs. The short-term precision for direct DXR has been reported to be highly satisfactory. However, long-term precision for this method has not been examined. Thus, the aim of this study was to examine the long-term in-vitro precision for the new direct digital version of DXR. MATERIALS AND METHODS The in-vitro precision for direct DXR was tested with cadaver phantoms on four different X-ray systems at baseline, 3 months, 6 months, and in one machine also at 12 months. At each time point, 31 measurements were performed. RESULTS The in-vitro longitudinal precision for the four radiographic systems ranged from 0.22 to 0.43% expressed as coefficient of variation (CV%). The smallest detectable difference (SDD) ranged from 0.0034 to 0.0054 g/cm(2). CONCLUSIONS The in vitro long-term precision for direct DXR was comparable to the previous reported short-term in-vitro precision for all tested X-ray systems. These data show that DXR is a stable method for detecting small changes in bone density during 6-12 months of follow-up.
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Affiliation(s)
- Alvilde Dhainaut
- INM, Rheumatology, Norwegian University of Science and Technology, MTS 7489 Trondheim, Norway
- Department of Rheumatology, St. Olav’s Hospital, Trondheim, Norway
| | - Mari Hoff
- INM, Rheumatology, Norwegian University of Science and Technology, MTS 7489 Trondheim, Norway
- Department of Rheumatology, St. Olav’s Hospital, Trondheim, Norway
| | | | - Stian Lydersen
- Unit for Applied Clinical Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kristina Forslind
- Section of Rheumatology, Helsingborgs Lasarett, Helsingborg, Sweden
- Section of Rheumatology at the Institution of Clinical Science, University Hospital, Lund, Sweden
| | - Glenn Haugeberg
- INM, Rheumatology, Norwegian University of Science and Technology, MTS 7489 Trondheim, Norway
- Department of Rheumatology, Sørlandet Hospital, Kristiansand S, Norway
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Forsblad-d'Elia H, Carlsten H. Bone mineral density by digital X-ray radiogrammetry is strongly decreased and associated with joint destruction in long-standing rheumatoid arthritis: a cross-sectional study. BMC Musculoskelet Disord 2011; 12:242. [PMID: 22024200 PMCID: PMC3226572 DOI: 10.1186/1471-2474-12-242] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 10/24/2011] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The aims were to explore bone mineral density (BMD) by digital X-ray radiogrammetry (DXR) in postmenopausal women with long-lasting rheumatoid arthritis (RA) in relation to dual x-ray absorptiometry (DXA)-BMD, joint destruction by conventional radiographs and disease related variables in a cross-sectional study. METHODS Seventy-five postmenopausal women with RA were examined by DXA measuring DXA-BMD of the forearm, total hip and lumbar spine, by scoring joint destruction on plain radiographs by the method of Larsen and by DXR-BMD in metacarpals two to four. The DXR-BMD results of the RA women were compared with an age and sex-matched reference database. A function of DXR-BMD in relation to age and disease duration was created. Associations were investigated by bivariate and multiple linear regression analyses. RESULTS DXR-BMD was strongly decreased in RA patients compared to the reference database (p < 0.001). Calculations showed that DXR-BMD was not markedly influenced the first years after diagnosis of RA, but between approximately 5-10 years of disease there was a steep decline in DXR-BMD which subsequently levelled off. In multiple regression analyses disease duration, CRP and DXR-BMD were independent variables associated with Larsen score (R2= 0.64). Larsen score and BMD forearm were independent determinants of DXR-BMD (R2 = 0.79). CONCLUSIONS DXR-BMD was strongly reduced and associated with both Larsen score and DXA-BMD forearm in these postmenopausal women with RA implying that DXR-BMD is a technique that reflects both the erosive process and bone loss adjacent to affected joints.
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Affiliation(s)
- Helena Forsblad-d'Elia
- Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Centre for Bone and Arthritis Research, Box 480, S-405 30 Gothenburg, Sweden.
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Fukae J, Isobe M, Kitano A, Henmi M, Sakamoto F, Narita A, Ito T, Mitsuzaki A, Shimizu M, Tanimura K, Matsuhashi M, Kamishima T, Atsumi T, Koike T. Radiographic prognosis of finger joint damage predicted by early alteration in synovial vascularity in patients with rheumatoid arthritis: Potential utility of power doppler sonography in clinical practice. Arthritis Care Res (Hoboken) 2011; 63:1247-53. [DOI: 10.1002/acr.20517] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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