Abstract
The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.
Highlights
Spondyloarthritis (SpA) is the second most common form of chronic inflammatory arthritis [1]
We assessed the effects of 5 weeks of dual blockade of tumor necrosis factor (TNF) and IL-17A, TNF inhibitor monotherapy, and IL-17A inhibitor monotherapy, compared to vehicle control, on the severity and the extent of spondyloarthritis manifestations in the M. tub.-induced HLAB27/huB2m tg rats (Figure 1a)
All treatment regimens showed a decrease in spondylitis severity compared to the vehicle treated group, which reached significance for the combination therapy (p = 0.031) and anti-TNF monotherapy groups (p = 0.031), while a numerical decrease was observed in the anti-IL17A monotherapy group without statistical significance (p = 0.164) (Figure 1b)
Summary
Spondyloarthritis (SpA) is the second most common form of chronic inflammatory arthritis [1]. The joints of SpA patients can be affected by bone remodeling, including pathological new bone formation which leads to ankylosis and often disability [2]. Blockade of either pathway clearly inhibits inflammation and improves key clinical outcomes, such as the Assessments of SpondyloArthritis International Society response (ASAS) criteria and patient-reported outcomes [7,10,11,12,13,14,15,16]. Some promising results imply that the IL-17A blockade might reduce new bone formation [19,20,21,22], the optimal strategy to halt this pathological process remains a clinical challenge
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