Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis

Objectives. ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion

Antibodies against cyclic citrullinated peptide don’t decrease after 6 months of infliximab treatment in refractory rheumatoid arthritis

Anti-citrullinated peptide antibodies (ACPA) and the rheumatoid factor (RF) are well-established serological markers for rheumatoid arthritis (RA). ACPA are very useful in the diagnosis of RA, especially at the early stages of the disease when ACPA have a greater diagnostic value than RF. The aim of the study was to assess the influence of infliximab treatment on RF IgM and ACPA serum levels and RA activity during 6 months of treatment. Thirty-two patients with refractory RA were treated with infliximab during a 6-month period. At baseline, 3 and 6 months of treatment the patients were examined for the number swollen and tender joints out of 28 (SJC, TJC) and the visual analogue scale of arthritis activity according to the patient (VAS). Serum samples were tested for erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), ACPA and RF IgM. The disease activity score (DAS-28) parameter was also calculated at the same time. During the course of our study, we observed statistically significant improvement in ESR, CRP, TJC, SJC, VAS DAS-28, and RF IgM after 3 and 6 months of infliximab treatment when compared to the baseline, whereas the ACPA level remained unchanged after 3 and 6 months of treatment (P = 0.96 and P = 0.85). The changes in the ACPA level are not a factor for evaluation of successful infliximab treatment but the changes in RF IgM are. According to different behavior of these antibodies during infliximab treatment, we suggest that the roles of ACPA and RF in the pathogenesis of RA are different

Dominant suppression of inflammation by glycan-hydrolyzed IgG [Retracted]

A unique anti-inflammatory property of IgG, independent of antigen specificity, is described. IgG with modification of the heavy-chain glycan on asparagine 297 by the streptococcal enzyme endo-beta-N-acetylglucosaminidase (EndoS) induced a dominant suppression of immune complex (IC)-mediated inflammation, such as arthritis, through destabilization of local ICs by fragment crystallizable-fragment crystallizable (Fc-Fc) interactions. Small amounts (250 mu g) of EndoS-hydrolyzed IgG were sufficient to inhibit arthritis in mice and most effective during the formation of ICs in the target tissue. The presence of EndoS-hydrolyzed IgG disrupted larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen-antibody binding per se was affected

Autoimmune manifestations in aged mice arise from early-life immune dysregulation.

Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren\u27s syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren\u27s pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious. Sci Transl Med 2016 Oct 19; 8(361):361ra13