Chronic Prostatitis is a symptom of Reiter's Syndrome.
- inflammation of the eyes (conjunctivitis); and
- inflammation of the genital, urinary or gastrointestinal systems.
Reiter's syndrome is also called "reactive arthritis."
It is felt that it involves an immune system which is reacting to
the presence of bacterial infections in the genital, urinary, or
Reiter's syndrome most frequently occurs in patients in their thirties or forties, but it can occur at any age. The form of Reiter's syndrome which occurs after genital infection occurs more frequently in males. The form which develops after bowel infection occurs in equal frequency in males and females.
Reiter's syndrome is considered a systemic rheumatic disease. This means it can affect other organs than the joints, such as the eyes, mouth, skin, kidneys, heart, and lungs. Reiter's syndrome shares many features with several other arthritic conditions, such as psoriatic arthritis, ankylosing spondylitis, and arthritis associated with Crohn's disease and ulcerative colitis. Each of these arthritic conditions can cause similar disease and inflammation in the spine and other joints, eyes, skin, mouth, and various organs. In view of their similarities and tendency to inflame the spine, these conditions are collectively referred to as "spondyloarthropathies."
As mentioned, Reiter's syndrome is felt in part to be genetic (Back to top) . There are certain genetic markers that are far more frequent in patients with Reiter's syndrome than in the normal population. For example, the HLA-B27 gene is commonly seen in patients with Reiter's syndrome. Even in patients who have the genetic background that predisposes them to developing Reiter's syndrome, exposure to certain infections seem to be required to trigger the onset of the disease.
Reiter's syndrome can occur after genital infections. The most common bacteria that has been associated with this form of Reiter's syndrome is an organism called Chlamydia. Reiter's syndrome also occurs after infectious dysentery, with bacterial organisms in the bowel, such as Salmonella, Shigella, Yersinia, and Campylobacter. Typically, the arthritis develops one to three weeks after the onset of the bacterial infection.
The symptoms of Reiter's (Back to top) syndrome can be divided into those which affect the joints and those which affect the non-joint areas. The classic joints that become inflamed in Reiter's syndrome are the knees, ankles, feet, and wrists. The particular joints involved are usually asymmetric, that is, one side of the body or the other is affected, rather than both sides simultaneously. The inflammation leads to stiffness, pain, swelling, warmth, and redness of the joints involved. Patients may develop inflammation of entire fingers or toes which can give the appearance of a "sausage digit." This is also seen in patients with another type of arthritis associated with psoriasis, called psoriatic arthritis. The arthritis of Reiter's syndrome can be associated with inflammation of the spine, leading to stiffness and pain in the back or neck (characteristic of all of the spondyloarthropathies). Cartilage can also become inflamed, especially around the breastbone where the ribs meet in the front of the chest, this condition is called costochondritis. Muscles attach to the bones by tendons. In Reiter's syndrome, the tendon insertion points can become inflamed (tendonitis), tender, and painful when exercised.
Non-joint areas that become inflamed and cause symptoms in Reiter's syndrome include the eyes, genitals, urinary tract (urethra, bladder and prostate gland), mouth lining, large bowel, and the aorta. Inflammation of the whites of the eye (conjunctivitis) and the iris of the eye (iritis) is frequently seen early in Reiter's syndrome and may be intermittent. When the whites of the eye are inflamed causing conjunctivitis, there may be no pain. When the colored part of the eye (iris) is inflamed, causing iritis, it can be very painful and especially worse when looking into bright lights. Urinary tract inflammation commonly involves the urethra, the tube that drains urine from the bladder. This inflammation (urethritis) can be associated with burning on urination and/or pus drainage from the end of the penis. The skin around the penis can become inflamed and scale. The bladder and prostate gland can also become inflamed, leading to an urge to urinate. The mouth can develop open sores (ulcerations) on the hard and soft palate, and even on the tongue. These may go unnoticed by the patient, as they are often painless. Inflammation of the large bowel (colitis) can cause diarrhea, or pus or blood in the stool. Inflammation of the aorta (aortitis) can be seen in a small percentage of patients who have Reiter's syndrome. It can lead to failure of the aortic valve of the heart, which can cause heart failure. The electrical conducting pathway of the heart can also become scarred in Reiter's syndrome, leading to irregular heartbeats (arrhythmias) that may require placement of a pacemaker to regulate the heartbeat.
Reactive Arthritis (Reiter's Syndrome)
Reactive arthritis refers to acute nonpurulent arthritis complicating an infection elsewhere in the body. In recent years, the term has been used primarily to refer to spondyloarthropathies following enteric or urogenital infections and occurring predominantly in individuals with the histocompatibility antigen HLA-B27. Included in this category is the constellation of clinical findings often referred to as Reiter's syndrome. Other forms of reactive arthritis not associated with HLA-B27 and showing a different spectrum of clinical features, such as rheumatic fever, are discussed elsewhere in this volume.
Historical Background (Back to top)
In 1916, Reiter described a patient who, following an episode of bloody diarrhea, developed a systemic illness with polyarthritis, conjunctivitis, and nongonococcal urethritis. Although similar cases had previously been described, this report served to focus attention on the triad of arthritis, urethritis, and conjunctivitis which subsequently was referred to as Reiter's syndrome. Additional clinical features, particularly mucocutaneous lesions, were later recognized to be frequent accompaniments of the syndrome.
In recent years, the identification of several bacterial species capable of triggering the clinical syndrome, as well as the finding that three-fourths of the patients possess the HLA-B27 antigen, have led to the unifying concept of reactive arthritis as a clinical syndrome triggered by a specific etiologic agent in a genetically susceptible host. It is now recognized that a similar spectrum of clinical manifestations can be triggered by enteric infection with any of several Shigella, Salmonella, Yersinia, and Campylobacter species or with Clostridium difficle, by genital infection with Chlamydia trachomatis, and possibly by other agents as well. Although Reiter's syndrome can be said to represent one part of the spectrum of the clinical manifestations of reactive arthritis, it can be reasonably argued that the term is now largely of historical interest.
Epidemiology (Back to top)
Like ankylosing spondylitis, reactive arthritis occurs predominantly in individuals who have inherited the HLAB27 gene; in most series, 60 to 85 percent of the patients are B27-positive. In epidemics of arthritogenic bacterial infection, e.g., Shigella flexneri, it has been estimated that reactive arthritis develops in -20 percent of the B27-positive individuals at risk. Some studies of families with multiple cases of AS or reactive arthritis have suggested that the two conditions tend to 'breed true"; whether this is caused by genetic or environmental factors is not known. The disease is most common in individuals 18 to 40 years of age, but it is well-recognized both in children over 5 years of age and in older adults.
Although Reiter's syndrome has long been described as a disease predominantly of men, this conclusion is probably overstated and related to the ascertainment of cases. The sex ratio in reactive arthritis following enteric infection is nearly 1:1, whereas venereally acquired reactive arthritis is predominantly a male disease. The overall prevalence and incidence of reactive arthritis are difficult to assess because of the variable prevalence of the triggering infections and genetic susceptibility factors in different populations. Certain populations, such as the Navajo Indians of the southwestern United States and the Inuit Eskimos of Greenland, show a very high occurrence of reactive arthritis, whereas the disease is quite uncommon in certain other populations, such as the Haida Indians, with an equally high prevalence of HLA-B27. The reasons for these differences are not clear.
A particularly severe form of reactive arthritis has been described in patients with the acquired immunodeficiency syndrome. Most of these patients are HLA-B27-positive. From the incidence figures it can be inferred that B27-positive individuals with human immunodeficiency virus infection develop reactive arthritis at a higher than expected frequency.
Laboratory And Radiographic Findings (Back to top)
The erythrocyte sedimentation rate is elevated during the acute phase of the disease. Mild anemia may be present, and acute phase reactants tend to be increased. Synovial fluid is nonspecifically inflammatory, showing an elevated white cell count with a predominance of neutrophils. In most ethnic groups, three-fourths of the patients possess the HLA-B27 antigen. Although it is unusual for the triggering infection to persist through the time of onset of the reactive disease, it may occasionally be possible to culture the organism, for example, in the case of Shigella- or Chlamydia-induced disease. Serologic evidence of a recent infection may be present, such as a marked elevation of antibodies to Yersinia or Chlamydia.
In early or mild disease, radiographic changes may be absent or confined to juxtaarticular osteoporosis. With long-standing persistent disease, marginal erosions and loss of joint space can be seen in affected joints. Periostitis with reactive new bone formation is characteristic of the disease, as it is with all of the spondyloarthropathies. Spurs at the insertion of the plantar fascia are common.
Sacroiliitis and spondylitis similar to those described for ankylosing spondylitis may be seen as late sequelae. However, sacroiliitis is more commonly asymmetric than in AS, and the spondylitis, rather than ascending symmetrically from the lower lumbar segments, can begin anywhere along the lumbar spine. The syndesmophytes may be coarse and nonmarginal, arising from the middle of a vertebral body, a pattern rarely seen in primary AS.
Pathology (Back to top)
Synovial histology is similar to that of other inflammatory arthropathies, including rheumatoid arthritis. Enthesitis is a common clinical finding in reactive arthritis; the histology of this lesion resembles that of ankylosing spondylitis. Microscopic histopathologic evidence of inflammation has been noted in the colon and ileum of patients with postvenereal as well as postenteritic reactive arthritis. The skin lesions of keratoderma blennorrhagica are histologically indistinguishable from psoriatic lesions.
Etiology And Pathogenesis (Back to top)
The first bacterial infection to be causally related to reactive arthritis was Shigella flexneri. An outbreak of shigellosis among Finnish troops in 1944 resulted in numerous cases of reactive arthritis. Of the four species of Shigella, sonnei, boydii, flexneri, and dysenteriae, S. flexneri has most often been implicated in cases of reactive arthritis, both sporadic and epidemic. S. sonnei, although responsible for the majority of cases of shigellosis in the United States, has only rarely been implicated in cases of reactive arthritis.
Other bacteria that have been definitively identified as triggers of reactive arthritis include several Salmonella species, Yersinia enterocolitica, and Campylobacter jejuni. There is suggestive evidence implicating several other microorganisms. including Brucella, Yersinia pseudotuberculosis. Clostridium difficile; the genitourinary pathogens Chlamydia trachomatis, Neisseria gonorrhoeae, and Urea-plasma urealyticum; and Streptococcus pyogenes. There are also numerous isolated reports of acute arthritis preceded by other bacterial. viral, or parasitic infections, but whether the microorganisms involved are actual triggers of reactive arthritis remains to be determined.
It has not been determined whether reactive arthritis occurs by the same pathogenetic mechanism following infection with each of these microorganisms, nor has the mechanism been fully elucidated in the case of any one of the known bacterial triggers. The immune response is presumed to play a principal role, but there is not yet general agreement on the relative importance of humoral versus cellular mechanisms. Most, if not all, of the triggering organisms share a capacity to invade host cells and survive intracellularly.
The largest body of data regarding the immune response in reactive arthritis has been generated by studies of Y. enterocolitica, particularly serotypes 0:3 and 0:9 in Finland, where these organisms frequently cause enteric infection in a population in which the prevalence of HLA-B27 is 14 percent. In comparison with individuals who fail to develop reactive arthritis following enteric infection with Yersinia, patients with Yersinia-triggered reactive arthritis show far fewer gastrointestinal symptoms attributable to the infection, a smaller initial 1gM response, stronger and more persistent IgA and lgG responses, higher levels of IgA anti-Yersinia antibodies with a secretory component. and reduced T-cell proliferative responses to Yersinia antigens. These findings suggest an unusual persistence of the immune response to the infecting organism in those individuals in whom reactive arthritis develops. Circulating immune complexes containing Yersinia antigens have been found in a higher proportion of arthritic than nonarthritic individuals, and occasionally in the inflamed joints, but the significance of these findings is not clear.
It is not known to what extent reactive arthritis represents an autoimmune response against host tissues, as opposed to an immune response against antigens of the triggering organism that have disseminated to the target tissues. Both mechanisms appear to operate in animal models. Chlamydial antigens have been demonstrated in the synovium of a few patients with venereally acquired reactive arthritis, but it is not known whether they are the inciting antigenic stimulus. Similarly, Yersinia enterocolitica antigen has been detected in synovial fluid cells in patients with Y. enterocolitica-induced reactive arthritis, but the significance of this is unclear.
The role of HLA-B27 in reactive arthritis has yet to be fully elucidated. At present. the evidence favors some form of molecular mimicry. or the sharing of antigenic determinants between the HLAB27 molecule and molecules encoded by the inciting microbial agent. Several reports have documented antigenic cross-reactivity between the B27 molecule and envelope glycoproteins of arthritogenic bacteria, including Shigella fiexneri and Yersinio pseudotuberculosis. but the pathogenetic significance of this is not known. Many but not all B27-negative individuals with reactive arthritis possess HLA-B alleles that are antigenically cross-reactive with HLA-B27, notably HLA-B7.
Treatment (Back to top)
Most patients with reactive arthritis are benefitted to some degree by nonsteroidal anti-inflammatory drugs, although rarely are symptoms of the acute arthritis completely ameliorated and some patients fail to respond at all. Indomethacin, 75 to 150 mg/d in divided doses, is the initial treatment of choice, with phenylbutazone, 100 mg tid or qid, being the NSAID of last resort because of its potentially serious side effects.
Patients with debilitating symptoms refractory to NSAID therapy may respond to cytotoxic agents such as azathioprine, 1 to 2 mg/kg per day, or methotrexate, 7.5 to 15 mg per week. Recent studies have suggested that sulfasalazine, up to 3 g/d in divided doses, also may be beneficial to patients with persistent reactive arthritis. There appears to be no place for systemic corticosteroids. antimalarials. gold, or penicillamine in the treatment of reactive arthritis. Although many clinicians routinely administer courses of antibiotics to patients with reactive arthritis, there is little evidence that this is beneficial.
Tendinitis and other enthesitic lesions occasionally may benefit from intralesional corticosteroids. Uveitis may require aggressive treatment with corticosteroids to prevent serious sequelae. Skin lesions ordinarily require only symptomatic treatment. In patients with HIV infection and reactive arthritis, many of whom have severe skin lesions, the skin lesions in particular appear to respond dramatically to systemic treatment with azidothymidine. Cardiac complications are managed conventionally; management of neurologic complications is symptomatic.
Patients need to be educated with regard to the nature of the disease and the factors that predispose to its recurrence. Comprehensive management includes counseling of patients in the use of condoms, avoidance of sexual promiscuity, and exposure to enteropathogens. Appropriate use of physical therapy, vocational counseling, and continued surveillance for long-term complications such as ankylosing spondylitis are also part of comprehensive care.
Diagnosis (Back to top)
Reactive arthritis is a clinical diagnosis, there being no definitively diagnostic laboratory test or radiographic finding. The diagnosis should be entertained in any patient with an acute inflammatory, asymmetric, additive arthritis or tendinitis. The evaluation of such a patient should include careful questioning regarding possible antecedent triggering events such as an episode of diarrhea or dysuria. On physical examination, careful attention must be paid to the distribution of the joint and tendon involvement and to possible sites of extraarticular involvement, such as the eyes, mucous membranes, skin, nails, and genitalia. Synovial fluid aspiration and analysis may be helpful in excluding septic or crystal-induced arthritis.
Although typing for B27 is not needed to secure the diagnosis in clear-cut cases, it has prognostic significance in terms of severity, chronicity, and the propensity for spondylitis and uveitis. Furthermore, it can be helpful diagnostically in atypical cases, a positive test increasing and a negative test decreasing the probability that the diagnosis of reactive arthritis is correct.
It is particularly important to differentiate reactive arthritis from disseminated gonococcal disease, both of which can be venereally acquired and associated with urethritis. Gonococcal arthritis and tenosynovitis tend to involve both upper and lower extremities equally, whereas in reactive arthritis the symptoms usually predominate in the lower extremities. Back pain is common in reactive arthritis but is not a feature of gonococcal disease, whereas the vesicular skin lesions characteristic of disseminated gonococcal disease are not found in reactive arthritis. A positive gonococcal culture from the urethra or cervix does not exclude a diagnosis of reactive arthritis; however, culturing gonococci from blood, skin lesion, or synovium establishes the diagnosis of disseminated gonococcal disease. Occasionally, the only definitive way to distinguish the two is through a therapeutic trial of antibiotics.
Reactive arthritis shares many features with psoriatic arthropathy, including the asymmetry of the arthritis, a propensity for sausage digits and nail involvement, an association with uveitis, and skin lesions of similar histology. However, psoriatic arthritis is usually gradual in onset, the arthritis tends to affect primarily the upper extremities, and there is far less associated periarthritis. Psoriatic arthritis is not associated with mouth ulcers, urethritis, or bowel symptoms; and there is a female predominance. Although psoriatic arthropathy shows some distinctive radiographic features that are not found in reactive arthritis, these only occur late in the disease and are of little help diagnostically. Only psoriatic spondylitis, not the peripheral arthritis, is associated with HLA-B27, about 50 percent of the patients being positive. Occasional patients, usually B27 positive, following what appears to be a typical episode of reactive arthritis, will develop typical psoriasis and persistent arthritis, such that the two entities become indistinguishable.
Clinical Features (Back to top)
The clinical manifestations of reactive arthritis constitute a spectrum that ranges from an isolated, transient monarthritis to a more severe multisystem disease. In the majority of cases, a careful history will elicit some evidence of an antecedent infection 1 to 4 weeks before the onset of symptoms of the reactive disease. However, in a sizeable minority, particularly in cases of relapse, no clinical or laboratory evidence of an antecedent infection can be found. In many cases of presumed venereally acquired reactive disease, there is a history of a recent new sexual partner, even in the absence of laboratory evidence of infection.
Constitutional symptoms are common, including fatigue, malaise, fever, and weight loss. The musculoskeletal symptoms are usually acute in onset. Arthritis is usually asymmetric and additive, with involvement of new joints occurring over a period of a few days to 1 or 2 weeks. The joints of the lower extremities, especially the knee, ankle, and subtalar, metatarsophalangeal, and toe interphalangeal joints, are the most common sites of involvement, but the wrist and fingers can be involved as well. The arthritis is usually quite painful, and tense joint effusions are not uncommon, especially in the knee. Dactylitis, or "sausage digit," a diffuse swelling of a solitary finger or toe, is a distinctive feature of both reactive arthritis and psoriatic arthritis. Tendinitis and fasciitis are particularly characteristic lesions, producing pain at multiple insertion sites, especially the Achilles insertion, the plantar fascia, and sites along the axial skeleton. Spinal and low back pain are quite common, and may be caused by insertional inflammation, muscle spasm, acute sacroiliitis, or presumably, arthritis in intervertebral articulations.
Urogenital lesions may occur throughout the course of the disease. In males, urethritis may be marked or relatively asymptomatic, and may be either an accompaniment of the triggering infection or a result of the reactive phase of the disease. Prostatitis is also common. Similarly, in females cervicitis or salpingitis may be caused either by the infectious trigger or the sterile reactive process.
Ocular disease is common, ranging from transient, asymptomatic conjunctivitis to an aggressive anterior uveitis that occasionally proves refractory to treatment and results in blindness.
Mucocutaneous lesions are frequent. Oral ulcers tend to be superficial, transient, and often asymptomatic. The characteristic skin lesion, keratoderma blennorrhagica, consists of vesicles that become hyperkeratotic, ultimately forming a crust before disappearing. It is most common on the palms and soles, but may occur elsewhere as well. In patients with HIV infection, these lesions are often extremely severe and extensive, dominating the clinical picture. Lesions on the glans penis (circinate balanitis) are common; these consist of vesicles that quickly rupture to form painless superficial erosions, which in circumcised individuals can form crusts similar to those of keratoderma blennorrhagica. Nail changes are common and consist of onycholysis, distal yellowish discoloration, and/or heaped up hyperkeratosis.
Less frequent or rare manifestations of reactive arthritis include cardiac conduction defects, aortic insufficiency, central or peripheral nervous system lesions, and pleuropulmonary infiltrates.
Long-term follow-up studies suggest that some joint symptoms persist in many, if not most, patients with reactive arthritis. Recurrences of the acute syndrome are common, and as many as 25 percent of patients either become unable to work or are forced to change occupations because of persistent joint symptoms. Chronic heel pain is often a particularly distressing symptom. Ankylosing spondylitis is also a common sequela. In most studies, HLA-B27-positive patients have a worse outcome than B27-negative patients. The extent to which the long-term prognosis varies with different inciting agents is not known. However, patients with Yersinia-induced arthritis appear to have less chronic disease than those whose initial episode follows epidemic shigellosis.
Plea to researchers (Back to top)
There is ample evidence that chronic nonbacterial prostatitis is an immunologically-driven inflammatory disease, and may accompany inflammation of other tissues in the body. Research has shown that Reiter's-associated prostatitis occurs predominantly in individuals with the histocompatibility antigen HLA-B27. In most series, 60 to 85 percent of Reiter's patients are B27-positive.
It seems imperative to me that one of the first studies which the NIH has to undertake in the search to find the cause of chronic nonbacterial prostatitis is to find out what proportion of chronic nonbacterial prostatitis patients are B27 positive. The percentage carrying HLA-B27 in the general population is about 8%. If it transpires that chronic nonbacterial prostatitis patients have a significantly higher percentage of B27-positive among them, then this is surely very significant, and could point the way forward by focussing investigations.
To those interested, please disseminate this message to the researchers involved.
(Note: Dr Shoskes found a low incidence of HLA-B27+ in a small survey of CP/CPPS patients).