Factors underlying chronic inflammation in rheumatoid arthritis

Rheumatoid arthritis (RA)is a debilitating chronic inflammatory disease whose characteristic pathology includes swollen, painful, and deformed joints. In recent decades, both clinical and basic scientific research have tried to determine the factors involved in the pathogenesis of this common disease. Although the cause of RA is still unknown, several factors that contribute to RA have been identified. Among these are the discoveries of: susceptibility genes, disease-causing immune cells, and cytokine and signal transduction networks involved in promoting persistence of inflammation. Various therapeutic strategies, including anti-tumor necrosis factor therapy, have been developed to target one or more of these factors. Although none of these therapeutic strategies can actually cure the disease, some of these novel agents have proven to be more effective than others. This implies that the success of a therapy is very much dependent on the therapeutic targets chosen. Therefore, improved understanding of the cellular and molecular events occurring in the rheumatoid joint during the pathogenesis of the disease is particularly important if we are to better combined therapeutic strategies. In this article we summarize current understanding of the factors that contribute to disease pathogenesis in RA and identify cellular and molecular events that could drive the development of the disease and represent potential new therapeutic targets.     

Contact radiotherapy of rheumatoid arthritis]

The authors have devised a method of contact radiotherapy with open radionuclides (198Au) to be used in the treatment of patients suffering from rheumatoid arthritis. Indications for therapy have been defined. In 360 patients suffering from rheumatoid arthritis, radioactive colloid gold was administered to the affected joints. The therapeutic effect was slow in development. The best clinical results were recorded at month 12. Considerable improvement was noticed in 70% of the patients, improvement in 20%, and in 10% of the patients, no therapeutic effect could be recorded. Good effect was ascertained in patients with X-ray Stage I and II disease (70%).     

Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis

The synovitis of rheumatoid arthritis (RA) was long regarded merely as an unspecific chronic inflammatory process of minor diagnostic value and therefore did not play a major role in the understanding of the pathogenesis of RA. It is only in recent years, along with the observation that T and B cells are expanded oligoclonally in synovial tissue and that B cells are able to undergo a local germinal center (GC) reaction, that the synovial tissue has come to be regarded as a site of specific immune processes. The analysis of the immunoglobulin (Ig) gene repertoire had great impact on the understanding of B cell response in lymphatic organs and was subsequently applied to B cells from RA patients. The analyses of the variable (V) regions of the Ig heavy (H) and light (lambda) chains suggested that an antigen specific activation and differentiation of B cells into plasma cells (Plc) takes place in the chronically inflamed synovial tissue of patients with RA. It seems that in a subset of RA patients the synovial tissue develops into an ectopic lymphoid tissue that supports a local GC reaction. Ectopic GC are characteristic of RA; however, they are in general absent from synovitis of osteoarthritis (OA). Here the accumulation of Plc follows a different mechanism. Highly mutated VH genes suggest that in OA memory B cells migrate into the synovial tissue with subsequent differentiation into Plc but without further V gene diversification. Therefore in synovitis two patterns of B cell activation can be differentiated: the maturative and the accumulative type. These two patterns are not definitely disease linked. The maturative type is only found in RA whereas the accumulative type occurs in both diseases. Clinically RA is defined via serum antibodies to the constant region of Ig, so-called rheumatoid factor. However, the spectrum of autoreactive B cells in RA patients is wide and is based on the study of antibody specificities in serum, in synovial fluid and B cell lines derived from peripheral blood, bone marrow, synovial fluid and synovial tissue. These analyses defined non-organ-specific and organ-specific antigens. One can reasonably assume that the disease is far too complex to be explained by only a single antigen. There is a whole combination of antigens acting in a multistep manner that is responsible for RA pathogenesis. It can be hypothesized that chronic synovitis, which is the underlying mechanism of joint destruction, follows a three-step process: (a) initiation, (b) destruction, and (c) perpetuation. The characterization of antigens driving the local synovial B cell maturation and accumulation could lead to an understanding of the process perpetuating the disease. Identification of arthritogenic antigens may yield new avenues for diagnostics and immunotherapy but also a new approach for prevention by vaccines with antigens probably defined by synovial B cell reactivity.     

Eicosanoid production in rheumatoid synovitis

Leukotriene B₄ (LTB₄) synthesis in rheumatoid synovitis was studied using peripheral and synovial fluid polymorphonuclear leukocytes (PMNs) and rheumatic synovial lining cells. No differences were found in LTB₄ synthesis between peripheral PMNs from healthy volunteers and rheumatoid arthritis patients. When peripheral and synovial PMNs from the same RA patient were compared, arachidonic acidinduced LTB₄ synthesis in synovial fluid PMNs was increased 1.7–7.2 fold, whereas the response to Ca ionophore A23187 stimulation was similar. This suggests 5-lipoxygenase stimulating factor(s) in inflamed joints. Rheumatic synovial lining cells in a primary cell culture produced small amounts of LTB₄, the concentrations being less than 0.1 per cent of those of prostaglandin E₂ (PGE₂). PGE₂ synthesis in synovial cells was increased when arachidonic acid or interleukin-1 was added to the culture, whereas LTB₄ production remained unaltered. The present results suggest that in inflamed joints LTB₄ originates mainly from PMNs whereas synovial lining cells are the source for PGE₂.     

Antibodies to citrullinated proteins in rheumatoid arthritis]

Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology, characterized by chronic joint inflammation that often leads to joint destruction. Diagnosis of RA is currently based on the revised classification criteria of the American College of Rheumatology (ACR); however, it remains imprecise, especially early in the course of disease. Rheumatoid factor (RF) has been widely used in clinical practice as a useful serological marker for diagnosis of RA. Although RF is the only serological test in the criteria of the ACR, its specificity is limited since RF can be also detected in other rheumatic diseases. Because the current therapeutic strategies in RA employ increasingly aggressive regimens from early stage of the disease, more specific serological markers than RF are desirable. Recently, anti-cyclic citrullinated peptide (anti-CCP) antibodies have attracted attention as a useful marker for the diagnosis of RA with high specificity. In addition to the diagnostic properties, anti-CCP antibodies showed to be a good prognostic marker for joint destructions. In this review, we will explain about the clinical usefulness of anti-CCP antibodies for the daily practice of RA.     

The pathogenic role and production system of autoantibody in rheumatoid arthritis]

Rheumatoid arthritis (RA) is an autoimmune disease that affects 1% of the population worldwide, however the pathogenic role remains elusive. Successful treatment with anti-CD20 therapy highlighted the importance of B cells in RA. Several antibodies (Abs) were identified from sera from RA patients such as rheumatoid factor, anti-CCP Abs, anti-glucose-6-phosphate isomerase Abs, anti-calpastatin Abs, anti-soluble gp130 Abs, anti-collagen type II Abs, etc. In this review, we will focus on the pathogenicity and production system of auto-Abs in RA, and also explain about recent advance from human study.     

Eosinophilic meningoencephalitis in a case of rheumatoid arthritis]

A 56-year-old man was admitted to our hospital due to gradually developing consciousness disturbance. He had an 11-year history of sero-negative rheumatoid arthritis (Stage III) maintained by daily administration of 10 mg of prednisolone and 300 mg of actarit. On admission, he showed meningeal irritation and a marked increase in eosinophils in his cerebrospinal fulid (CSF) (457/microliter), while eosinophils in his peripheral blood were not increased (0/microliter). Shortly after admission he fell into a coma. Upon measurement in the coma state, his peripheral blood eosinophil count was found to be increased (max: 1742/microliter). Parasitic infection, Angiostrongylus cantonensis in particular, was excluded both by repeated microscopic examination of CSF and by immunological approaches for CSF and serum. Serum examinations showed broad cross-reaction between various parasitic antigens and positive myeloperoxdase-antineutrophil cytoplasmic antibody (18 EU/ml). Three pulses of methylprednisolone (500 mg/day) followed by conventional prednisolone therapy (60 mg/day) was effective for alleviating the signs and symptoms of eosinophilic meningoencephalitis. In this patient, it was considered that the cerebrospinal angiitis resulting in eosinophilic meningoencephalitis had been elicited by immunological abnormalities.     

Epstein-Barr virus etiology in rheumatoid synovitis

The etiology of rheumatoid arthritis (RA) has remained unknown, although it has been investigated and speculated that both genetic and environmental components contribute to the cause of this disease. Epstein-Barr virus (EBV) has been a strong candidate about for over 25 years as environmental infectious agent(s). There are many circumstantial evidence for association between EBV and RA, but definite evidence is wanting. In present article, we review an increase circumstantial proof which has been investigated so far and demonstrate direct evidence for the presence of EBV in inflamed synovial cells in patients with RA and discuss on the recent finding of signaling lymphocytic-activation molecule (SLAM)-associated protein (SAP), which opened a new approach to understand on impaired function of cytotoxic T cell for EBV in patients with RA.