TGFß signaling pathway is altered by HLA-B27 expression, resulting in pathogenic consequences relevant for spondyloarthritis.

BACKGROUND: Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-ß2 microglobulin (hß2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. METHODS: Genetic interaction was studied between activin/transforming growth factor ß (TGFß) pathway and HLA-B27/hß2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hß2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFß pathways induced by its ligands, and the transcript level of target genes of the TGFß pathway, were evaluated. RESULTS: In HLA-B27/hß2m transgenic Drosophila, inappropriate signalling through the activin/TGFß pathway, involving Baboon (Babo), the type I activin/TGFß receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hß2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hß2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFß receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFß1 was increased in T cells from B27 rats, showing evidence for deregulated TGFß pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFß exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. CONCLUSIONS: This study shows that HLA-B27 alters the TGFß pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.

Risankizumab Efficacy in Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Remission: A Case Report on Rheumatologic and Dermatologic Disease Manifestations with Literature Review.

SAPHO syndrome is a complex disease that encompasses both inflammatory arthritis and/or osteitis and dermatologic manifestations. It is considered a rare disease, in fact, no clinical trials have been conducted on its therapy and management. Therefore, therapeutic approach is based on small case studies. Here, we described the case of a 63-year-old woman affected by SAPHO syndrome, treated with the selective IL-23p19 antagonist, Risankizumab, after unsuccessful therapies with Methotrexate, Infliximab, Adalimumab, and an allergic reaction to Secukinumab. At the beginning of therapy, in November 2022, the patient presented with arthritis in both knees associated with palmar pustulosis and guttate psoriasis on the trunk. DAPSA score was 24, PtGA 80 mm, PASI score 11.1, and BSA 40%. Thereafter, Risankizumab was started at the standard dosage of 150 mg. At week 24 patient achieved clinical remission, DAPSA score was 8, PtGA was 30 mm, PASI was 1, and BSA 2.5. Patient maintained clinical remission state at the subsequent week 52 evaluation. At the same time, the patient did not report any adverse effects. Health-related quality of life was also assessed at the same time points aforementioned, showing significant improvement. In conclusion, this case report wants to point out the efficacy and safety of Risankizumab in SAPHO syndrome, reporting a sustained disease remission through a 12 months long follow-up period. We can consider IL-23p19 targeted therapy as a novel treatment option for SAPHO-with a high efficacy potential-especially on patients that have already been treated with other biologics.