History of ReA

Paralleling the controversy regarding the exact role that the bacterial triggers play in disease maintenance of ReA, there has also been confusion over the proper terminology of the disease itself. The literature is replete with multiple terms and eponyms used to describe this condition. Two of the more popular eponyms used in the literature include Reiter syndrome and Feissinger Leroy syndrome. The former was first penned in 1942 when two Harvard researchers (Bauer and Engelmann) recognised the group of symptoms that encompass ReA as one clinical syndrome. Upon their review of the literature, they realised that Hans Reiter had described this same syndrome in 1916 when he published a case of a German soldier who developed the clinical triad of arthritis, non-gonococcal urethritis and conjunctivitis after an episode of bloody diarrhoea . Interestingly, two French physicians (Feissinger and Leroy) described the same syndrome in the same year . Therefore, both eponyms have been used until recently. Waelsch’s syndrome and Ruhr’s syndrome are other more obscure eponyms which have also used to describe ReA.

Apparently, ReA had been rather well described in the literature hundreds of years prior to Reiter’s or Feissinger and Leroy’s publications. Pierre van Forest described a case of “secondary arthritis and urethritis” in 1507 , Thomas Sydenham associated arthritis with diarrhoea in 1686 , Stoll documented arthritis following dysentery in 1776 and Yvan described a French captain who developed ‘ophthalmia’ and inflammatory arthritis primarily of the lower extremities 15 days after a venereal infection . In 1897, Launois made the distinction between septic and aseptic arthritis and that patients with the latter occasionally develop cutaneous lesions on the plantar surface of the feet (possibly keratoderma blenorrhagicum) . During this same time period in 1824, Cooper proposed the concept of the relationship between venereal infection and arthritis, particularly of the lower extremities .

Perhaps the most compelling description of ReA was by Sir Benjamin Brodie in 1818 when he described five patients with classic ReA in his treatise Pathological and Surgical Observations on the Diseases of the Joints Not only did Brodie accurately describe the various clinical symptoms associated with ReA, he recognised that these various symptoms represented one syndrome. Even further, some of his patients developed chronic ReA and he astutely described the relapsing course of this condition and surmised that the recurrent symptoms were all directly related to their initial infection. Brodie’s treatment of choice was vinum colchici (wine of the Colchicum seed).

Various descriptive terms exist in the literature to describe ReA. These include conjunctivo–urethro–synovial syndrome and blennorhoeal idiopathic arthritis. There have also been attempts to create new terminology for the different variants of ReA. One such term used in the literature is sexually acquired reactive arthritis or sexually associated reactive arthritis (SARA). Other names for the individual variants include arthritis urethritica and polyarthritis enterica.

As discussed later in this article, controversy exists regarding the pathophysiology and treatment of ReA. The brief review above highlights the confusion associated even with the terminology of the condition itself. In recent years, the accepted terminology for this syndrome has been ReA. There are several reasons for this strong push to clarify the terminology, most notably outlined earlier. Other reasons include the fact that some previously felt that the ‘classic clinical triad’ described by Reiter and others was a subset of ReA. It is now clear that this is not a distinct subset . Others have relied too heavily on this clinical triad before making the diagnosis of ReA, thereby leading to underdiagnosis, as only a minority of patients with ReA present with the ‘classic triad’. Finally, ReA is a more descriptive term. It is a necessity that the literature uses consistent terminology – ReA – to better define the condition.

Epidemiology

In keeping with previous controversy regarding proper terminology, the true incidence and prevalence of ReA is enigmatic. The Office of Rare Diseases of the National Institutes of Health lists ReA as a ‘rare disease’. This means that ReA affects less than 200,000 people in the United States. Orphanet, who are a consortium of European partners for rare diseases and orphan drugs, also lists ReA as a ‘rare disease’, meaning that it affects less than 1 person in 2000. Two previous surveys have attempted to define the incidence of ReA. A US survey suggested the age-adjusted incidence rate for males under the age of 50 years was 3.5 cases per 100,000 men . Similarly, a survey in Norway estimated a minimum incidence rate of approximately five cases per 100,000 . However, the true incidence of ReA continues to be debated because of the protean nature of its symptoms, as well as a lack of consensus in defining the syndrome. Further, the true number of post-chlamydial ReA cases is equally difficult to document because the triggering infection can be asymptomatic or never definitively diagnosed.

Prospective data assessing the attack rate of ReA in patients after an acute C. trachomatis infection suggest a much higher incidence. A US study in 1996 that followed patients after a venereal infection demonstrated that 4.1% of the patients developed ReA after a C. trachomatis infection, specifically . Importantly, the majority of these patients with post-chlamydial ReA developed their condition after an asymptomatic infection. Further, this study was performed on an urban population with a rather high African-American study population. African-Americans are known to have a lower prevalence of the human leucocyte antigen (HLA)-B27. Therefore, this could represent an underestimate of the true attack rate. We have recently completed a similar study of 368 subjects and found a ReA attack rate of 8.1% in patients after a C. trachomatis infection (unpublished data).

The Centers for Disease Control in the US estimates the annual incidence of C. trachomatis infections to be 3 million in persons of the ages 15–44 years . By using the attack rate of 4.1% in 3 million people, 123,000 new cases of post-chlamydial ReA should be estimated in the US every year. This estimate is likely low for reasons cited earlier; further, it does not include cases of ReA secondary to Cpn. For comparison, the estimated annual incidence of rheumatoid arthritis (RA) in the US is 44.6/100,000 , translating into a very similar number, that is, about 125,000 new cases of RA per year. Indeed, a 2002 study in Sweden found the annual incidence of ReA to be higher than that of RA . In spite of this, a range of clinical evidence tells us that RA is diagnosed far more often than ReA.

A variety of explanations exist for the apparent underdiagnosis of CiReA. The most obvious explanation is that CiReA will spontaneously remit in 50–70% of cases; therefore, the condition could resolve before the patient is diagnosed. Another compelling explanation relates to the fact that asymptomatic Ct infections could account for as many as 78–88% of cases of CiReA . An over-reliance on the classic triad of symptoms and/or HLA-B27 positivity, the more subtle clinical presentation in women and the lack of specific diagnostic criteria are other factors that likely contribute to underdiagnosis. Finally, a recent survey by our group suggests that a large percentage of patients with ReA could be misdiagnosed with psoriatic arthritis sine psoriasis, palmoplantar–pustular psoriasis with arthritis or even seronegative rheumatoid arthritis .

Epidemiology

In keeping with previous controversy regarding proper terminology, the true incidence and prevalence of ReA is enigmatic. The Office of Rare Diseases of the National Institutes of Health lists ReA as a ‘rare disease’. This means that ReA affects less than 200,000 people in the United States. Orphanet, who are a consortium of European partners for rare diseases and orphan drugs, also lists ReA as a ‘rare disease’, meaning that it affects less than 1 person in 2000. Two previous surveys have attempted to define the incidence of ReA. A US survey suggested the age-adjusted incidence rate for males under the age of 50 years was 3.5 cases per 100,000 men . Similarly, a survey in Norway estimated a minimum incidence rate of approximately five cases per 100,000 . However, the true incidence of ReA continues to be debated because of the protean nature of its symptoms, as well as a lack of consensus in defining the syndrome. Further, the true number of post-chlamydial ReA cases is equally difficult to document because the triggering infection can be asymptomatic or never definitively diagnosed.

Prospective data assessing the attack rate of ReA in patients after an acute C. trachomatis infection suggest a much higher incidence. A US study in 1996 that followed patients after a venereal infection demonstrated that 4.1% of the patients developed ReA after a C. trachomatis infection, specifically . Importantly, the majority of these patients with post-chlamydial ReA developed their condition after an asymptomatic infection. Further, this study was performed on an urban population with a rather high African-American study population. African-Americans are known to have a lower prevalence of the human leucocyte antigen (HLA)-B27. Therefore, this could represent an underestimate of the true attack rate. We have recently completed a similar study of 368 subjects and found a ReA attack rate of 8.1% in patients after a C. trachomatis infection (unpublished data).

The Centers for Disease Control in the US estimates the annual incidence of C. trachomatis infections to be 3 million in persons of the ages 15–44 years . By using the attack rate of 4.1% in 3 million people, 123,000 new cases of post-chlamydial ReA should be estimated in the US every year. This estimate is likely low for reasons cited earlier; further, it does not include cases of ReA secondary to Cpn. For comparison, the estimated annual incidence of rheumatoid arthritis (RA) in the US is 44.6/100,000 , translating into a very similar number, that is, about 125,000 new cases of RA per year. Indeed, a 2002 study in Sweden found the annual incidence of ReA to be higher than that of RA . In spite of this, a range of clinical evidence tells us that RA is diagnosed far more often than ReA.

A variety of explanations exist for the apparent underdiagnosis of CiReA. The most obvious explanation is that CiReA will spontaneously remit in 50–70% of cases; therefore, the condition could resolve before the patient is diagnosed. Another compelling explanation relates to the fact that asymptomatic Ct infections could account for as many as 78–88% of cases of CiReA . An over-reliance on the classic triad of symptoms and/or HLA-B27 positivity, the more subtle clinical presentation in women and the lack of specific diagnostic criteria are other factors that likely contribute to underdiagnosis. Finally, a recent survey by our group suggests that a large percentage of patients with ReA could be misdiagnosed with psoriatic arthritis sine psoriasis, palmoplantar–pustular psoriasis with arthritis or even seronegative rheumatoid arthritis .

Chlamydiae

All chlamydial species are obligate intracellular bacterial parasites of eukaryotic cells. For the most part, chlamydiae are incapable of generating their own energy; therefore, they rely on the host cell’s adenosine triphosphate (ATP) for energy. There are several different chlamydial species, but our focus will be on C. trachomatis and C. pneumoniae , as these are the only chlamydial species known to cause CiReA.

The term Chlamydia first appeared in the literature in 1945. It is derived from the ancient Greek word ‘chlamys’ that means cloak. The name was given to these intracellular pathogens which were believed to cloak the nucleus of the infected cell. They were once felt to be viruses due to this dependence on the host cell. Older names for these organisms include ‘ Bedsonia ’, ‘Miyagawanella’ and ‘Halprowia’. Important animal data from the 1960s and early 1970s demonstrated that Bedsonia recovered from patients with ReA caused arthritis 100% of the time when injected into rabbits; in addition, intra-articular injection of these same organisms often caused ocular involvement . These important findings demonstrated that not only were these organisms arthritogenic, but they were also able to disseminate causing clinical disease in distant organs.

Chlamydial infections are initiated at mucosal surfaces. For C. trachomatis , the sites of primary infection are the epithelial surfaces of the urogenital system or the ocular conjunctivae and C. pneumoniae , a respiratory pathogen, is acquired through the nasal and pulmonary mucosae . At their sites of primary infection, each organism can cause acute disease or be asymptomatic. The pathology engendered by each chlamydial species is a function of their particular biology and of the immune response they elicit. The chlamydial developmental life cycle is biphasic ; interestingly, the names used to describe the developmental stages of Chlamydia were coined when it was still felt to be a viral pathogen. In the first phase, the elementary body (a term borrowed from virologists), the infectious extracellular form of the organism, attaches to the appropriate host cell and is brought in a membrane-bound vesicle into the host cell cytoplasm. It is within this inclusion that the elementary body reorganises into the non-infectious form, the reticulate body; the contents of each reticulate body were “reticulated” or homogeneous. The reticulate body undergoes several rounds of division reorganising back into elementary bodies, which are then released from the host cell to cause further infection. This developmental cycle takes around 48 h to complete. Chlamydiae in the normal developmental life cycle are rather easily detected with traditional culture techniques.

The traditional description of CiReA is that of a sterile or aseptic arthritis that occurs after exposure to the organism. It was termed a ‘sterile arthritis’ because early studies performed in the 1970s and 1980s using traditional culture techniques failed to demonstrate live chlamydial organisms in the synovial fluid . However, electron microscope (EM) studies performed during that same time period did show what appeared to be intact chlamydiae along with elementary bodies and/or reticulate bodies from synovial samples of patients with a prior infection of that same organism .

After an acute infection with C. trachomatis and C. pneumoniae , these organisms have the ability to disseminate from their site of primary infection and establish long-term residence at distant anatomic locations . It is at these sites that the organism enters into an unusual biological state referred to as “persistence” . In the persistent state, a block in gene expression impedes completion of the developmental life cycle and the organisms exhibit aberrant morphological and transcriptional factors. The means by which persistent chlamydiae might cause pathology is poorly understood, but they do elicit an immunopathogenic response . Importantly, these persistent chlamydiae cannot be detected with traditional culture techniques, but are readily detectable by EM or polymerase chain reaction (PCR).

The pattern of gene expression associated with persistent chlamydiae is significantly different than that seen during normal acute infections. For example, during persistence, expression of the major outer membrane protein ( omp1 ) gene and several genes required for the cell division process are severely down-regulated; this is coupled with an up-regulation of heat shock proteins (HSPs). HSPs, in general, are paramount to the persistent state of both Ct and Cpn, as they provide many functions involved with cell survival. Under stressful conditions, HSPs allow cells to survive lethal assaults by preventing protein denaturation . The HSP-60 molecule, specifically, has many functions that appear to be important to the pathophysiology of CiReA. HSP-60 has been shown to be pivotal in the maintenance of the persistent state. These molecules prevent chlamydial-infected cells to undergo apoptosis , play a role in antibiotic resistance and are potentially immunogenic .

There appears to be differences even between chlamydial species in terms of chlamydial persistence and CiReA. In the persistent state, there are different HSP-60 paralog genes seen in C. trachomatis , whereas there are no similar paralog genes in the case of C. pneumoniae . There have also been differences in cytokine and chemokine messenger RNA (mRNA) profiles demonstrated in human synovial tissue chronically infected with C. trachomatis versus C. pneumoniae . Perhaps these differences explain the apparent arthritogenic virulence difference between these two chlamydial species.

Very recent data dictate that the arthritogenic potential of C. trachomatis might exist at an even more basic level. It is important to remember that there are different serovars of C. trachomatis . Serovars A through C are ocular serovars and the genital serovars include serovars D through K. As their name implies, serovars A through C cause ocular disease and genital infections are caused by serovars D through K. Because CiReA results after genital infections, it was natural to assume that all or some of the D through K serovars would be responsible. Remarkably, a recent study analysing the chlamydial serovars of 36 subjects with known Ct-induced ReA demonstrated that all 36 synovial tissue samples were positive for the ocular serovars, not for the genital serovars . Interestingly, the ocular strains are rarely passed with genital infections, sometimes as part of a multiclonal infection . This might explain, at least in part, the conundrum of why only a small percentage of patients with acute genital chlamydial infections develops CiReA. That the ocular strains are arthritogenic might also account for the fact that many patients with ReA develop eye disease (conjunctivitis and/or iritis/uveitis). Finally, these data suggest that the ocular strains might be much more likely to disseminate compared with the genital strains, perhaps vacating the initial site of the inoculum entirely.

The true meaning of synovial-based chlamydiae has been questioned. The mere presence of persistent chlamydial organisms in synovial tissue is not diagnostic of CiReA, as these same organisms have been detected in the synovial tissue of patients with other types of arthritis, namely osteoarthritis (OA), rheumatoid arthritis and even normal controls . PCR or real-time-PCR (RT-PCR) detection of synovial-based chlamydiae in these non-ReA patients, although limited, has ranged from 5% to as high as 20% of samples. However, the prevalence of chlamydiae in the synovial tissue of patients with other conditions is significantly less compared with synovial tissue of patients with CiReA . A recent study that directly compared the PCR positivity rate for synovial-based chlamydiae in patients with suspected ReA versus OA resulted in 62% versus 12% positivity, respectively ( p < 0.0001) . It appears clear that patients with suspected ReA, or CiReA specifically, are much more likely to harbour these persistent organisms in their synovial tissue, but it is not pathognomonic for the condition. The fact that a small percentage of patients with OA and even a smaller percentage of normal controls harbours these same synovial-based organisms highlights the important potential differences in host genetics/tolerance and possibly specific factors about the organism itself that determines arthritogenic virulence, such as the specific serovar. None of these studies have specifically examined the C. trachomatis serovar type in the synovial samples from patients with these other conditions.

Host response in CiReA

CiReA represents the classic interplay between host and environment in which both parties play a role in disease susceptibility. The exact role that each plays is still not clearly defined. Although the causative bacteria of ReA have been known for many years, the traditional focus in determining disease susceptibility has been on the host. HLA-B27 is a class I surface antigen, encoded in the major histocompatibility complex (MHC) on the short arm of chromosome 6 and presents antigenic peptides to T cells. B27 as an HLA allele was discovered in 1969 and shortly thereafter was demonstrated to show a very strong association with ankylosing spondylitis, but it is not pathognomonic for the condition. Later, it was linked to all subsets of SpA, although the strength of this association varies with the type of SpA and the population studied. HLA-B27 shows remarkable polymorphism and there are over 70 known alleles and 62 subtypes. Not all of the subtypes are associated with disease and, quite remarkably, some of the subtypes that are not associated with disease differ by a single amino acid from those that are . The presence of HLA-B27 in ankylosing spondylitis has also been shown to influence the clinical manifestations of the disease; HLA-B27-positive patients have earlier disease onset, higher prevalence of eye involvement and more hip arthritis .

Could current concepts regarding HLA-B27 in ankylosing spondylitis represent lessons learned for CiReA? This appears to be the case. Older literature placed a heavy emphasis on the potential role of HLA-B27 in the pathogenesis of ReA. Attempts to link infection with disease included the demonstration of sequence homology between B27 and these arthritogenic pathogens, so called molecular mimicry. An in vitro model suggested that Chlamydia could break self-tolerance of B27 ; however, definitive proof of molecular mimicry or autoreactivity as the underlying mechanism of ReA has never been established. It was previously felt that as many as 70–80% of patients with ReA were HLA-B27 positive . However, more recent large epidemiological studies indicate that, in reality, about 30–50% of ReA patients are positive for this antigen . Some studies report no association with HLA-B27 and ReA . However, these data are primarily derived from epidemiologic data after large food-borne illness outbreaks; therefore, the true background prevalence of the HLA-B27 antigen in patients with CiReA is less well defined.

Rather than truly increasing disease susceptibility, HLA-B27 might portend a different prognosis. Several large studies are in agreement that HLA-B27-positive patients have more severe symptoms, thereby making the condition more clinically apparent . HLA-B27-positive patients with ReA also appear to be more likely to develop the complete triad of symptoms . Therefore, HLA-B27 could actually function as a surrogate marker of severity of disease rather than a true genetic susceptibility locus. This might further explain the apparent underdiagnosis of CiReA previously discussed.

The first line of host defence is innate immunity. Whether the causative organism disseminates from the initial site of infection as a viable and intact pathogen, as is the case with chlamydiae, or fragments of the pathogen, as appears to be the case with the enteric triggers of ReA, the innate immune system likely plays a key role in the early events underlying ReA. Toll-like receptors (TLRs) function as an integral part of innate immunity. There are significant polymorphisms in the TLR families and recent studies with ReA have demonstrated that single nucleotide polymorphisms (SNPs) in TLR2 increase disease susceptibility to ReA . However, these studies were performed in patients with post-enteric ReA. Whether these same SNPs in TLR2 play a role in CiReA is unknown, but animal models do indicate that TLR2 plays a critical role in acute genital infections of C. trachomatis , leading to downstream inflammatory activation . Other data indicate that the pro-inflammatory cytokine response generated by C. trachomatis involves the TLR2/TLR1/TLR6 pathways, but not TLR4 . The latter is somewhat surprising since lipopolysaccharide, which is abundant on the cell wall of chlamydiae, directly stimulates TLR4. The C. trachomatis- generated inflammatory response via these various TLRs is thought to be mediated, at least in part, by macrophage inhibitory potentiator (Mip); Mip has recently been demonstrated to be a ‘classic bacterial peptide’. Conversely, data suggest that TLR4 is associated with chlamydial infections via the HSP-60 pathway. It has been shown that HSP-60 from both C. trachomatis and C. pneumoniae activates TLR4 through the MyD88 pathway . Regardless of the exact role of TLRs, it is possible that certain bacterial peptides, referred to as pathogen-associated molecular patterns (PAMPs), might be important in disease generation, and the specific peptides expressed could help determine the resulting clinical syndrome.

Downstream from the TLRs, cytokines and chemokines play a key role in disease expression. In vitro data suggest that background cytokine and chemokine levels in the host are important in promoting or maintaining persistent chlamydial infections. It has been well documented in several different laboratories that decreased expression of tumour necrosis factor (TNF)-alpha and/or interferon (IFN)-gamma promotes the persistent state, and as levels of these two cytokines decrease, chlamydial replication increases . A Chlamydia -induced animal model demonstrated that susceptible rats mounted a lesser initial TNF-alpha, IFN-gamma and interleukin-4 (IL-4) response to an acute infection with C. trachomatis compared with non-susceptible rats . Along these same lines, treatment of established CiReA in a murine model resulted in induction of cytokines IFN-gamma, IL-4 and IL-10 with suppression of chemokines macrophage inflammatory protein (MIP)-2 and IFN-gamma inducible protein (IP)-10 . These cytokine and chemokine changes were coupled with a decreased synovial chlamydial load. It has also been shown that TNF receptor p55 knockout mice develop more severe arthritis with concomitant impaired bacterial clearance in the joints, spleen and mesenteric lymph nodes along with excessive mRNA expression of pro-inflammatory cytokines compared with their wild-type counterparts; however, these data were in a post-enteric ReA model .

Interesting correlates with these in vitro results can be made with emerging in vivo data. Recently, a study analysing both peripheral blood and synovial fluid mononuclear cells from patients with ReA demonstrated that IL-17-positive CD4+ T-cells were increased in the latter and this was coupled with attenuated IFN-γ expression . In parallel, cervical washes from women with acute C. trachomatis infections have been compared with normal controls demonstrating up-regulation of IL-17 with a lesser response of IFN-γ in the infected samples . Another recent study analysed the gene-expression profile from three patients with ReA revealing a remarkably high proportion of IP-10 along with ENA-78 and IL-8 . Our group completed a clinical trial assessing combination antibiotics as a treatment for CiReA that will be described later in this review. A cytokine analysis follow-up to this clinical trial was recently completed, demonstrating a significant treatment effect on IL-12p70 . Interestingly, IL-12p70 is required for optimal IFN-gamma response against intracellular pathogens and endocervical IL-12 expression has been shown to decrease with clearance of C. trachomatis . Taken together, these in vitro and in vivo data suggest that low initial expression of pro-inflammatory cytokines, such as IFN-γ and TNF-α, with acute chlamydial infections might promote the development of CiReA. This mirrors epidemiological data suggesting that asymptomatic infections appear to be a common cause of CiReA. If the triggering infection is often occult in nature, it renders the correct diagnosis of CiReA nearly impossible, further strengthening the supposition that CiReA is underdiagnosed. These same cytokine and chemokine changes also appear to promote the proper environment for establishment of the persistent chlamydial state and recent data are hopeful that successful treatment is accompanied with alterations of this abnormal cytokine signature.

C. trachomatis versus C. ( Chlamydophila ) pneumoniae ReA

Whereas both C. trachomatis and C. pneumoniae are known triggers of ReA, C. trachomatis is a much more common cause. Although both are very common causes of bacterial infections worldwide, it is widely accepted that C. pneumoniae is more prevalent. However, it is difficult to know the true incidence and prevalence of C. pneumoniae infections worldwide. Further, these rates could vary depending on the year or country studied.

Acute infections with C. pneumoniae cause bronchitis or pneumonia; however, the majority of the time it is felt to be asymptomatically acquired with some data suggesting this is true as frequently as 90% of the time . Approximately 50% of young adults and 75% of older individuals have serological evidence of previous infection and the pathogen is estimated to cause 10–20% of community-acquired pneumonia cases among adults . When symptomatic, the incubation period is approximately 3–4 weeks. The onset is usually gradual and may be biphasic.

Much of the difficulty in defining the true incidence and prevalence of C. pneumoniae has to do with the lack of a simple and definitive diagnostic test. A prospective study in the US demonstrated that seroconversion for C. pneumoniae , as demonstrated by a rise in specific immunoglobulin G (IgG) titres, occurred at an annual rate of 9.2% in those between the ages of 5 and 10 years and dropped to 1.5% in those over the age of 20 years . However, the true importance of seroconversion with C. pneumoniae specific titres is unknown, as this is not always coupled with a clinical infection. Perhaps this is indicative of asymptomatic acquisition of the organism, but this, too, is poorly understood. Debate exists regarding the importance of IgG- versus IgA-specific antibodies, but the majority of the studies suggest that IgA antibodies do not add additional diagnostic value . Finally, studies have shown that C. pneumoniae can be isolated from the nasopharynx of up to 4.7% of subjectively healthy subjects, but the pathophysiologic importance of this finding is not entirely clear .

In spite of the diagnostic difficulties associated with C. pneumoniae , the organism is known to be a very common pathogen that exists throughout the world. Although this pathogen is frequently encountered, it is equally clear that it is a trigger of CiReA less often than is C. trachomatis . The explanation for this disconnect is unknown. In spite of the fact that both organisms are from the same genus, there are some important interspecies differences. A study analysing the synovial tissue of patients CiReA sought to determine differences in cytokine or chemokine expression in those infected with C. trachomatis versus C. pneumoniae . In C. trachomatis- infected synovial tissue samples, high levels of IL-10 mRNA were present, with less mRNA for IL-8, IL-15, IFN-γ and TNF-α. Synovial tissues from patients with synovial C. pneumoniae only showed significant levels of mRNA for IL-8 and IL-1β . As previously stated, persistent C. trachomatis organisms demonstrate differential expression of three separate HSP-60 paralog genes (Ct110, Ct604 and Ct755), whereas these same paralog genes do not exist with persistent C. pneumoniae . The different chlamydial species could also have an additive or synergistic effect in determining ReA attack rate or incidence. Previous exposure to Cpn could have an effect on a subsequent response to a Ct infection. Reports have demonstrated that prior Cpn infection primes a Th1T-cell response to Ct antigens . Perhaps these differences explain the apparent discordant arthritogenic virulence of each organism. Finally, the common, yet cryptic, acquisition of C. pneumoniae might help further explain the apparent underdiagnosis of CiReA, in general.