Abstract
There are problems in attributing causality in inflammatory arthritis. So far as C. trachomatis and sexually acquired reactive arthritis are concerned, there is much in favour of a causal relationship, although there are important caveats which need to be explored before it is possible to say unreservedly that C. trachomatis plays a causative role in reactive arthritis. For example, micro-organisms have never been cultured from synovial effusions in early disease, and only once has substantial benefit of antimicrobial treatment been reported. The claim that ocular strains of C. trachomatis are of over-riding importance in pathogenesis needs confirmation before it can be accepted. No conclusion can be made about the possibility of other small intracellular bacteria in joints having a role in causing disease. However, if it can be shown that eradication of the micro-organism, which may be difficult to prove, coincides with clinical recovery, it would go some way to recognising causality. In spite of the recognised difficulties, antibiotic studies have an important role in identifying aetiology. They need to focus on very early disease and on eradication of intra-articular bacteria. Treatment of established disease is likely to be less informative. Although a combination of antibiotics might have a future in treating established disease, diagnosing and treating non-gonococcal urethritis as soon as possible should be the aim in order to prevent the development of reactive arthritis.
Keywords
Introduction
It has long been suspected that some forms of inflammatory arthritis are caused by bacterial infection. Recent studies in rheumatoid arthritis have pointed to a potential role for Porphyromonas gingivalis,1,2 but it is in reactive arthritis (ReA) that the case for individual causal bacteria has been most cogently made. Several groups, including ourselves, have reported microbiological and epidemiological findings that suggest causal links between specific bacterial infections, especially by Chlamydia trachomatis, and sexually acquired reactive arthritis (SARA). Indeed, the terms ‘chlamydia-induced reactive arthritis’ and ‘post-chlamydial reactive arthritis’ have entered medical parlance.
In recent years, many reports have addressed the role of C. trachomatis in ReA, seemingly on the premise that causation is more or less established. The science of chlamydial genomics, structure and intracellular behaviour has developed rapidly, and sophisticated studies of intracellular bacterial persistence in joint tissue from subjects with ReA, as well as data on which possible mechanisms might be based, are numerous. However, none would deny that the attribution of causality in this context is difficult, and it is worth revisiting some of the key issues so as to avoid premature conclusions.
Observations related directly to C. trachomatis
Almost 50 years ago, chlamydiae (at that time termed Bedsonia) were reported to have been isolated, rather than detected immunologically, from synovial fluid of patients with Reiter’s syndrome. 3 However, this claim was never substantiated by the findings of other studies. More than 30 years ago, serological studies pointed to the possibility that C. trachomatis might have a role in Reiter’s syndrome and SARA.4,5 The subsequent detection of C. trachomatis elementary bodies (EBs) in the joints of patients with SARA by a micro-immunofluorescence technique6,7 and by electron microscopy 8 provided an even more compelling case for an aetiological association. The confirmation of these findings led to the detection of C. trachomatis DNA by using the polymerase chain reaction (PCR) technique9,10 and to reports of intra-articular C. trachomatis RNA. 11 Rapidly, the idea that Reiter’s syndrome and ReA, which are essentially the same condition, are a response in the joint to an extra-articular stimulus, 12 namely an infectious agent in the genitourinary tract, was supplanted by the notion that the stimulus was itself within the joint. Finding specific RNA and DNA suggested viability of the intra-articular bacteria,13,14 though isolation of viable micro-organisms from the joint remains elusive.
Apart from these observations, there are four issues that we consider important and worth exploring in the context of understanding whether C. trachomatis and/or other micro-organisms play a direct causal role in ReA.
Pathogens other than C. trachomatis in non-gonococcal urethritis and SARA
In discussing the role that C. trachomatis might have in inducing SARA, it is important to not ignore other micro-organisms that might play a part in SARA. In this regard, a range of micro-organisms has been implicated in the causation of non-gonococcal urethritis (NGU). Since the discovery of Mycoplasma genitalium in 1980, 15 numerous studies have left no doubt that it is a cause of acute and chronic NGU, being involved in almost as high a proportion of this disease as C. trachomatis. 16 This conclusion regarding causality is based not only on identification of the micro-organism in human genital tract material but also on the production of urethritis in male chimpanzees and entry of the organism into the blood stream of some. It is plausible, therefore, that this Mycoplasma might be involved in SARA. Its detection has been reported in the joint of one patient with SARA 17 ; although it is an undoubted cause of NGU, its prevalence and potential for arthritogenicity in SARA are unknown.
In addition, ureaplasmas have been isolated from the joints of hypogammaglobulinaemic patients with septic arthritis and this, together with successful antimicrobial treatment, leaves no doubt that ureaplasmas are pathogenic and a cause of that disease. 18 Less certainly, ureaplasmas have been implicated as a cause of acute and chronic NGU, their involvement appearing to be less frequent than that of C. trachomatis or M. genitalium. 19 In one study, viable ureaplasmas were isolated from joint material of patients with Reiter’s disease 20 and lymphocyte proliferation to Ureaplasma urealyticum antigens has been demonstrated. 21 However, these data are insufficient to regard ureaplasmas as a cause of ReA. M. fermentans exists frequently in the throat and genital tract of both healthy and diseased individuals. It has been identified by PCR technology in the joints of some patients with ReA, and a role has been considered in rheumatoid arthritis. 22 More recent bacterial candidates for a causal role in NGU include Leptotrichia/Sneathia spp. 23 and Corynebacterium propinquum, 24 though data relating them to arthritis are unavailable. Some, most or all of these candidate causes of NGU must also be candidates for inducing SARA. That one or all of them cause SARA is feasible, but an equally satisfactory explanation would be that the cause of the NGU is not directly related to the arthritis.
Bystander or pathogen?
A second factor for consideration is the likelihood that the bacteria from one site of current infection are transported within macrophages to sites of extant inflammation. It is notable that an increased adhesion capacity of peripheral blood mononuclear cells and their ability to transmigrate through unstimulated cell monolayers has been demonstrated. 25 Assuming that the transportation supposition is correct, bacteria arrive at the joint either before or after the arthritis has been initiated; if the latter is the case, they cannot be considered causal. They may be innocent bystanders, having no part to play in the disease process, or those that foster the persistence of an inflammatory response, so leading to chronic disease.
The identification of many bacterial species in the joints of patients with ReA, rheumatoid arthritis and osteoarthritis by Kempsell and coworkers26,27 would be consistent with a bystander effect. However, although it is possible, it is perhaps beyond reason to believe that C. trachomatis behaves only as a bystander.
What the term ‘bystander’ or pathogen means is further exemplified by considering the role of C. pneumoniae in both joint and arterial disease. Apart from respiratory disease where the micro-organism has a definite pathogenic role, it has been associated with a wide range of diseases, in at least some of which the link would appear to be extremely tenuous and, at most, a bystander function. Being present but having no involvement would seem to be an apt description of the situation. However, in arthritis 28 and arteriosclerotic disease, 29 there is evidence for a more genuine association between the micro-organism and the disease. So far as ReA is concerned, the first evidence of an association was based on lymphocyte proliferation and positive serological findings, 30 although subsequently, C. pneumoniae DNA was identified in joint tissue. 31 Serological evidence also points to potential involvement of C. pneumoniae in juvenile arthritis, 32 although the proportion of individuals in whom C. pneumoniae might possibly have a causal role is unknown. About 40% of atheromatous arterial specimens from subjects with cardiovascular disease have been found to have C. pneumoniae in plaques, 29 but in this disease where the temporal relationship between development of plaques and detection of the organisms is particularly obscure, and in arthritis too, the distinction between pathogen and bystander behaviour is far from clear.
Ocular strains of C. trachomatis as a possible cause of ReA
An interesting possibility regarding causation is raised by further studies of Carter and coworkers. 33 In these studies, strains of C. trachomatis detected in joints of patients with ReA have been identified as ocular strains; the hypothesis is that ocular strains found in the genital tract of a very small proportion of subjects 34 travel to the joints to induce arthritis. In this scenario, genital strains of C. trachomatis are not recognised as being involved in the development of arthritis. However, a causal association between arthritis and only ocular C. trachomatis strains would be surprising especially as genital strains are pathogenic in many other anatomical sites. Whether a primary infection of the eye by ocular strains of C. trachomatis could lead to arthritis is of interest. Certainly, if ocular (trachoma) strains are responsible, then ReA might be expected to be relatively common in trachoma-endemic countries. Whether this is the case is unknown, but it would be a potentially fruitful area for further study, as would be the hypothesis mentioned above.
A non-specific effect of bacteria is suggested by the results of studies in animal models of HLA-B27-associated disease. In HLA-B27-transgenic rats, the spontaneous development of arthritis is dependent upon the presence of normal rat bacterial flora rather than any specific micro-organisms. 35 This is consistent with the proposal that gut microbiota may play a role in stimulating local production of IL-2336,37 which may itself lead to some or all of the pathological lesions in spondyloarthritis.38,39 In these scenarios, bacteria which do not cause clinical infection may play a role in development of disease. However, the effect appears to be bacteria non-specific rather than implicating a specific micro-organism.
Inferences from antimicrobial treatment of ReA
The growth cycle of C. trachomatis and other chlamydial species is one in which infecting EBs develop into reticulate bodies (RBs) which release a new generation of viable EBs. These have a high metabolic rate and may be readily eradicated by appropriate antibiotic therapy. However, some RBs assume a low metabolic rate in synovial tissue and may not develop further; these may persist, causing chronic infection which is more difficult to eradicate by antibiotic therapy. Eradication of micro-organisms from the joint and resolution of arthritis in the face of antimicrobial therapy would therefore constitute a basis for judging causality. Nevertheless, this ideal may be hard to achieve as demonstrating the absence of micro-organisms in joints which have returned to normal and eradicating micro-organisms which have entered a state of low metabolic activity may be difficult. Nonetheless, numerous trials of antibiotic therapy have been undertaken. 40 In spite of using a range of appropriate antibiotics over short, medium and long periods of time, the results have been disappointing, efficacy being uncertain. 41 In this respect, the result of the trial by Carter et al. 42 is remarkable, particularly as it comprised patients with chronic arthritis. Of those with PCR evidence of C. trachomatis in peripheral blood or synovium, 63% responded clinically to combination antibiotic treatment regimens including doxycycline and rifampicin and azithromycin plus rifampicin compared with 22% of controls. Over the ensuing months, the majority had negative tests for C. trachomatis in peripheral blood mononuclear cells and in a few whose joint material was tested at follow-up. Although patients were deemed to have been potentially exposed to C. trachomatis or C. pneumoniae, infection-specific tests for an infection focus were not undertaken. It is interesting, however, that the same group of investigators has recently reported low levels of chlamydial load even during remitting disease. 43 Clearly, in this population of patients with peripheral spondyloarthritis, comparisons with patients with acute ReA and active demonstrable genital tract infections may not be appropriate, though further studies to assess the degree of eradication or inactivity of chlamydiae within the joints and potential sites of infection would be informative.
Before the advent of azithromycin, tetracyclines were used routinely for the treatment of NGU. This was not always successful, particularly if M. genitalium was present, as this Mycoplasma, along with others, may become intracellular and protected from antibiotics, or the organism may develop antibiotic resistance. As a consequence, persistent infection and chronic disease may follow. 16 Inadequate treatment might allow micro-organisms to escape from the genital tract, perhaps in mononuclear cells, to the joints. It would be of interest, therefore, to know whether patients with SARA are more likely to have developed arthritis after treatment with tetracyclines than when their original genital tract infection was treated with azithromycin. This would provide some indication, albeit indirect, of the important role of C. trachomatis and/or M. genitalium in the development of ReA. In this respect, the study of Bardin et al., 44 although limited by its observational nature, suggests, tantalisingly, that eradication of the primary infection by appropriate antimicrobial treatment may prevent or minimise the development of ReA. It does not, however, inform the debate about specificity of causal micro-organisms. Irrespective of this, there is considerable anecdotal evidence that SARA is seen less frequently in the UK than a decade or more ago. Although unproven, this is likely to be due to treatment of NGU with antibiotics that have been more effective in recent times than hitherto. In contrast to the effect of the antibiotics mentioned below, this would seem to be a good example of being able to thwart the development of disease, that is arthritis, by effective treatment of NGU rather than by treating arthritis when it has occurred.
In the context of associating the cause of ReA with a particular micro-organism by the response to antibiotics, it is also appropriate to consider the possible association between C. pneumoniae and atherosclerotic disease, mentioned above. 29 In spite of evidence of persistent C. pneumoniae infection, treatment with azithromycin for one year, or gatifloxacin for two years, was not associated with an outcome that was significantly different from that following the use of a placebo. 45 This might be explained by the antibiotic being given too late in the disease that was already well established, and such an explanation could apply to C. trachomatis involvement in ReA. A combination of antibiotics with high anti-chlamydial activity such as azithromycin together with rifampicin, each of which has a different mechanism of action, might be useful 46 but requires in-depth evaluation.
Conclusions
We have previously drawn attention to the problems of attributing causality in inflammatory arthritis and suggested some measures which would support a causal role for a specific micro-organism. 47 Clearly, so far as C. trachomatis and SARA are concerned, some of these criteria are met and it must be the front-runner. However, evidence of culturable micro-organisms in very early disease has yet to be presented, and in only one of many studies has substantial benefit of antimicrobial treatment been reported and that in patients with chronic disease. Moreover, the evidence that ocular, not genital, strains of C. trachomatis are of over-riding importance in pathogenesis needs confirmation before its veracity can be accepted. Observation of other small intracellular bacteria in joints does not allow any firm conclusion to be made as to whether they are pathogenic or not, or even incidental. However, if eradication of the micro-organism, difficult to prove, coincides with clinical recovery, it would go some way in establishing causality. Although there seems a powerful argument in favour of C. trachomatis underpinning ReA following or concomitant with a chlamydial genital infection, we have pointed out important caveats which need to be explored before it is possible to say without any question that C. trachomatis plays a causal role in ReA.
In spite of the recognised difficulties, antibiotic studies have an important role in identifying aetiology. They need to focus on very early disease, as in the study of Bardin et al., 44 and on eradication of intra-articular bacteria. Treatment of established late disease is likely to be less informative. To diagnose and treat NGU as soon as it is possible should be the aim in order to prevent the development of ReA.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors thank the Medical Research Council (UK) for financial support for some of the work mentioned in this review.