Shivika Guleria

Background HLA-B27 is a susceptibility factor for enthesitis-related arthritis. HLA-B27 transgenic rats do not develop disease in a germ-free state, suggesting involvement of the gut in the pathogenesis of the disease. There is limited data on the effect of HLA-B27 carriage and gut flora in JIA-ERA. Methods Stool samples from 10 HLA-B27-positive and 5 HLA-B27-negative JIA-ERA patients, and 10 HLA-B27-negative healthy controls were collected after consent. Fecal calprotectin and serum LPS levels were measured using ELISA. The fecal flora was assessed using 16S rRNA based sequencing. Results HLA-B27-positive patients had higher fecal calprotectin levels (p < 0.001) compared to HLA-B27-negative patients and HC. However, serum LPS levels were not different. Alpha and beta diversity of fecal flora were similar in HLA-B27-positive and negative patients, but different compared to HC. HLA-B27-positive patients had higher abundance of family Veillonellaceae, Prevotellaceae and genera Moryella, Intestinimonas, Fournierella, Leyella, Massiliprevotella, Segatella, and Bilophila and lower abundance of genera Bifidobacterium compared to HC. At the species level, the abundance of Coprococcus eutactus and Prevotella copri was higher while that of Dorea longicatena was lower in HLA-B27-positive patients compared to HC. In addition, there was lower abundance of the genera Fusicatenibacter and Lachnospiraceae NC2004 group, species belonging to genera Agathobacter, Fusicatenibacter, Butyricicoccus, and Acutalibacter and higher abundance of genera Leyella in HLA-B27-positive patients compared to HLA-B27-negative patients. Conclusion Lower abundance of anti-inflammatory and higher abundance of pro-inflammatory bacteria in HLA-B27-positive JIA-ERA patients by inducing gut inflammation may play a role in disease pathogenesis. Key Points • The presence of HLA-B27 in JIA-ERA patients is associated with a decline in the population of beneficial bacteria with anti-inflammatory properties and an increase in gut inflammation. • Exploration of supplementation with butyrate or SCFA to improve gut health may be beneficial in patients with JIA-ERA.

Enthesitis-related arthritis (ERA) is a category of juvenile idiopathic arthritis which belongs to the spectrum of diseases that are included in juvenile spondyloarthropathy. In recent years, there have been significant advances in understanding pathogenesis, tools to assess disease activity, early recognition of the axial disease, and targeted therapy using IL-17 inhibitors and small molecule inhibitors. The current narrative review highlights these new advances. Among many hypotheses linking HLA B27 to ERA, one of them is the effect of HLA B27 on gut dysbiosis. However, recent data suggest that gut dysbiosis is probably not determined by HLA B27. Though children present with arthritis and enthesitis, axial disease is present in 50–60% on MRI. Using data-driven approach, discriminative MRI finding for active and chronic diseases has been defined for children. This will help in the early recognition of disease. An abridged version of juvenile spondyloarthropathy disease activity (JSpADA) score without the need for acute phase reactants and Schober test performed as well as the original score may increase its acceptance in routine practice. Secukinumab (anti-IL-17 antibody) has shown a more than 75% response rate in children with ERA and may be a good alternative to anti-TNF therapy. Initial data with tofacitinib also look promising. All these will translate into better outcomes for children with ERA.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in pathogenesis of ankylosing spondylitis (AS). CD 74 is the receptor for MIF and IgA antiCD74 autoantibodies have been described from different parts of the world in patients with AS. As enthesitis-related arthritis (ERA) is a form of juvenile spondyloarthropathy, we studied the serum and synovial fluid levels of MIF in ERA and looked for the IgA antiCD74 antibodies in patients with ERA in our population. Patients with JIA (ILAR classification) were studied. Serum MIF levels were measured by ELISA in 101 patients of ERA (synovial fluid also where available) and compared to 28 patients of other categories of JIA, 25 patients each of ankylosing spondylitis and rheumatoid arthritis, and 38 healthy controls. In addition, association of MIF with disease activity was assessed. Ig A antiCD74 antibodies were measured in sera of ERA, AS and healthy controls. Median serum MIF levels were higher in ERA [2.50 (1.20–4.85) ng/ml] than in healthy controls [0.28 (0.16–0.48); p < 0.0001] and patients with RA [1.13 (0.44–2.45); p < 0.01] MIF levels in ERA were comparable to other categories of JIA [2.63 (1.70–4.05)] and patients with AS [3.62 (0.52–6.51)]. Synovial fluid MIF levels were higher than serum levels (p < 0.01). Serum MIF level had an association with the JSpADA score (r = 0.29, p < 0.01). Serum MIF levels had no association with presence of inflammatory markers, enthesitis, inflammatory back pain or sacroiliitis. IgA AntiCD74 antibody was positive only in 3/88 (3.41%) of ERA patients and was not detected in any patients of AS or healthy controls. Patients with ERA have high MIF levels that show modest correlation with disease activity. Higher synovial fluid MIF levels suggest that it may play a role in synovitis seen in ERA. IgA antiCD74 antibodies are rarely seen in ERA.