Reactive arthritis or post-infective arthritis?

Infective mechanisms probably underlie a wide range of inflammatory arthropathies. There appears to be a spectrum of mechanisms ranging from the frankly septic, through low-grade infection with very small numbers of microorganisms in the joint to arthritides in which no hard evidence for an infective cause exists. In the midst of the spectrum lie 'post-infective' and 'reactive' arthritides, characterized clinically, genetically and by epidemiological links with infection. Identification of bacterial components within joint material from such patients suggested that the causes of the arthritis had been found. It is now clear that many bacteria are present in inflamed joints; establishing their significance will be of crucial importance, but not easy.     

Reactive arthritis or chronic infectious arthritis?

Microbes reach the synovial cavity either directly during bacteraemia or by transport within lymphoid cells or monocytes. This may stimulate the immune system excessively, triggering arthritis. Some forms of ReA correspond to slow infectious arthritis due to the persistence of microbes and some to an infection triggered arthritis linked to an extra-articular site of infection.     

Is the enthesitis-related arthritis subtype of juvenile idiopathic arthritis a form of chronic reactive arthritis?

OBJECTIVE: Enteric organisms are known to trigger reactive arthritis. The enthesitis-related arthritis (ERA) form of juvenile idiopathic arthritis (JIA) clinically resembles reactive arthritis. Therefore, we looked for a role of enteric bacteria in ERA. METHODS: Synovial fluid (SF) was obtained from 26 patients with ERA and 10 patients with rheumatoid arthritis (RA). Blood specimens were also obtained from patients with ERA and from 10 normal individuals. Lymphocyte proliferation assays were done on whole blood and SF mononuclear cells using as antigens crude lysates of the enteric bacteria Salmonella typhimurium, Yersinia enterocolitica, Shigella flexneri and Campylobacter jejuni. Crude lysate of Escherichia coli was used as a control antigen. HLA-B27 typing was done using the polymerase chain reaction. Homing of gut-specific T cells (CD103+) to the synovial compartment was studied using tri-colour flow cytometry. The antigen-specific cytokine profile was determined by flow cytometry. RESULTS: Antigen-specific lymphoproliferative responses were observed in 14 of 26 patients. Among these patients, 12 showed a response in SF (four each to S. typhimurium and C. jejuni, and in two each to S. flexneri and Y. enterocolitica), and two patients in blood (S. typhimurium in both). None of the healthy controls showed a response in the blood. Lymphoproliferative responses in SF were more frequent in patients with JIA (12/26) than in controls with RA (1/10, P < 0.05). Patients with an antigen-specific response had a higher ratio of SF/blood CD103+ T cells compared with those with no antigen-specific response (P < 0.01). Antigen-specific as well as mitogen-stimulated cytokine production showed a Th1 bias. CONCLUSION: Enteric bacteria may have a role in exacerbation of disease in patients with ERA. The immune response in patients with ERA is Th1-dominant.     

A modified juvenile arthritis damage index to improve articular damage assessment in juvenile idiopathic arthritis—enthesitis-related arthritis (JIA-ERA)

Juvenile arthritis damage index (JADI) consists of two parts which measure articular (JADI-A) and extra-articular (JADI-E) damage in patients with juvenile idiopathic arthritis (JIA). It does not include assessment of cardiac dysfunction and joint areas commonly affected in enthesitis-related arthritis (ERA) category of JIA. We have tried to study if modification of JADI will improve its performance in JIA-ERA. We studied 101 consecutive patients of JIA-ERA. JADI-A was modified (JADI-AM) to include damage assessment of tarsal joints and lumbar spine. JADI-E was modified (JADI-EM) to include assessment of symptomatic cardiac dysfunction. The performances of the modified and standard JADI were compared. Ninety-seven patients were male. The median age was 18 years (9–36). At a median disease duration of 6 years (1–24), joint damage was observed in 47 as assessed by JADI-A. JADI-AM could identify 11 more patients (N = 58) with articular damage. JADI-AM had good correlation with number of joints with limitation of movement (Spearman’s [rS] = 0.9) and low to moderate correlation (rS < 0.7) with measures of disease activity and functional status. JADI-AM discriminated well among patients with different disability levels. Extra-articular damage was observed in 35, and modification of JADI-E with inclusion of cardiac dysfunction did not identify any additional patient. Thus, we propose a modification of the JADI-A (JADI-AM). In JIA-ERA, modification of JADI-A improves its ability to identify articular damage. Modification of the JADI-E may not be needed as symptomatic cardiac involvement is rare.     

Is early rheumatoid arthritis the same disease process as late rheumatoid arthritis?

Thoughts on treatment for the early control of synovitis have stimulated research on pathobiological events at the site of inflammation in patients with early rheumatoid arthritis. Several studies have thus been conducted to examine synovial biopsy samples at various stages of the disease. The most important conclusion from these studies is that all features of chronic synovial inflammation can be observed in so-called early rheumatoid arthritis. This suggests that no arguments exist for the effect of therapeutic intervention on synovitis varying in different phases of rheumatoid arthritis. In end-stage rheumatoid arthritis, factors that are secondary to the disease may contribute to the perpetuation of synovial inflammation. Mutations in key regulatory genes could play a role in the autonomous progression of the disease. In addition, it is conceivable that the release of bone and cartilage fragments might elicit an inflammatory response in patients with destructive rheumatoid arthritis.     

Is rheumatoid arthritis disappearing?

During the past decades a number of studies have examined the incidence of rheumatoid arthritis (RA) in different geographical settings and at different times. Some studies from the 1970s and 1980s reported a higher incidence of RA than seen during recent years, where reported incidence numbers seems to have flattened out at a lower level. Besides a real time dependent decline of RA incidence, changing methodology in classification may be an equally important explanation. Today we may assume that annually 25-50 people from a population of 100,000 will develop typical RA.     

Are early arthritis clinics necessary?

Landmark studies published in the 1980s were the first to reveal the long-term consequences of rheumatoid arthritis (RA). Instead of the benign outcomes previously reported from early population studies, disability, deformity and excess mortality were evident. At this time, the conventional pyramid approach was the standard for therapeutic intervention. Patients were initially treated with non-steroidal anti-inflammatory drug with rest and splinting a approach. Disease-modifying anti-rheumatic drugs and corticosteroids were reserved for patients with joint damage and disability, who had 'earned their treatment' and the perceived risk of toxicity. Thus irreversible damage and disability occurred prior to effective therapy being instituted, with the consequences of poor outcomes. The late 1980s saw the introduction of the concept of early intervention in RA and, shortly after, the introduction of specialist clinics for early assessment of patients with inflammatory arthritis (IA), so-called 'early arthritis clinics' (EACs). Such clinics, initially in large research units, targeted patients with early RA or IA with the potential to evolve to RA, with the aim of early case definition and treatment. After all, the common sense approach to treatment of a chronic inflammatory, destructive condition would be to treat it effectively from its onset, prior to the development of irreversible damage. The detailed documentation undertaken in these clinics subsequently provided much information regarding persistence and prognosis in early IA. Since their initial introduction, EACs have become commonplace, not only in academic units, but also kas part of clinical service provision in many institutions. This review details what an EAC is, who should be referred and when, and the benefits and potential future benefits of their introduction.     

How does Chlamydia cause arthritis?

Because the bacterial cause of CIA has been identified and proven to persist at the site of inflammation, the understanding of how Chlamydia cause arthritis has made much progress. The site of entry and the route of dissemination have been identified, the molecular state of persistence is increasingly described, some mechanisms of how Chlamydia can persist despite an actively reacting immune system have been identified, and data regarding how persistent Chlamydia induce inflammation have been obtained. What needs to be achieved in the future--in addition to better understanding the molecular basis of persistence--is to reveal how persisting bacteria can be eliminated. If this information is insufficient for a cure of the disease, it must be determined how the inflammation can be treated more specifically and effectively to cure CIA early and prevent the development of chronic forms that develop into spondyloarthritis.     

Two forms of reactive arthritis?

Inflammatory arthritides developing after a distant infection have so far been called reactive or postinfectious, quite often depending on the microbial trigger and/or HLA-B27 status of the patient. For clarity, it is proposed that they all should be called reactive arthritis, which, according to the trigger, occurs as an HLA-B27 associated or non-associated form. In addition to the causative agents and HLA-B27, these two categories are also distinguished by other characteristics. Most important, HLA-B27 associated arthritis may occur identical to the Reiter's syndrome with accompanying ureteritis and/or conjunctivitis, whereas in the B27 non-associated form this has not been clearly described. Likewise, only the B27 associated form belongs to the group of spondyloarthropathies.     

Does early rheumatoid arthritis exist?

The 'life cycle' of established rheumatoid arthritis can be divided into four phases. The first is the period leading up to the onset of arthritis. The second is the period during which persistence or remission is determined. The third is the evolution into a specific form of inflammatory arthritis, and the fourth is the outcome/severity of that arthritis. In some patients, these four phases follow in rapid succession; however, in other patients, the time course is prolonged over several months or years. This chapter explores the hypothesis that these four phases are distinct in the majority of patients, and that different genetic and environmental factors influence the various phases. It investigates the suggestion that a defect in the hypothalamic-pituitary-adrenal axis may underlie the persistence of inflammatory arthritis. It suggests that the term 'early rheumatoid arthritis' is not appropriate and that patients either have established rheumatoid arthritis or an undifferentiated inflammatory arthritis.