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

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).

Inflammation and structural changes of the bone, including new bone formation, are key pathologic processes in SpA. TNF and IL-17 are key pathogenic cytokines in SpA and may act differently on these processes. Our studies showed that TNF inhibitors(i) had a more profound effect on systemic immune responses than IL-17i, which suggests that IL-17i may have a lesser impact on immune cells but more on non-immune cells or that IL-17i mainly affect cells in target tissues. Analysing synovial tissue, we observed that L-17i modulated multiple pathways related to new bone formation. Investigating systemic bone changes, we observed similar effects of both treatments on volumetric bone mineral density, stiffness and failure load estimates. In addition, PET-CT analysis demonstrated comparable efficacy of TNFi and IL-17Ai on inhibition of axial new bone formation. In summary, we showed that, in part, both inhibitors show an overlapping effect on systemic bone changes but differentially impact systemic immune responses.

Clinical trials performed over the past decade have demonstrated that monoclonal antibodies targeting the proinflammatory cytokine interleukin (IL)-17A are effective in treating axial spondyloarthritis (axSpA). As a result, patients affected by axSpA now have the choice between Tumor necrosis factor alpha (TNF)-blockers and IL-17A inhibitors. The availability of two different drugs benefits patients, but it also raises important questions concerning their work mechanisms. The main goal of this research project was to understand how these two drugs act in patients. Our results demonstrate that, in part, TNFi and IL-17 show an overlapping effect on systemic bone changes and new bone formation, but differentially impact systemic immune responses. Particularly, anti-TNF therapy has major effects on systemic immune responses with potential implications for increased susceptibility to infectious microorganisms. In contrast, IL-17 inhibitors had a lesser impact on systemic immune responses than TNF-blockers, suggesting that they may act mainly on non-immune cells and/or directly in inflamed tissues. These data are supported by the modulation of disease-relevant immune and stromal pathways in the targeted tissues (synovium and skin) in response to IL-17Ai.

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