|
1
|
Baraliakos X, Deodhar A, van der Heijde D, Van den Bosch F, Magrey M, Maksymowych WP, Tomita T, Xu H, Massow U, Vaux T, Prajapati C, Manente M, Marten A, Gensler LS. Long-term safety and efficacy of bimekizumab in axial spondyloarthritis: 2-year results from two phase 3 studies. Rheumatology (Oxford) 2025; 64:3534-3546. [PMID: 39798135 DOI: 10.1093/rheumatology/keaf009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/20/2024] [Accepted: 12/21/2024] [Indexed: 01/15/2025] Open
Abstract
OBJECTIVES Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, previously demonstrated efficacy and was well tolerated to 1 year in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). Here, we report bimekizumab safety and efficacy to 2 years. METHODS Patients completing week 52 in the phase 3 studies BE MOBILE 1 (nr-axSpA; NCT03928704) and 2 (r-axSpA; NCT03928743) were eligible for an ongoing open-label extension (OLE; NCT04436640). All OLE patients received subcutaneous bimekizumab 160 mg every 4 weeks. Safety outcomes for patients who received ≥1 bimekizumab dose, and efficacy outcomes for all randomized patients, are reported to week 104. RESULTS In the OLE (weeks 52 - 104), 70.8% (367/518) of patients reported ≥1 treatment-emergent adverse event (TEAE). Most frequent TEAEs [exposure-adjusted incidence rate per 100 patient-years (EAIR/100PY)] were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across weeks 0 - 52 and 52 - 104.At week 104, >50% of randomized patients (N = 586) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40); ∼60% achieved Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity (<2.1) and >30% achieved ASDAS inactive disease (<1.3). Bimekizumab demonstrated sustained suppression of MRI inflammation at week 104, with >57% of patients achieving MRI remission. CONCLUSIONS The safety profile of bimekizumab remained consistent with prior reports, with no new safety signals identified. 1-year efficacy was sustained to 2 years across patients with nr-axSpA and r-axSpA.
Collapse
Affiliation(s)
| | - Atul Deodhar
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR, USA
| | | | - Filip Van den Bosch
- Department of Internal Medicine and Pediatrics, Ghent University and VIB Center for Inflammation Research, Ghent, Belgium
| | - Marina Magrey
- Case Western Reserve University, University Hospitals, Cleveland, OH, USA
| | | | - Tetsuya Tomita
- Graduate School of Health Science, Morinomiya University of Medical Science, Osaka, Japan
| | - Huji Xu
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Affiliated to Second Military Medical University, Shanghai, People's Republic of China
| | | | | | | | | | | | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California, San Francisco, CA, USA
| |
Collapse
|
|
2
|
Mease PJ, Gensler LS, Orbai AM, Warren RB, Bajracharya R, Ink B, Marten A, Massow U, Shende V, Manente M, Peterson L, White K, Landewé R, Poddubnyy D. Long-term safety of bimekizumab in adult patients with axial spondyloarthritis or psoriatic arthritis: pooled results from integrated phase IIb/III clinical studies. RMD Open 2025; 11:e005026. [PMID: 40194794 PMCID: PMC11977475 DOI: 10.1136/rmdopen-2024-005026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/02/2025] [Indexed: 04/09/2025] Open
Abstract
OBJECTIVE To assess the long-term safety profile of bimekizumab (BKZ) in patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). METHODS Safety data pooled from six integrated phase IIb/III studies in axSpA and PsA are reported (to the July 2022 data-cut for phase III) for patients who received ≥1 dose of BKZ 160 mg every 4 weeks. Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rate per 100 patient-years (EAIR/100 PY). RESULTS The axSpA and PsA safety pools included 848 (total BKZ exposure: 2034.4 PY) and 1407 patients (2590.8 PY), respectively. TEAEs occurred at an EAIR/100 PY of 136.9 in axSpA and 139.6 in PsA; study discontinuation due to TEAEs was low (axSpA: 2.7/100 PY; PsA: 3.1/100 PY). The three most frequently reported TEAEs were SARS-CoV-2 (COVID-19) infection (axSpA: 7.8/100 PY; PsA: 8.8/100 PY), nasopharyngitis (axSpA: 8.2/100 PY; PsA: 7.7/100 PY) and upper respiratory tract infection (axSpA: 5.0/100 PY; PsA: 5.6/100 PY). EAIR/100 PY of oral candidiasis was 3.7 in axSpA and 4.2 in PsA; most events were mild/moderate. EAIR of BKZ discontinuation due to oral candidiasis was low (both axSpA and PsA: 0.3/100 PY). No systemic fungal infections or cases of active tuberculosis were reported. EAIRs of adjudicated definite/probable inflammatory bowel disease, uveitis, adjudicated major adverse cardiovascular events and adjudicated suicidal ideation/behaviour were low. CONCLUSION Overall, BKZ demonstrated good tolerability, with TEAE EAIRs comparable between axSpA and PsA cohorts, remaining stable over extended treatment periods. No new safety signals were identified. TRIAL REGISTRATION NUMBERS NCT02963506 (BE AGILE); NCT03355573 (BE AGILE 2); NCT03928704 (BE MOBILE 1); NCT03928743 (BE MOBILE 2); NCT04436640 (BE MOVING); NCT02969525 (BE ACTIVE); NCT03347110 (BE ACTIVE 2); NCT03895203 (BE OPTIMAL); NCT03896581 (BE COMPLETE); NCT04009499 (BE VITAL).
Collapse
Affiliation(s)
- Philip J Mease
- Department of Rheumatology, Swedish Medical Center/Providence St. Joseph Health, Seattle, Washington, USA
- University of Washington, Seattle, Washington, USA
| | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California, San Francisco, San Francisco, California, USA
| | - Ana-Maria Orbai
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Richard B Warren
- Dermatology Centre, Northern Care Alliance NHS Foundation Trust, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | | | | | | | | | | | | | | | | | - Robert Landewé
- Amsterdam Rheumatology & Clinical Immunology Center, Amsterdam, The Netherlands
- Zuyderland MC, Heerlen, The Netherlands
| | - Denis Poddubnyy
- Division of Rheumatology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
3
|
Brown MA, Rudwaleit M, van Gaalen FA, Haroon N, Gensler LS, Fleurinck C, Marten A, Massow U, de Peyrecave N, Vaux T, White K, Deodhar A, van der Horst-Bruinsma I. Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials. Ann Rheum Dis 2024; 83:1722-1730. [PMID: 38977276 PMCID: PMC12056585 DOI: 10.1136/ard-2024-225933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024]
Abstract
OBJECTIVES Acute anterior uveitis ('uveitis') is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management. We report pooled analyses of uveitis incidence in patients receiving bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, from phase 2b/3 trials. METHODS Data were pooled for patients receiving BKZ 160 mg or placebo in the double-blind treatment period of the phase 3 BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and BE MOBILE 2 (NCT03928743; radiographic axSpA) trials. Data were separately pooled for patients treated with at least one BKZ dose in the BE MOBILE trials and their ongoing open-label extension (OLE; NCT04436640), and the phase 2b BE AGILE trial (NCT02963506; radiographic axSpA) and its ongoing OLE (NCT03355573). Uveitis rates and exposure-adjusted incidence rates (EAIR)/100 patient-years (PYs) are reported. RESULTS In the BE MOBILE 1 and 2 double-blind treatment period, 0.6% (2/349) of patients receiving BKZ experienced uveitis vs 4.6% (11/237) receiving placebo (nominal p=0.001; EAIR (95% CI): 1.8/100 PYs (0.2 to 6.7) vs 15.4/100 PYs (95% CI 7.7 to 27.5)). In patients with history of uveitis, EAIR was lower in patients receiving BKZ (6.2/100 PYs (95% CI 0.2 to 34.8); 1.9%) vs placebo (70.4/100 PYs (95% CI 32.2 to 133.7); 20.0%; nominal p=0.004). In the phase 2b/3 pool (N=848; BKZ exposure: 2034.4 PYs), EAIR remained low (1.2/100 PYs (95% CI 0.8 to 1.8)). CONCLUSIONS Bimekizumab, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.
Collapse
Affiliation(s)
- Matthew A Brown
- Genomics England, London, UK
- Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | | | - Floris A van Gaalen
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Nigil Haroon
- University Health Network, Schroeder Arthritis Institute, Department of Medicine/Rheumatology, University of Toronto, Toronto, Ontario, Canada
| | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California, San Francisco, California, USA
| | | | | | | | | | | | | | - Atul Deodhar
- Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, Oregon, USA
| | | |
Collapse
|
|
4
|
Meyer A. Illuminating the impact of γδ T cells in man and mice in spondylarthritides. Eur J Immunol 2024; 54:e2451071. [PMID: 39077953 DOI: 10.1002/eji.202451071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/31/2024]
Abstract
Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.
Collapse
MESH Headings
- Animals
- Humans
- Mice
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Disease Models, Animal
- Interleukin-23/immunology
- Interleukin-23/metabolism
- Interleukin-23/genetics
- Interleukin-17/immunology
- Interleukin-17/metabolism
- HLA-B27 Antigen/genetics
- HLA-B27 Antigen/immunology
- Genetic Predisposition to Disease
- Spondylarthritis/immunology
- Receptors, Interleukin/genetics
- Receptors, Interleukin/metabolism
- Receptors, Interleukin/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
Collapse
Affiliation(s)
- Anja Meyer
- Center for Molecular Neurobiology Hamburg, Institute for Systems Immunology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
5
|
Dawalibi A, Alosaimi AA, Mohammad KS. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments. Int J Mol Sci 2024; 25:8163. [PMID: 39125732 PMCID: PMC11311339 DOI: 10.3390/ijms25158163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.
Collapse
Affiliation(s)
- Ahmad Dawalibi
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Amal Ahmed Alosaimi
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh 11432, Saudi Arabia;
| | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| |
Collapse
|
|
6
|
Mease PJ, Gladman DD, Merola JF, Nash P, Grieve S, Laliman-Khara V, Willems D, Taieb V, Prickett AR, Coates LC. Comparative efficacy and safety of bimekizumab in psoriatic arthritis: a systematic literature review and network meta-analysis. Rheumatology (Oxford) 2024; 63:1779-1789. [PMID: 38218744 PMCID: PMC11215990 DOI: 10.1093/rheumatology/kead705] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/09/2023] [Accepted: 12/02/2023] [Indexed: 01/15/2024] Open
Abstract
OBJECTIVES To understand the relative efficacy and safety of bimekizumab, a selective inhibitor of IL-17F in addition to IL-17A, vs other biologic and targeted synthetic DMARDs (b/tsDMARDs) for PsA using network meta-analysis (NMA). METHODS A systematic literature review (most recent update conducted on 1 January 2023) identified randomized controlled trials (RCTs) of b/tsDMARDs in PsA. Bayesian NMAs were conducted for efficacy outcomes at Weeks 12-24 for b/tsDMARD-naïve and TNF inhibitor (TNFi)-experienced patients. Safety at Weeks 12-24 was analysed in a mixed population. Odds ratios (ORs) and differences of mean change with the associated 95% credible interval (CrI) were calculated for the best-fitting models, and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine relative rank. RESULTS The NMA included 41 RCTs for 22 b/tsDMARDs. For minimal disease activity (MDA), bimekizumab ranked 1st in b/tsDMARD-naïve patients and 2nd in TNFi-experienced patients. In b/tsDMARD-naïve patients, bimekizumab ranked 6th, 5th and 3rd for ACR response ACR20/50/70, respectively. In TNFi-experienced patients, bimekizumab ranked 1st, 2nd and 1st for ACR20/50/70, respectively. For Psoriasis Area and Severity Index 90/100, bimekizumab ranked 2nd and 1st in b/tsDMARD-naïve patients, respectively, and 1st and 2nd in TNFi-experienced patients, respectively. Bimekizumab was comparable to b/tsDMARDs for serious adverse events. CONCLUSION Bimekizumab ranked favourably among b/tsDMARDs for efficacy on joint, skin and MDA outcomes, and showed comparable safety, suggesting it may be a beneficial treatment option for patients with PsA.
Collapse
Affiliation(s)
- Philip J Mease
- Swedish Medical Center and Providence St. Joseph Health, University of Washington, Seattle, WA, USA
| | - Dafna D Gladman
- Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, ON, Canada
| | - Joseph F Merola
- Department of Dermatology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Rheumatology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
| | - Peter Nash
- School of Medicine, Griffith University, Brisbane, QLD, Australia
| | - Stacy Grieve
- Department of RWA Health Economics, Cytel, Inc, Waltham, MA, USA
| | | | | | | | | | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford and Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
| |
Collapse
|
|
7
|
Dubreuil M, Navarro-Compán V, Boonen A, Gaffney K, Gensler LS, de la Loge C, Vaux T, Fleurinck C, Massow U, Taieb V, Mørup MF, Deodhar A, Rudwaleit M. Improved physical functioning, sleep, work productivity and overall health-related quality of life with bimekizumab in patients with axial spondyloarthritis: results from two phase 3 studies. RMD Open 2024; 10:e004202. [PMID: 38834351 PMCID: PMC11163688 DOI: 10.1136/rmdopen-2024-004202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024] Open
Abstract
OBJECTIVE To assess the impact of bimekizumab on physical functioning, sleep, work productivity and overall health-related quality of life (HRQoL) in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) in the phase 3 studies BE MOBILE 1 and 2. METHODS Patients were randomised to subcutaneous bimekizumab 160 mg or placebo every 4 weeks; from Week 16, all patients received bimekizumab 160 mg every 4 weeks. We report the following outcomes to Week 52: Bath Ankylosing Spondylitis Functional Index (BASFI), Medical Outcomes Study Sleep Scale Revised (MOS-Sleep-R) Index II, Work Productivity and Activity Impairment: axSpA (WPAI:axSpA), Short Form-36 Physical and Mental Component Summary (SF-36 PCS/MCS) and Ankylosing Spondylitis Quality of Life (ASQoL). RESULTS At Week 16, bimekizumab-randomised patients demonstrated significantly greater improvement from baseline versus placebo in BASFI, SF-36 PCS and ASQoL (p<0.001), and numerically greater improvements in MOS-Sleep-R Index II and WPAI:axSpA scores. Higher proportions of bimekizumab-randomised versus placebo-randomised patients at Week 16 achieved increasingly stringent thresholds for improvements in BASFI (0 to ≤4), and thresholds for meaningful improvements in SF-36 PCS (≥5-point increase from baseline) and ASQoL (≥4-point decrease from baseline). Responses were sustained or further improved to Week 52, where 60%-70% of bimekizumab-treated patients achieved BASFI ≤4 and meaningful improvements in SF-36 PCS and ASQoL, regardless of whether originally randomised to bimekizumab or placebo. CONCLUSION Bimekizumab treatment led to early improvements in physical function, sleep, work productivity and overall HRQoL at Week 16 in patients across the full axSpA disease spectrum. Improvements were sustained to Week 52. TRIAL REGISTRATION NUMBERS NCT03928704; NCT03928743.
Collapse
Affiliation(s)
- Maureen Dubreuil
- Department of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, USA
| | | | - Annelies Boonen
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands
- Care and Public Health Research Institute (Caphri), Maastricht University, Maastricht, The Netherlands
| | - Karl Gaffney
- Norfolk and Norwich University Hospital NHS Trust, Norfolk, UK
| | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California San Francisco, San Francisco, California, USA
| | | | | | | | | | | | | | - Atul Deodhar
- Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, Oregon, USA
| | | |
Collapse
|
|
8
|
Deodhar A, Machado PM, Mørup M, Taieb V, Willems D, Orme M, Pritchett D, Gensler LS. Comparative efficacy and safety of bimekizumab in axial spondyloarthritis: a systematic literature review and network meta-analysis. Rheumatology (Oxford) 2024; 63:1195-1205. [PMID: 37947318 PMCID: PMC11065447 DOI: 10.1093/rheumatology/kead598] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/19/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVES To compare the efficacy and safety of bimekizumab 160 mg every 4 weeks, a selective inhibitor of IL-17F and IL-17A, with those of biologic/targeted synthetic DMARDs (b/tsDMARDs) in non-radiographic axial SpA (nr-axSpA) and AS. METHODS A systematic literature review identified randomized controlled trials until January 2023 for inclusion in Bayesian network meta-analyses (NMAs), including three b/tsDMARDs exposure networks: predominantly-naïve, naïve, and experienced. Outcomes were Assessment of SpondyloArthritis international Society (ASAS)20, ASAS40 and ASAS partial remission (PR) response rates at 12-16 weeks. A safety NMA investigated discontinuations due to any reason and serious adverse events at 12-16 weeks. RESULTS The NMA included 36 trials. The predominantly-naïve network provided the most comprehensive results. In the predominantly-naïve nr-axSpA analysis, bimekizumab had significantly higher ASAS20 response rates vs secukinumab 150 mg [with loading dose (LD)/without LD], and comparable response rates vs other active comparators. In the predominantly-naïve AS analysis, bimekizumab had significantly higher ASAS40 response rates vs secukinumab 150 mg (without LD), significantly higher ASAS-PR response rates vs secukinumab 150 mg (with LD) and comparable response rates vs other active comparators. Bimekizumab demonstrated similar safety to that of other b/tsDMARDs. CONCLUSION Across ASAS outcomes, bimekizumab was comparable with most b/tsDMARDs, including ixekizumab, TNF inhibitors and upadacitinib, and achieved higher response rates vs secukinumab for some ASAS outcomes in predominantly b/tsDMARD-naïve nr-axSpA and AS patients at 12-16 weeks. In a pooled axSpA network, bimekizumab demonstrated comparable safety vs other b/tsDMARDs.
Collapse
Affiliation(s)
- Atul Deodhar
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR, USA
| | - Pedro M Machado
- Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK
| | | | | | | | | | | | - Lianne S Gensler
- Department of Medicine/Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
9
|
Zhao Z, Du Y, Yan K, Zhang L, Guo Q. Exercise and osteoimmunology in bone remodeling. FASEB J 2024; 38:e23554. [PMID: 38588175 DOI: 10.1096/fj.202301508rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/20/2024] [Accepted: 02/28/2024] [Indexed: 04/10/2024]
Abstract
Bones can form the scaffolding of the body, support the organism, coordinate somatic movements, and control mineral homeostasis and hematopoiesis. The immune system plays immune supervisory, defensive, and regulatory roles in the organism, which mainly consists of immune organs (spleen, bone marrow, tonsils, lymph nodes, etc.), immune cells (granulocytes, platelets, lymphocytes, etc.), and immune molecules (immune factors, interferons, interleukins, tumor necrosis factors, etc.). Bone and the immune system have long been considered two distinct fields of study, and the bone marrow, as a shared microenvironment between the bone and the immune system, closely links the two. Osteoimmunology organically combines bone and the immune system, elucidates the role of the immune system in bone, and creatively emphasizes its interdisciplinary characteristics and the function of immune cells and factors in maintaining bone homeostasis, providing new perspectives for skeletal-related field research. In recent years, bone immunology has gradually become a hot spot in the study of bone-related diseases. As a new branch of immunology, bone immunology emphasizes that the immune system can directly or indirectly affect bones through the RANKL/RANK/OPG signaling pathway, IL family, TNF-α, TGF-β, and IFN-γ. These effects are of great significance for understanding inflammatory bone loss caused by various autoimmune or infectious diseases. In addition, as an external environment that plays an important role in immunity and bone, this study pays attention to the role of exercise-mediated bone immunity in bone reconstruction.
Collapse
Affiliation(s)
- Zhonghan Zhao
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Yuxiang Du
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Kai Yan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Lingli Zhang
- College of Athletic Performance, Shanghai University of Sport, Shanghai, China
| | - Qiang Guo
- Department of Orthopaedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| |
Collapse
|
|
10
|
Navarro-Compán V, Ramiro S, Deodhar A, Mease PJ, Rudwaleit M, de la Loge C, Fleurinck C, Taieb V, Mørup MF, Massow U, Kay J, Magrey M. Association of clinical response criteria and disease activity levels with axial spondyloarthritis core domains: results from two phase 3 randomised studies, BE MOBILE 1 and 2. RMD Open 2024; 10:e004040. [PMID: 38599650 PMCID: PMC11015249 DOI: 10.1136/rmdopen-2023-004040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/25/2024] [Indexed: 04/12/2024] Open
Abstract
OBJECTIVE To assess how achievement of increasingly stringent clinical response criteria and disease activity states at week 52 translate into changes in core domains in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). METHODS Patients in BE MOBILE 1 and 2 achieving different levels of response or disease activity (Assessment of SpondyloArthritis International Society (ASAS) and Ankylosing Spondylitis Disease Activity Score (ASDAS) response criteria, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50)) at week 52 were pooled, regardless of treatment arm. Associations between achievement of these endpoints and change from baseline (CfB) in patient-reported outcomes (PROs) measuring core axSpA domains, including pain, fatigue, physical function, overall functioning and health, and work and employment, were assessed. RESULTS Achievement of increasingly stringent clinical efficacy endpoints at week 52 was generally associated with sequentially greater improvements from baseline in all PROs. Patients with nr-axSpA achieving ASAS40 demonstrated greater improvements (CfB) than patients who did not achieve ASAS40 but did achieve ASAS20, in total spinal pain (-5.3 vs -2.8, respectively), Functional Assessment of Chronic Illness-Fatigue subscale (12.7 vs 6.7), Bath Ankylosing Spondylitis Function Index (-3.9 vs -1.8), European Quality of Life 5-Dimension 3-Level Version (0.30 vs 0.16), Work Productivity and Activity Impairment-axSpA presenteeism (-35.4 vs -15.9), overall work impairment (-36.5 vs -12.9), activity impairment (-39.0 vs -21.0) and sleep (9.0 vs 3.9). Results were similar for ASDAS and BASDAI50. Similar amplitudes of improvement were observed between patients with nr-axSpA and r-axSpA. CONCLUSIONS Patients treated with bimekizumab across the full axSpA disease spectrum, who achieved increasingly stringent clinical response criteria and lower disease activity at week 52, reported larger improvements in core axSpA domains.
Collapse
Affiliation(s)
| | - Sofia Ramiro
- Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
- Department of Rheumatology, Zuyderland Medical Centre Heerlen, Heerlen, Netherlands
| | - Atul Deodhar
- Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, Oregon, USA
| | - Philip J Mease
- School of Medicine, Swedish Medical Center and University, Seattle, Washington, USA
| | - Martin Rudwaleit
- Internal Medicine and Rheumatology, Klinikum Bielefeld Rosenhöhe, Bielefeld, Germany
| | | | | | | | | | | | - Jonathan Kay
- Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Marina Magrey
- Case Western Reserve University, Cleveland, Ohio, USA
| |
Collapse
|
|
11
|
Srinath A, Nakamura A, Haroon N. Sequence of Events in the Pathogenesis of Axial Spondyloarthritis: A Current Review-2023 SPARTAN Meeting Proceedings. Curr Rheumatol Rep 2024; 26:133-143. [PMID: 38324125 DOI: 10.1007/s11926-024-01136-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2024] [Indexed: 02/08/2024]
Abstract
PURPOSE OF REVIEW Over the past two decades, significant progress has been made to untangle the etiology of inflammation and new bone formation (NBF) associated with axial spondyloarthritis (axSpA). However, exact mechanisms as to how the disease initiates and develops remain elusive. RECENT FINDINGS Type 3 immunity, centered around the IL-23/IL-17 axis, has been recognized as a key player in the pathogenesis of axSpA. Multiple hypotheses associated with HLA-B*27 have been proposed to account for disease onset and progression of axSpA, potentially by driving downstream T cell responses. However, HLA-B*27 alone is not sufficient to fully explain the development of axSpA. Genome-wide association studies (GWAS) identified several genes that are potentially relevant to disease pathogenesis leading to a better understanding of the immune activation seen in axSpA. Furthermore, gut microbiome studies suggest an altered microbiome in axSpA, and animal studies suggest a pathogenic role for immune cells migrating from the gut to the joint. Recent studies focusing on the pathogenesis of new bone formation (NBF) have highlighted the importance of endochondral ossification, mechanical stress, pre-existing inflammation, and activated anabolic signaling pathways during the development of NBF. Despite the complex etiology of axSpA, recent studies have shed light on pivotal pieces that could lead to a better understanding of the pathogenic events in axSpA.
Collapse
Affiliation(s)
- Archita Srinath
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Akihiro Nakamura
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, ON, Canada
- School of Medicine, Translational Institute of Medicine, Queen's University, Kingston, ON, Canada
- Kingston Health Science Centre, Kingston, ON, Canada
| | - Nigil Haroon
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.
- Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
| |
Collapse
|
|
12
|
Tanaka Y, Shaw S. Bimekizumab for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2024; 20:155-168. [PMID: 37909894 DOI: 10.1080/1744666x.2023.2277266] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/26/2023] [Indexed: 11/03/2023]
Abstract
INTRODUCTION Interleukin (IL)-17A and IL-17F have overlapping roles in pro-inflammatory signaling and have been implicated in the pathogenesis of psoriatic disease. Bimekizumab is the first human monoclonal antibody to selectively inhibit IL-17F in addition to IL-17A. Bimekizumab has been studied in several phase II/III trials and has been approved for the treatment of patients with psoriatic arthritis (PsA) in the EU and UK. AREAS COVERED A literature search identified clinical trials examining the efficacy and safety of bimekizumab for PsA, which were critically appraised. EXPERT OPINION Clinical trials of bimekizumab in PsA have demonstrated rapid and sustained treatment responses and depth of response across the multiple disease domains. High levels of efficacy were sustained to 152 weeks in phase IIb trials, and to 52 weeks in phase III trials. Bimekizumab was generally well tolerated. As expected, due to the role of IL-17 in the immune response to fungal pathogens, there was an increase in mild-to-moderate, localized fungal infections with bimekizumab treatment, very few of which led to discontinuation. Studies over longer time periods, with relevant comparators from the IL-17A inhibitor class, and real-world data will be important to further define the role of bimekizumab among currently available treatments for PsA. [Figure: see text].
Collapse
Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan
| | | |
Collapse
|
|
13
|
Nakamura A, Towheed T. Pathogenesis, assessment, and management of bone loss in axial spondyloarthritis. Semin Arthritis Rheum 2024; 64:152345. [PMID: 38103486 DOI: 10.1016/j.semarthrit.2023.152345] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION Axial spondyloarthritis (axSpA) presents a complex scenario where both new bone formation in entheseal tissues and significant trabecular bone loss coexist, emphasizing the intricate nature of bone dynamics in this context. METHODS A search of the literature was conducted to compose a narrative review exploring the pathogenesis, possible assessment methods, and potential management options for axSpA. RESULTS While chronic systemic and local inflammation contribute to bone loss, the mechanisms behind axSpA-associated bone loss exhibit distinct characteristics influenced by factors like mechanical stress and the gut microbiome. These factors directly or indirectly stimulate osteoclast differentiation and activation through the RANK-RANKL axis, while simultaneously impeding osteoblast differentiation via negative regulation of bone anabolic pathways, including the Wnt signaling pathway. This disruption in the balance between bone-resorbing osteoclasts and bone-forming osteoblasts contributes to overall bone loss in axSpA. Early evaluation at diagnosis is prudent for detecting bone changes. While traditional dual x-ray absorptiometry (DXA) has limitations due to potential overestimation from spinal new bone formation, alternative methods like trabecular bone score (TBS), quantitative CT (QCT), and quantitative ultrasound (QUS) show promise. However, their integration into routine clinical practice remains limited. In addition to approved anti-inflammatory drugs, lifestyle adjustments like regular exercise play a key role in preserving bone health. Tailoring interventions based on individual risk profiles holds potential for mitigating bone loss progression. CONCLUSION Recognizing the pivotal role of bone loss in axSpA underscores the importance of integrating regular assessments and effective management strategies into clinical practice. Given the multifaceted contributors to bone loss in axSpA, a multidisciplinary approach is essential.
Collapse
Affiliation(s)
- Akihiro Nakamura
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Translational Institute of Medicine, School of Medicine, Queen's University, Ontario, Canada; Kingston Health Science Centre, Kingston, Ontario, Canada.
| | - Tanveer Towheed
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Translational Institute of Medicine, School of Medicine, Queen's University, Ontario, Canada; Kingston Health Science Centre, Kingston, Ontario, Canada.
| |
Collapse
|
|
14
|
Baraliakos X, Deodhar A, van der Heijde D, Magrey M, Maksymowych WP, Tomita T, Xu H, Massow U, Fleurinck C, Ellis AM, Vaux T, Shepherd-Smith J, Marten A, Gensler LS. Bimekizumab treatment in patients with active axial spondyloarthritis: 52-week efficacy and safety from the randomised parallel phase 3 BE MOBILE 1 and BE MOBILE 2 studies. Ann Rheum Dis 2024; 83:199-213. [PMID: 37793792 DOI: 10.1136/ard-2023-224803] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/06/2023] [Indexed: 10/06/2023]
Abstract
OBJECTIVES Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated superior efficacy versus placebo in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) at Week 16. Here, the objective is to report the efficacy and safety of BKZ at Week 52. METHODS BE MOBILE 1 (nr-axSpA; NCT03928704) and BE MOBILE 2 (r-axSpA; NCT03928743) comprised a 16-week, double-blind, placebo-controlled period, then a 36-week maintenance period. From Week 16, all patients received subcutaneous BKZ 160 mg every 4 weeks. RESULTS Improvements versus placebo in Assessment of SpondyloArthritis International Society ≥40% response (primary endpoint), Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels and MRI inflammation of the sacroiliac joints/spine at Week 16 were sustained to Week 52 in BKZ-randomised patients. At Week 52, responses of patients switching from placebo to BKZ at Week 16 were comparable to BKZ-randomised patients. At Week 52, ≥1 treatment-emergent adverse events (TEAEs) were reported in 183 (75.0%) and 249 (75.5%) patients with nr-axSpA and r-axSpA, respectively. Serious TEAEs occurred in 9 (3.7%) patients with nr-axSpA and 20 (6.1%) patients with r-axSpA. Oral candidiasis was the most frequent fungal infection (nr-axSpA: 18 (7.4%); r-axSpA: 20 (6.1%)). Uveitis occurred in three (1.2%) and seven (2.1%) patients with nr-axSpA and r-axSpA, and inflammatory bowel disease in two (0.8%) and three (0.9%). CONCLUSIONS At Week 52, dual inhibition of IL-17A and IL-17F with BKZ resulted in sustained efficacy across the axSpA spectrum; the safety profile was consistent with the known safety of BKZ. TRIAL REGISTRATION NUMBER NCT03928704; NCT03928743.
Collapse
Affiliation(s)
| | - Atul Deodhar
- Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, Oregon, USA
| | | | - Marina Magrey
- University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA
| | - Walter P Maksymowych
- Department of Medicine, University of Alberta Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada
| | - Tetsuya Tomita
- Graduate School of Health Science, Morinomiya University of Medical Sciences, Osaka City, Osaka, Japan
| | - Huji Xu
- Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Affiliated to Second Military Medical University, Shanghai, China
| | | | | | | | | | | | | | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California San Francisco, San Francisco, California, USA
| |
Collapse
|
|
15
|
Siderius M, Kieskamp SC, Wink F, Kroese FGM, Arends S, Spoorenberg A. The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice. Biologics 2023; 17:161-166. [PMID: 38115870 PMCID: PMC10728592 DOI: 10.2147/btt.s434318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 10/27/2023] [Indexed: 12/21/2023]
Abstract
Background Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. Results 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. Conclusion This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.
Collapse
Affiliation(s)
- Mark Siderius
- Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Stan C Kieskamp
- Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Freke Wink
- Rheumatology, Medical Centre Leeuwarden, Groningen, the Netherlands
| | - Frans G M Kroese
- Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Suzanne Arends
- Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Anneke Spoorenberg
- Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| |
Collapse
|
|
16
|
Fassio A, Atzeni F, Rossini M, D’Amico V, Cantatore F, Chimenti MS, Crotti C, Frediani B, Giusti A, Peluso G, Rovera G, Scolieri P, Raimondo V, Gatti D, on behalf of the Study Group on Osteoporosis and Skeletal Metabolic Diseases of the Italian Society of Rheumatology. Osteoimmunology of Spondyloarthritis. Int J Mol Sci 2023; 24:14924. [PMID: 37834372 PMCID: PMC10573470 DOI: 10.3390/ijms241914924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/15/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA.
Collapse
Affiliation(s)
- Angelo Fassio
- Dipartimento di Medicina, Università di Verona, 37124 Verona, Italy; (M.R.); (D.G.)
| | - Fabiola Atzeni
- Unità Operativa Complessa di Reumatologia Azienda Ospedaliero Universitaria Policlinico “G. Martino” di Messina, 35128 Messina, Italy; (F.A.); (V.D.)
| | - Maurizio Rossini
- Dipartimento di Medicina, Università di Verona, 37124 Verona, Italy; (M.R.); (D.G.)
| | - Valeria D’Amico
- Unità Operativa Complessa di Reumatologia Azienda Ospedaliero Universitaria Policlinico “G. Martino” di Messina, 35128 Messina, Italy; (F.A.); (V.D.)
| | - Francesco Cantatore
- Unità Operativa Complessa di Reumatologia Universitaria, Polic. “Riuniti” di Foggia, 71122 Foggia, Italy;
| | - Maria Sole Chimenti
- Dipartimento di Medicina dei Sistemi, Reumatologia, Allergologia e Immunologia Clinica Università di Roma Tor Vergata, 00133 Rome, Italy;
| | - Chiara Crotti
- UOC Osteoporosi e Malattie Metaboliche dell’Osso Dipartimento di Reumatologia e Scienze Mediche ASST-G. Pini-CTO, 20122 Milan, Italy;
| | - Bruno Frediani
- Department of Medical, Surgical and Neuroscience Sciences, Rheumatology University of Siena, 53100 Siena, Italy;
| | - Andrea Giusti
- SSD Malattie Reumatologiche e del Metabolismo Osseo, Dipartimento delle Specialità Mediche, ASL3, 16132 Genova, Italy;
| | - Giusy Peluso
- UOC di Reumatologia-Fondazione Policlinico Universitario Agostino Gemelli-IRCSS, 00168 Rome, Italy;
| | - Guido Rovera
- Ospedale S. Andrea, Divisione Reumatologia, 13100 Vercelli, Italy;
| | - Palma Scolieri
- Ambulatorio di Reumatologia Ospedale Nuovo Regina Margherita ASL ROMA1, 00153 Rome, Italy;
| | | | - Davide Gatti
- Dipartimento di Medicina, Università di Verona, 37124 Verona, Italy; (M.R.); (D.G.)
| | | |
Collapse
|
|
17
|
Navarro-Compán V, Puig L, Vidal S, Ramírez J, Llamas-Velasco M, Fernández-Carballido C, Almodóvar R, Pinto JA, Galíndez-Aguirregoikoa E, Zarco P, Joven B, Gratacós J, Juanola X, Blanco R, Arias-Santiago S, Sanz Sanz J, Queiro R, Cañete JD. The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases. Front Immunol 2023; 14:1191782. [PMID: 37600764 PMCID: PMC10437113 DOI: 10.3389/fimmu.2023.1191782] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/05/2023] [Indexed: 08/22/2023] Open
Abstract
Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain overlapping functions. In general, IL-17A and IL-17F play important roles in chronic inflammation and autoimmunity, controlling bacterial and fungal infections, and signaling mainly through activation of the nuclear factor-kappa B (NF-κB) pathway. The role of IL-17A and IL-17F has been established in chronic immune-mediated inflammatory diseases (IMIDs), such as psoriasis (PsO), psoriatic arthritis (PsA), axial spondylarthritis (axSpA), hidradenitis suppurativa (HS), inflammatory bowel disease (IBD), multiple sclerosis (MS), and asthma. CD4+ helper T cells (Th17) activated by IL-23 are well-studied sources of IL-17A and IL-17F. However, other cellular subtypes can also produce IL-17A and IL-17F, including gamma delta (γδ) T cells, alpha beta (αβ) T cells, type 3 innate lymphoid cells (ILC3), natural killer T cells (NKT), or mucosal associated invariant T cells (MAIT). Interestingly, the production of IL-17A and IL-17F by innate and innate-like lymphocytes can take place in an IL-23 independent manner in addition to IL-23 classical pathway. This would explain the limitations of the inhibition of IL-23 in the treatment of patients with certain rheumatic immune-mediated conditions such as axSpA. Despite their coincident functions, IL-17A and IL-17F contribute independently to chronic tissue inflammation having somehow non-redundant roles. Although IL-17A has been more widely studied, both IL-17A and IL-17F are overexpressed in PsO, PsA, axSpA and HS. Therefore, dual inhibition of IL-17A and IL-17F could provide better outcomes than IL-23 or IL-17A blockade.
Collapse
Affiliation(s)
| | - Luis Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Silvia Vidal
- Immunology-Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Julio Ramírez
- Arthritis Unit, Department of Rheumatology, Hospital Clínic and Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mar Llamas-Velasco
- Department of Dermatology, Hospital Universitario La Princesa, Madrid, Spain
| | | | - Raquel Almodóvar
- Department of Rheumatology, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain
| | - José Antonio Pinto
- Department of Rheumatology, Complejo Hospitalario Universitario de A Coruña, Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
| | | | - Pedro Zarco
- Department of Rheumatology, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain
| | - Beatriz Joven
- Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Jordi Gratacós
- Department of Rheumatology, Medicine Department Autonomus University of Barcelona (UAB), I3PT, University Hospital Parc Taulí Sabadell, Barcelona, Spain
| | - Xavier Juanola
- Department of Rheumatology, University Hospital Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Ricardo Blanco
- Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Salvador Arias-Santiago
- Department of Dermatology, Hospital Universitario Virgen de las Nieves, Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- Department of Dermatology, Facultad de Medicina, Universidad de Granada, Granada, Spain
| | - Jesús Sanz Sanz
- Department of Rheumatology, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain
| | - Rubén Queiro
- Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
| | - Juan D. Cañete
- Arthritis Unit, Department of Rheumatology, Hospital Clínic and Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| |
Collapse
|
|
18
|
van der Heijde D, Deodhar A, Baraliakos X, Brown MA, Dobashi H, Dougados M, Elewaut D, Ellis AM, Fleurinck C, Gaffney K, Gensler LS, Haroon N, Magrey M, Maksymowych WP, Marten A, Massow U, Oortgiesen M, Poddubnyy D, Rudwaleit M, Shepherd-Smith J, Tomita T, Van den Bosch F, Vaux T, Xu H. Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials. Ann Rheum Dis 2023; 82:515-526. [PMID: 36649967 PMCID: PMC10086273 DOI: 10.1136/ard-2022-223595] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/26/2022] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Axial spondyloarthritis (axSpA) is a complex disease with diverse manifestations, for which new treatment options are warranted. BE MOBILE 1 (non-radiographic (nr)-axSpA) and BE MOBILE 2 (radiographic axSpA (r-axSpA)) are double-blind, phase 3 trials designed to evaluate efficacy and safety of bimekizumab, a novel dual interleukin (IL)-17A and IL-17F inhibitor, across the axSpA spectrum. METHODS In parallel 52-week trials, patients with active disease were randomised 1:1 (nr-axSpA) or 2:1 (r-axSpA) to bimekizumab 160 mg every 4 weeks:placebo. From week 16, all patients received bimekizumab 160 mg every 4 weeks. Primary (Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40)) and secondary endpoints were assessed at week 16. Here, efficacy and treatment-emergent adverse events (TEAEs) are reported up to week 24. RESULTS 254 patients with nr-axSpA and 332 with r-axSpA were randomised. At week 16, primary (ASAS40, nr-axSpA: 47.7% bimekizumab vs 21.4% placebo; r-axSpA: 44.8% vs 22.5%; p<0.001) and all ranked secondary endpoints were met in both trials. ASAS40 responses were similar across TNFi-naïve and TNFi-inadequate responder patients. Improvements were observed in Ankylosing Spondylitis Disease Activity Score (ASDAS) states and objective measures of inflammation, including high-sensitivity C-reactive protein (hs-CRP) and MRI of the sacroiliac joints and spine. Most frequent TEAEs with bimekizumab (>3%) included nasopharyngitis, upper respiratory tract infection, pharyngitis, diarrhoea, headache and oral candidiasis. More fungal infections (all localised) were observed with bimekizumab vs placebo; no major adverse cardiovascular events (MACE) or active tuberculosis were reported. Incidence of uveitis and adjudicated inflammatory bowel disease was low. CONCLUSIONS Dual inhibition of IL-17A and IL-17F with bimekizumab resulted in significant and rapid improvements in efficacy outcomes vs placebo and was well tolerated in patients with nr-axSpA and r-axSpA.
Collapse
Affiliation(s)
| | - Atul Deodhar
- Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, Oregon, USA
| | | | | | - Hiroaki Dobashi
- Division of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Maxime Dougados
- Department of Rheumatology, Hôpital Cochin, University Paris Cité, Paris, France
| | - Dirk Elewaut
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
| | | | | | - Karl Gaffney
- Norfolk and Norwich University Hospital NHS Trust, Norfolk, UK
| | - Lianne S Gensler
- Department of Medicine/Rheumatology, University of California, San Francisco, California, USA
| | - Nigil Haroon
- University Health Network, Schroeder Arthritis Institute, Department of Medicine/Rheumatology, University of Toronto, Toronto, Ontario, Canada
| | - Marina Magrey
- University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA
| | | | | | | | | | - Denis Poddubnyy
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | | | - Tetsuya Tomita
- Graduate School of Health Science, Morinomiya University of Medical Sciences, Osaka City, Osaka, Japan
| | - Filip Van den Bosch
- Department of Internal Medicine and Pediatrics, Ghent University and VIB Center for Inflammation Research, Ghent, Belgium
| | | | - Huji Xu
- Affiliated to Second Military Medical University, Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Shanghai, China
| |
Collapse
|
|
19
|
Braun J, Kiltz U, Baraliakos X. Emerging therapies for the treatment of spondyloarthritides with focus on axial spondyloarthritis. Expert Opin Biol Ther 2023; 23:195-206. [PMID: 36511882 DOI: 10.1080/14712598.2022.2156283] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Spondyloarthritides (SpA) such as axial spondyloarthritis (axSpA) including ankylosing spondylitis (AS) and psoriatic arthritis (PsA) including psoriasis are chronic immune-mediated disorders with involvement of tumor necrosis factor (TNF), interleukin (IL)-17 cytokines, and janus kinases (JAK) in their pathogenesis, with IL-23 clearly also playing a role in psoriasis, PsA, and chronic inflammatory bowel diseases. AREAS COVERED In this narrative review, we focus on a biologic disease modifying anti-rheumatic drug (bDMARD), the bispecific IL-17A and IL-17 F inhibitor bimekizumab, and a targeted synthetic (ts) DMARD, the JAK inhibitor (i) filgotinib - emerging agents for the treatment of axSpA. Upadacitinib, another JAKi that has recently been reviewed intensively by us is already approved for axSpA and PsA in Europe. EXPERT OPINION In contrast to inhibition of IL-17, JAKi also work in rheumatoid arthritis (RA), while agents inhibiting IL-17 are not, even though some effect may be there. Indeed, 4 JAKi including filgotinib are approved for RA. There are several head-to-head trials with bimekizumab in plaque psoriasis. The last one showed that the bispecific inhibition of IL-17A and IL-17 F with bimekizumab may indeed be superior to inhibition of IL-17A alone with 300 mg secukinumab (usual dosage). Whether this is also the case for treatment of axSpA and PsA remains to be shown.
Collapse
Affiliation(s)
- Juergen Braun
- Rheumazentrum Ruhrgebiet, Ruhr University Bochum, Herne, Germany
| | - Uta Kiltz
- Rheumazentrum Ruhrgebiet, Ruhr University Bochum, Herne, Germany
| | | |
Collapse
|
|
20
|
Abstract
Over the past two decades, advancements in understanding the pathogenesis of axial spondyloarthritis have led to discoveries of new therapeutic targets, particularly the interleukin-17, tumor necrosis factor axis, and Janus kinase-signal transducer and activator of transcription pathway. While many of the available agents have proven to be efficacious and safe for the treatment of axial spondyloarthritis, a remarkable percentage of patients either fail or cannot tolerate these medications. This has prompted researchers to look for new targets that would maximize efficacy and minimize toxicity. In this article, we review novel agents that were recently approved, in trials, and possible future targets or mechanisms. We also discuss their role as it pertains to the prevention of radiographic progression and the management of extra-musculoskeletal manifestations.
Collapse
Affiliation(s)
- Mohamad Bittar
- The University of Tennessee Health Science Center, Division of Connective Tissue Disease (Rheumatology), 956 Court Avenue, Coleman Building, Suite G326, Memphis, TN 38163, USA.
| | - Philip Mease
- Swedish Medical Center/Providence St. Joseph Health and University of Washington School of Medicine, Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, WA 98102, USA.
| |
Collapse
|
|
21
|
Daoussis D, Kanellou A, Panagiotopoulos E, Papachristou D. DKK-1 Is Underexpressed in Mesenchymal Stem Cells from Patients with Ankylosing Spondylitis and Further Downregulated by IL-17. Int J Mol Sci 2022; 23:ijms23126660. [PMID: 35743102 PMCID: PMC9224314 DOI: 10.3390/ijms23126660] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 02/01/2023] Open
Abstract
Dickkopf-1 (Dkk-1) is a key regulator of bone remodeling in spondyloarthropathies. Nevertheless, data regarding its expression in cells of pathophysiologic relevance, such as mesenchymal stem cells (MSCs), are lacking. Herein, we aimed to address DKK1 gene expression and Wnt pathway activation in MSCs from patients with ankylosing spondylitis (AS) and explore the effect of IL-17 on MSCs with respect to DKK-1 expression and Wnt pathway activation. Primary MSCs were isolated from the bone marrow of the femoral head of two patients with AS and two healthy controls undergoing orthopedic surgery. MSCs were cultured for 7 days in expansion medium and for 21 days in osteogenic medium in the presence or absence of IL-17A. Gene expression of DKK-1 and osteoblastic markers was determined by RT-PCR. Alkaline phosphatase activity, alizarin red and Van Kossa staining were used to assess osteoblastic function and mineralization capacity. DKK-1 was significantly downregulated in MSCs and osteoblasts from patients with AS compared to controls. Moreover, MSCs and osteoblasts from AS patients displayed increased Wnt pathway activation and enhanced osteoblastic activity, as indicated by increased expression of osteoblast marker genes and alkaline phosphatase activity. IL-17 downregulated DKK-1 expression and increased osteoblastic activity and mineralization capacity. DKK-1 is underexpressed in MSCs from AS patients compared to controls, whereas IL-17 has an inhibitory effect on DKK-1 expression and stimulates osteoblastic function. These data may have pathogenetic and clinical implications in AS.
Collapse
Affiliation(s)
- Dimitrios Daoussis
- Department of Rheumatology, University of Patras Medical School, Patras University Hospital, 26504 Patras, Greece
- Correspondence: (D.D.); (A.K.); Tel.: +30-2613-603-693 (D.D.); Fax: +30-2610-993-982 (D.D.)
| | - Anastasia Kanellou
- Laboratory of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University of Patras Medical School, 26504 Patras, Greece;
- Correspondence: (D.D.); (A.K.); Tel.: +30-2613-603-693 (D.D.); Fax: +30-2610-993-982 (D.D.)
| | - Elias Panagiotopoulos
- Department of Orthopedics, University of Patras Medical School, Patras University Hospital, 26504 Patras, Greece;
| | - Dionysios Papachristou
- Laboratory of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University of Patras Medical School, 26504 Patras, Greece;
| |
Collapse
|
|
22
|
Lems W, Miceli-Richard C, Haschka J, Giusti A, Chistensen GL, Kocijan R, Rosine N, Jørgensen NR, Bianchi G, Roux C. Bone Involvement in Patients with Spondyloarthropathies. Calcif Tissue Int 2022; 110:393-420. [PMID: 35066596 DOI: 10.1007/s00223-021-00933-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/24/2021] [Indexed: 11/02/2022]
Abstract
Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.
Collapse
Affiliation(s)
- Willem Lems
- Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands.
| | - Corinne Miceli-Richard
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
- Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France
| | - Judith Haschka
- I Medical Department, Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of OEGK & Hanusch Hospital Vienna, Heinrich-Collin-Straße 30, 1140, Vienna, Austria
- Karl Landsteiner Institute for Rheumatology and Gastroenterology, Rheuma-Zentrum Wien-Oberlaa, 1100, Vienna, Austria
| | - Andrea Giusti
- Rheumatology Unit, Department of Medical Specialties, Local Health Trust 3, Via Missolungi 14, 16147, Genoa, Italy
| | | | - Roland Kocijan
- Medical Faculty of Bone Diseases, Sigmund Freud University Vienna, Freudplatz 1, 1020, Vienna, Austria
| | - Nicolas Rosine
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
- Sorbonne Université, Service de Rhumatologie Hôpital Pitié Salpêtrière, APHP, Paris, France
| | | | - Gerolamo Bianchi
- Rheumatology Unit, Department of Medical Specialties, Local Health Trust 3, Via Missolungi 14, 16147, Genoa, Italy
| | - Christian Roux
- INSERM U 1153, Université de Paris-APHP.Centre, Service de Rhumatologie, Hopital Cochin, Paris, France
| |
Collapse
|
|
23
|
Soós B, Szentpétery Á, Raterman HG, Lems WF, Bhattoa HP, Szekanecz Z. Effects of targeted therapies on bone in rheumatic and musculoskeletal diseases. Nat Rev Rheumatol 2022; 18:249-257. [PMID: 35273387 DOI: 10.1038/s41584-022-00764-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2022] [Indexed: 12/17/2022]
Abstract
Generalized bone loss (osteoporosis) and fragility fractures can occur in rheumatic and musculoskeletal diseases including rheumatoid arthritis and spondyloarthritis (SpA; including ankylosing spondylitis and psoriatic arthritis). In addition, rheumatoid arthritis can involve localized, periarticular bone erosion and, in SpA, local (pathological) bone formation can occur. The RANK-RANKL-osteoprotegerin axis and the Wnt-β-catenin signalling pathway (along with its inhibitors sclerostin and Dickkopf 1) have been implicated in inflammatory bone loss and formation, respectively. Targeted therapies including biologic DMARDs and Janus kinase (JAK) inhibitors can stabilize bone turnover and inhibit radiographic joint damage, and potentially also prevent generalized bone loss. Targeted therapies interfere at various points in the mechanisms of local and generalized bone changes in systemic rheumatic diseases, and they effect biomarkers of bone resorption and formation, bone mass and risk of fragility fractures. Studies on the effects of targeted therapies on rates of fragility fracture are scarce. The efficacy of biologic DMARDs for arresting bone formation in axial SpA is debated. Improved understanding of the most relevant therapeutic targets and identification of important targeted therapies could lead to the preservation of bone in inflammatory rheumatic and musculoskeletal diseases.
Collapse
Affiliation(s)
- Boglárka Soós
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ágnes Szentpétery
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.,Department of Medical Sciences, Rheumatology, Uppsala University Hospital, Uppsala, Sweden
| | | | - Willem F Lems
- Amsterdam Rheumatology and Immunology Centre, Amsterdam, Netherlands
| | - Harjit P Bhattoa
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| |
Collapse
|
|
24
|
Batko B. Exploring the Diverse Immune and Genetic Landscape of Psoriatic Arthritis. J Clin Med 2021; 10:jcm10245926. [PMID: 34945224 PMCID: PMC8706996 DOI: 10.3390/jcm10245926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 11/16/2022] Open
Abstract
Psoriatic arthritis (PsA) is characterized by delays in diagnosis and modest effect of treatment in terms of joint response. An understanding of molecular pathomechanisms may aid in developing diagnostic and prognostic models. Genetic susceptibility (e.g., HLA class I genes, IL-23-related genes) can be responsible for the pattern of psoriatic manifestations and affinity for tissue involvement. Gene expression analysis indicates an inflammatory profile that is distinct for PsA, but disparate across tissues. This has clinical implications, as for example, dual blockade of IL-17A and IL-17F can lead to superior clinical effects if there is differential expression of IL-17 receptors in tissues. Structural and functional impairment of barrier tissue, including host-microbiome interactions, may be the source of immune activation. Interplay between different cell populations of innate and adaptive immunity is emerging, potentially providing a link between the transition of skin-to-joint disease. Th17 subsets, IL-17A, IL-17F and IL-23 are crucial in PsA pathogenesis, with both clinical and experimental evidence suggesting a differential molecular landscape in cutaneous and articular compartments.
Collapse
Affiliation(s)
- Bogdan Batko
- Department of Rheumatology and Immunology, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski University, 30-705 Krakow, Poland
| |
Collapse
|
|
25
|
Krstić J, Mojsilović S, Mojsilović SS, Santibanez JF. Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation. World J Stem Cells 2021; 13:1696-1713. [PMID: 34909118 PMCID: PMC8641017 DOI: 10.4252/wjsc.v13.i11.1696] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/14/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs’ osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.
Collapse
Affiliation(s)
- Jelena Krstić
- Gottfried Schatz Research Center, Medical University of Graz, Graz 8010, Austria
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade 11129, Serbia
| | - Sonja S Mojsilović
- Group for Immunology, Institute for Medical Research, National Institute of Republic of Serbia, Belgrade 11129, Serbia
| | - Juan F Santibanez
- Group for Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
- Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O’Higgins, Chile 8370993, Chile
| |
Collapse
|
|
26
|
Wang R, Maksymowych WP. Targeting the Interleukin-23/Interleukin-17 Inflammatory Pathway: Successes and Failures in the Treatment of Axial Spondyloarthritis. Front Immunol 2021; 12:715510. [PMID: 34539646 PMCID: PMC8446672 DOI: 10.3389/fimmu.2021.715510] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/10/2021] [Indexed: 12/24/2022] Open
Abstract
The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.
Collapse
Affiliation(s)
- Runsheng Wang
- Division of Rheumatology, Columbia University Irving Medical Center, New York, NY, United States
- Garden State Rheumatology Consultants, Union, NJ, United States
| | - Walter P. Maksymowych
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- CARE Arthritis, Edmonton, AB, Canada
| |
Collapse
|
|
27
|
Kusuda M, Haroon N, Nakamura A. Complexity of enthesitis and new bone formation in ankylosing spondylitis: current understanding of the immunopathology and therapeutic approaches. Mod Rheumatol 2021; 32:484-492. [PMID: 34918137 DOI: 10.1093/mr/roab057] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 01/20/2023]
Abstract
Despite increasing availability of treatments for spondyloarthritis (SpA) including tumour necrosis factor (TNF) and interleukin-17 (IL-17) inhibitors, there is no established treatment that abates new bone formation (NBF) in ankylosing spondylitis (AS), a subset of SpA. Recent research on TNF has revealed the increased level of transmembrane TNF in the joint tissue of SpA patients compared to that of rheumatoid arthritis patients, which appears to facilitate TNF-driven osteo-proliferative changes in AS. In addition, there is considerable interest in the central role of IL-23/IL-17 axis in type 3 immunity and the therapeutic potential of blocking this axis to ameliorate enthesitis and NBF in AS. AS immunopathology involves a variety of immune cells, including both innate and adoptive immune cells, to orchestrate the immune response driving type 3 immunity. In response to external stimuli of inflammatory cytokines, local osteo-chondral progenitor cells activate intra-cellular anabolic molecules and signals involving hedgehog, bone morphogenetic proteins, receptor activator of nuclear factor kappa-B ligand, and Wnt pathways to promote NBF in AS. Here, we provide an overview of the current immunopathology and future directions for the treatment of enthesitis and NBF associated with AS.
Collapse
Affiliation(s)
- Masaki Kusuda
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Nigil Haroon
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Spondylitis Program, Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.,Division of Rheumatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Akihiro Nakamura
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Spondylitis Program, Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.,Division of Rheumatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
28
|
Wei JCC, Kim TH, Kishimoto M, Ogusu N, Jeong H, Kobayashi S. Efficacy and safety of brodalumab, an anti-IL17RA monoclonal antibody, in patients with axial spondyloarthritis: 16-week results from a randomised, placebo-controlled, phase 3 trial. Ann Rheum Dis 2021; 80:1014-1021. [PMID: 33827787 PMCID: PMC8292606 DOI: 10.1136/annrheumdis-2020-219406] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 03/12/2021] [Accepted: 03/13/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To investigate the efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with axial spondyloarthritis (axSpA). METHODS In a multicentre, placebo-controlled phase 3 study (NCT02985983) conducted at 48 sites across Japan, Korea and Taiwan, patients with axSpA were randomised 1:1 to receive subcutaneous brodalumab 210 mg (n=80) or placebo (n=79) at baseline, weeks 1 and 2 and every 2 weeks thereafter, during the 16-week double-blind period. The primary endpoint was the proportion of patients with Assessment of SpondyloArthritis International Society (ASAS) 40 response at week 16. Secondary endpoints included the proportion of patients with ASAS 20 response and change in Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) at week 16 and safety. RESULTS ASAS 40 response rate (n/N; 95% CI) was 43.8% (35/80; 32.7, 55.3) with brodalumab vs 24.1% (19/79; 15.1, 35.0) with placebo (rate difference, 19.7% (5.3, 34.1); p=0.018 by stratified Cochran-Mantel-Haenszel test). ASAS 20 response rate (n/N; 95% CI) was 67.5% (54/80; 56.1, 77.6) vs 41.8% (33/79; 30.8, 53.4) and least squares mean change (95% CI) from baseline (brodalumab, 2.660; placebo, 2.716) in ASDAS-CRP was -1.127 (-1.322, -0.931) with brodalumab vs -0.672 (-0.872, -0.473) with placebo at week 16. Treatment-emergent adverse events were reported in 44 (55%) and 45 (57%) patients in the brodalumab and placebo groups, respectively. CONCLUSION Brodalumab demonstrated a significant improvement at week 16 in patients with active axSpA. Safety of brodalumab was consistent with that reported in previous global/Japanese psoriasis studies.
Collapse
Affiliation(s)
- James Cheng-Chung Wei
- Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tae-Hwan Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, The Republic of Korea
| | - Mitsumasa Kishimoto
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Naoki Ogusu
- Clinical Development Center, R&D Division, Kyowa Kirin Co, Ltd, Tokyo, Japan
| | - Haeyoun Jeong
- Development Department, Kyowa Kirin Korea Co., Ltd, Seoul, The Republic of Korea
| | - Shigeto Kobayashi
- Department of Internal Medicine and Rheumatology, Juntendo University Koshigaya Hospital, Saitama, Japan
| |
Collapse
|
|
29
|
Yeremenko N. Out of the shadow of interleukin-17A: the role of interleukin-17F and other interleukin-17 family cytokines in spondyloarthritis. Curr Opin Rheumatol 2021; 33:333-340. [PMID: 34001692 PMCID: PMC8183488 DOI: 10.1097/bor.0000000000000805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW The last decade has witnessed tremendous advances in revealing an important role for the interleukin (IL)-17 cytokine family in the pathogenesis of spondyloarthritis (SpA). Although most attention has been focused on IL-17A, a potential role of other IL-17 family members in inflammation and tissue remodelling is emerging. Herein, I review recent studies covering the role of IL-17B-F cytokines in the pathogenesis of SpA. RECENT FINDINGS Several recent studies provided new insights into the cellular source, regulation and function of IL-17F. IL-17F/IL-17A expression ratio is higher in psoriatic skin compared to SpA synovitis. IL-17F-expressing T cells produce different proinflammatory mediators than IL-17A-expressing cells, and IL-17F and IL-17A signal through different receptor complex. Dual IL-17A and IL-17F neutralization resulted in greater suppression of downstream inflammatory and tissue remodelling responses. Furthermore, there is additional evidence of IL-23-independent IL-17 production. In contrast to IL-17A, IL-17F and IL-17C, which play proinflammatory roles in skin and joint inflammation, an anti-inflammatory function is proposed for IL-17D. An increase in IL-17E is associated with subclinical gut microbiome alterations after anti-IL-17A therapy in SpA patients. SUMMARY IL-17 family cytokines may act as agonists or antagonists to IL-17A contributing in concert to local inflammatory responses. Understanding their function and identifying their cellular sources, and molecular mechanisms driving their expression will be the key to designing rational therapies in SpA.
Collapse
Affiliation(s)
- Nataliya Yeremenko
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology
- Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
30
|
Łukasik Z, Gracey E, Venken K, Ritchlin C, Elewaut D. Crossing the boundaries: IL-23 and its role in linking inflammation of the skin, gut and joints. Rheumatology (Oxford) 2021; 60:iv16-iv27. [PMID: 33961030 PMCID: PMC8527243 DOI: 10.1093/rheumatology/keab385] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/17/2021] [Indexed: 11/17/2022] Open
Abstract
Several lines of evidence point towards the central role of IL-23 as a crucial inflammatory mediator in the pathogenesis of SpA—a group of inflammatory arthritic diseases whose symptoms span the skin, gastrointestinal tract and joints. While therapeutic blockade of IL-23 proved successful in the treatment of IBD, psoriatic skin disease and peripheral SpA, it failed in patients suffering from SpA with predominantly axial involvement. Here we review state-of-the-art discoveries on IL-23 signalling pathways across target tissues involved in SpA. We discuss the discrepancies in resident IL-23–responding cells and their downstream activities across skin, gut and joint that shape the unique immunological landscape of SpA.
Collapse
Affiliation(s)
- Zuzanna Łukasik
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Eric Gracey
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Koen Venken
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Christopher Ritchlin
- Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Dirk Elewaut
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium.,Ghent Gut Inflammation Group, Ghent University, Ghent, Belgium
| |
Collapse
|
|
31
|
Nakamura A, Haroon N. Recent Updates in the Immunopathology of Type 3 Immunity-Mediated Enthesitis. Curr Rheumatol Rep 2021; 23:31. [PMID: 33893896 DOI: 10.1007/s11926-021-00995-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Enthesitis is a cardinal feature of spondyloarthritis (SpA). Despite increasing available treatments, challenges remain in adequately controlling inflammation and subsequent new bone formation (NBF) in entheses; thus, a better understanding of the immunopathogenesis is warranted. RECENT FINDINGS Increasing evidence has identified immune cells playing key roles in enthesitis such as γδ T cells and group 3 innate lymphoid cells (ILC3), possibly with site-specific regulatory systems. The presence of T cells producing interleukin (IL)-17 independent of IL-23 in human spinal entheses was recently reported, which may corroborate the discrepancy between recent clinical trials and pre-clinical studies. In addition, the contribution of myeloid cells has also been focused in both human and pre-clinical SpA models. Moreover, not only the IL-23/IL-17 signaling, but other key type 3 immunity mediators, such as IL-22 and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been reported as pivotal cytokines in inflammation and NBF of entheses. Immune cells demonstrating distinct features orchestrate entheses, leading to the complex landscape of enthesitis. However, recent advances in understanding the immunopathogenesis may provide new therapeutic targets and future research directions.
Collapse
Affiliation(s)
- Akihiro Nakamura
- Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.,Spondylitis Program, University Health Network, Toronto, Ontario, Canada.,Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Nigil Haroon
- Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada. .,Spondylitis Program, University Health Network, Toronto, Ontario, Canada. .,Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada. .,Division of Rheumatology, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. .,Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
32
|
Oliveira DG, Faria R, Torres T. An Overview of Bimekizumab for the Treatment of Psoriatic Arthritis: The Evidence so Far. Drug Des Devel Ther 2021; 15:1045-1053. [PMID: 33727793 PMCID: PMC7955739 DOI: 10.2147/dddt.s267405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/25/2021] [Indexed: 12/24/2022] Open
Abstract
Psoriatic arthritis is a complex and heterogeneous disease with potential significant disability and impaired quality of life. Although in the last decades new treatment options have led to a better management of this disease, there are still significant unmet therapeutic needs. Dual inhibitor antibodies target two different cytokines simultaneously, potentially offering a better disease control. In psoriatic arthritis, there is evidence for a pathogenic role not only of IL-17A but also the structurally homologous IL-17F. It is postulated that differential expression of both in several targets of PsA could account for disparities in clinical response to IL-17A inhibition alone (such as with secukinumab or ixekizumab). Here we review the evidence so far for the use in psoriatic arthritis of bimekizumab, the first humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. A Phase 2b trial reports better outcomes over both placebo and IL-17A inhibition alone. Very recently encouraging results from open-label extensions with regards to both safety and maintenance of response were presented. Phase III trials are ongoing with the first results awaited in 2021.
Collapse
Affiliation(s)
- Daniel G Oliveira
- Department of Internal Medicine, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Raquel Faria
- Clinical Immunology Unit (UIC), Centro Hospitalar e Universitário do Porto, Porto, Portugal
- Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar – University of Porto, Porto, Portugal
| | - Tiago Torres
- Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar – University of Porto, Porto, Portugal
- Department of Dermatology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| |
Collapse
|
|
33
|
Baeten D, Adamopoulos IE. IL-23 Inhibition in Ankylosing Spondylitis: Where Did It Go Wrong? Front Immunol 2021; 11:623874. [PMID: 33679714 PMCID: PMC7935519 DOI: 10.3389/fimmu.2020.623874] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/22/2020] [Indexed: 12/29/2022] Open
Abstract
Axial spondyloarthritis is a prevalent form of chronic arthritis which is related to psoriatic arthritis and skin psoriasis. TNF and IL-17A as well as IL-17F are key cytokines contributing to the pathobiology of this disease, as evidence by the therapeutic efficacy of inhibition of these factors. Despite the evidence that IL-23 acts as an upstream driver of Th17 cells, the T lymphocytes producing IL-17, and that IL-23 inhibition shows profound efficacy in psoriasis, blocking IL-23 failed to show any evidence of clinical efficacy in axial spondyloarthritis. In this viewpoint article, we revisit the reasons-to-believe in a role of IL-23 in the pathobiology of axial spondyloarthritis, discuss what we have learned on the pathobiology of this disease in general and on the function of the IL-23/IL-17 axis in particular, and share a handful of lessons learned that are of relevance for the translation of emerging biological insights into clinical therapeutics.
Collapse
Affiliation(s)
- Dominique Baeten
- Clinical Immunology and Rheumatology, Amsterdam University Medical Center, Amsterdam, Netherlands.,Immunology Therapeutic Area, UCB, Slough, United Kingdom
| | - Iannis E Adamopoulos
- Department of Medicine, Division of Rheumatology and Clinical Immunology, Beth Israel Medical Deaconess Center, Boston, MA, United States
| |
Collapse
|
|
34
|
Russell T, Watad A, Bridgewood C, Rowe H, Khan A, Rao A, Loughenbury P, Millner P, Dunsmuir R, Cuthbert R, Altaie A, Jones E, McGonagle D. IL-17A and TNF Modulate Normal Human Spinal Entheseal Bone and Soft Tissue Mesenchymal Stem Cell Osteogenesis, Adipogenesis, and Stromal Function. Cells 2021; 10:cells10020341. [PMID: 33562025 PMCID: PMC7915379 DOI: 10.3390/cells10020341] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/28/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022] Open
Abstract
Objective: The spondylarthritides (SpA) are intimately linked to new bone formation and IL-17A and TNF pathways. We investigated spinal soft tissue and bone mesenchymal stem cell (MSC) responses to IL-17A and TNF, including their osteogenesis, adipogenesis, and stromal supportive function and ability to support lymphocyte recruitment. Methods: Normal spinal peri-entheseal bone (PEB) and entheseal soft tissue (EST) were characterized for MSCs by immunophenotypic, osteogenic, chondrogenic, and adipogenic differentiation criteria. Functional and gene transcriptomic analysis was carried out on undifferentiated, adipo- differentiated, and osteo-differentiated MSCs. The enthesis C-C Motif Chemokine Ligand 20-C-C Motif Chemokine Receptor 6 (CCL20-CCR6) axis was investigated at transcript and protein levels to ascertain whether entheseal MSCs influence local immune cell populations. Results: Cultured MSCs from both PEB and EST displayed a tri-lineage differentiation ability. EST MSCs exhibited 4.9-fold greater adipogenesis (p < 0.001) and a 3-fold lower osteogenic capacity (p < 0.05). IL-17A induced greater osteogenesis in PEB MSCs compared to EST MSCs. IL-17A suppressed adipogenic differentiation, with a significant decrease in fatty acid-binding protein 4 (FABP4), peroxisome proliferator-activated receptor gamma (PPARγ), Cell Death Inducing DFFA Like Effector C (CIDEC), and Perilipin-1 (PLIN1). IL-17A significantly increased the CCL20 transcript (p < 0.01) and protein expression (p < 0.001) in MSCs supporting a role in type 17 lymphocyte recruitment. Conclusions: Normal spinal enthesis harbors resident MSCs with different in vitro functionalities in bone and soft tissue, especially in response to IL-17A, which enhanced osteogenesis and CCL20 production and reduced adipogenesis compared to unstimulated MSCs. This MSC-stromal-enthesis immune system may be a hitherto unappreciated mechanism of “fine tuning” tissue repair responses at the enthesis in health and could be relevant for SpA understanding.
Collapse
Affiliation(s)
- Tobias Russell
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Abdulla Watad
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine “B”, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Ramat Aviv 69978, Israel
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Hannah Rowe
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Almas Khan
- Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK; (A.K.); (A.R.); (P.L.); (P.M.); (R.D.)
| | - Abhay Rao
- Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK; (A.K.); (A.R.); (P.L.); (P.M.); (R.D.)
| | - Peter Loughenbury
- Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK; (A.K.); (A.R.); (P.L.); (P.M.); (R.D.)
| | - Peter Millner
- Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK; (A.K.); (A.R.); (P.L.); (P.M.); (R.D.)
| | - Robert Dunsmuir
- Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK; (A.K.); (A.R.); (P.L.); (P.M.); (R.D.)
| | - Richard Cuthbert
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Ala Altaie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (T.R.); (A.W.); (C.B.); (H.R.); (R.C.); (A.A.); (E.J.)
- Correspondence: ; Tel.: +44(0)-113-392-4747
| |
Collapse
|
|
35
|
Russell T, Bridgewood C, Rowe H, Altaie A, Jones E, McGonagle D. Cytokine "fine tuning" of enthesis tissue homeostasis as a pointer to spondyloarthritis pathogenesis with a focus on relevant TNF and IL-17 targeted therapies. Semin Immunopathol 2021; 43:193-206. [PMID: 33544244 PMCID: PMC7990848 DOI: 10.1007/s00281-021-00836-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
A curious feature of axial disease in ankylosing spondylitis (AS) and related non-radiographic axial spondyloarthropathy (nrAxSpA) is that spinal inflammation may ultimately be associated with excessive entheseal tissue repair with new bone formation. Other SpA associated target tissues including the gut and the skin have well established paradigms on how local tissue immune responses and proven disease relevant cytokines including TNF and the IL-23/17 axis contribute to tissue repair. Normal skeletal homeostasis including the highly mechanically stressed entheseal sites is subject to tissue microdamage, micro-inflammation and ultimately repair. Like the skin and gut, healthy enthesis has resident immune cells including ILCs, γδ T cells, conventional CD4+ and CD8+ T cells and myeloid lineage cells capable of cytokine induction involving prostaglandins, growth factors and cytokines including TNF and IL-17 that regulate these responses. We discuss how human genetic studies, animal models and translational human immunology around TNF and IL-17 suggest a largely redundant role for these pathways in physiological tissue repair and homeostasis. However, disease associated immune system overactivity of these cytokines with loss of tissue repair “fine tuning” is eventually associated with exuberant tissue repair responses in AS. Conversely, excessive biomechanical stress at spinal enthesis or peripheral enthesis with mechanically related or degenerative conditions is associated with a normal immune system attempts at cytokine fine tuning, but in this setting, it is commensurate to sustained abnormal biomechanical stressing. Unlike SpA, where restoration of aberrant and excessive cytokine “fine tuning” is efficacious, antagonism of these pathways in biomechanically related disease may be of limited or even no value.
Collapse
Affiliation(s)
- Tobias Russell
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Hannah Rowe
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Ala Altaie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK.
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds, UK.
| |
Collapse
|