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Increased understanding of the biology and survival tactics of Chlamydia trachomatis is suggesting that the post-infectious chronic arthritis experienced by many patients may actually be curable.

The possibility of a cure for an arthritic condition with antimicrobial treatment has long been a dream in the rheumatology community. "We've always had this notion that some of our diseases may be infectious in origin," said , professor of medicine and immunology at the University of Toronto.

Each year in the U.S., 3 million new cases of genital infections by Chlamydia trachomatis are reported to the CDC, and more than 100 million new infections are estimated to occur annually worldwide.

Some 4% to 8% of infected individuals go on to develop the arthritis, usually 1 to 6 weeks after the acute infection. In about 70% of cases, the symptoms clear spontaneously over a period of weeks. But in the remainder, the reactive arthritis can persist for years or even decades, usually in a relapsing-remitting form, and has proven consistently resistant to treatment.

The Acute Infection

Genital infection with C. trachomatis can be associated with urethritis or cervicitis or can even be asymptomatic, and pulmonary infection with a related pathogen, C. pneumoniae, is a common cause of upper respiratory tract illness. Both microbes have been implicated in the chronic spondylarthropathy following infection acquired across a mucosal surface.

Affected individuals develop articular swelling and stiffness, usually of a knee or ankle joint, although any joint can be affected, according to , chief of rheumatology at the University of South Florida in Tampa.

The joint manifestations are often accompanied by enthesitis and sometimes by axial and ocular involvement as well as psoriatic lesions on the palms and soles.

At present, the post-infection arthritis is a clinical diagnosis, according to Carter. "The strongest evidence that someone probably has Chlamydia-induced arthritis is synovial biopsy and PCR or electron microscopy to look for the organism, because you can't culture it. But this isn't a practical test in the clinic," he told 乌鸦传媒.

An Unusual Pathogen

Chlamydia is an obligate intracellular organism. "It sets up shop in mammalian cells and harnesses the host's metabolic machinery to survive," Inman said in an interview.

Pathogens of the Chlamydiaceae family are characterized by an unusual life cycle consisting of two phases. In one form, where they are known as elementary bodies, they are infectious, metabolically inert, and exist extracellularly, traveling via monocytes and macrophages to the synovial tissue.

Upon arrival at this favored site, they attach to host cells and move into the cytoplasm where they form membrane-bound inclusion bodies that then develop into noninfectious, metabolically active reticulate bodies.

However, once in the joints, chlamydiae can persist in an aberrant form, still viable and metabolically active, but with altered and downregulated gene expression, Carter explained. They can remain in that intracellular persistent state for weeks or even months, transcribing DNA and producing proteins, and also causing an inflammatory arthritis.

"It's not fully understood why the host immune system doesn't just clear the organism," said , professor emeritus in the department of microbiology and immunology at Wayne State University in Detroit.

A possible mechanism by which Chlamydia evade the effects of the immune system is through inhibition of apoptosis of the host cell, thereby permitting its own survival.

C. trachomatis isn't responsible only for genital infections. In the less developed world, trachoma still is the leading preventable cause of blindness, and multiple strains, or serovars, associated with genital and ocular infections have been identified, with the A, B, Ba, and C serovars being ocular and the D through K serovars being genital, according to Hudson.

The strains differ in antigenic structure at the major outer membrane protein, which is encoded by omp1, and around the Ct166 cytotoxin gene.

A question that had long puzzled researchers was whether there was a particularly arithrogenic genital strain that was responsible for post-chlamydial arthritis.

To explore this, Hudson, Carter, and others analyzed multiple samples from synovial biopsies from 36 patients, and in results Hudson described as "astounding," they found that

"We know that ocular strains can cause genital infections and vice versa, they're just not very effective at it," Hudson told 乌鸦传媒.

But the paradoxical finding implicating ocular strains in arthritis explains some of the epidemiologic data, he said.

Fewer than 10% of individuals who have documented chlamydial infections develop the arthritis. "So the question is, why doesn't everybody get the arthritis?" Hudson said.

"There's something particularly nasty about the ocular strains," he said. He believes that the acute infection most often actually is with the genital strains, but in a minority of cases, there are some of the ocular strains mixed in with the inoculum -- these are not clonal infections -- and it's those strains that disseminate to the joints and cause the inflammation.

The observation that it's the ocular strains that are arithrogenic also helps explain the common finding of conjunctivitis and iritis in patients with the reactive arthritis, he noted.

Approaches to Treatment

There are two schools of thought on treatment of Chlamydia-induced arthritis, according to Carter.

"One says that the pathogen triggers an autoimmune response that you should treat like any chronic autoimmune condition, while the other says that because the trigger is bacterial, and if you can demonstrate evidence of the viable -- if aberrant -- bacteria in the synovium, antibiotics could be used," Carter explained.

Most experience in treating this reactive arthritis as an autoimmune disease has involved sulfasalazine, which appeared in studies done in the 1990s to provide only .

More recently, there have been small studies of treatment with tumor necrosis factor (TNF) inhibitors. who had previously received multiple nonsteroidal anti-inflammatory drugs and anti-rheumatic therapies, nine responded with improvements in joints and extra-articular symptoms.

However, in another report, a patient with Chlamydia-induced arthritis who was given etanercept (Enbrel) appeared to respond clinically, but on a post-treatment synovial biopsy the microbialload had increased ten-fold, Carter said.

"In vitro data suggest that Chlamydia can actually become more active with lower levels of TNF," he noted.

The role for biologics in treatment of this type of arthritis, therefore, remains controversial.

Most experience to date has focused on the antimicrobial approach. Early studies using antibiotic monotherapy with agents used for the acute infection such as azithromycin or doxycycline were largely unsuccessful.

One possible reason why the earlier studies were negative was that they included patients with Chlamydia-induced reactive arthritis as well as patients whose reactive arthritis followed infection with a gastrointestinal pathogen such as Salmonella, and there's no evidence that antimicrobial therapy will help in those non-Chlamydia cases, Carter said.

In addition, just getting the antibiotic to the pathogen in the intracellular, persistent state is challenging. First the drug must cross the host cell membrane, then across the occlusion membrane within the cytoplasm, and then across the bacterial membrane. "All three of these membranes are completely different, and it's really difficult to get the drug in there at effective concentrations," Hudson said.

Moreover, in vitro tests of traditional antibiotics such as doxycycline used for Chlamydia showed that the drug doesn't necessarily kill the pathogen -- it can actually drive it into the persistent state, according to Hudson. "So the whole notion of treating a reactive arthritis with doxycycline is exactly what you don't want to do," he said.

The Randomized Trial

Some early studies suggested the possibility that lengthy antibiotic treatment might help, and because combination therapy has shown efficacy for other persistent infections such as tuberculosis, Carter and colleagues undertook

They enrolled 42 patients who had serologic evidence of Chlamydia infection and longstanding arthritis, which averaged 10 years.

The treatment included rifampin because of its powerful tissue penetration, "which is mandatory when treating obligate intracellular pathogens such as Chlamydia," and its ability to interfere with the organism's gene transcription. To this was added doxycycline or azithromycin to block the pathogen's synthesis of protein.

The primary endpoint of 20% clinical improvement after 6 months of treatment was achieved by 63% of patients receiving combination treatment compared with 20% of those given placebo (P=0.01).

In addition, PCR analysis showed that 70% of the patients receiving the antibiotics had cleared the pathogen at 6 months, compared with 27% of those randomized to placebo (P=0.03).

"The results of this study are encouraging for the management of chronic post-Chlamydia [reactive arthritis]. These data suggest that there is potential for eradication of this persistent infection and that improvement in the clinical sequelae that are the results of these infections can be achieved in a substantial number of patients," the researchers wrote in Arthritis & Rheumatism.

But they noted that the optimal regimen, dosing, and duration of treatment were still to be determined.

"This study created a lot of interest in the rheumatology community," said Inman, who was a co-investigator.

"We still get queries about that trial. At least there's a precedent in the literature for antibiotic treatment from a randomized study," he added.

A larger, confirmatory study has been submitted to the National Institutes of Health for funding.

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