This randomized 9-month prospective, blinded study demonstrated that a 6 month course of combination antibiotics resulted in a significantly higher response rate in subjects with chronic Chlamydia-induced ReA compared to placebo. Although cases of acute ReA often remit spontaneously, the fact that all of the subjects in this study had disease duration of at least 6 months (with mean >10 years) makes it extremely unlikely that their ReA would improve or resolve spontaneously. Many of the individual clinical response measurements (e.g., modified SJC, TJC, Physician Global VAS, ESR) also significantly improved in the subjects who received active therapy compared to placebo. Twenty-two percent of the subjects on combination antibiotics felt that their ReA symptoms completely resolved. Finally, only those subjects who were PCR positive for chlamydiae were randomized to therapy, and there were significantly more subjects who became PCR negative at month 6 in the active therapy group than in the placebo group.
Importantly, the results presented here constitute the first blinded study to indicate a benefit of prolonged combination antimicrobial therapy in patients with chronic Chlamydia
-induced ReA. The results of previous trials assessing antimicrobial therapy in the setting of ReA have been equivocal. One previous trial which suggested that antimicrobials are efficacious in the setting of ReA analyzed this treatment approach in acute ReA only and not in chronic patients.25
Notably, all previous trials evaluated antimicrobial monotherapy (rather than combination therapy) and only one28
attempted to restrict enrollment to patients with the post-chlamydial form of ReA. It seems likely to us that these two important changes in the study protocol resulted in improved efficacy. Our data suggest that it is advantageous to attempt attenuation of chlamydial production of HSP's with rifampin, which binds to the beta-subunit of prokaryotic RNA polymerase and thereby prevents initiation of transcription of HSP's29
in combination with antibiotics that block protein synthesis to ensure eradication of the persistent form of this organism. This is best accomplished when treated with a prolonged combination of antibiotics, as is the case with other persistent intracellular organisms (i.e., Mycobacterium tuberculosis
and Helicobacter pylori
Probably the most significant aspect of the present trial is that it suggests an avenue of effective therapy in a patient cohort with chronic arthritis not responsive to NSAIDs or DMARDs. Persistently infecting chlamydiae are recognized to be the driving force underlying Chlamydia
-induced ReA, and organisms in that infectious state have been demonstrated to be refractory to antibiotic treatment.21
The data presented here indicate that while these viable, persistently infectious organisms respond poorly to single antibiotic treatment, they do appear to be susceptible to combination antimicrobial therapy. Thus, a cure theoretically exists. Our study subjects had mean disease duration of more than 10 years; more than 20% of patients on active therapy felt that their disease process did completely resolve and 26% of these same subjects met a 70% or greater response criteria by post-hoc analysis. This observation is strengthened by the fact that significantly more subjects on active therapy than those on placebo became PCR-negative at month 6. Further, there was no indication of clinical worsening from months 6 to 9, demonstrating that the response was sustained after cessation of antibiotic therapy.
The most common adverse events in subjects on active therapy were gastrointestinal in nature. This is in keeping with the known side effects of the medications studied. Doxycycline is known to cause GERD and esophagitis42
and azithromycin can cause nausea, abdominal pain, and diarrhea; this has been demonstrated in trials assessing the long-term administration of azithromycin in other disease states.43
These adverse events were mild in nature and no subject on active therapy had to discontinue their study drugs because of gastrointestinal complaints.
Some questions remain to be addressed. This study did not determine which combination of antibiotics is the most effective, and it was not powered to compare the two different antibiotic regimens. In spite of this limitation, 5/6 subjects who felt their disease went into remission were on the combination of azithromycin and rifampin and 33% of the subjects randomized to this treatment strategy achieved remission; these data suggest that this combination might be superior to the other tested. As stated, in vitro
data has shown that this same combination of antibiotics is capable of eradicating chlamydiae in a cell culture model 8 days after infection.22
The most appropriate dosing for long-term administration remains unknown, particularly with azithromycin, and the proper duration of therapy can still be questioned. Of course, alternative antimicrobial combinations may well exist that could be more efficacious. The administration of long-term antibiotics also poses the risk of bacterial resistance. This could be true for the target organism itself or normal flora. The month 6 PCR data are reassuring that this is not the case for the former, but we have no long-term data in these patients regarding the latter. 12/17 subjects randomized based on a positive PBMC PCR cleared their PBMC PCR at month 6; 2 of these 12 again had a positive PBMC PCR at month 9 (both for C trachomatis
). Although the numbers are small, this suggests possible reinfection from a sexual partner who is an asymptomatic carrier for that organism. More data are needed in this regard. Also, the vast majority of patients with ReA have peripheral arthritis and many have axial involvement. This was true of the patients in our trial, but 3 (7%) subjects had no peripheral arthritis (only axial arthritis) at screening. The relapsing course of the arthritis in some patients with chronic ReA is a possible explanation, but an alternate diagnosis, such as ankylosing spondylitis, cannot be excluded in these 3 subjects. Finally, the utility of diagnostic testing with PCR in similar patients in a clinical setting is still unproven. However, recent data suggest that synovial sample PCR analysis is the method of choice to establish the diagnosis of Chlamydia
-induced arthritis in patients with ReA and undifferentiated oligoarthritis.44
This same study demonstrated that there is no correlation with chlamydial specific serological response. This was also true in our study. Other data agree that chlamydial serological testing is subjective45
; it has also been demonstrated that chlamydial serologies have poor reproducibility46
, may not be chlamydial species specific47
, and perhaps not even chlamydial specific48
. Because of the trial design, we have no data to address whether combination antibiotic treatment would be effective in undifferentiated SpA patients who are negative for chlamydiae on PCR testing. Potential for false positive PCR tests exists, particularly in those patients who are PCR-positive on PBMC for C pneumoniae
. In this trial, 7 subjects were randomized based on a positive PBMC PCR for this respiratory pathogen (5 to active therapy, 2 to placebo). Of the 5 subjects on active therapy, only 1 was a responder. Perhaps the results could be improved upon by restricting treatment to those subjects who are PCR positive for C trachomatis
The results of this study are encouraging for the management of chronic post-Chlamydia ReA. These data suggest that the potential for eradication of this persistent infection exist, and improvement in the clinical sequelae that are the result of these infections can be achieved in a substantial number of patients. Clearly, more studies are needed. A diagnostic test that is specific for Chlamydia-induced ReA would be important in designing such studies. The most efficacious combination of antimicrobial therapy, including dosing and duration, as a potential cure for Chlamydia-induced ReA warrants further study.