580 REVIEW Ann Rheum Dis: first published as 10.1136/ard.61.7.580 on 1 July 2002. Downloaded from Reactive arthritis or chronic infectious arthritis? J Sibilia, F-X Limbach ............................................................................................................................. Ann Rheum Dis 2002;61:580–587 Microbes reach the synovial cavity either directly during hence active multiplication of the bacteria. bacteraemia or by transport within lymphoid cells or These findings thus suggest that microbes can survive in small numbers in the articular cavity monocytes. This may stimulate the immune system in certain forms of ReA (table 1). excessively, triggering arthritis. Some forms of ReA • The phenomenon has grown since 1995 with correspond to slow infectious arthritis due to the discovery of DNA of most other classical persistence of microbes and some to an infection arthritogenic agents in synovial samples from patients with ReA.18–21 One must nevertheless triggered arthritis linked to an extra-articular site of take a fairly critical point of view because infection. although the results are convincing for C .......................................................................... trachomatis, they are much less so for entero- bacteria. It is true that DNA of Yersinia, Shigella, or Campylobacter has been identified in some eactive arthritis (ReA) was first described in studies, but these are few and include very few 1916 during the first world war by Fiessinger patients.18 19 21 22 Thus, Ekman et al identified and Leroy in France and Reiter in Germany. R DNA of Salmonella in synovial samples,23 but It was, however, only in 1969 that a Scandinavian could not repeat their results. This might have team rationalised the concept of ReA by defining it as a transient non-purulent (reactive) arthritis been owing to technical artefacts, which lead appearing in the weeks following a digestive to false positives, or to a very small amount of infection.1 Actually, this notion of exclusively bacterial DNA in the synovium. Despite these aseptic ReA has been repeatedly contradicted by reservations, the list of arthritogenic agents different observations.2–5 continues to grow from year to year, even if for many of them there is no confirmation of their intrasynovial persistence (table 2).18 19 24–33 MICROBIOLOGICAL HISTORY OF Chlamydia pneumoniae and Borrelia burgdorferi, REACTIVE ARTHRITIS: FROM for instance, have been associated with cases of MICROSCOPY TO MOLECULAR BIOLOGY monarthritis or oligoarthritis comparable with http://ard.bmj.com/ A study of the microbiological history of ReA is those seen in ReA.34–37 In this context, it is instructive as it illustrates well the influence of interesting to return to the case described by technological progress and, in particular, the Reiter in 1916 and his publication entitled impact of molecular biology on the evolution of “Über eine bisher unerkannte Spirochätenin- such concepts. fektion (Spirochaetosis arthritica)”.38 • As early as the 1970s, the first studies disclosed One might wonder, in view of the high preva- microscopic intracellular inclusions in synovial lence of B burgdorferi infections in Central on September 30, 2021 by guest. Protected copyright. tissues which could correspond to Chlamydia Europe, whether this spirochaete rheumatism trachomatis, the principal arthritogenic microbe was not one of the first reports of Lyme arthritis? involved in ReA.6 Confirmation of this work Identical observations have been made in other was, however, hindered for many years by the situations quite closely related to ReA. Propioni- fact that most of these bacteria are very bacterium acnes, a microbe implicated in difficult or almost impossible to cultivate from inflammatory outbreaks of acne, was recently synovial samples.7–11 identified in articular samples from SAPHO • Since the beginning of the 1990s, the explosive patients, suggesting an infectious origin of this syndrome often regarded as a form of development of new molecular biology tech- 39 niques has led to the detection (by polymerase spondyloarthropathy. Mycobacterium bovis, used chain reaction methods) of small quantities of in BCG (Bacille Calmette-Guérin) treatment, is 12–16 known to cause, presumably aseptic, oligo- C trachomatis DNA in the articular cavity. 40 41 These first results immediately raised a large arthritis and polyarthritis, but we have also See end of article for number of questions. Did they indicate the detected bacterial DNA in synovial fluid from authors’ affiliations presence of viable bacteria in the joint, or were patients with arthropathy triggered by intravesi- ....................... 42 these simply genomic vestiges of bacteria cal injection of BCG. In other situations, the Correspondence to: passively transported into the joint by macro- Professor J Sibilia, Service phages? The reply was provided by the discov- de Rhumatologie, Hôpital ................................................. de Hautepierre, 1 avenue ery of messenger and ribosomal RNA of C Abbreviations: IFN, interferon; IL, interleukin; LFA, Molière, 67098 trachomatis using a reverse transcriptase- Strasbourg, Cedex, France; polymerase chain reaction (RT-PCR) method.17 leucocyte function associated antigen; LPS, [email protected] lipopolysaccharide; MOMP, major outer membrane The presence of these nucleic acids, which have protein; Osp, outer surface protein; ReA, reactive arthritis; Accepted 4 March 2002 a very short half life in tissues (some minutes), RT-PCR, reverse transcriptase-polymerase chain reaction; ....................... implies the occurrence of transcription and TNF tumour necrosis factor www.annrheumdis.com Reactive arthritis or chronic infectious arthritis? 581 Recent original work has confirmed the simultaneous pres- Ann Rheum Dis: first published as 10.1136/ard.61.7.580 on 1 July 2002. Downloaded from Table 1 The principal detectable microbes in ence of RNA of numerous bacterial species in synovial samples reactive arthritis and undifferentiated arthritis: analysis from patients with rheumatoid arthritis, unexplained arthri- of the different methods of identification tis, and osteoarthritis, but not in samples taken during meniscectomy from presumably healthy subjects.47 In this Antigens DNA RNA Culture study employing RT-PCR, respectively 92 and 50 different C trachomatis ++++/− bacterial species were identified by sequencing in the synovial Y enterocolitica ++*21 ND − fluid of rheumatoid arthritis and osteoarthritis. Only six spe- Y pseudotuberculosis + − +†22 − cies (Corynebacterium, Escherichia coli, Streptococcus, Pseu- 18 − S flexneri and sonnei ++*ND domonas, Leptospira, and Methylobacterium) were detected S typhimurium and enteritidis ++*108 ND − C jejuni − +*18 ND − exclusively in rheumatoid arthritis, although without proof U urealyticum ++−+ of this being an argument in favour of their pathogenic role. C pneumoniae +++− These astounding results, apparently obtained by reliable B burgdorferi ++ND+ methods, demonstrate that the synovium is not a sterile T whippelii ++ND+ structure, but more probably an interfacial zone which can be ND, not done. colonised by bacteria originating from the environment and *The detection of nucleic acid of enterobacteria in the synovium is the endogenous flora. subject to caution for reasons related to the different techniques employed and the very small numbers of patients studied; †RNA has only been detected in one case. “The synovium is not sterile but can be colonised by bacteria from the environment” Recently, a description was given of arthritogenic microbes Table 2 List of the “classical” and “new” detectable in synovial samples not only in cases of presumably arthritogenic agents implicated in reactive arthritis ReA but also in other forms of inflammatory “Classical” candidates “New” candidates rheumatism.12 48–50 In fact, C trachomatis and pneumoniae are present in the synovial fluid of patients with rheumatoid poly- • Chlamydia trachomatis • Chlamydia pneumoniae 51 • Ureaplasma urealyticum • Mycoplasma hominis and arthritis in respectively 30% and 15% of cases ; identical • Yersinia enterocolitica and fermentans observations have been reported for Mycoplasma pneumoniae pseudotuberculosis • Neisseria gonorrhoeae and fermentans.48 49 Sometimes several microbes may be found • Shigella flexneri and sonnei • Borrelia burgdorferi • Salmonella typhimurium, enteritidis • Clostridium difficile together in the same joint, as suggested by the RT-PCR study and others • â-Haemolytic streptococci described above.47 This unusual association was observed for C • Campylobacter jejuni • Propionibacterium acnes trachomatis and pneumoniae and for C trachomatis and B burgdor- • Escherichia coli feri in synovial samples from patients with spondyloarthrop- • Helicobacter pylori 51 • Brucella abortus athy, unexplained arthritis, and even rheumatoid arthritis. • Calmette – Guerin Bacillus One should nevertheless maintain a critical attitude until these • Leptospira results have been confirmed by other studies. Thus, one report • Bartonella published only in abstract form suggests that the presence of • Trophyrema whippelii intrasynovial bacterial DNA might after all be an exceptional http://ard.bmj.com/ • Gardnerella vaginalis 52 • Giardia lamblia phenomenon. In this work, a search by PCR analysis for the bacterial 16S and 23S ribosomal RNA genes proved negative in the synovium of 81 patients (42 rheumatoid arthritis, 8 other cases of inflammatory rheumatism, 31 osteoarthritis) when using drastic