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J Sibilia, F-X LimbachCorrespondence to: Professor J Sibilia, company de Rhumatologie, Hôpital de Hautepierre, 1 way Moliére, 67098 Strasbourg, Cedex, France; jean.sibiliaatwanadoo.fr


Microbes with the synovial cavity either directly during bacteraemia or by carry within lymphoid cell or monocytes. This might stimulate the immune system excessively, triggering arthritis. Some forms of ReA correspond to slow infectious arthritis due to the persistence the microbes and also some to an infection prompted arthritis connected to one extra-articular site of infection.

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reactive arthritisseptic arthritisarthritogenic bacteriabacterial virulenceIFN, interferonIL, interleukinLFA, leucocyte duty associated antigenLPS, lipopolysaccharideMOMP, major outer membrane proteinOsp, external surface proteinReA, reactive arthritisRT-PCR, reverse transcriptase-polymerase chain reactionTNF tumour necrosis factor


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Reactive arthritis (ReA) was an initial described in 1916 throughout the very first world battle by Fiessinger and also Leroy in France and Reiter in Germany. The was, however, only in 1969 the a Scandinavian team rationalised the concept of ReA by specifying it together a transient non-purulent (reactive) arthritis showing up in the weeks adhering to a cradle infection.1 Actually, this id of specifically aseptic ReA has actually been repeatedly contradicted by various observations.2–5


A examine of the microbiological background of ReA is instructive together it illustrates well the influence of technological progress and, in particular, the affect of molecular biology ~ above the development of such concepts.

View this table:
Table 1

The major detectable microbes in reactive arthritis and also undifferentiated arthritis: analysis of the different methods the identification

View this table:
Table 2

List that the “classical” and “new” arthritogenic agents implicated in reactive arthritis

One can wonder, in watch of the high ubiquity of B burgdorferi epidemic in central Europe, even if it is this spirochaete rheumatism was not among the an initial reports that Lyme arthritis? the same observations have actually been do in other cases quite carefully related come ReA. Propionibacterium acnes, a microbe implicated in inflammatory outbreaks that acne, was recently established in articular samples from SAPHO patients, saying an infectious origin of this syndrome often regmmsanotherstage2019.comed as a type of spondyloarthropathy.39Mycobacterium bovis, provided in BCG (Bacille Calmette-Guérin) treatment, is recognized to cause, presumably aseptic, oligoarthritis and also polyarthritis,40,41 but we have likewise detected bacter DNA in synovial fluid from patients through arthropathy motivated by intravesical injection the BCG.42 In other situations, the exploration of inflammation articular manifestations, sometimes of unusual recurrent arthritis following documented infection, says the possibility of reactive arthritis “in the large sense that the term”.27,28,43,44 However, in the majority of these cases, the proof is no tangible, although sufficient for one to save in psychic the hypothesis.

Recently, in 1998, brand-new observations pertained to light which complicated the picture: the share is not a sterile medium, as displayed by the exploration of DNA that C trachomatis (by PCR) in synovial samples from healthy and balanced volunteers and patients through osteoarthritis (in dong 9% and 20% the cases).45 In this study, just PCR amplifications using primers hybridising through 16S RNA or plasmid gene were positive, when attempts come amplify the significant outer membrane protein (MOMP) gene were constantly negative. This suggests, suspect these outcomes to be pertinent, that the bacteria persist in a “particular” form. It should nonetheless be noted that the variability the the PCR results have the right to equally be described by differences in sensitivity concerned the amplification target. Similarly, use of the “generic” an approach known together “universal” bacter gene amplification has enabled the detection that a certain variety of unexpected intrasynovial microbes, the pathogenic definition of which continues to be to it is in confirmed, due to the fact that this kind of method carries the danger of amplifying a commensal bacter or contaminant gene that no specific importance.46

Recent original job-related has confirmed the simultaneous presence of RNA of plenty of bacterial species in synovial samples native patients v rheumatoid arthritis, inexplicable arthritis, and osteoarthritis, yet not in samples taken during meniscectomy native presumably healthy subjects.47 In this research employing RT-PCR, respectively 92 and also 50 various bacterial varieties were determined by sequencing in the synovial fluid of rheumatoid arthritis and also osteoarthritis. Just six varieties (Corynebacterium, Escherichia coli, Streptococcus, Pseudomonas, Leptospira, and also Methylobacterium) to be detected specifically in rheumatoid arthritis, although without proof that this gift an debate in favour of their pathogenic role. These astounding results, apparently acquired by trustworthy methods, show that the synovium is not a sterile structure, but more probably one interfacial ar which have the right to be colonised by bacteria originating indigenous the environment and the endogenous flora.

“The synovium is not sterile but can be colonised by bacteria indigenous the environment”

Recently, a description was given of arthritogenic microbes detectable in synovial samples not just in situations of may be ReA but also in other develops of inflammatory rheumatism.12,48–50 In fact, C trachomatis and also pneumoniae are current in the synovial fluid of patients with rheumatoid polyarthritis in respectively 30% and 15% the cases51; the same observations have actually been reported for Mycoplasma pneumoniae and also fermentans.48,49 periodically several microbes may be discovered together in the same joint, as argued by the RT-PCR study defined above.47 This inexplicable association was observed for C trachomatis and also pneumoniae and for C trachomatis and B burgdorferi in synovial samples indigenous patients with spondyloarthropathy, unexplained arthritis, and even rheumatoid arthritis.51 One should however maintain a an essential attitude till these results have actually been confirmed by other studies. Thus, one report published just in abstract type suggests that the presence of intrasynovial bacter DNA could after all be superb phenomenon.52 In this work, a find by PCR evaluation for the bacterial 16S and 23S ribosom RNA genes proved an unfavorable in the synovium the 81 patients (42 rheumatoid arthritis, 8 other instances of inflammatory rheumatism, 31 osteoarthritis) as soon as using drastic conditions of sterility.


The many original microbiological observations defined in the previous ar raise a number of questions which require an answer to assist to understand the pathogenesis of reactive arthritis.

How execute these bacteria persist in the articular cavity and also escape indigenous the immune device of the host?

function of antigenic modulation

Several current studies have presented that C trachomatis can survive in a particular kind whereby it under regulates the expression of membrane antigens (MOMP), while continuing to synthesise immunomodulatory protein like heat shock proteins.53 that has more been presented that these adjustments can it is in induced in vitro by an extensive antibiotic treatment (ciprofloxacin),54 which can have necessary practical implications for future therapeutic strategies.

B burgdorferi can likewise modulate the expression of surface ar antigens. On start the host, this bacter in reality down regulates expression the the principal membrane external surface protein A (OspA) and also expresses larger quantities of an additional membrane protein OspC.55 together antigenic modifications may allow these bacteria to escape from the immune device of the host.

function of intracellular localisation the the bacter

As mentioned by Zinkernagel, plenty of circumstances exist in i beg your pardon micro-organisms (especially viruses) escape indigenous the immune device by persisting in non-lymphoid cells (papillomavirus in keratinocytes, Epstein-Barr virus in epithelial cells).56 Similarly, details arthritogenic bacteria deserve to enter and also persist in the synoviocytes (or other cells such as endothelial cells), sometimes regardless of use of antibiotics, as has actually been presented for C trachomatis and B burgdorferi.7,57–62

“Arthritogenic bacteria can persist in synoviocytes in spite of antibiotic treatment”

The situation is less clear in the case of enterobacteria and differs follow to the microbe. Yersinia and also Salmonella can persistently infect the mucosa the the intestine and also the digestive ganglions however not the synovium. This microbes are additionally present in monocytes, i m sorry serve maybe as a reservoir but over all as “transporters” indigenous extra-articular sites right into the joint.63–65Shigella, conversely, just infects digestive epithelial cells and cannot survive in monocytes and its instrument of persistence and also transport are less well known.

duty of molecule mimicry

Certain bacteria have actually constituents which display solid homology through proteins the the hold (YopH that Y pseudotuberculosis and CD45, M fermentans and CD4). This molecular mimicry can give rise come a tolerance to part microbes, i m sorry may thus escape from the immune mechanism of the host. One recently described example is the situation of Lyme borreliosis. It has actually been shown that a dominant epitope of OspA of B burgdorferi (usually presented by HLA-DRB1*04 01) has actually close succession homology through leucocyte role associated antigen-1 (LFA-1), i beg your pardon is a β2-integrin expressed at the surface ar of lymphocytes, polynuclear granulocytes, and monocytes.66 as a result, OspA can bind to intracellular adhesion molecule-1 (ICAM-1), a ligand of LFA-1 expressed by synoviocytes, permitting the bacterium to persist in the synovium. Top top the other hand, the mimicry may additionally be differently understood by the host due to the fact that the homology in between this bacterial constituent and also an antigen of the articular cavity have the right to induce an “autoimmune” synovitis, as will be debated later.

function of interactions with the immunogenetic attributes of the host

To fix an infection, specifically with intracellular bacteria, cytokines such as interferon γ (IFNγ) produced by T cells play a major part.67 It has actually been presented that in ReA the antibacterial Th1 cytokine solution (production of IFNγ, interleukin 2 (IL2) and IL12) is impaired in favour the a Th2 solution (IL4 and also IL10).68–73 Thus, in the absence of a “good” antibacterial reaction, the microbes have the right to survive. Tiny is known around the pathogenesis of this Th1/Th2 imbalance, yet it is most likely that genetic determinants of the host are causally involved. Among these factors, the polymorphism that cytokine genes is probably implied. For instance, in Finnish patients, the microsatellites IL10.G10 and IL10.G12 from the promoter region of the IL10 gene it seems ~ to it is in protective against the advance of ReA.74 In a German study, it has actually been demonstrated the the level of tumour necrosis element α (TNFα) secretion by T cell at ReA start is inversely proportional to the disease duration and severity.75 However, ReA cannot be described merely through cytokine manufacturing or polymorphism and other susceptibility factors certainly play a part. One of them is that arthritogenic bacteria favor Yersinia or Salmonella have the right to modulate HLA-B27 (modification of the messenger RNA splicing, peptide modification) and, possibly, the lymphocyte response.76 this interferences may facilitate the persistence the the bacteria within cell or tissues.

How deserve to these bacteria, i beg your pardon seem come escape from the immune device of the host, cause arthritis?

An evaluation of the microbiological and immunological data says the existence of two forms of reactive arthritis.

Reactive arthritis of the form chronic infectious arthritis

Certain forms of ReA might represent yes, really chronic infectious arthritis led to by slow cultivation organisms which room very challenging to cultivate and also hence impossible to determine by the normal microbiological methods. In the irradiate of existing knowledge, this theory would appear to hold for Chlamydia, Mycoplasma, and Borrelia, although not for enterobacteria. Together microbes get in the articular cavity throughout bacteraemia or within monocytes 77,78 and can survive in small numbers in a “vegetative” state, probably with intermittent periods of replication prompted by tho unknown phenomena.7,53,57,58 This has been plainly demonstrated for C trachomatis, which persists in the form of “atypical” reticulated bodies.79,80

These microbes have an attenuated virulence, uneven those responsible because that septic arthritis. Such forms of ReA are therefore related to a “slow” intrasynovial infection, a condition also called “slow transmittable arthritis” or “infection reactive arthritis”.4,81 Similarly, that is by invoking the exact same mechanisms that one defines today the arthritis of Whipple"s disease, vice versa, for countless years it to be not possible to identify or maintain this slow cultivation organism.29,30

Reactive arthritis of the form infection triggered aseptic arthritis

Some forms of ReA are probably aseptic and if so it is the persistence of bacter antigens (lipopolysaccharides, warmth shock proteins) which may define the illustration of an inflammatory reaction in the synovium. This theory applies over all to enterobacteria (Yersinia, Salmonella . . .), microbes not found in the joint except possibly in authentic (but rare) instances of acute septic arthritis.82–86 In chronic forms, the is unlikely the viable and energetic bacteria persist in the synovium, return it has actually occasionally been feasible to detect bacterial DNA18,19,21–23 and also even recently intrasynovial RNA in a case of ReA resulted in by Yersinia pseudotuberculosis.22 Conversely, that is likely that these bacteria survive at an extra-articular site, in details in the mucosal membrane of the digestive mechanism and/or the lymphatic ganglions, and also are brought to the joint by monocytes, more than likely in recurrent fashion.63–65 In assistance of this theory, over there is some proof indicating the a preferential link exists in between gut and joints. It has been observed the mucosal leucocytes collected from patients through an inflammation bowel disease can tie well to synovial vessels.87 This homing implies many receptors and also their ligands, which different according come the leucocyte subset, and mononuclear cell from peripheral blood execute not re-superstructure the binding attributes of gut obtained cells. Although these outcomes only issue inflammatory bowel diseases, the concept can probably be used to enteric ReA. ~ the homing, the bacter antigens can subsequently persist occasionally for a long time in the synovium, in particular cases in the form of bacter “ghosts” without main point acid.84,85 This type of arthritis, triggered by bacterial antigens originating indigenous an extra-articular website in the lack of any viable intra-articular microbe, may be referred to as “infection motivated reactive arthritis”.

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What are the bacterial factors and the immunogenetic factors of the host which are essential to define the figure of arthritis?

Although the over description of the two develops of reactive arthritis provides a reasonably simple picture, that is feasible that the future will expose a an ext “heterogeneous” reality. In any type of case, the appearance of arthritis is a an effect of the encounter in between an arthritogenic bacterium and also a predisposed host. Hence the an essential to the secret of ReA will undoubtedly lie in a thorough study of this host-bacterium interactions, of i beg your pardon we already know few of the subtleties.