Index
It is an autoimmune disease that develops in response to an infection.
Reactive arthritis (ReA), formerly known as Reiter’s syndrome, has been associated with gastrointestinal (GI) infections with Shigella, Salmonella, Campylobacter, and other organisms, as well as with genitourinary disorders (GU) (especially with Chlamydia trachomatis).
Signs and symptoms of Reiter’s syndrome
The classic triad of Reiter syndrome symptoms (found in only one-third of patients) consists of the following:
- Noninfectious urethritis.
- Arthritis .
- Conjunctivitis.
In post-adrenic Reiter syndrome, diarrhea and dysenteric syndrome (usually mild) are commonly followed by the clinical triad in 1-4 weeks. Some add a fourth component (mucocutaneous findings) to form a diagnostic tetrad.
You can see the following:
- Acute onset of Reiter’s syndrome, with malaise, fatigue, and fever.
- Asymmetric oligoarthritis, predominantly of the lower extremities, is the main presenting symptom, sometimes with early myalgias.
- Initial non-gonococcal urethritis, frequent dysuria, urgency, and urethral discharge.
- In addition to conjunctivitis, ophthalmological symptoms include erythema, burning, lacrimation, photophobia, pain, and decreased vision (rare).
- Recurrent mild abdominal complaints after a precipitating episode of diarrhea.
- In patients with HIV, severe psoriasiform dermatitis commonly involves push-ups, scalp, palms, and soles.
The physical findings in Reiter’s syndrome may include the following:
Musculoskeletal system: asymmetric oligoarthritis that affects the joints that support weight, predominantly of the lower extremities; finger in the form of sausage (dactylitis); enthesopathy; sacroiliitis.
Skin and nails: Keratoderma blennorrhagicum; erythema nodosum (rare).
Eyes: conjunctivitis, anterior uveitis, keratitis, scleritis, episcleritis, cataracts, hypotonia, glaucoma, corneal ulceration, disc or retinal edema, retinal vasculitis, optic neuritis, dacryoadenitis.
Genitourinary tract: meatal edema and erythema and clear mucoid discharge, prostatitis, vulvovaginitis, circinate balanitis (balanitis circinata), cervicitis, cystitis, salpingo-oophoritis, pyelonephritis, bartholinitis.
Gastrointestinal tract: diarrhea, abdominal pain, lesions that resemble inflammatory bowel disease in ileocolonoscopy
Other systems: cardiac (aortitis, aortic regurgitation, anomalies of transient conduction, myocarditis, pericarditis ), renal ( proteinuria, microhematuria, amyloid deposits, immunoglobulin A [IgA] nephropathy)
Diagnosis
The diagnosis of Reiter’s syndrome is clinical, based on history and physical examination. No laboratory study or image finding is diagnostic.
The following laboratory studies may be helpful:
- White blood cell (WBC) and red blood cell (RBC) count.
- Globular sedimentation rate (ESR).
- C-reactive protein (CRP) and other acute-phase reagents.
- IgA antibodies against specific bacterial antigens.
- Serology and cultures (blood, urine, feces, cervix, urethra), particularly for Chlamydia.
- Human leukocyte antigen (HLA) -B27.
- Tuberculin skin test.
- VIH.
- Urine analysis.
The modalities of images that can be considered include the following:
- Simple x-ray (reveals findings in only 40-70% of cases).
- Mammography of the whole body.
- Positron emission tomography.
- Magnetic resonance imaging (MRI), especially of the sacroiliac joints.
- Computed tomography (CT).
- Ultrasonography or echocardiography.
Other studies to consider include the following:
- Arthrocentesis, synovial fluid analysis, and synovial biopsy (often necessary to rule out an infectious process, especially in monoarticular arthritis with constitutional symptoms).
- Antistreptolysin O (ASO) or anti-DNase B test (if the post-streptococcal infection is suspected).
- Electrocardiography (an electrocardiogram in patients with a prolonged course of Reiter’s syndrome).
Treatment
There is no curative treatment; instead, the goal of treatment is to relieve symptoms and is based on the severity of the symptoms. Almost two-thirds of patients have a self-limiting course; up to 30% develop chronic symptoms, posing a therapeutic challenge.
Pharmacological agents that can be used in the treatment of Reiter’s syndrome include the following:
Nonsteroidal anti-inflammatory drugs (NSAIDs): are the pillars of the therapy.
- Corticosteroids (topical, intraarticular, and systemic).
- Antibiotics (for ReA related to Chlamydia in particular) – Tetracyclines are commonly administered.
Disease-modifying antirheumatic drugs (DMARDs): Generally, when NSAIDs are ineffective or contraindicated, they include sulfasalazine, methotrexate, and anti-tumor necrosis factors (TNF) medications, such as etanercept and infliximab.
No specific surgical treatment is indicated, although ophthalmologic surgery may be justified to treat specific ocular manifestations of the disease.
Physical therapy can be instituted to prevent muscle wasting and reduce pain.
History of Reiter’s Syndrome
Reactive arthritis (ReA) is an autoimmune disease that develops due to an infection. Reiter’s syndrome has been associated with gastrointestinal (GI) infections with Shigella, Salmonella, Campylobacter, and other organisms, as well as with genitourinary disorders (GU) (especially with Chlamydia trachomatis).
Reiter’s syndrome was described by the German physician Hans Reiter in 1916, and for a time, the disorder became known as Reiter’s syndrome.
This eponymous is no longer used due to Reiter’s activities as a Nazi war criminal, and also because it was not the first description of Reiter’s syndrome and wrongly characterized the pathogenesis.
Reiter’s syndrome encompasses the older concepts of complete and incomplete reactive arthritis and a clinical syndrome of arthritis with or without extra-articular features that develop within one month of infectious diarrhea or GU infection.
The classic triad associated with this condition includes noninfectious urethritis, arthritis, and conjunctivitis (although this triad is not found in all cases).
Reiter’s syndrome is frequently associated with the haplotype of human leukocyte antigen (HLA) -B27 (HLA-B27).
It is classified into seronegative spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, arthropathy of associated inflammatory bowel disease, juvenile ankylosing spondylitis, juvenile chronic arthritis, and undifferentiated spondyloarthritis.
A study by Kaarela et al. reported that Reiter’s syndrome and ankylosing spondylitis appear to be identical. When evaluating the long-term results of reactive arthritis and ankylosing spondylitis to identify similarities in the manifestations of the disease, the researchers found several similarities.
Among these was the determination that sacroiliitis, peripheral arthritis, and iritis developed more frequently in chronic ReA and ankylosing spondylitis.
The majority of ReA patients are young men. Young children tend to have the post dysenteric form, while adolescents and young men are more likely to develop Reiter’s syndrome after a genitourinary infection.
Some authors, interpreting the mucocutaneous findings as pustular psoriasis and seronegative arthritis like psoriatic arthritis, believe that ReA is better classified as psoriasis.
Definition of criteria
The classic triad of Reiter’s syndrome, namely, arthritis, conjunctivitis, and noninfectious urethritis, occurs in only about a third of patients at baseline. The less stringent diagnostic criteria have specified a 1-month duration of arthritis associated with urethritis, cervicitis, or both.
However, it has been suggested that the syndrome is best described as a triad consisting of arthritis, conjunctivitis, or iridocyclitis and non-bacterial urethritis or cervicitis.
Some prefer to describe it as a tetrad, adding the mucocutaneous findings of balanitis circinata and keratoderma blennorrhagicum to the classical triad. In this view, complete and incomplete forms of Reiter’s syndrome can be identified by the presence or absence of mucocutaneous involvement.
Causes
A GU or GI infection usually triggers Reiter’s syndrome (see Etiology). The evidence indicates that a previous respiratory infection with Chlamydia can also trigger Reiter’s syndrome.
The frequency of Reiter’s syndrome after enteric infection is 1-4%, but it varies greatly, even between outbreaks of the same organism.
Although severely symptomatic gastrointestinal infections are associated with an increased risk of Reiter’s syndrome, asymptomatic venereal infections often cause this disease. About 10% of patients do not have a previous symptomatic infection.
Reiter syndrome is associated with HLA-B27, an MHC class I molecule involved in presenting T cell antigens. The results for HLA-B27 are positive in 65-96% of patients (average, 75%) with Reiter’s syndrome.
Patients with HLA-B27, as well as those with a robust familial clustering of the disease, tend to develop more severe and long-lasting illnesses.
The mechanism by which the interaction of the instigating organism with the host (often HLA-B27-positive) leads to the development of Reiter’s syndrome is not known.
It is unclear whether microbial antigens cross-react with autoproteins, stimulating and perpetuating an autoimmune response mediated by type 2 T helper (Th2) cells.
Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to a decrease in bacterial clearance.
Synovial fluid cultures are negative for enteric organisms or Chlamydia species.
However, a systemic and intrasynovial immune response has been found in organisms with intraarticular antibodies and T cells reactive with bacteria. In addition, bacterial antigen has been found in the joints. Therefore, the elements for a mediated immune synovitis are present.
Proinflammatory cytokines mediate synovitis in Reiter’s syndrome.
Under the influence of transforming growth factor (TGF) -β and other cytokines, such as interleukin (IL) -6, Naive T cells differentiate into Th17 effector cells, which then produce IL-17. IL-17 is one of the central elevated cytokines in the synovial fluid of these patients.
Deficiencies in regulatory mechanisms may increase proinflammatory cytokine production and worse outcomes.
Toll-like receptors (TLR) recognize different extracellular antigens as part of the innate immune system. TLR-4 recognizes gram-negative lipopolysaccharide (LPS).
Studies in mice and humans showed abnormalities in antigen presentation due to downregulation of TLR-4 co-stimulatory receptors in patients with ReA. Subsequent studies implicated the TLR-2 polymorphism associated with acute ReA; however, his role is still disputed.
Molecular evidence of bacterial DNA (obtained by polymerase chain reaction [PCR]) in synovial fluids has been found only in Reiter’s syndrome related to Chlamydia.
A placebo-controlled trial of a tetracycline derivative (i.e., lymecycline) has shown a reduction in the duration of acute Reiter’s syndrome related to Chlamydia but not associated with enteritis.
This suggests that persistent infection may play a role in some cases of Chlamydia-associated ReA.
In a subsequent trial, the combination of doxycycline and rifampin was superior to doxycycline alone in reducing morning stiffness and inflamed and tender joints in patients with undifferentiated spondyloarthropathy.
The role of HLA-B27 in this scenario remains to be fully defined. The following theories have been proposed:
Molecular mimicry: this hypothesis suggests a similarity at the molecular level between the molecule of HLA-B27 and the inciting organisms, which allows the triggering of an immune response and the subsequent development of clinical disease.
HLA-B27 as a receptor for certain bacteria: at present, there is little evidence to confirm or refute this hypothesis
Defective class, I antigen-mediated cellular response: this hypothesis suggests that the HLA-B27 molecule may be a lousy molecule associated with an aberrant cytotoxic T cell response.
Reiter’s syndrome can occur in patients with HIV infection or AIDS, most likely because both conditions can be acquired sexually rather than because Reiter’s syndrome is triggered by HIV.
The course of Reiter’s syndrome in these patients tends to be severe, with a generalized rash that resembles psoriasis, profound arthritis, and frank AIDS.
The frequency of HLA-B27 is the same as that associated with Reiter’s syndrome, not related to AIDS in a similar demographic group.
This association points out the possible importance of CD8 + cytotoxic T cells compared to Th CD4 + cells in the pathogenesis of Reiter’s syndrome.
Reiter’s syndrome is sometimes divided into an epidemic and endemic forms. While a triggering agent can be identified for epidemic Reiter’s syndrome, none have been identified for the endemic Reiter syndrome.
Differentiation between the two types of Reiter’s syndrome can be difficult in some cases; however, it is not essential for diagnosis or treatment.
Infectious causes
Reiter’s syndrome is usually triggered by a gastrointestinal or gastrointestinal infection and is sometimes classified as venereal or dysenteric.
Such infections are mainly the result of gram-negative, obligate, or intracellular facultative pathogens. The organisms that have been associated with Reiter’s syndrome include the following:
- C trachomatis/C pneumoniae.
- Ureaplasma urealyticum.
- Lymphogranuloma venereum (serotype L2).
- Neisseria gonorrhoeae.
- Shigella flexneri.
- Salmonella enterica serovares Typhimurium, Enteritidis y Hadar.
- Mycoplasma pneumoniae.
- Mycobacterial tuberculosis.
- Cyclospora.
- Yersinia enterocolitica y pseudotuberculosis.
- Campylobacter jejuni y coli.
- Clostridium difficile.
- Beta-hemolytic (for example, group A) and viridans streptococci.
The data suggest that chlamydial Reiter syndrome is underdiagnosed, and asymptomatic chlamydia infections may be a common cause.
An essential difference between Reiter’s syndrome induced by Chlamydia (post-venereal) and Post-censorian Reiter syndrome is the presence of viable but aberrant chlamydial organisms in the synovial fluid (called persistence of Chlamydia).
The PCR assay to detect C. trachomatis DNA in synovial samples may be an excellent method to diagnose Chlamydia-induced arthritis in patients with Reiter’s syndrome.
The prevalence of different serotypes of antibodies against C. trachomatis and the incidence of Reiter’s syndrome induced by Chlamydia was studied among patients with early arthritis in a defined population in Finland.
Antibodies against C. trachomatis were more common in patients with arthritis because cases with Reiter’s syndrome induced by Chlamydia are included in this subgroup.
It is known that Ureaplasma organisms are capable of causing non-gonococcal experimental and clinical urethritis.
Synovial mononuclear cells from the arthritic joints of patients with Reiter’s syndrome react with Ureaplasma antigens; This organism has been isolated from a patient with Reiter’s syndrome.
The enteric pathogen that most commonly results in Reiter’s syndrome is Campylobacter (C jejuni, 90-95%; C coli, 5-10%).
Patients with Reiter’s syndrome with arthritic symptoms are more frequently infected with strains of C. jejuni with lipo-oligosaccharides of sialic acid. In addition, the sialylation of lipo-oligosaccharides of C jejuni is associated with more enteric severe disease.
Group A streptococci are known to be capable of causing post-streptococcal ReA. Patients with this condition demonstrate an increase in antistreptolysin O (ASO) antibodies and an increase in the rate of erythrocyte sedimentation (ESR). ReA can also be induced by tonsillitis.
In one study, 13 of 21 patients were positive for ASO, and 12 were positive for group A Streptococcus.
Acute tuberculosis can sometimes cause Reiter’s syndrome. The resulting condition is known as Poncet’s disease, which is a different entity from tuberculous arthritis.
Other possible links include infection with C difficile and Bacillus Calmette-Guérin (BCG). BCV intravesical instillation for bladder cancer has been associated with reactive arthritis. Reiter’s syndrome has also been shown to occur after vaccination against tetanus and rabies.
Genetic factors
Reiter’s syndrome has a significant genetic component; it tends to group in certain families and affects almost exclusively men, and HLA-B27 is identified in 70-80% of patients.
HLA-B27 can share molecular characteristics with bacterial epitopes, facilitating instrumental autoimmune cross-reactions in pathogenesis. HLA-B27 contributes to the pathogenesis of the disease and reportedly increases the risk of Reiter’s syndrome 50-fold.
It has also been shown that the HLA-B51 and HLA-DRB1 alleles are associated with Reiter’s syndrome.
Rihl et al. found a high proportion of proangiogenic factors that account for a genetically determined susceptibility to Reiter’s syndrome.
Other factors of Reiter’s syndrome
It has been described that Reiter’s syndrome is triggered by adalimumab and leflunomide in a patient with ankylosing spondyloarthropathy and Crohn’s disease.
The duration of diarrhea and weight loss are also considered risk factors in the development of Reiter’s syndrome after enteric infections.
Epidemiology of Reiter’s Syndrome
Infections that prompt Reiter’s syndrome may vary depending on geographic location. For example, Yersinia enterocolitica is more commonly identified in Europe than in North America and, therefore, is responsible for more cases of Reiter syndrome in countries such as Finland and Norway.
Reiter syndrome appears to be related to the prevalence of HLA-B27 in a population and the rate of urethritis/cervicitis and infectious diarrhea.
More than 40 subtypes of HLA-B27 are known; those associated with spondyloarthropathies are HLA-B2702, B2704, and B2705. These subtypes can be geographically segregated.
For example, subtype B2705 is predominantly found in Latin America, Brazil, Taiwan, and parts of India. It is noteworthy that the subtypes HLA-B2706 and B2709, which are found in Indonesia and Sardinia, respectively, may be partially protective against Reiter’s syndrome.
In Norway, an annual incidence of 4.6 cases per 100,000 inhabitants was reported for chlamydial ReA and an incidence of 5 points per 100,000 population for ReA induced by enteric bacteria from 1988-to 1990.
In Finland, it was found that almost 2% of men had ReA after non-gonococcal urethritis; the incidence of HLA-B27 is higher in the Finnish population. In the United Kingdom, the incidence of ReA after urethritis is around 0.8%.
In the Czech Republic, the annual incidence of ReA in adults from 2002-to 2003 was reported in 9.3 cases per 100,000 population.
Demographic data of Reiter’s syndrome related to age, sex, and race
Reiter’s syndrome is more common in young men, with the appearance peak in the third decade of life.
It rarely happens in children; when it does, the enteric form of the disease is predominant. Most pediatric patients present symptoms after the age of 9 years.
In a study of 100 patients with Reiter’s syndrome, Lahu and his colleagues found that most patients were between 20 and 40 years old and that the first attack occurred earlier in men than in women.
Of the 100 patients studied, 66% were male. Urogenital and nasopharyngeal infections were more common among male patients.
Reiter’s syndrome after enteric infections transmitted by food is equally common in men and women.
However, the male-female relationship for the disease associated with acquired venereal infections has been estimated from 5: 1 to 10: 1. A possible prostatic focus of persistent illness is postulated to explain the male predominance of ReA.
The frequency of Reiter’s syndrome seems to be related to the prevalence of HLA-B27 in the population.
As with other spondyloarthropathies, HLA-B27 and ReA are more common in white people than black people. When ReA occurs in black people, it is often harmful B27.
Forecast
Reiter’s syndrome has a variable natural history but generally follows a self-limiting course, with a resolution of symptoms of 3 to 12 months, even in patients who are acutely incapacitated.
A fatal result is rarely reported, but death can occur and is usually related to the adverse effects of the treatment. Postdysenteric cases are associated with a better prognosis than post-venereal cases.
The presence of HLA-B27 can predict a more prolonged course and a severe outcome, as well as infections triggered by Yersinia, Salmonella, Shigella, or Chlamydia.
Reiter’s syndrome has a high tendency to recur (15-50% of cases), particularly in individuals who are HLA-B27-positive. A new infection or another stress factor could cause the reactivation of the disease.
Approximately 15-30% of patients with Reiter’s syndrome develop arthritis, enthesitis, or long-term spondylitis, sometimes destructive. A 1994 study analyzed seven factors as predictors of long-term outcomes in spondyloarthropathies.
In this study, the number of patients with Reiter’s syndrome was low, and a valid subgroup analysis was impossible.
The presence of the hip joint involvement, a VSG greater than 30, and the lack of response to nonsteroidal anti-inflammatory drugs (NSAIDs) are likely to augur a severe outcome or chronicity in Reiter’s syndrome.
Patient education on Reiter’s syndrome
Poor quality of life related to health and deterioration of daily physical functioning is observed in patients with refractory or chronic Reiter syndrome. Strategies focused on improving or maintaining functional status are essential in the treatment.
The educational measures that may be useful include the following:
- Encourage patients to control themselves for any change in symptoms.
- Help patients become aware of this syndrome’s chronic or recurrent nature and accept the need for long-term medications.
- Inform patients that their condition puts them at a higher than average risk for elective eye surgery.
- Discourage inactivity and immobilization.
- Encourage stretching exercises and range of motion.
- Provide adolescent patients with information about the prevention of sexually transmitted diseases and the use of condoms.
