Mechanistic studies of IL-17 versus TNF blockade in Spondyloarthritis (SpA)

We aim to identify specific biological effects by systematic translational comparison of IL-17A versus TNF blockade in SpA patients using combined molecular, cellular and imaging approaches with the overall goal to establish a path towards stratified medicine.

• Kick-off meeting in March 2017
• First-patient-in in the 4 key studies (tissue immunopathology, cytokine profiles, PET-CT, micro-CT)
• Last-patient-out in the 4 key studies
• Analysis of the individual data sets
• Integration of the different data sets
• Completion of the publications and reports

Molecular and cellular pathways of inflammation

We examined gene expression profiles in biopsies retrieved from SpA patients before and after aIL_17A treatment (Fig. 1). Pathway analysis revealed that genes down-regulated upon the treatment genes were significantly enriched in biological processes related to immune and inflammatory responses and leukocyte activation and trafficking. Of interest, aIL-17 treatment did not affect expression of TNF. Surprisingly, the overlap in regulated genes between aIL-17A and aTNF treatments was rather small. Commonly and uniquely modulated by each treatment pathways are under investigation.

Leukocytes cytokines responses

Analysis via whole-blood stimulation systems revealed that aTNF therapy induces profound changes in patients’ innate immune response. Modular transcriptional repertoire analysis showed that aTNF therapy affects immune responses via direction of macrophage polarization and the inhibition of TNF- and IL-1-dependent feed-forward loops of NF-kB activation. aTNF treatment did not affect the IL-6/Th17 arm of the immune response, supporting the importance of IL-17 blockade as an alternative treatment for SpA. Furthermore we found that high expression of genes associated with leukocyte invasion/migration and inflammatory processes at baseline predisposes to favorable outcome of aTNF therapy, while high-level expression of cytotoxic molecules is associated with poor therapeutic responses to TNF-blockers.

Microarchitectural peripheral bone changes

IL-17A blockade led to significant improvement of signs and symptoms of PsA. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions and enthesiophytes did not show any progression, and structural integrity and functional bone strength remained stable.

Axial inflammation and new bone formation

[18F]-fluoride PET-CT scans have been performed in 10 AS patients before and 12 weeks after aTNF treatment, and in 5 AS patients starting aIL-17A treatment (baseline). After aTNF treatment quantitative [18F]-fluoride uptake decreased significantly in the costovertebral and SI joints of clinical responders (p<0.03), in contrast to non-responders (Fig. 2). In the secukinumab cohort, at least one PET-positive lesion per patient was found in the cervical, thoracic and/or lumbar spine at locations such as anterior corners of vertebrae and in bridging syndesmophytes (Fig. 3).

• 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. 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. Arthritis Res Ther. 2018 Jul 27;20(1):153. doi: 10.1186/s13075-018-1653-5
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• Menegatti S, Guillemot V, Latis E, Yahia-Cherbal H, Mittermüller D, Rouilly V, Mascia E, Rosine N, Koturan S, Millot G, Leloup C, Duffy D, Gleizes A, Hacein-Bey-Abina S; Milieu Intérieur Consortium, Sellam J, Berenbaum F, Miceli C, Dougados M, Bianchi E, Rogge L. Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo. Ann Rheum Dis. 2020 Dec 2:annrheumdis-2020-218304. doi: 10.1136/annrheumdis-2020-218304. Online ahead of print.PMID: 33268443
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• Menegatti S, Bianchi E, Rogge L. Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses. Frontiers in Immunology, Front. Immunol., 19 March 2019 | https://doi.org/10.3389/fimmu.2019.00382
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• Fiechter R.H., de Jong H. M, van Mens L. J.J., Fluri I.A., Tas S. W., Baeten D. L. P., Yeremenko N. G., van de Sande M. G. H. IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt. Front Immunol 4 March 2021. doi: 10.3389/fimmu.2021.611656
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• Yeremenko N. (2021). Out of the shadow of interleukin-17A: the role of interleukin-17F and other interleukin-17 family cytokines in spondyloarthritis. Current opinion in rheumatology, 33(4), 333–340. https://doi.org/10.1097/BOR.0000000000000805 
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• N. Yeremenko. Out of the shadow of IL-17A: the role of Il-17F and other IL-17 family cytokines in spondyloarthritis. Current Opinion in Rheumatology

A lay advisory board of patients will be instrumental in the interpretation of the data, in particular in addressing the question if and how the anticipated biologic profiles can be applied in a useful way to stratify individual patients or patient groups to aTNF versus aIL-17A treatment.