Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid.

Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non-erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper-associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE-derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)-γ and interleukin (IL)-17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co-morbidities such as osteoarthritis or overlap with RA. IL-17A and IL-6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+ , a marker associated with T helper type 17 (Th17) cells. IL-17A-production was validated among CD4+ CCR6+ T cells following in-vitro stimulation. Furthermore, a strong IFN-γ production was observed in both CD4+ and CD8+ cells. Our study shows high IL-17A and IL-6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis.

Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus - distinct roles of BAFF and APRIL.

Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/µl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.

Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis.

OBJECTIVE: To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. METHODS: Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. RESULTS: The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. CONCLUSION: The HS1,2A allele *2 associates with early and longstanding RA.

Immunologic and genetic links between spondylarthropathies and inflammatory bowel diseases.

BACKGROUND AND OBJECTIVE: Spondyloarthritis (SpA) is a well recognized extraintestinal manifestation of Inflammatory Bowel Diseases (IBDs), either Crohn's Disease(CD) or Ulcerative Colitis (UC). A much larger percentage of SpA patients have subclinical gut inflammation manifested either by endoscopic findings or by histology. The aim of the present article is to review clinical and experimental evidences regarding the immunological and genetic links between gut and joint inflammation in IBDs and SpA. EVIDENCE AND INFORMATION SOURCES: A systematic review using PubMed database entering IBD and SpA as key words was performed. STATE OF THE ART: The association with HLA-B27 is less strong in IBD-associated SpA than in Idiopathic Ankylosing Spondylitis (AS) and there is some evidence for an association between gut inflammation in SpA and CD related CARD15 mutations. A common inflammatory pathogenic pathway has been suggested in gut and joint inflammation in IBD. Treatment of SpA associated with IBD has gained major advances in recent years with the advent of anti-TNF-alpha therapy. PERSPECTIVES: The adaptive immune response in IBD is thought to be strictly differentiated between Th1 and Th2 in CD and UC respectively. Recent findings, however, suggest that novel effector pathways could drive tissue damage. The most important pathway now emerging is the IL-23/IL-17 axis. CONCLUSIONS: Present and future advancements of knowledge on mechanisms of inflammation will likely lead to new therapeutic targets.

Cytoprotective and antisecretory effects of 11-deoxy-13,14-didehydro-16(s)-methyl PGE2 methylester (FCE 20700).

A new, chemically stable analogue of PGE2, 11-deoxy-13,14-didehydro-16(S)-methyl PGE2 methylester (FCE 20700) was studied for the prevention of different gastrointestinal ulcers and for the inhibition of basal gastric acid secretion in the rat. The diarrhoea-inducing activity was also investigated. FCE 20700 was more potent than PGE2 in the prevention of stress-induced gastric ulcers (ED50 = 262 and 787 mcg/kg) and indomethacin-induced intestinal ulcers (ED50 = 557 and 4569 mcg/kg), and showed the same potency as PGE2 in the prevention of ethanol (ED50 = 9.2 and 14.8 mcg/kg) and indomethacin-induced gastric ulcers (ED50 = 37.8 and 22.3 mcg/kg). FCE 20700 weakly affects gastric acid secretion with an ED50 of 2385 mcg/kg, showing clear separation of antisecretory activity and gastric antiulcer potency. FCE 20700 does not induce diarrhoea in rats at doses up to 6.25 mg/kg, 10 to 600 times the effective antiulcer doses.