3 Reactive arthritis: the role of bacterial antigens in inflammatory arthritis R O D N E Y HUGHES A N D R E W KEAT

The identification of the agents and events which induce inflammatory synovitis remains a key step in the process of understanding and effectively treating inflammatory arthritis. Recent advances in genetics have highlighted the potential role of environmental factors, including microorganisms, as triggers of arthritis. In particular, the discovery of the capacity of major histocompatibility complex determinants to present microbederived peptides to T lymphocytes has reawakened interest in the search for an Underlying causal infection in aseptic infla/nmatory arthritis. Not for the first time, therefore, it has become logical to consider the role of bacteria in the induction of arthritis and the possibility, amongst others, that bacterial fragments may be deposited within the synovium and play a central l'ole in the induction of the inflammatory reaction. Close links between infection and aseptic arthritis have long been suspected. In 1916 Reiter reached the conclusion that the arthritis which complicated dysentery in his now famous patient was caused by a spirochaete isolated from the blood (Reiter, 1916). These observations turned out to be of doubtful significance, but the conclusions were entirely consistent with contemporary views of bacteria as potential causes of a wide variety of both conventionally septic and aseptic diseases (Metchnikoff, 1907). Although evidence of links between human arthritis and transmissible disease was restricted to associations with urethritis (Brodie, 1818; Launois, 1899), dysentery (Woodward, 1879) and tonsillitis (Browne, 1900), the search for bacterial causes of inflammatory arthritis was well under way by the turn of the twentieth century (Poynton and Paine, 1900). Then, as now, the distinction between septic and aseptic joint lesions posed real difficulties. As early as 1892 'long encapsulated bacilli' were reported in synovial fluid from a patient with gout (Grun, 1892a), whilst 'minute cocci' apparently 'saturated' the joint in acute rheumatism (Grun, 1892b). In 1893 'dumb-bell bacilli' were described in active synovitis (Bannatyne and Wohlmann, 1896), and Bannatyne also reviewed the aetiology and pathology of rheumatoid arthritis, claiming to have isolated a specific cocco-bacterium from synovial fluid aspirates in 24 of 25 patients with rheumatoid arthritis. It was speculated that these organisms gained access to the blood via 'chronic Bailli~re's ClinicalRheumatology--

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catarrh of the gastrointestinal or genitourinary systems' and that, having entered the circulation, 'micro-organisms pass through freely to all the organs of the body thus explaining the symmetry of the disorder and why one joint after another should be affected'. In 1914 Rosenow excised hypertrophic lymph nodes, under local anaesthesia, from patients with 'arthritis deformans' and isolated microorganisms in all but three of 38 cases, the duration of disease ranging from 2 to 17 years. Streptococci were found in 14, staphylococci in three and gonococci in one. These micro-organisms, it was asserted, not only showed affinity for 'joints and muscles in dogs and rabbits after intravenous injections' but administration of the same bacteria, heat-killed, appeared to aid recovery (Rosenow, 1914). It was postulated that patients with arthritis but no overt source of bacterial infection must harbour occult infective loci from which causal micro-organisms disseminate to the joint to initiate inflammation. Thus emerged the theory of 'focal sepsis'. 'Every effort should be made to find any such (focus) and prompt treatment carried out' wrote McCray in Osler's Principles and Practice of Medicine in 1938. Edentulation, tonsillectomy and bowel enemas were therefore applied assiduously as treatments for arthritis, whilst vaccines of Micrococcus deformans and heat-killed streptococci were given at the Charterhouse Rheumatology Clinic in London (Crowe, 1932). Such treatments, though imaginative, were not subject to rigorous scientific evaluation so that their real value, if any, remains uncertain. With the recognition that rheumatoid arthritis, septic arthritis and reactive arthritis comprise different entities, and with improved aseptic techniques, reports of isolation of specific micro-organisms from the joint in non-suppurative arthritis have become extremely rare. However, the case for an environmental trigger in many forms of inflammatory arthritis has remained. In reactive arthritis, more than any other form of aseptic arthritis, epidemiological and circumstantial evidence implicate an infective cause, arthritis usually following symptoms of gut or genitourinary infection within 28 days (Keat, 1983). Although other possibilities need to be considered, this chapter focuses on the role of bacteria and their products in the pathogenesis of aseptic arthritis. PORTALS OF ENTRY

Bacteria could promote arthritis through either indirect or direct effects. In either event, bacteria or their products must be exposed to the immune system. It is possible that immune responses stimulated at a mucosal surface may lead to tissue damage at the joint through immunological cross-reactivity between bacterial antigens and joint components. Alternatively, the presence of micro-organisms at one site may be linked with inflammation at another through dissemination of complete micro-organisms, or fragments of them, via the circulation, with subsequent deposition in the target tissue. Such access to the circulation could be via the skin, gut, genitourinary system, respiratory tract or conjunctiva, and either pathogenic or commensal bacteria

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might be important. In reactive arthritis, foci of infection are recognized in the gastrointestinal or genitourinary tract, although in many patients with identical clinical features but without detectable infection it is possible that occult foci exist at these or other sites. The possibility of other undetected foci of infection still requires further investigation. The gastrointestinal tract is potentially the major site from which bacterial antigens can gain access to the circulation. Even in the absence of infection, countless millions of commensal bacteria make the gut their home and many micro-organisms pass through the gastrointestinal tract each day. There is, therefore, considerable potential for the passage of bacteria or degraded bacterial fragments from the gut to the bloodstream. In healthy mice, a meal of inert latex particles with a diameter of 2 Ixm results in uptake of the spheres into Peyer's patches in the small intestine and their passage to local lymph nodes (Le Fevre et al, 1978). In other animal experiments passage from gut to bloodstream of viable micro-organisms (Schatten, 1954) and soluble bacterial components such as endotoxin (Gans and Matsumoto, 1974) has been demonstrated in surgically isolated bowel loops. In humans gastrointestinal mucosal abnormalities, with increased bowel permeability, have been linked to the development of several forms of inflammatory arthritis. In the absence of primary bowel pathology, artificially induced changes in bowel function and/or flora can lead to significantly increased gut permeability. The role of diet-induced changes in bowel flora in the induction of arthritis in pigs has been clearly demonstrated (Olhagen and Mansson, 1969). In man, overgrowth of bacteria in blind loops of bowel (Mezey et al, 1974) formed at small bowel bypass surgery for morbid obesity has als~ been associated with the development of arthritis. As many as 25% of patients developed migratory polyarthritis following bypass surgery, some suffering severe persistent symptoms (Shagrin et al, 1971; Wands et al, 1976). Jejunoileostomy replaced jejunocolostomy as a treatment since it was associated with fewer major metabolic complications and a lower, but still significant, incidence of arthritis (Buchanan and Willkens, 1972; FernandezHerlihy, 1977). Such 'bypass' arthritis may also be associated with skin lesions ranging from erythematous nodules to pustulosis (Stein et al, 1981). That the abnormal function and alteration in bowel flora are significant factors in the aetiology of bypass arthritis is suggested by the amelioration of the arthritis by tetracycline treatment (Delamere et al, 1983) and its cure by reversal of the surgical shunt (Left et al, 1983a). Experimental evidence shows that antigens from the bowel undergo widespread dissemination following small bowel bypass surgery. Active joint inflammation is associated with the detection of soluble circulating immune complexes (CICs) (Rose et al, 1977). Such immune complexes have been shown to contain antibody against Escherichia coli or Bacillus fragilis (Wands et al, 1976) and antigens of E. coli (Utsinger, 1980) or group D streptococci (Clegg et al, 1980). These CICs can apparently both fix and activate complement (Moake et al, 1977). The pathogenic significance of CICs is uncertain since they may be detected in post-bypass patients both with and without arthritis (Zapante et al, 1979; Left et al, 1983b). In the only

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study in which the ileal lumens of patients with long-standing jejunoileal bypass were visualized, the small bowel was dilated and inflamed and cultures of the ileal wall yielded E. coli in four of seven cases (Stein et al, 1981). In addition, the mesenteric lymph nodes associated with the inflamed ileal walls were enlarged. It appears likely that inflammation occurring secondary to the intestinal bypass procedure results in increased mucosal permeability which, in association with abnormal bowel flora, leads to the passage of bowel micro-organisms or bacterial antigens through the mucosa and into the circulation. Crohn's disease (CD) and ulcerative colitis (UC) are also associated with increased bowel permeability to macromolecules such as polyethylene glycol (PEG) 400 (Hollander et al, 1986). Both diseases are associated with an increased prevalence of peripheral arthritis, sacroiliitis, ankylosing spondylitis and inflammatory lesions at other sites, including uveitis and erythema nodosum (Bywaters and Ansell, 1958; Ansell and Wigley, 1964; Wright and Watkinson, 1965). In patients with UC and arthritis, an exacerbation of the bowel symptoms may be accompanied by a worsening of the joint inflammation. There is a relationship between the extent of colonic involvement and the likelihood of the development of peripheral arthritis. In one study arthritis occurred in 20% of 46 women with total colitis, 9% of 46 with left-sided colitis and only 2.6% of 38 who had rectal involvement alone (Wright and Watkinson, 1965). The observation that total colectomy in UC abolishes peripheral joint disease in some patients (Brook, 1954) supports the notion that synovitis in these indi~ciduals is secondary to bowel inflammation. Bowel permeability to PEG may also be increased in healthy blood relatives of patients with CD, suggesting the influence of genetic factors (Hollander et al, 1986). CICs have been detected in serum from patients with UC and CD (Hodgson et al, 1977), but the antigenic constituents have not been characterized, so that the possible contribution made by gut bacterial antigens is unclear. An important constituent of many commensal and pathogenic gut bacteria is lipopolysaccharide (LPS), which also contains the endotoxin activityl The presence of circulating endotoxin may be a reflection of increased intestinal permeability. In neither animals nor humans is there convincing evidence that endotoxin is absorbed from undamaged gut; chromium-51-1abelled endotoxin does not leak from the gut lumen in healthy dogs (Sanford and Noyes, 1958). However, significant endotoxaemia has been reported in animals following gut ischaemia (Papa et al, 1983), chemical peritonitis, surgery and exposure to radiation (van Deventer et al, 1988). Increased levels of circulating vasoactive amines facilitate absorption of gut endotoxin, as does the absence of bile from the bowel lumen, lack of food, the presence of milk and overgrowth with E. coli (Walker, 1978). In humans, endotoxin has not been detected in portal venous blood in health, but endotoxaemia does occur following intestinal disruption. Endotoxin has been detected in blood from patients with UC undergoing surgery to the bowel (Palmer et al, 1980), during colonoscopy (van Deventer et al, 1988) and in a few patients with uncomplicated

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inflammatory bowel disease (Wellman et al, 1984). Unfortunately the detection of endotoxin in blood is hampered by the lack of a sensitive and reliable assay. The most sensitive test available is the Limulus amoebocyte lysate gel clot assay which is difficult to use with biological fluids owing to the presence of varying amounts of naturally occurring inhibitors and enhancing factors which interfere with the reaction (Levin et al, 1970). In one study using the Limulus amoebocyte lysate assay, plasma endotoxin levels above 10 pg/ml were reported in 31% of patients with ankylosing spondylitis, 50% with sacroiliitis and peripheral arthritis and 46% of patients with rheumatoid arthritis in the absence of apparent bowel disease (Wagener et al, 1988). Patients with other inflammatory arthritides have been investigated for bowel inflammation and increased bowel permeability, even in the absence of gut-related symptoms. Unsuspected inflammatory bowel disease was found in three of 47 patients with ankylosing spondylitis (Jayson et al, 1970), whilst a study of 59 patients with rheumatoid arthritis apparently revealed a significantly higher prevalence of gut inflammation than in healthy controls (Marcolongo et al, 1979). However, these studies were not controlled for non-steroidal anti-inflammatory drug (NSAID) treatment, now known to cause inflammation and increased permeability throughout the gut (Bjarnason et al, 1984). In another study macroscopic inflammation of the terminal ileum or colorectum was demonstrated in 30% of 211 patients with seronegative arthritis, including 41 with no intestinal symptoms; 61% of patients had histological evidence of inflammation, but this was found in only one control patient (de Vos et al, 1989). Using chromium-51-ethylenediaminetetraacetic acid (EDTA) absorption, significantly increased gut permeability was found in a group of patients with spondyloarthr~pathy regardless of NSAID intake (Mielants et al, 1991). Other conditions which may be associated with increased bowel permeability, including coeliac disease (Bourne et al, 1985) and Whipple's disease (Whipple, 1907; Maizel et al, 1970), also predispose to arthritis. In coeliac disease both increased jejunal permeability and CICs (Hamilton et al, 1982) have been described. In Whipple's disease intracellular bacilluslike structures, similar to those present in the lamina propria of the small intestine (Yardley and Hendrix, 1961) and regional mesenteric lymph nodes, have been detected in inflamed synovium (Hawkins et al, 1976), although organisms have not been isolated in culture. Both Whipple's and coeliac disease may represent diseases where primary disturbances in the integrity of the bowel wall mucosa allow bacterial antigens to pass via regional lymph nodes and the circulation into joints. The respiratory tract represents another potentially important portal of entry to the circulation for foreign particulate matter. The alveolar-capillary membrane covers a vast expanse, with only 0.2 txm separating air from blood. Although protected by saliva and bronchial ciliary action, particles of less than 5 txm can readily reach the alveoli. The passage of inert particles such as carbon across the lung epithelium is seen in town dwellers, whose pulmonary lymph nodes at post mortem are slate grey when compared with their rural counterparts. When fluorescent microspheres 1.3 pomin diameter were instilled into the lungs of previously healthy dogs they could be

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recovered from alveolar macrophages within 7 days and were also found intracellularly within tracheobronchial lymph nodes (Harmsen et al, 1985). However, it is unlikely that live micro-organisms regularly gain access to the circulation via healthy lungs unless the microbes possess special properties that enable them to evade elimination by cilia or uptake and inactivation by alveolar macrophages. Pseudomonas spp., for example, produce several different ciliostatic exotoxins that facilitate lung infection, whilst Mycoplasma pneumoniae has specialized receptors for neuraminic acid to allow attachment to lung tissue. However, in damaged or infected lungs it is likely that disruption of the alveolar-capillary membrane allows passage of micro-organisms into the circulation. For instance, Streptococcus pneumoniae and Staphylococcus aureus can cause septicaemia secondary to pneumonia. In both acute and chronic lung disease breakdown of the normal protective mechanisms might allow access of pathogenic or commensal bacteria to the circulation. Such a mechanism could underlie the development of arthritis in association with Mycoplasma pneumoniae pneumonia, bronchiectasis (Steinfort et al, 1987) and cystic fibrosis (Dixey et al, 1988), where colonization and infection of the lungs with bacteria, including Pseudomonas spp., is invariable. The capacity of bacterial mucosal infection to induce cross-reactive immune responses is well illustrated by the development of rheumatic fever in association with upper respiratory tract infection with [3-haemolytic streptococci. The potential of the respiratory tract as a portal of entry for arthritogenic micro-organisms in reactive arthritis needs further investigation. Dissemination of whole bacteria from the genitourinary tract during acute infection at any site is well recognized. Neisseria gonorrhoeae infection, especially of the upper genitourinary tract, may be complicated by bacteraemia and septicaemia, and chlamydial salpingitis may lead on to the Curtis-Fitzhugh syndrome, Chlamydia trachomatis being isolated from the liver capsule (Muller-Schoop et al, 1978). Both endocarditis (van der BelKahn et al, 1978) and hepatitis (Dan et al, 1987) have been reported in association with infection by genital serotypes of C. trachomatis. However, the lower genitourinary tract is normally colonized by a wide range of micro-organisms and it is unclear to what extent, if any, such microbes or antigenic fragments of them gain access to the circulation either in health or in localized, uncomplicated genital tract infection. As in the respiratory tract, the extensive mucosal surfaces and tissue-blood interface of the genitourinary tract must represent a possible portal of entry for many micro-orgamsms. DISSEMINATION OF ANTIGEN The hypothesis that arthritis might result from the deposition of bacterial antigen in the synovium after transport in the circulation has been based on much experimental evidence showing that substances of various molecular weights can pass from the blood into the joint tissue (Brewerton, 1988). Phenolphthalein in solution and colloids containing immunoglobulin or

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other experimentally introduced foreign proteins readily enter uninflamed joints (Kling, 1938). Larger molecules of trypan blue administered by either subcutaneous injection or nasogastric feeding were also found in the synovial histiocytes of non-arthritic rats (Kuhns and Weatherford, 1936). Such studies also showed that small particulate matter gained access to synovium readily, whilst larger particles of Indian ink were excluded from normal joints, implying a block at the vascular-endothelial barrier. Deposition of particles was increased when joints were inflamed or traumatized, possibly reflecting alterations in endothelial permeability. Carbon particles introduced into the circulation of rabbits could not be detected in intact vascular endothelium; deposition could, however, be induced by treatment with vasoactive amines such as histamine (Benacerraf et al, 1959). The arthritogenic significance of inert particles entering the synovium is not entirely clear. However, in humans silicone from breast implants has been implicated in the pathogenesis of reversible joint disease (Sergott et al, 1986). In addition, the prevalence of rheumatoid disease appears to be increased in quarry workers exposed to high quantities of airborne silica over long periods (Klockars et al, 1987), implying that even inert material of this kind may be important in the development of inflammatory arthritis. The dissemination of biologically active material may be of greater aetiological significance. If the presence of bacterial antigens in the joint is important in inducing inflammatory arthritis, two patterns of antigen dissemination are possible. Antigens might localize selectivity to the sites of subsequent disease; alternatively, dissemination might be widespread and other factors, including, perhaps, genetically determined host characteristics or additional environmental influences, could dictate whetl~er an inflammatory response occurs. Following systemic injection of bacteria into rabbits, selective deposition of antigen has been shown, with bacteria detectable in normal joints but not in spinal fluid, aqueous humour or urine (Schaffer and Bennett, 1939). Selective uptake of bacteria by joint tissue was further suggested by an experiment using Streptobacillus moniliforrnis isolated from a patient with 'rat bite fever' and then injected into chick embryos. Inflammation was found exclusively in the embryo synovium, from where bacteria could be reisolated (Budding, 1944). Growth of S. moniliformis in joint tissue may indicate selective localization of the bacteria or unique compatibility of this tissue with the growth requirements of this micro-organism. In rats, however, systemic injection of rhodamine-labelled mycobacteria leads to widespread, non-selective deposition of bacteria, although inflammation only occurs at joints and related structures (VernonRoberts et al, 1976). It is likely that the pattern of dissemination of bacterial antigen is determined by many factors, including the nature of the antigen, the host species and the portal of entry. The mechanism of antigen transport in the blood and how it is carried to the joints is still the subject of speculation. In certain circumstances bacterial antigens may travel in solution complexed with antibody. The dissemination of bacterial fragments after absorption from the bowel in bypass arthritis was investigated in a study of five patients with active joint disease. On day 3 following ingestion of iodine-131-1abelled E. coli cell walls, the iodine-131

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label could be detected as CICs in three of the five patients. By day 6 radioactivity was present in the synovial fluid (Utsinger, 1981). In bypass arthritis, CICs have been detected in synovial fluid, and deposition of immunoglobulin and complement has been demonstrated within inflamed synovium (Zapante et al, 1979). In patients with bypass arthritis and dermatitis, immune complexes and E. coli antigens have been observed at the dermo-epidermal junction in lesional skin (Utsinger et al, 1978). In a lone patient with associated glomerulonephritis, E. coli antigen was demonstrated within the glomerular basement membrane. It is likely that bacterial antigens also circulate within inflammatory cells, including macrophages and polymorphs. Many of the micro-organisms which have been linked to human aseptic arthritis are obligate or facultative intracellular parasites. It is possible, therefore, that this capacity to survive in an intracellular milieu may allow dissemination from the portal of entry within the relatively protected environment of living cells, cellular transport mechanisms being potentially of great significance in this regard. Inert particles can be taken up from skin and lung surfaces by monocytes, from where they are transported to regional lymph nodes (Harmsen et al, 1985). It is likely that polymorphonuclear cells are also involved in the transport of bacterial antigens to the joint (Granfors et al, 1990a), but subcellular bacterial antigens such as endotoxins may circulate free in plasma. Once an antigen is in the circulation, access to all tissues, including the joints, is determined by the permeability of the vascular endothelium. Local trauma, neural manipulation and bacterial endotoxin have all been shown to alter the access of particulate matter to joints (Kuhns and Weatherford, 1936). This is probably a consequence of increased endothelial permeability (Schumacher, 1969; Crone, 1986). Circulating endotoxins can influence endothelial integrity and hence vascular permeability, probably via the action of cytokines (Howes et al, 1970; Jirik et al, 1989).

INDUCTION OF ARTHRITIS The dissemination of bacteria from a peripheral injection site to the joint has been the basis for experiments to investigate the potential arthritogenicity of bacterial components when administered to laboratory animals. Schwab and colleagues demonstrated the proinflammatory properties of group A streptococcal cell wall materialin skin and synovium (Schwab and Cromartie, 1957; Cromartie et al, 1977). Intraperitoneal injections of group A streptococcal cell walls or peptidoglycan-polysaccharide complexes into SpragueDawley rats led to polyarthritis; cell wall material could be identified in the synovium within 3 h of injection and was shown to persist for many months (Schwab et al, 1967). Similarly, cell wall preparations of Staphylococcus aureus, Lactobacillusplantarum and L. casei (Kohashi et al, 1976; Lehman et al, 1984) were shown to produce severe arthritis in Lewis rats. However, streptococci without cell walls (L forms) can also be shown to induce inflammatory joint disease (Cook et al, 1969), so that bacterial components

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other than cell wall material must also be important in the induction of arthritis. The ability of streptococcal cell wall arthritis to be induced in naive recipient rats by the transfer of T lymphocytes (de Joy et al, 1989) raises important questions about the precise role of bacterial components in this model. Naturally occurring arthritis in pigs can be mimicked by systemic injection of Erysipelothrix rhusiopathiae (Collins and Goldie, 1940). Arthritis may also be induced in rabbits by systemic injection of cell-free extracts of E. rhusiopathiae (White and Puls, 1969). As with streptococcal cell wall arthritis, fluorescein-labelled E. rhusiopathiae antigen could be detected within the joints in association with synovial inflammation (White et al, 1971). Disease persists for many weeks, with subsequent cartilage and bone damage (Astorga, 1969). Classical adjuvant arthritis (Pearson, 1956) shares some similarity with these models, but differs in requiring simultaneous administration of mineral oil in water. Dissemination of Mycobacterium butyricum to joint tissue is readily demonstrable (Vernon-Roberts et al, 1976). The wax D component of mycobacterial peptidoglycan is highly proinflammatory in various tissues (Koga and Pearson, 1973), the peptidoglycan moiety being essential for arthritogenicity (Wood et al, 1969). Several strands of indirect evidence have suggested a role for bacterial heat shock proteins in the induction or maintenance of synovitis. In adjuvant arthritis passive transfer experiments have shown that synovitis can be induced in a healthy recipient animal of the same strain by intravenous injection of purified living mononuclear cells from lymph node (Flax and Waksman, 1963), spleen (Pearson and Wood, 1964) or thoraciq duct (Whitehouse et al, 1969). More recently these observations have been refined (Holoshitz et al, 1983); arthritis may be transferred to irradiated recipients by T lymphocytes sensitized against an octapeptide of the 65 kDa mycobacterial heat shock protein. In contrast, another clone of T cells sensitized against the same antigen was able to confer protection against the induction of adjuvant disease. Thus, in adjuvant arthritis it appears inescapable that the target antigen in the joint may be separate from the observed mycobacteria in joint tissue. Molecular studies have indicated a link protein in articular cartilage (van Eden et al, 1988) as a possible candidate, although no other evidence of the involvement of this protein has yet been advanced. A further bacterial component with demonstrable capacity to induce synovitis is LPS or endotoxin. When released into the circulation endotoxin can produce a myriad of toxic biological effects, including hypotension, disseminated intravascular coagulation, vascular endothelial damage and multiple organ failure (Bayston and Cohen, 1990). Endotoxin can cause a localized inflammation in various tissues. Intravenous injection of LPS from different gram-negative bacteria caused uveitis but not arthritis in Lewis rats (Rosenbaum et al, 1980). Injection of purified LPS from Proteus vulgaris or Salmonella abortus into the suprapatellar bursae of rabbits was associated with a short-lived synovial inflammation (Hollingsworth and Atkins, 1965). Arthritis could be induced in rabbits by direct intra-articular injection of

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purified LPS from Neisseria gonorrhoeae (Goldenburg et al, 1984). The influence of LPS on the induction of arthritis in animals is complex. The administration of LPS in an adjuvant may protect rats from subsequent induction of mycobacterial adjuvant disease (Wood and Pearson, 1962), whilst, conversely, colonization of animals with certain gram-negative bacteria may predispose to a more severe form of adjuvant disease (Kohashi et al, 1985). Other bacterial components may also be implicated in the aetiology of arthritis in humans. Antibodies to peptidoglycanpolysaccharide complexes have been detected in the sera of some patients with juvenile rheumatoid arthritis (Moore et al, 1988) and also in patients with adult rheumatoid disease (Park et al, 1984) or seronegative arthritis (Rahman et al, 1990). It is likely that many factors determine the persistence or chronicity of arthritis in animal models; one factor may be persistence of the antigen. The streptococcal polysaccharide-peptidoglycan complex active in the Schwab model of arthritis is resistant to degradation by human and rat macrophages in vitro and by mouse cells in vivo (Adler et al, 1973; Smialowicz and Schwab, 1977). In contrast, cell walls from group D streptococci, which possess less arthritogenic potential, could be eliminated readily within 6-8 days. In the joints of animals with streptococcal cell wall-induced arthritis the streptococcal polysaccharide-peptidoglycan complex could be detected up to 6 months after initiation of the arthritis (Schwab et al, 1967). Similarly, in arthritis induced by Erysipelothrix and Freund's complete adjuvant, specific bacterial antigens persist in joint tissue long into the course of disease (Astorga, 1969). However, the persistence of antigen alone cannot explain the observed clinical disease. In the models described, bacteria or bacterial components disseminate widely throughout the body and, indeed, in different animal species different organs may be affected. Thus in adjuvant arthritis mycobacteria are detectable in non-inflamed as well as inflamed joints (Vernon-Roberts et al, 1976) and streptococcal cell wall material is detectable in many non-inflamed tissues, including the liver and spleen, as well as the joints (Cromartie et al, 1977). In these animal models considerable strain and species variability in terms of susceptibility to, and site of, inflammation suggest the importance of genetic factors (Wilder et al, 1983). So too does the development of more severe disease in females (Wilder et al, 1982). Systemic injection of cell walls from Lactobacillus casei and Staphylococcus aureus caused severe polyarthritis in Lew/N rats but only mild disease in F344/N rats (Lehman et al, 1984). A genetic influence on the localization of disease, rather than of bacterial antigen, is suggested by the induction of arthritis in Sprague-Dawley rats by mycobacterial wax D whilst administration by a similar route in guinea pigs leads to encephalomyelitis. Similarly, injection of streptococcal cell walls into mice leads to carditis rather than arthritis (Cromartie and Craddock, 1966). The genetic influences are therefore complex, determining the sites at which inflammatory reactions occur and the severity of the resultant lesions. In spite of some similarities in principle between these various model systems, it remains unclear to what extent the basic mechanisms of pathogenesis are common to each. Precise identification of the target

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antigen is central to understanding both experimental and human arthritis. Although transfer experiments imply immune responses to 'self' antigens as central to some forms of arthritis, the finding of bacterial antigen in inflamed joints and the induction of arthritis by natural and synthetic subcellular fractions suggest that, in some circumstances at least, persisting exogenous bacterial antigen is the target against which the immune response is directed. Many groups have attempted to induce arthritis in animals using microorganisms, including human gastrointestinal or genitourinary pathogens, thought to be of more direct relevance to human reactive arthritis. Persistent or fluctuating arthritis has been induced in Lewis rats by intravenous administration of live Salmonella enteritidis (Volkman and Collins, 1973). However, salmonellae may be isolated from the joint in the initial weeks of disease. Similarly, arthritis can be induced in adult Lewis rats by intravenous injection of live Yersinia enterocolitica (Hill and Yu, 1987). In this model the joints remained sterile. Administration of micro-organisms by alternative routes, including the gut, did not result in arthritis. Studies with the human genitourinary pathogen Chlamydia trachomatis have met with only limited success. Arthritis induced in mice by direct intra-articular inoculation of chlamydial antigen into animals presensitized by subcutaneous immunization was mild and short-lived (Hough and Rank, 1988). Systemic injection of C. trachomatis has not been shown to induce arthritis in a reproducible manner in natural or human leucocyte antigen (HLA) B27-positive transgenic mice (S. C. Knight, A. Stagg, B. J. Thomas and D. Taylor-Robinson, personal communication), although widespread dissemination of antigen to the spleen and joints has been demonstrated (Tuffrey et al, 1984). In contrast, C. psittaci has been shown to induce~both naturally occurring and experimental arthritis in lambs and calves (Shupe and Storz, 1964; Storz et al, 1966). Viable micro-organisms are present in the joint early in the disease, but after 28 days the arthritis is apparently aseptic. It remains unclear as to whether bacterial antigen persists in the joint at this stage. There is thus ample evidence that the introduction of a wide variety of bacteria at a site distant from the joint in many animal species is followed by dissemination of antigen, deposition of antigen in the synovium and the induction of arthritis. It is also clear that several bacterial components, including degradation products such as LPS, peptidoglycans and heat shock proteins, may be responsible for the induction of inflammation. Circumstantial evidence indicates that it is the arrival of such bacterial material in the joint which initiates the joint pathology. Previous sensitization to the antigen, the rate of degradation of the antigen and genetic elements of the immune response but not specific patterns of distribution of antigen appear to influence the development of arthritis. REACTIVE ARTHRITIS. IN MAN Studies of the role of bacteria in the induction of human reactive arthritis have centred upon isolation of micro-organisms from joint tissue, testing of

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antibody and cellular immune responses, immunochemical detection of bacterial antigens in joint tissue, and searches for bacterial D N A using the polymerase chain reaction (PCR). In rheumatoid arthritis the search for bacteria has proved fruitless (Ziff, 1976), not least because there are few, if any, clues as to the identities of aetiologically relevant micro-organisms. By contrast, in reactive arthritis there are clear indications as to the identity of some trigger bacteria and many clinical studies, based on the animal work cited above, have led to the formulation and testing of reasoned hypotheses. The definition of reactive arthritis as arthritis associated with infection elsewhere in the body but without micro-organisms within the joint is also a hypothesis which can be tested. Epidemiological studies have implicated several specific infections of the gut and genitourinary tract in the onset of reactive arthritis (Keat, 1983). Gut infections with Salmonella enteritidis, S. typhimurium, Shigella flexneri and Campylobacter jejuni have been linked with reactive arthritis through studies of outbreaks. In addition, the relatively high prevalence of Yersinia enterocolitica and Y. pseudotuberculosis infections in Scandinavia has allowed the demonstration of a clear association between these microorganisms and reactive arthritis (Ahvonen et al, 1969). However, in many instances arthritis follows non-specific gastrointestinal symptoms with no causal pathogen being identified, so that it is possible that other gastrointestinal pathogens may also precipitate arthritis. Anecdotally, arthritis has been associated with Giardia lamblia (Gabrielle et al, 1938), Clostridium difficile (Bolton et al, 1981; Lofgren et al, 1984) and Entamoeba histolytica (Graby and Graby, 1949). The role of genitourinary pathogens is less clear. Clinical and immunological studies have linked reactive arthritis with Chlamydia trachomatis infection. However, it is not clear that this infection carries an increased risk of sexually acquired reactive arthritis (SARA) compared with other causes of acute sexually transmitted genital tract infection (Keat et al, 1978); C. trachomatis infection is identified in approximately 50% of patients with both uncomplicated non-gonococcal urethritis and SARA (Kousa et al, 1978; Keat et al, 1983; Martin et al, 1984). Therefore, other infectious agents may also be associated with the induction of SARA. In addition, Neisseria gonorrhoeae and genital mycoplasmas have been isolated from the genital tracts of patients with acute SARA, so that aetiological roles for these micro-organisms also have to be considered. Attempts to isolate bacteria from the joints of patients with reactive arthritis have proved largely negative; the significance of occasional reports of isolates remains difficult to assess. Attempts to isolate gut bacteria from joint specimens from patients with reactive arthritis have proved universally negative (Toivanen and Toivanen, 1988). Initially encouraging findings of the isolation of mycoplasmas from synovial fluid from a patient with Reiter's syndrome (Kuzell and Mankle, 1960) have not been confirmed, although isolation of Ureaplasma urealyticum from joint fluid from a child with Reiter's syndrome has been reported (Kossman et al, 1980). There are many case reports of septic mycoplasmal arthritis in immunodeficient patients,

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and this may also occasionally occur in immunocompetent individuals (Verinder, 1978), but the clinical features are distinct from those of reactive arthritis. More recent studies (Keat, 1990) have failed to confirm an association between mycoplasmas and reactive arthritis. Although reactive arthritis may be associated with Neisseria gonorrhoeae infection, isolation of this micro-organism from the joint signifies a septic basis for the disease and responsiveness to antibiotic therapy. By definition, such a condition is generally considered distinct from reactive arthritis. Many groups have sought to isolate Chlamydia trachomatis from the joint in SARA. In the absence of specific confirmation, chlamydia-like inclusions were reported in synovial fluid cells from patients with Reiter's syndrome (Amor et al, 1965; Levy et al, 1966). Isolation of C. trachomatis from the joint has also been reported using egg culture techniques (Schachter et al, 1966; Dunlop et al, 1968), although the validity of these findings has been questioned. More recently, using the highly sensitive cell culture techniques which are difficult to apply to synovial fluid, a handful of joint isolates from patients with Reiter's syndrome have been reported (Shatkin et al, 1973; Vilppula et al, 1981), with others failing to isolate despite conventional evidence of chlamydial infection (Keat et al, 1983). Antibody studies have strengthened the link between certain bacteria and reactive arthritis. In Yersinia infection the development of arthritis is associated with a prolonged immunoglobulin (Ig) A class-specific antibody response (Granfors et al, 1988). In SARA, serial studies have shown higher titres of IgG and IgM serum chlamydial antibody than in individuals with uncomplicated NGU (Kousa et al, 1978; Keat et al, 1983; Martin et al, 1984). Titres are higher in synovial fluid than in paired serum samples (Hughes et al, 1989), suggesting local antibody synthesis. Studies of antibody specificity have indicated a broad range of antigenic reactivity indistinguishable from that seen in patients with uncomplicated Yersinia (Granfors et al, 1988) or Chlamydia (Inman et al, 1987; Kihlstrom et al, 1989) infection. The formation and persistence of CICs containing bacterial antigen has also been documented in arthritis associated with yersiniosis (Lahesmaa-Rantala et al, 1987) and salmonellosis (Manicourt and Orloff, 1981). Studies of cellular immunity have implied that bacterial antigens are both presented and recognized within the joint. Measurement of in vitro proliferative responses of peripheral blood mononuclear cells to microbial antigens have yielded conflicting responses. However, several groups have reported that synovial fluid lymphocytes from patients with reactive arthritis produce enhanced proliferative responses to various micro-organisms compared with peripheral blood cells (Ford et al, 1985; Gaston et al, 1989; Sieper et al, 1991). Moreover, such enhanced responses appear to correspond with the micro-organisms suspected of causing the arthritis. These findings are consistent with those in Lyme arthritis (Sigal et al, 1986), in which the causal microorganism, Borrelia burgdorferi, is present in the joint. Such results have therefore been interpreted as indicating the presence of microbial antigens in the inflamed joint as a target for specific cellular responses. However, the precise interpretation of data from in vitro

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proliferation experiments is uncertain, as the results depend on many variables, including relative cell concentrations, antigen dose and reaction time (Keat and Knight, 1990). In addition, many of the activated lymphocytes in inflamed joints may be recruited non-specifically (Pelton et al, 1985). The conclusion that activated T lymphocytes in synovial fluid are responding to microbial antigens within the joint has been supported by recent antigen presentation experiments. Bone marrow-derived dendritic cells isolated from synovial fluid from inflamed joints of patients with chlamydial arthritis proved potent stimulators of autologous Chlamydiaresponsive but not PPD-responsive lymphoblastoid cell lines (Stagg et al, 1991). The introduction of monoclonal antibodies to Chlamydia trachomatis has provided a sensitive and specific means of detection of Chlamydia outer membrane protein (MOMP) and LPS antigens in cells and tissue. Using such reagents in a direct immunofluorescence test, intra-articular chlamydial elementary bodies---the infective particles of Chlamydia--were detected in the synovium and/or synovial fluid cell deposits of five of eight patients with SARA (Keat et al, 1987). Intra-articular chlamydial antigen was also detected in a single case with visualization by electron microscopy of an intracellular inclusion (Ishikawa et al, 1986). Using a rabbit polyclonal antibody to C. trachomatis in an electron microscopic immunoperoxidase study, chlamydial antigen was reported in association with synovial fluid cells and in synovium taken from two patients with Reiter's syndrome of less than 4 weeks' duration (Schumacher et al, 1988). Similar imrnunofluorescence findings subsequently have been reported by other workers (Inman et al, 1989), and chlamydial antigen has also been reported in synovium and synovial fluid cell deposits from patients with seronegative arthritis but without evidence of preceding or associated infection (Taylor-Robinson et al, 1988; Hughes et al, 1991a). In only one of the cases reported by Hughes et al (1991b) were both chlamydial LPS and MOMP antigens detected. The detection of Yersinia pseudotuberculosis antigen in synovium from an inflamed knee of a patient with reactive arthritis was reported using immunofluorescence microscopy with polyclonal and monoclonal antibodies (Toivanen et al, 1987). The same group reported the detection of Y. enterocolitica antigens in association with synovial fluid cells in patients with reactive arthritis (Granfors et al, 1989). In ten of 15 synovial fluid samples, yersinial outer membrane protein and LPS antigen were detected in association with polymorphs or monocytes. Western blotting was used to confirm these findings. Two further studies have subsequently demonstrated probable intracellular Yersinia antigens in monocytes in inflamed synovium from patients with Yersinia reactive arthritis (Hammer et al, 1990; Merilahti-Palo et al, 1991). Antigen was extremely sparse and scattered throughout the synovium. The detection of outer membrane protein and degraded LPS antigen of Salmonella enteritidis in synovial fluid cell deposits from patients with reactive arthritis secondary to Salmonella infection has also recently been reported (Granfors et al, 1990b; Hughes et al, 1991a). The precise nature of the intra-articular antigen and the form in which it is present in the joint is so far unclear. Although attempts to isolate bacteria

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from the joint have been unsuccessful, the broad specificity of the antibody response would be consistent with the persistence of whole bacteria. The potential site of persistence and the possibility of continued viability of bacteria are of immense practical significance. The prospect of a reservoir of infection in the genital tract has long been considered. Several studies have implied that the prostate might be a seat of persistent infection, especially in individuals with ankylosing spondylitis (Romanus, 1953; Mason et al, 1958). However, although symptoms of prostatitis do occur in a minority of patients and urethritis may certainly recur without reinfection in patients with reactive arthritis, the role of the prostate remains unclear. Criteria for the diagnosis of prostatitis are uncertain and no detailed biopsy studies have been undertaken to demonstrate inflammation or the presence of persisting infection. Comparable evidence that persistent low grade salpingitis might underlie sacroiliitis in some women has also been proffered (Julkunen and Pietila, 1964; Szanto and Hagenfeldt, 1979). Nevertheless, the prevalence of sacroiliitis in men with known prostatitis would appear to be low (Moiler et al, 1980), so that the true significance of persistent inflammation at these sites is uncertain. The possibility that the gut may also act as a reservoir of infection has recently been explored. Persistent or recurrent bowel colonization by Klebsiella spp. has been linked to the activity of ankylosing spondylitis (Ebringer et al, 1977), but the significance of these findings is disputed (Keat, 1986). The possibility of covert persistence of bacteria within the gut mucosa was raised by a study of gut mucosal biopsies obtained from patients with seronegative arthritis (De Koning et al, 1989); in a proportion of biopsies, using antibodies to Yersinia enterocolitica, immunofluorescence appearances indicative of Y. enterocolitica antigen within~the bowel wall were found. It is clearly important that the possibility of asymptomatic reservoirs of arthritogenic bacteria be further explored. The possibility that viable bacteria may persist in the joint or elsewhere has important therapeutic implications. Therefore, several groups have sought specific bacterial DNA in joint samples using the PCR. Initial searches for plasmid and genomic D N A of both Chlamydia trachomatis (Wordsworth et al, 1990; Poole et al, 1992) and Yersinia enterocolitica (Viitanen et al, 1991) have proved negative. However, further studies on this are in progress. The finding of bacterial antigens in the joint fluid without detectable DNA raises several possibilities. The antigen being visualized by immunofluorescence might no longer be present in the samples tested by PCR. Alternatively the antigen may already be processed and degraded, without any associated DNA. It is conceivable that failure to detect plasmid D N A is the result of selective plasmid loss, either as a feature of micro-organisms associated with the development of arthritis, or as a result of conditions prevailing within the joint. There is a precedent for selective plasmid loss in intact viable Chlamydia trachomatis (Peterson et al, 1990). Another possibility is that the PCR techniques used might not be sufficiently sensitive to detect the small quantities of DNA present; this is unlikely as one group have already shown that the PCR technique, in their hands, could detect as little as one elementary body in the test specimen (Wordsworth et al, 1990).

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In spite of the currently conflicting evidence, if viable bacteria do persist in the joint or elsewhere and contribute to the persistence of arthritis, it is pertinent to reconsider the issue of antibiotic treatment. Conventional approaches have recommended short courses of antibiotic treatment for acute genital tract infection only, on the basis of limited evidence that such treatment does not influence the arthritis (Popert et al, 1964). It is certainly the case that arthritis may develop after appropriate antibiotic therapy has been initiated. However, this issue is now being re-evaluated in several controlled studies. The treatment of patients with established S A R A with a tetracycline (lymecycline) for 3 months was associated with more rapid resolution of the arthritis than in untreated controls (Lauhio et al, 1991). No effect was discernible with regard to patients with arthritis associated with gastrointestinal infection. A retrospective study of patients with previous episodes of reactive arthritis exposed to further acute genital tract infections (Bardin et al, 1990) has also implied that the risk of recurrence of arthritis is reduced by early antibiotic treatment of the urethritis. Further work will have to be done before firm conclusions can be drawn, but such studies clearly have important implications for both the pathogenesis of seronegative arthritis and the management of patients. Many unanswered questions remain regarding the exact nature and importance of intra-articular bacterial antigens in reactive arthritis. It is not clear whether bacterial antigens are present only in inflamed joints, whether their presence precedes inflammation and migh t, therefore, be a trigger, or whether their arrival in already inflamed joints is a relatively common post hoc event unrelated to the cause of the synovitis. The nature of the relationship between such bacterial antigens and H L A B27 also remains an enigma. The probability that class I antigens may play a central role in the presentation of bacteria-derived peptides, especially of intracellular bacteria, has been raised (Kaufman, 1988), but none of the data discussed above help to support or refute such a mechanism. An alternative approach to this issue might involve the therapeutic use of specific antibodies given intra-articularly or systemically to bind specifically to H L A B27 or CD8 receptors or to bacterial components known to be present in the joint. Current experience of similar therapeutic intervention in rheumatic disease is already indicating that such approaches are less toxic than might be expected and it is time for bold advances in treatment, especially those that stand to advance our understanding of disease pathogenesis as well as make the patient better. SUMMARY

For more than 100 years it has been suspected that bacteria or products derived from them are deposited in joints and cause arthritis without suppuration. Over this time a vast amount of evidence, much of which is still unchallenged, has accumulated to demonstrate that whole bacteria and subcellular bacterial elements do pass, under certain circumstances, from sites of mucosal colonization or infection into the circulation and thence into

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joints. Similarly, experimental studies have demonstrated that the deposition of both inert material and bacterial components within synovium is sometimes, but not always, associated with the development and persistence of synovitis. In human reactive arthritis aseptic synovitis follows localized bacterial infection in the gut or genitourinary tract. A genetic predisposition, associated with the HLA B27 antigen, is recognized, and interaction between class I HLA determinants and bacteria-derived antigens may underlie the development of arthritis. Although much remains to be learned about the dissemination of antigens from the primary site of infection in reactive arthritis, strong evidence implicates the deposition of antigenic elements of Chlamydia, Yersinia, Salmonella and perhaps other microorganisms within the synovium. Immunological findings Support the notion that such antigens are being presented within the joint and participating in the induction and/or maintenance of synovitis. It is not yet clear whether such bacteria are complete or viable or whether persistence at an extraarticular site is important to the persistence of arthritis. The possibility that reactive arthritis, and perhaps other forms of seronegative arthritis also, is caused and perpetuated by bacterial antigens within the joint poses new questions about the role of HLA B27 in pathogenesis. It also raises important and exciting issues regarding treatment. Already, studies of antimicrobial therapy have yielded encouraging initial findings, and it is now possible to design and evaluate therapies aimed at blocking specific antigen recognition within the joint.

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Reactive arthritis: the role of bacterial antigens in inflammatory arthritis.

For more than 100 years it has been suspected that bacteria or products derived from them are deposited in joints and cause arthritis without suppurat...
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