Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study

Eleni Kampylafka, Isabelle d'Oliveira, Christina Linz, Veronika Lerchen, Fabian Stemmler, David Simon, Matthias Englbrecht, Michael Sticherling, Jürgen Rech, Arnd Kleyer, Georg Schett, Axel J Hueber, Eleni Kampylafka, Isabelle d'Oliveira, Christina Linz, Veronika Lerchen, Fabian Stemmler, David Simon, Matthias Englbrecht, Michael Sticherling, Jürgen Rech, Arnd Kleyer, Georg Schett, Axel J Hueber

Abstract

Background: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA.

Methods: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded.

Results: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable.

Conclusions: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA.

Trial registration: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.

Keywords: Bone; Enthesiophytes; Erosions; Psoriatic arthritis; Synovitis; bDMARDs.

Conflict of interest statement

Ethics approval and consent to participate

In the PSARTROS study (ClinicalTrials.gov Identifier: NCT02483234), all patients provided written informed consent, and institutional review board/ethics committee (Ethik-Kommission der Friedrich-Alexander-Universität Erlangen-Nürnberg) approved the protocol (EC 63_15Az; IRB 2355/01).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Prevalence of inflammatory and structural changes in the joints of patients with psoriatic arthritis. a On left, baseline imaging analysis and comparative presentation of the prevalence of synovitis, bone erosions, and enthesiophytes in power Doppler ultrasound (PDUS), magnetic resonance imaging (MRI), and high-resolution peripheral quantitative computed tomography (HR-pQCT); on right, prevalence of enthesiophytes according to size using HR-pQCT (grade 1: height < 4 mm, grade 2: height ≥ 4 mm, grade 3: diffuse proliferation). b Coronal and axial images of the same enthesiophytes (upper panel: grade 1, lower panel: grade 3) in MRI and HR-pQCT. Arrow indicates the lesion. Abbreviation: N/A not applicable
Fig. 2
Fig. 2
Effects of secukinumab treatment on the inflammatory changes in the joints of patients with psoriatic arthritis. a Comparison of inflammatory changes in the joints of psoriatic arthritis (PsA) patients using magnetic resonance imaging (MRI) at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. Psoriatic arthritis MRI scores (PsAMRIS) for synovitis and total PsAMRIS scores are shown. b Representative coronal T1-weighted fat-suppressed post-gadolinium MRI images of the hand of the same patient with PsA at baseline and after 24 weeks are depicted. Baseline image shows synovitis (arrows) and periarticular inflammation at enthesial sites (arrowheads), which resolved after 24 weeks of secukinumab treatment. c Comparison of inflammatory changes in the joints of PsA patients using power Doppler ultrasound (PDUS) at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. OMERACT ultrasound scores for synovial hypertrophy and power Doppler activity as well as global OMERACT ultrasound scores are shown. Data are presented as median and interquartile ranges. *P ≤0.05; **P ≤0.01
Fig. 3
Fig. 3
Effects of secukinumab treatment on the articular and extra-articular structural bone changes in patients with psoriatic arthritis. a Comparison of bone erosions in the joints of psoriatic arthritis (PsA) patients using magnetic resonance imaging (MRI, left) and high-resolution peripheral quantitative computed tomography (HR-pQCT, right) at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. MRI data represent Psoriatic arthritis MRI scores (PsAMRIS) for erosions, and HR-pQCT data represent erosion volumes. b Comparison of enthesiophytes in the joints of PsA patients using MRI (left) and HR-pQCT (right) at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. MRI data represent Psoriatic arthritis MRI scores (PsAMRIS) for proliferations, and HR-pQCT data represent enthesiophyte grades according to size. c Comparison of bone micro-structural data of the distal radius of PsA patients using HR-pQCT at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. Cortical and trabecular volumetric bone density (vBMD), cortical thickness, and trabecular numbers are shown. d Comparison of biomechanical properties of radial bones of PsA patients using HR-pQCT measurements at baseline (BL) and after 24 weeks (Wk24) of secukinumab treatment. Data show failure load and bone stiffness based on micro-finite element analysis. Data are presented as median and interquartile ranges. Abbreviations: kN kiloNewton, mgHA/cm3 milligram of hydroxyapatite per cube centimeter, N Newton

References

    1. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. N Engl J Med. 2017;376(21):2095–2096.
    1. Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 2015;67(1):128–139. doi: 10.1002/art.38892.
    1. Mease P. New pathways of treatment for psoriatic arthritis. Lancet (London, England) 2017;389(10086):2268–2270. doi: 10.1016/S0140-6736(17)31427-7.
    1. Veale DJ. Psoriatic arthritis: recent progress in pathophysiology and drug development. Arthritis Res Ther. 2013;15(6):224. doi: 10.1186/ar4414.
    1. Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat Med. 2013;19(7):822–824. doi: 10.1038/nm.3260.
    1. McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 2015;386(9999):1137–1146. doi: 10.1016/S0140-6736(15)61134-5.
    1. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich RS, Shuler CL, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79–87. doi: 10.1136/annrheumdis-2016-209709.
    1. Mease PJ, McInnes IB, Kirkham B, Kavanaugh A, Rahman P, van der Heijde D, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015;373(14):1329–1339. doi: 10.1056/NEJMoa1412679.
    1. van der Heijde D, Landewe RB, Mease PJ, McInnes IB, Conaghan PG, Pricop L, et al. Brief report: Secukinumab provides significant and sustained inhibition of joint structural damage in a phase III study of active psoriatic arthritis. Arthritis Rheumatol. 2016;68(8):1914–1921. doi: 10.1002/art.39685.
    1. Schett G, Lories RJ, D’Agostino MA, Elewaut D, Kirkham B, Soriano ER, et al Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13(12):731–741. doi: 10.1038/nrrheum.2017.188.
    1. Koenders MI, Lubberts E, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, Di Padova FE, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol. 2005;167(1):141–149. doi: 10.1016/S0002-9440(10)62961-6.
    1. Adamopoulos IE, Chao CC, Geissler R, Laface D, Blumenschein W, Iwakura Y, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther. 2010;12(1):R29. doi: 10.1186/ar2936.
    1. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–2682. doi: 10.1084/jem.20061775.
    1. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345–1352. doi: 10.1172/JCI5703.
    1. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–1076. doi: 10.1038/nm.2817.
    1. Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018–1019. doi: 10.1038/nm.2854.
    1. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Oberdorfer L, et al. Interleukin-23-dependent gamma/delta T cells produce Interleukin-17 and accumulate in the Enthesis, aortic valve, and Ciliary body in mice. Arthritis Rheumatol. 2016;68(10):2476–2486. doi: 10.1002/art.39732.
    1. Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo-Ortega H, et al. Brief report: group 3 innate lymphoid cells in human Enthesis. Arthritis Rheumatol. 2017;69(9):1816–1822. doi: 10.1002/art.40150.
    1. Uluckan O, Jimenez M, Karbach S, Jeschke A, Grana O, Keller J, et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med. 2016;8(330):330ra337. doi: 10.1126/scitranslmed.aad8996.
    1. Kocijan R, Englbrecht M, Haschka J, Simon D, Kleyer A, Finzel S, et al. Quantitative and qualitative changes of bone in psoriasis and psoriatic arthritis patients. J Bone Miner Res. 2015;30(10):1775–1783. doi: 10.1002/jbmr.2521.
    1. Faustini F, Simon D, Oliveira I, Kleyer A, Haschka J, Englbrecht M, et al. Subclinical joint inflammation in patients with psoriasis without concomitant psoriatic arthritis: a cross-sectional and longitudinal analysis. Ann Rheum Dis. 2016;75(12):2068–2074. doi: 10.1136/annrheumdis-2015-208821.
    1. Ostergaard M, McQueen F, Wiell C, Bird P, Boyesen P, Ejbjerg B, et al. The OMERACT psoriatic arthritis magnetic resonance imaging scoring system (PsAMRIS): definitions of key pathologies, suggested MRI sequences, and preliminary scoring system for PsA hands. J Rheumatol. 2009;36(8):1816–1824. doi: 10.3899/jrheum.090352.
    1. Bruyn GA, Naredo E, Iagnocco A, Balint PV, Backhaus M, Gandjbakhch F, et al. The OMERACT ultrasound working group 10 years on: update at OMERACT 12. J Rheumatol. 2015;42(11):2172–2176. doi: 10.3899/jrheum.141462.
    1. D’Agostino MA, Boers M, Wakefield RJ, Berner Hammer H, Vittecoq O, Filippou G, et al. Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study. RMD Open. 2016;2(1):e000237. doi: 10.1136/rmdopen-2015-000237.
    1. Figueiredo CP, Kleyer A, Simon D, Stemmler F, d’Oliveira I, Weissenfels A, et al. Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT) Semin Arthritis Rheum. 2018;47(5):611–618. doi: 10.1016/j.semarthrit.2017.09.011.
    1. Finzel S, Sahinbegovic E, Kocijan R, Engelke K, Englbrecht M, Schett G. Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis. Arthritis Rheumatol. 2014;66(11):2968–2975. doi: 10.1002/art.38794.
    1. Macneil JA, Boyd SK. Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone. 2008;42(6):1203–1213. doi: 10.1016/j.bone.2008.01.017.
    1. Smolen JS, Schoels M, Aletaha D. Disease activity and response assessment in psoriatic arthritis using the disease activity index for PSoriatic arthritis (DAPSA). A brief review. Clin Exp Rheumatol. 2015;33(5 Suppl 93):S48–S50.
    1. Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment. Ann Rheum Dis. 2010;69(1):48–53. doi: 10.1136/ard.2008.102053.
    1. Lackner A, Duftner C, Ficjan A, Gretler J, Hermann J, Husic R, et al. The association of clinical parameters and ultrasound verified inflammation with patients’ and physicians’ global assessments in psoriatic arthritis. Semin Arthritis Rheum. 2016;46(2):183–189. doi: 10.1016/j.semarthrit.2016.05.010.
    1. Finzel S, Englbrecht M, Engelke K, Stach C, Schett G. A comparative study of periarticular bone lesions in rheumatoid arthritis and psoriatic arthritis. Ann Rheum Dis. 2011;70(1):122–127. doi: 10.1136/ard.2010.132423.
    1. Finzel S, Kraus S, Schmidt S, Hueber A, Rech J, Engelke K, et al. Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors. Ann Rheum Dis. 2013;72(7):1176–1181. doi: 10.1136/annrheumdis-2012-201580.
    1. Shaw AT, Maeda Y, Gravallese EM. IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res Ther. 2016;18(1):104. doi: 10.1186/s13075-016-0998-x.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever