Journal of Infection (1992) 25, Supplement z, 47-49
REVIEW Extra-genital Chlamydia trachomatis infection as sexuallya c q u i r e d reactive arthritis Andrew Keat Rheumatology Department, Westminster Hospital, I7 Page Street, London S W I P 2AP, U.K.
Chlamydial infection is closely associated with several forms of inflammatory arthritis in both animals and man. In m a n arthritis is a well-recognised complication 1 of acute genital-tract infection, lymphogranuloma venereum and psittacosis so that a direct role of chlamydial micro-organisms in the aetiology of inflammatory arthritis has long been considered. Approximately 1% of m e n presenting to genito-urinary medicine clinics with non-gonococcal urethritis ( N G U ) develop acute aseptic arthritis. This has been referred to as sexually-acquired reactive arthritis (SARA), ~ approximately one third of patients having Reiter's syndrome. Initial isolation studies indicated a prevalence of acute Chlamydia trachomatis genital-tract infection ranging from o-69 % at the onset of acute SARA, 3 findings comparable with isolation rates in uncomplicated urethritis. Prospective follow-up of patients with chlamydiapositive and chlamydia-negative urethritis failed to reveal a difference in the incidence of acute arthritis between the two groups. However, serological studies have indicated that titres of I g G chlamydial antibody in both serum 3 and synovial fluid 4 of patients with SARA are raised compared with patients with uncomplicated genital-tract infection and rheumatic disease controls. IgA class chlamydial antibody has been reported in serum by some workers 5 but not others. 4 Specificity of antibody both in serum and synovial fluid has been investigated by I n m a n et al. 6 and Kihlstrom et al. 7 using separation of chlamydial protein antigens on polyacrylamide gel and immunoblotting techniques. Antibody, both in serum and synovial fluid, has been shown to be of broad specificity; no antigens have been detected by this technique which are specific to synovial fluid or to patients with arthritis. Antibodies to Chlamydia pneumoniae have been detected in both serum and synovial fluid of some patients with SARA t h o u g h in the absence of controlled data the significance of these findings is unclear. 4 Studies of cellular i m m u n i t y to C. trachomatis in patients with SARA have shown enhanced lymphocyte proliferative responses especially in cells obtained from the joint. 8 T h e finding of enhanced synovial fluid cellular responses to C. trachomatis compared with peripheral blood lymphocyte responses has been interpreted by Ford et al. 8 as indicating that the stimulatory antigen is present within the joint and may therefore be intimately involved in the pathogenesis of the arthritis. Although an attractive concept which has merited further investigation, these findings are susceptible to alternative explanations so that their true significance is unclear. Attempts to isolate chlamydia from joint samples have produced results which are also difficult to interpret. Early studies using culture in embryonated oi63-4453/92/Sloo47 +03 $03.00/0
© 1992 The British Society for the Study of Infection
48
A. KEAT
hens' eggs resulted in several chlamydial isolates from joint material obtained from patients with Reiter's syndrome. However, the introduction of more sensitive cell culture techniques has been associated with a reduction in the n u m b e r of reported joint isolates to very low levels. More recent attempts to identify chlamydial antigen in joint material by immunochemical means have been more successful. Electron microscopic appearances suggestive of a C. t r a c h o m a t i s inclusion seen in a synovial biopsy from a m a n with longstanding Reiter's syndrome were reported by Ishikawa et al. 9 in I986. Subsequently Keat et al., 1° using a fluorescein-linked monoclonal antibody to chlamydial major outer m e m b r a n e protein ( M O M P ) reported the detection of fluorescing bodies with the physical characteristics of chlamydial elementary bodies in synovial fluid cell deposits or synovial m e m b r a n e biopsies obtained from five of eight patients with typical acute SARA. Chlamydial elementary bodies were also detected by Schumacher e t a l . 11 in synovial material from two patients with Reiter's syndrome using immuno-electron microscopy and a polyclonal rabbit anti-serum. F u r t h e r studies have confirmed the detection of chlamydial elementary bodies in joint material from patients with SARA t h o u g h it is clear that such antigenic material is sparsely distributed and detectable in only a small proportion of patients. No typical inclusion bodies have been demonstrated. In the light of findings in patients with reactive arthritis, patients with other forms of seronegative arthritis have also been investigated. Hughes et al. 1~ studied joint material (synovial biopsies and synovial fluid cell deposits) obtained from individuals with undifferentiated seronegative arthritis who had knee effusions but who were examined and found to have no evidence of genital-tract infection. Using immunofluorescence microscopy with monoclonal antibodies to C. t r a c h o m a t i s M O M P (MicroTrak; Syva) and lipopolysaccharide (LPS) (Ideia; Novo Nordisk) typical appearances of chlamydial elementary bodies were seen in four of I9 m e n and one of 2i women, most of w h o m had had symptoms of arthritis for more than 6 months. Confirmation of the chlamydial nature of the observed fluorescent antigen and a guide to its potential viability has been sought through D N A identification. A t t e m p t e d amplification of segments of chlamydial plasmid D N A using the polymerase chain reaction have been reported by Wordsworth et al. ~5 with negative results. T h e s e findings are comparable with experience in other forms of reactive arthritis in which yersinia antigen can be demonstrated in joint material t h o u g h yersinia D N A has not been detected. Preliminary evidence of presentation of chlamydial antigens by synovial fluid cells has been p u t forward by Stagget al. 14 Cultured lymphoblastoid cell lines have been obtained from peripheral blood and synovial fluid of three patients with reactive arthritis and evidence of recent chlamydial infection. After stimulation by antigen and expansion by IL-2 both peripheral blood and synovial fluid-derived lines responsive to P P D and to C. t r a c h o m a t i s serovar L I were obtained. These cells were then stimulated by synovial fluid dendritic cell-enriched populations. T h e chlamydial cell lines but not the P P D cell lines showed vigorous proliferation responses. No evidence is yet available as to the potential identity of such stimulating antigens. T h e possibility that arthritis may be perpetuated by the persistence of viable micro-organisms has recently been tested by antibiotic treatment studies.
C. trachomatis in reactive arthritis
49
Following 3 - m o n t h courses of lymecycline or placebo, Lauhio et al. 15 have demonstrated diminished duration of active arthritis in the active treatment group. In a follow-up study of probands who had had one episode of SARA, Bardin et al. 1~ have proffered evidence that treatment of acute urethritis with tetracycline may have value in preventing the development of reactive arthritis compared with treatment with penicillin or no treatment. F u r t h e r evaluation of treatment strategies is clearly necessary. Evidence is slowly accumulating, therefore, that C. trachomatis does enter the joint in some patients with seronegative arthritis, even when evidence of genital-tract infection is not present. What role such antigen plays in the triggering or perpetuation of the synovitis remains to be elucidated but there are strong grounds for believing that further investigation will be productive and useful. References
I. Keat A, Thomas BJ, Taylor-Robinson D. Chlamydial infection in the aetiology of arthritis. Br Med Bull I983; 39: I68-I74. 2. Keat AC, Maini RN, Pegrum GD, Scott JT. The clinical features and HLA-associations of reactive arthritis associated with non-gonococcal urethritis. Q J Med I979; 48: 323-342. 3. Keat A. Reiter's syndrome and reactive arthritis in perspective. N EnglJ Med I983 ; 3o9: I6O6-I615. 4. Hughes RA, Treharne JD, Keat AC. Comparison of serum and synovial fluid chlamydial antibody titres. Arthritis Rheum I989; 32 (Suppl): I33. 5. Zeidler H, Wollenhaupt J, Schneider C, Krech T. Specific IgA-antibodies in chlamydialinduced arthritis. Proceedings of the European Society for Chlamydia Research. Bologna. May/June I988. S.E. Esculapio I67. 6. Inman RD, Johnstone MEA, Chiu B, Falk J, Petric M. Immunochemical analysis of immune response to Chlamydia trachomatis in Reiter's syndrome and non-specific urethritis. Clin Exp Immunol I987; 69: 246-254. 7. Kihlstrom E, Gronberg A, Bengtsson A. Immunoblot analysis of antibody response to Chlamydia trachomatis in patients with reactive arthritis and ankylosing spondylitis. Scand J Rheumatol I989; I8: 377-388. 8. FordDK, daRozaDM, ShahP. Cell-mediatedimmuneresponsesofsynovialmononuclear cells to sexually transmitted, enteric and mumps antigens in patients with Reiter's syndrome, rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 1981 ; 8: 220-232. 9- Ishikawa H, Ohno O, Yamasaki K, Ikuta S, Hirohata K. Arthritis presumably caused by chlamydia in Reiter's syndrome. J Bone Joint Surg I986; 68a: 777-779. IO. Keat A, Thomas B, Dixey J, Osborn M, Sonnex C, Taylor-Robinson D. Chlamydia trachomatis and reactive arthritis--the missing link. Lancet I987; 294, 7z-74. I I. Schumacher HR, Magge S, Cherian PV et al. Light and electron microscopic studies on the synovial membrane in Reiter's syndrome. Arthritis Rheum I988 ; 31: 937-946. I2. Hughes RA, Hyder E, Treharne JD, Keat ACS. Intra-articular chlamydial antigen and inflammatory arthritis. Q J Med I99I; 80: 575-588. I3. Wordsworth BP, Hughes RA, Allan I e t al. Failure to identify chlamydial DNA from the synovium in patients with reactive arthritis using the polymerase chain reaction. Br J Rheum I99O; 29: 2o8-2IO. I4. Stagg AJ, Harding B, Hughes R, Keat A, Ward ME, Knight SC. Cell mediated immune responses to chlamydial antigens in sexually acquired reactive arthritis. In: Bowie WR, Cauldwell HD, Jones RP et al., Eds. Chlamydial infections. Cambridge: Cambridge University Press, r99o: I89-I92. 15. Lauhio A, Leirisalo-Repo M, Lahdevirta J, Saikku P, Repo H. Double-blind, placebocontrolled study of three-month treatment with Lymecycline in reactive arthritis, with special reference to chlamydia arthritis. Arthritis Rheum I991; 34: 6-I4. I6. Bardin T, Enel C, Lathrop MG. Treatment by tetracycline or erythromycin ofurethritides allows significant prevention of post-venereal arthritic flares in Reiter's syndrome patients. Br J Rheum 199o; 29: (Suppl :~) 9z.
REVIEW Extra-genital Chlamydia trachomatis infection as sexuallya c q u i r e d reactive arthritis Andrew Keat Rheumatology Department, Westminster Hospital, I7 Page Street, London S W I P 2AP, U.K.
Chlamydial infection is closely associated with several forms of inflammatory arthritis in both animals and man. In m a n arthritis is a well-recognised complication 1 of acute genital-tract infection, lymphogranuloma venereum and psittacosis so that a direct role of chlamydial micro-organisms in the aetiology of inflammatory arthritis has long been considered. Approximately 1% of m e n presenting to genito-urinary medicine clinics with non-gonococcal urethritis ( N G U ) develop acute aseptic arthritis. This has been referred to as sexually-acquired reactive arthritis (SARA), ~ approximately one third of patients having Reiter's syndrome. Initial isolation studies indicated a prevalence of acute Chlamydia trachomatis genital-tract infection ranging from o-69 % at the onset of acute SARA, 3 findings comparable with isolation rates in uncomplicated urethritis. Prospective follow-up of patients with chlamydiapositive and chlamydia-negative urethritis failed to reveal a difference in the incidence of acute arthritis between the two groups. However, serological studies have indicated that titres of I g G chlamydial antibody in both serum 3 and synovial fluid 4 of patients with SARA are raised compared with patients with uncomplicated genital-tract infection and rheumatic disease controls. IgA class chlamydial antibody has been reported in serum by some workers 5 but not others. 4 Specificity of antibody both in serum and synovial fluid has been investigated by I n m a n et al. 6 and Kihlstrom et al. 7 using separation of chlamydial protein antigens on polyacrylamide gel and immunoblotting techniques. Antibody, both in serum and synovial fluid, has been shown to be of broad specificity; no antigens have been detected by this technique which are specific to synovial fluid or to patients with arthritis. Antibodies to Chlamydia pneumoniae have been detected in both serum and synovial fluid of some patients with SARA t h o u g h in the absence of controlled data the significance of these findings is unclear. 4 Studies of cellular i m m u n i t y to C. trachomatis in patients with SARA have shown enhanced lymphocyte proliferative responses especially in cells obtained from the joint. 8 T h e finding of enhanced synovial fluid cellular responses to C. trachomatis compared with peripheral blood lymphocyte responses has been interpreted by Ford et al. 8 as indicating that the stimulatory antigen is present within the joint and may therefore be intimately involved in the pathogenesis of the arthritis. Although an attractive concept which has merited further investigation, these findings are susceptible to alternative explanations so that their true significance is unclear. Attempts to isolate chlamydia from joint samples have produced results which are also difficult to interpret. Early studies using culture in embryonated oi63-4453/92/Sloo47 +03 $03.00/0
© 1992 The British Society for the Study of Infection
48
A. KEAT
hens' eggs resulted in several chlamydial isolates from joint material obtained from patients with Reiter's syndrome. However, the introduction of more sensitive cell culture techniques has been associated with a reduction in the n u m b e r of reported joint isolates to very low levels. More recent attempts to identify chlamydial antigen in joint material by immunochemical means have been more successful. Electron microscopic appearances suggestive of a C. t r a c h o m a t i s inclusion seen in a synovial biopsy from a m a n with longstanding Reiter's syndrome were reported by Ishikawa et al. 9 in I986. Subsequently Keat et al., 1° using a fluorescein-linked monoclonal antibody to chlamydial major outer m e m b r a n e protein ( M O M P ) reported the detection of fluorescing bodies with the physical characteristics of chlamydial elementary bodies in synovial fluid cell deposits or synovial m e m b r a n e biopsies obtained from five of eight patients with typical acute SARA. Chlamydial elementary bodies were also detected by Schumacher e t a l . 11 in synovial material from two patients with Reiter's syndrome using immuno-electron microscopy and a polyclonal rabbit anti-serum. F u r t h e r studies have confirmed the detection of chlamydial elementary bodies in joint material from patients with SARA t h o u g h it is clear that such antigenic material is sparsely distributed and detectable in only a small proportion of patients. No typical inclusion bodies have been demonstrated. In the light of findings in patients with reactive arthritis, patients with other forms of seronegative arthritis have also been investigated. Hughes et al. 1~ studied joint material (synovial biopsies and synovial fluid cell deposits) obtained from individuals with undifferentiated seronegative arthritis who had knee effusions but who were examined and found to have no evidence of genital-tract infection. Using immunofluorescence microscopy with monoclonal antibodies to C. t r a c h o m a t i s M O M P (MicroTrak; Syva) and lipopolysaccharide (LPS) (Ideia; Novo Nordisk) typical appearances of chlamydial elementary bodies were seen in four of I9 m e n and one of 2i women, most of w h o m had had symptoms of arthritis for more than 6 months. Confirmation of the chlamydial nature of the observed fluorescent antigen and a guide to its potential viability has been sought through D N A identification. A t t e m p t e d amplification of segments of chlamydial plasmid D N A using the polymerase chain reaction have been reported by Wordsworth et al. ~5 with negative results. T h e s e findings are comparable with experience in other forms of reactive arthritis in which yersinia antigen can be demonstrated in joint material t h o u g h yersinia D N A has not been detected. Preliminary evidence of presentation of chlamydial antigens by synovial fluid cells has been p u t forward by Stagget al. 14 Cultured lymphoblastoid cell lines have been obtained from peripheral blood and synovial fluid of three patients with reactive arthritis and evidence of recent chlamydial infection. After stimulation by antigen and expansion by IL-2 both peripheral blood and synovial fluid-derived lines responsive to P P D and to C. t r a c h o m a t i s serovar L I were obtained. These cells were then stimulated by synovial fluid dendritic cell-enriched populations. T h e chlamydial cell lines but not the P P D cell lines showed vigorous proliferation responses. No evidence is yet available as to the potential identity of such stimulating antigens. T h e possibility that arthritis may be perpetuated by the persistence of viable micro-organisms has recently been tested by antibiotic treatment studies.
C. trachomatis in reactive arthritis
49
Following 3 - m o n t h courses of lymecycline or placebo, Lauhio et al. 15 have demonstrated diminished duration of active arthritis in the active treatment group. In a follow-up study of probands who had had one episode of SARA, Bardin et al. 1~ have proffered evidence that treatment of acute urethritis with tetracycline may have value in preventing the development of reactive arthritis compared with treatment with penicillin or no treatment. F u r t h e r evaluation of treatment strategies is clearly necessary. Evidence is slowly accumulating, therefore, that C. trachomatis does enter the joint in some patients with seronegative arthritis, even when evidence of genital-tract infection is not present. What role such antigen plays in the triggering or perpetuation of the synovitis remains to be elucidated but there are strong grounds for believing that further investigation will be productive and useful. References
I. Keat A, Thomas BJ, Taylor-Robinson D. Chlamydial infection in the aetiology of arthritis. Br Med Bull I983; 39: I68-I74. 2. Keat AC, Maini RN, Pegrum GD, Scott JT. The clinical features and HLA-associations of reactive arthritis associated with non-gonococcal urethritis. Q J Med I979; 48: 323-342. 3. Keat A. Reiter's syndrome and reactive arthritis in perspective. N EnglJ Med I983 ; 3o9: I6O6-I615. 4. Hughes RA, Treharne JD, Keat AC. Comparison of serum and synovial fluid chlamydial antibody titres. Arthritis Rheum I989; 32 (Suppl): I33. 5. Zeidler H, Wollenhaupt J, Schneider C, Krech T. Specific IgA-antibodies in chlamydialinduced arthritis. Proceedings of the European Society for Chlamydia Research. Bologna. May/June I988. S.E. Esculapio I67. 6. Inman RD, Johnstone MEA, Chiu B, Falk J, Petric M. Immunochemical analysis of immune response to Chlamydia trachomatis in Reiter's syndrome and non-specific urethritis. Clin Exp Immunol I987; 69: 246-254. 7. Kihlstrom E, Gronberg A, Bengtsson A. Immunoblot analysis of antibody response to Chlamydia trachomatis in patients with reactive arthritis and ankylosing spondylitis. Scand J Rheumatol I989; I8: 377-388. 8. FordDK, daRozaDM, ShahP. Cell-mediatedimmuneresponsesofsynovialmononuclear cells to sexually transmitted, enteric and mumps antigens in patients with Reiter's syndrome, rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 1981 ; 8: 220-232. 9- Ishikawa H, Ohno O, Yamasaki K, Ikuta S, Hirohata K. Arthritis presumably caused by chlamydia in Reiter's syndrome. J Bone Joint Surg I986; 68a: 777-779. IO. Keat A, Thomas B, Dixey J, Osborn M, Sonnex C, Taylor-Robinson D. Chlamydia trachomatis and reactive arthritis--the missing link. Lancet I987; 294, 7z-74. I I. Schumacher HR, Magge S, Cherian PV et al. Light and electron microscopic studies on the synovial membrane in Reiter's syndrome. Arthritis Rheum I988 ; 31: 937-946. I2. Hughes RA, Hyder E, Treharne JD, Keat ACS. Intra-articular chlamydial antigen and inflammatory arthritis. Q J Med I99I; 80: 575-588. I3. Wordsworth BP, Hughes RA, Allan I e t al. Failure to identify chlamydial DNA from the synovium in patients with reactive arthritis using the polymerase chain reaction. Br J Rheum I99O; 29: 2o8-2IO. I4. Stagg AJ, Harding B, Hughes R, Keat A, Ward ME, Knight SC. Cell mediated immune responses to chlamydial antigens in sexually acquired reactive arthritis. In: Bowie WR, Cauldwell HD, Jones RP et al., Eds. Chlamydial infections. Cambridge: Cambridge University Press, r99o: I89-I92. 15. Lauhio A, Leirisalo-Repo M, Lahdevirta J, Saikku P, Repo H. Double-blind, placebocontrolled study of three-month treatment with Lymecycline in reactive arthritis, with special reference to chlamydia arthritis. Arthritis Rheum I991; 34: 6-I4. I6. Bardin T, Enel C, Lathrop MG. Treatment by tetracycline or erythromycin ofurethritides allows significant prevention of post-venereal arthritic flares in Reiter's syndrome patients. Br J Rheum 199o; 29: (Suppl :~) 9z.
