Treatment of Reactive Arthritis

AbstractReactive arthritis follows infections of the urogenital or enteric tract with bacteriasuch as Chlamydia, Yersinia, Shigella, Salmonella or Campylobacter. Typically,one knee or ankle are affected for weeks to several months, with up to 20% ofpatients experiencing a chronic course of more than 1 year. The acute arthritis is treated nonspecifically with nonsteroidal anti-inflammatorydrugs (NSAIDs), local measures such as arthrocentesis, cold pads and rest of theaffected joint. If the triggering bacterium can be isolated in Chlamydia-induced urogenital reactive arthritis, the infection should be treatedspecifically with antibacterials. Doxycycline 100mg twice daily, or erythromycin500mg 4 times daily, for 10 to 14 days are effective for Chlamydia,as is a single dose of azithromycin 1g. To prevent reinfections, the sexual partnershould be treated concurrently. Although remnants of bacteria and even bacterial RNA, suggesting live bacteria,can be demonstrated in the joint, treatment with antibacterials, even for long periods,does not show any benefit over placebo in enteric forms of reactive arthritis. For Chlamydia-induced reactive arthritis, antibacterials given for 3months in the absence of positive cultures from the urogenital tract may providesome benefit; however, further studies are needed before such treatment isrecommended. For reactive arthritis lasting longer than 6 months, patients may benefit fromsulfasalazine 2 g/day in addition to continued use of NSAIDs. In severalplacebo-controlled studies, sulfasalazine was well tolerated and moderately superiorto placebo. Other disease-modifying antirheumatic drugs (DMARDs) can be tried inindividual patients who do not respond to sulfasalazine. However, since nocontrolled studies are available to date for DMARDs other than sulfasalazine, therisk-benefit ratio of such treatment should be carefully discussed with the patient.     

Reactive Proliferative Lesions in Lymph Nodes from Rheumatoid Arthritis Patients

In 22 cases of rheumatoid arthritis (RA), including 4 cases of malignant RA (MRA), reactive proliferative lymph node lesions were studied clinicopathologically and immunohis-tochemically. This series included 5 males and 17 females. The period between disease onset and lymph node biopsy ranged from 3 months to 41 years. Generalized lymphadenopathy was noted in 13 cases and constitutional symptoms in 8. The histological findings characteristic of RA were 1) follicular hyperplasia with active germinal centers and 2) polyclonal plasma cell infiltration in the interfollicular area. Studies of intracytoplasmic immunoglobulin showed that γ-heavy chain-expressing plasma cells were a major component in the interfollicular area in 17 RA cases. However, in 4 MRA cases, a prominent increase of μ chain-expressing plasma cells was recognized in the same area. In the 3 cases for which fresh tissue sections were stained with monoclonal antibodies against lymphocytes, we found that the majority of T cells in the interfollicular area had helper/inducer markers. The identical locations of the T cell population and plasma cells indicated that both played a role in the proliferation and/or differentiation of B cells in lymph nodes in RA.     

Cell-Mediated Immune Response in the Diseased Joints in Patients with Reactive Arthritis

To evaluate the level of lymphocyte activation in reactive and rheumatoid arthritis, density gradient-isolated, synovial fluid mononuclear cells were stained with a panel of antisera directed at lymphocyte activation markers using an avidin-biotin-peroxidase complex (ABC) method. More specifically, we studied the expression of immune response-associated class II HLA antigen (Ia), of receptors for interleukin 2 (Tac) and transferrin (T9), as well as of gp 40/80 glycoprotein (4F2). Although Ia+ cells formed about 60% of all the synovial fluid mononuclear cells in both disease conditions, the proportion of Tac+ (33 +/- 4% vs 3 +/- 1%, P less than 0.001), T9+ (34 +/- 4% vs 5 +/- 2%, P less than 0.001), and 4F2+ (48 +/- 6% vs 3 +/- 2%, P less than 0.001) cells was high only in reactive arthritis. All the patients who had reactive arthritis followed a favourable clinical course during the 4-month-long prospective follow-up, whereas disease activity was stable in patients with rheumatoid arthritis. These findings suggest that the diseased joints in reactive arthritis are a site for an active, but normally down-regulated, cell-mediated immune response.     

Solute Carrier Family 11 Member A1 Gene Polymorphisms in Reactive Arthritis

To investigate the role of SLC 11A1 polymorphisms in the development of reactive arthritis, 91 patients with reactive arthritis and 163 healthy controls were enrolled in this study. The SLC 11A1 polymorphisms were determined by the method of polymerase chain reaction/restriction fragment length polymorphism. The genotype distributions of SLC 11A1 274, 823, 1703, and 1729+ 55 del 4 were significantly different between the patients with reactive arthritis and controls. The genotype frequency of SLC 11A1 274C/C was significantly decreased in the patients with reactive arthritis when compared with that of the controls. In contrast, the SLC 11A1 274C/T showed a significant association with reactive arthritis. The patients with reactive arthritis have a significantly higher frequency of SLC 11A1 823C/C than the controls. However, SLC 11A1 823T/T was resistant to the development of reactive arthritis. The allele frequencies of SLC 11A1 274T and 823C were significantly increased in the patients with reactive arthritis in comparison with those of the controls, independent of HLA-B27. On the contrary, the allele frequencies of SLC 11A1 274C and 823T were significantly decreased in the patients with reactive arthritis. The estimated haplotype frequency of SLC 11A1 274C 823T 1703G 1729+55del 4 TGTG+ was significantly decreased in the patients with reactive arthritis when compared with that of the controls. In contrast, the estimated haplotype frequency of SLC 11A1 274T 823C 1703G 1729+55 del 4 TGTG+ was significantly increased in the patients with reactive arthritis. This study shows that the SLC 11A1 274T and 823C alleles are associated with susceptibility to reactive arthritis independently of HLA-B27 in Taiwan. The SLC 11A1 274T 823C 1703G 1729+55 del 4 TGTG+ haplotype is associated with the development of reactive arthritis in Taiwan. In contrast, the SLC 11A1 274C 823T 1703G 1729+55 del 4 TGTG+ haplotype may be a protective factor.     

Alteration in T Cell/Macrophage Ratio may Reveal Lymphocyte Proliferation Specific for the Triggering Antigen in Reactive Arthritis

It has previously been shown that synovial fluid (SF) mononuclear cells (MNC) from patients with reactive arthritis (ReA) and some patients with undifferentiated oligoarthritis (UOA) respond specifically to the triggering bacterium (specific responders). However, in some patients there is a response to two or more bacteria (non-specific responders) and in a third group no response is found (non-responders). We assessed whether the proportion of synovial MNC which were macrophage-monocyte (MaMo) differed among the specific responder, non-specific responder and non-responder groups. There was no difference between the specific (33 +/- 9) and the non-specific (32 +/- 26) groups; non-responders had a higher percentage of MaMo (61.3 +/- 31%) although the difference was not significant. We also investigated whether the specificity of the response to antigen in ReA or UOA SF was altered by changing the T-cell/MaMo ratio. In all five specific responders the immune response remained specific whatever the ratio tested. However, four of the five non-specific responders, but none of the non-responders, developed a specific response to one of the tested antigens by increasing the T cell/MaMo ratio. We conclude that in some patients with a non-specific response, alteration of the T cell/MaMo ratio uncovers a specific response which may identify the triggering antigen.     

Psoriatic Arthritis

Psoriatic arthritis is an inflammatory arthritis associated with psoriasis, which is usually negative for rheumatoid factor. The disease displays a wide spectrum of articular and periarticular features which may progress with time. Although psoriatic arthritis was thought to be a benign condition, it is now clear that up to 20% of patients progress to significant joint damage and functional disability. Recently, several predictors for progression have been described and suggest the need for earlier, more aggressive, use of therapy in these patients. The ideal treatment for psoriatic arthritis is unclear, and few randomised controlled trials have been reported to date in this condition. Prospective evaluation of the treatment of early disease is now required to assess the effect of current and future therapies on the clinical, radiological and functional outcomes of this condition.     

Reactive lymphadenopathies

Reactive lymphadenopathies often pose a diagnostic problem. The distinction of a reactive from a neoplastic lymph node requires the application of general histologic criteria that traditionally have involved the evaluation of cytologic features including cellular polymorphism v monomorphism and the presence or absence of cytologic atypia. Although these cytologic criteria remain valid, they are not inviolate and exceptions exist that may result in diagnostic ambiguity. In addition, the interpretation of a reactive process in a lymph node is predicated on the evaluation of the dominant histologic architectural pattern and on a systematic approach to the diagnosis. The patterns specifically include whether the nodal architecture is predominantly diffuse, mixed interfollicular and follicular, follicular, or sinusoidal. Under each of these dominant architectural configurations, a host of benign reactive diagnoses may be assigned. An awareness of the various diagnostic categories for each major histologic pattern, the range and subtleties of their histologic expression, and the application of new methods, such as immunology to determine clonality, have resulted in simultaneous narrowing of the diagnostic possibilities and expansion of our comprehension of the reactive lymphadenopathies.     

Reactive microgliosis

Damage to the central nervous system (CNS) elicits the activation of both astrocytes and microglia. This review is focused on the principal features that characterize the activation of microglia after CNS injury. It provides a critical discussion of concepts regarding microglial biology that include the relationship between microglia and macrophages, as well as the role of microglia as immunocompetent cells of the CNS. Mechanistic and functional aspects of microgliosis are discussed primarily in the context of microglial neuronal interactions. The controversial issue of whether reactive microgliosis is a beneficial or a harmful process is addressed, and a resolution of this dilemma is offered by suggesting different interpretations of the term 'activated microglia' depending on its usage during in vivo or in vitro experimentation.     

Juvenile Idiopathic Arthritis

Overexpression of cytokines in inflamed joints plays an important role in joint inflammation and in damage to articular tissue. Biological agents aimed at specifically antagonising tumour necrosis factor (TNF) are effective in the treatment of adult rheumatoid arthritis. A recent trial of etanercept, a genetically engineered fusion protein consisting of the Fc domain of human IgG1 and the TNF receptor p75, has demonstrated that this agent is also well tolerated and effective in patients with juvenile idiopathic arthritis (JIA). Etanercept offers a promising new alternative for patients with JIA who have persistently active arthritis despite treatment with methotrexate. Further studies are needed to clarify whether etanercept is equally effective in the various onset types of JIA (oligoarthritis, polyarthritis and systemic arthritis), whether it can modify disease progression and whether it can be administered safely for long periods of time to children.     

Yersinia Enterocolitica O:3 Isolated from Patients with or without Reactive Arthritis Induces Polyclonal Activation of B Cells and Autoantibody Production In Vivo

The mechanisms by which arthritis-provoking pathogens such as Yersinia enterocolitica interact with the human immune system to produce inflammatory synovitis are not well known. One of the immunomodulating mechanisms used against these pathogens is the polyclonal activation of lymphocytes. In this study, we investigated the extent of the B-lymphocyte activation induced in mice by a strain of Y. enterocolitica O:3 (FCF 526) isolated from a patient with arthritis, and compared it with two other strains, a virulent one (FCF 397[+]) isolated from a patient without arthritis and its plasmidless isogenic pair (FCF397[-]). Also we investigated the production of autoantibodies in mice infected with these different strains. SPF Swiss mice were infected intravenously with a suspension of Y. enterocolitica. Spleen cells were taken on days 7, 14, 21 and 28 after infection and the number of cells secreting nonspecific and specific antibodies of IgG¹, IgG^2a, IgG^2b, IgG³, IgM and IgA isotypes were determined by the ELISPOT technique. The presence of autoantibodies in mouse serum was investigated by the dot-blot assay. The pattern of infection of the three bacterial strains were almost the same. We observed a general increase in the number of nonspecific Ig-secreting cells with all three strains, and the greatest increases observed were in the IgG^2a and IgG³ isotypes. Only a small fraction of the immunoglobulins detected were antibacterial, suggesting that the rest resulted from polyclonal B cell activation. The strain isolated from the patient with arthritis (FCF526) induced the greatest production of autoantibodies, coinciding with the period in which the greatest activation of nonspecific B lymphocytes was seen. There were no signs of arthritis or inflammation in the joints of the infected animals. Based on our results, we were unable to determine whether there is an association between the arthritogenic capability of Y. enterocolitica and polyclonal activation of B cells.     

Infection of Synovial Fibroblasts in Culture by Yersinia enterocolitica and Salmonella enterica Serovar Enteritidis: Ultrastructural Investigation with Respect to the Pathogenesis of Reactive Arthritis

Synovial fibroblasts were infected with Yersinia enterocolitica or Salmonella enterica serovar Enteritidis and analyzed by electron microscopy and fluorescence in situ hybridization. Intracellular bacterial replication was followed by degradation leading to "ghosts" possessing lipopolysaccharides but not DNA. However, single bacteria survived for more than 2 weeks. Therefore, transient intra-articular infection might be the missing link between initial intestinal infection and late synovial inflammation in the pathogenesis of reactive arthritis.