Enthesitis: from pathophysiology to treatment

Schett, Georg; Lories, Rik; D'Agostino, Maria Antonietta; Elewaut, Dirk; Kirkham, Bruce; Soriano, Enrique R.; McGonagle, Dennis

doi:10.1038/nrrheum.2017.188

Cited by 333 publications

(263 citation statements)

References 88 publications

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“…It primarily manifests on the skin, resulting in plaques on the elbows, knees, or scalp, which may extend to other areas of the body 5,10,11. PsA and AS are part of spondyloarthritis (SpA), which are enthesitis driven, lifelong, painful, and debilitating immune-mediated inflammatory diseases affecting the joints and/or spine that can lead to irreversible structural bone damage caused by years of inflammation 6,12–15. The prevalence of PsA in the general population has been reported to range from 0.01% in Asia16 to 0.67% in Norway,17 while the prevalence of AS ranges from 0.1% to 1.4% globally 18…”

Section: Introductionmentioning

confidence: 99%

Budget impact model of secukinumab for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and ankylosing spondylitis in Italy: a cross-indication initiative

Colombo

Matteo²,

Martinotti³

et al. 2018

CEOR

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ObjectiveSecukinumab, a fully human monoclonal IgG1 antibody that selectively neutralizes the proinflammatory cytokine IL-17A, has been approved in Europe in 2015 for the treatment of adult patients with moderate-to-severe plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). This analysis assessed the budget impact of introduction of secukinumab to the Italian market for all three indications from the perspective of the Italian National Health Service.Materials and methodsA cross-indication budget impact model was developed and included biologic-treated adult patients diagnosed with psoriasis, PsA, and AS. The analyses were conducted over a 3-year time horizon and included direct costs (drug therapy costs, administration costs, diseases-related costs, and adverse events costs). Model input parameters (epidemiology, market share projections, resource use, and costs) were obtained from the published literature and other Italian sources. The robustness of the results was tested via one-way sensitivity analyses: secukinumab cost, secukinumab market share, intravenous administration costs, and adverse events costs were varied by ±10%.ResultsThe total patient population for secukinumab over the 3-year timeframe was projected to be 6,648 in the first year, increasing to 12,001 in the third year, for all three indications combined (psoriasis, PsA, and AS). Compared to a scenario without secukinumab in the market, the introduction of secukinumab in the market for the treatment of psoriasis, PsA, and AS showed a cumulative 3-year incremental budget impact of −5%, corresponding to savings of €66.1 million and per patient savings of about €1,855. The majority of the cost savings came from the adoption of secukinumab in AS (58%), followed by PsA (29%) and psoriasis (13%). Sensitivity analyses confirmed the robustness of the results.ConclusionResults from this cross-indication budget impact model show that secukinumab is a cost-saving option for the treatment of PsA, AS, and psoriasis patients in Italy.

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Section: Introductionmentioning

confidence: 99%

Budget impact model of secukinumab for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and ankylosing spondylitis in Italy: a cross-indication initiative

Colombo

Matteo²,

Martinotti³

et al. 2018

CEOR

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“…Interestingly, ALK2 mutations are responsible for the rare mendelian disorder, Fibrodysplasia Ossifians Prgogressiva that mimicks AS (Ref). Background: Enthesitis is a hallmark of spondyloarthropaties [1], with mechanical stress or damage in the tendon being proposed as a trigger for the development of inflammation at the enthesis that propagates to the synovial compartment through what has been termed "synovio-enthesial complex" [2]. Increasing evidence supports the role that stromal cells play in the shift of the inflammatory process towards chronicity promoting T cell migration, retention and survival [3].…”

Section: Discussionmentioning

confidence: 99%

FRI0353 MISREGULATION OF BMP/TGFβ SHEDS LIGHT ON THE PATHOGENICITY OF HLA-B27 IN SPONDYLOARTHRITIS

Grandon

Rincheval

Jah

et al. 2019

Spondyloarthritis – Etiology, Pathogenesis and Animal Models

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BackgroundThe class I MHC allele, HLA-B27 is the main genetic factor predisposing to ankylosing spondylitis (AS) and related spondyloarthritis (SpA), a group of osteo-articular disorders combining inflammation with ossification. Until now, hypotheses to explain such striking association discovered 45 years have speculated either on the presentation of particular peptides to CD8+ T cells or on aberrant behaviors of the HLA-B27 molecule independent of its antigen presenting function, including slow folding and homodimers formationObjectivesTo unravel aberrant function(s) of HLA-B27 independent of antigen presentation that may explain its pathogenicity.Methods Drosophila transgenic for SpA-associated HLA-B*27:04 or HLA-B*27:05 or non-SpA -associated HLA-B*07:02, alone or in combination with human β2-microglobulin (hβ2m) were produced. Genetic interaction tests were used to identify altered pathway(s). Protein-protein interactions were evidenced by proximity ligation assay. Phosphorylation of Smad2/3 was tested on CD4+ T cells from HLA-B27+ SpA patients and HLA-B27-neg healthy controls (6-10/group) by PhosFlow.Results Drosophila transgenic for HLA-B*27:04 or HLA-B*27:05 but not for control HLA-B*07:02 allele, in the presence of hβ2m that allows expression of well-folded HLA-B molecules at the cell surface, developed crossveinless phenotype. This was due to a disturbance of BMP signaling by HLA-B27/hβ2m which repressed Saxophone (Sax) BMP type I receptor (BMPR1) function, resulting in widening of phosphorylated Mad, the Drosophila receptor-mediated Smad, gradient, and increased expression of its target genes dpp and omb. Consistently, HLA-B27/hβ2m well-folded conformers co-localized with Sax at the surface of Drosophila cells and also with Sax mammal ortholog ALK2, on immune cells from SpA patients. As predicted, given that Sax orthologs ALK1 and ALK2 are known to exert antagonistic function on TGFβ/BMP signaling, we found heighthened p-Smad in response to TGFβ or Activin A in CD4+ T cells from HLA-B27+ SpA patients (p<0.05).ConclusionThe pathogenic role of HLA-B27 in SpA may result from a TGFβ/BMP signaling misregulation due to specific antagonistic interaction with ALK1/ALK2 BMPR1, at the crosstalk between inflammation and ossification. Interestingly, ALK2 mutations are responsible for the rare mendelian disorder, Fibrodysplasia Ossifians Prgogressiva that mimicks AS (Ref).References[1] Hatsell, S. J. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin. Science Translational Medicine7, 303ra137-303ra137 (2015).Disclosure of InterestsBenjamin Grandon: None declared, Auroe Rincheval: None declared, Nadège Jah: None declared, Jean-Marc Corsi: None declared, Luiza M. Araujo: None declared, Simon Glatigny: None declared, Delphine Roche: None declared, Gilles Chiocchia: None declared, Isabelle Guénal: None declared, Sébastein Gaumer: None declared, Maxime Breban Grant/research support from: Pfizer, UCB, Novartis, MSD, Consultant for: UCB

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“…PGE2 also known as dinoprostone has been discussed as potential early mediator of enthesitis . The importance of PGE2 in enthesitis is cemented by the responsiveness of axial and peripheral enthesitis to NSAID treatment . NSAID mode of action is by inhibiting the enzymes COX‐1 and COX‐2; these are key to the synthesis of prostaglandins .…”

Section: The Concept Of Il‐23–independent Il‐17 Productionmentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Enthesitis: from pathophysiology to treatment

Cited by 333 publications

References 88 publications

Budget impact model of secukinumab for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and ankylosing spondylitis in Italy: a cross-indication initiative

Budget impact model of secukinumab for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and ankylosing spondylitis in Italy: a cross-indication initiative

FRI0353 MISREGULATION OF BMP/TGFβ SHEDS LIGHT ON THE PATHOGENICITY OF HLA-B27 IN SPONDYLOARTHRITIS

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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