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Reactive Arthritis: A Review
Journal of Adolescent Health 44 (2009) 309–315
Review article
Reactive Arthritis: A Review Paul S. Kim M.D.,a,*, Thomas L. Klausmeier, M.D.b, and Donald P. Orr, M.D.a a
Section of Adolescent Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana Section of Pediatric Rheumatology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana Manuscript received June 23, 2008; manuscript accepted December 4, 2008
b
Abstract
This review article summarizes the available literature on adolescent reactive arthritis. A review of the pathophysiology, diagnosis, and treatment guidelines will be helpful to better diagnose and treat reactive arthritis. Ó 2009 Society for Adolescent Medicine. All rights reserved.
Keywords:
Adolescent; Reactive arthritis; Reiter syndrome; Arthritis; Spondyloarthritis; Enthesitis-related arthritis
Joint symptoms are common among adolescents. Most often the symptoms are related to trauma or overuse, are transient, and are not serious; however arthritis must be included in the differential diagnosis. Reactive arthritis (ReA) is one of the types known to primarily affect young men. Because it can be a complication of sexually transmitted infections, ReA is an important topic in adolescent medicine. Although the disease is usually self-limiting, patients with ReA may experience relapses, develop chronic arthritis or ankylosing spondylitis, and experience cardiac or other complications [1,2]. This article reviews current literature to enable adolescent practitioners to better identify and treat this disease. The condition known as ReA was described by Hans Reiter in 1916 and was known as Reiter Syndrome. The classic triad of Reiter Syndrome consists of postinfectious arthritis, nongonococcal urethritis, and conjunctivitis. However, Hans Reiter was held accountable for war crimes during the Second World War, and in 2003 the term ‘‘Reiter Syndrome’’ was replaced with ‘‘reactive arthritis’’ [3]. ReA is classified as a type of spondyloarthritis. This group of joint diseases features mono- or oligoarthritis, often associated with extra-articular inflammatory manifestations involving the musculoskeletal, ophthalmologic, dermatologic, and genitourinary systems. These were previously referred to as seronegative spondyloarthritides because the rheumatoid factor (RF) is usually negative. The diagnostic subgroups of the spondyloarthritis family and its classifica-
*Address correspondence to: Paul S. Kim, M.D., Department of Pediatrics, Indiana University School of Medicine, 410 W 10th Street, Room 1001, Indianapolis, IN 46202. E-mail address: [email protected]
tion criteria are listed in Table 1 [2,4–7]. This entire group has a strong association with genetic marker human leukocyte antigen B27 (HLA-B27) and a tendency for familial aggregation. Undifferentiated arthritis describes those patients whose clinical features do not fit exactly in any one of the categories within the spondyloarthritis family. Of note, for children and adolescents less than 16 years of age, the International League of Associations for Rheumatology recently proposed to classify childhood reactive arthritis under the umbrella of Juvenile Idiopathic Arthritis (JIA) [8], as enthesitis-related arthritis (ERA). However, the authors state that before this is used in the clinical setting, this classification scheme requires validation. Despite the proposed difference in classification for reactive arthritis patients in relation to their age, these are essentially the same disease processes. In this article we will use the adult classification system. Epidemiology ReA occurs worldwide and predominantly occurs in adults aged 20–40 years. It begins with an enteric, urogenital, or possibly an upper respiratory tract infection by a triggering microorganism (Table 2) [2]. The male:female ratio is 3:1. Women often have less severe disease than men. Bas et al [9] postulates that the male predominance of urogenital ReA may be due to a less potent antibody production in response to chlamydial infection in men compared with women, which may lead to systemic dissemination of the organisms to the joints. ReA occurs in 1–4% of patients a few days to 6 weeks after infection of the urogenital or enteric tract, and 30– 70% of these patients are positive for HLA-B27 [4]. It is important to note that the arthritic symptoms may be present
1054-139X/09/$ – see front matter Ó 2009 Society for Adolescent Medicine. All rights reserved. doi:10.1016/j.jadohealth.2008.12.007
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Table 1 The spondyloarthropathy family—classification criteria Reactive arthritis
Enteropathic arthritis
Ankylosing spondylitis
Psoriatic Arthritis
Arthritis pattern Asymmetric mono or oligoarthritis, often of lower extremities
Diagnosis Preceding infection; Laboratory tests: CBC, ESR, CRP, RF, ANA, HLAB27; Imaging: X-ray
Large joints affected: hip, knee, wrists in 10-20% of patients; Arthritic symptoms correlates to disease activity Inflammatory back pain; SI joint tenderness; Limited spinal / chest mobility
Compatible symptoms; Colonoscopy / biopsy; Laboratory tests: CBC, ESR, CRP, ASCA, atypical p-ANCA
Inflammatory, asymmetric oligoarthritis; Distal joints can be affected
Inflammatory arthritis, enthesitis or back pain; Skin lesions; Nail lesions; RF negative; Juxtaarticular bone formation on X-ray
Compatible symptoms; Imaging: evidence of sacroiliitis; Modified Schober testa; Chest expansion testb; Laboratory tests: HLA-B27, CRP
Other/Extra-articular Sx May also have ophthalmologic, musculoskeletal, genitourinary, dermatologic, or cardiovascular signs and symptoms May cause growth failure and delayed puberty
Positive family history provides support of diagnosis; May affect extraspinal structures such as peripheral joints, enthesis, eyes or aorta, especially in cases of juvenile ankylosing spondylitis Different presentations possible: asymmetric oligoarthritis, symmetric polyarthritis, arthritis mutilans, spondyloarthropathy
ANA ¼ antinuclear antibody; ASCA ¼ anti–Saccharomyces cerevisiae mannan antibodies test; CBC ¼ complete blood count; CRP ¼ C-reactive protein; ESR ¼ erythrocyte sedimentation rate; HLA-B27 ¼ hHHuman leukocyte antigen B27; p-ANCA ¼ perinuclear staining antineutrophil cytoplasmic antibodies; RF ¼ rheumatoid factor; SI ¼ sacroiliac. a Modified Schober test: With the patient standing erect, the position of the fifth lumbar spinous process is marked; additional marks are made 10 cm above and 5 cm below in the midline. The patient then bends forward maximally, and the distance between the upper and lower marks is measured. Persons with normal spinal mobility have increase in measured distance of 5 cm. Of note, adolescents may have increased normal range because of hypermobility. b Chest expansion test: Measured at the level of the fourth intercostal space. Arms should be elevated above and hands folded behind the head. The patient is instructed to exert maximal forced expiration followed by maximal inspiration. The expansion is usually 5 cm or more. An expansion of less than 2.5 cm is abnormal.
before the full resolution of the initial infection. The prevalence in adolescents and young adults varies widely by country and is difficult to accurately estimate because of differences in classification between adults and children and lack of national registries. Ravelli and Martini estimate that ERA accounts for 3–11% of those diagnosed with JIA [10]. Among adult populations, the prevalence is estimated to be 30–40 per 100,000 persons [4]. The incidence of ReA is related to the population prevalence of HLA-B27 and the incidence of urethritis, cervicitis, and infectious diarrhea caused by a predisposing organism. In Europe, the incidence of ReA is estimated to be 10–30 per 100,000 persons [4]. Some studies have shown the incidence of the enteric type to be as high as 7% after shigella [11] and 29% after Salmonella enteritidis [12]. Rich et al [13] examined the incidence of urogenital ReA in an urban STD clinic in Alabama using a survey and confirmatory physical examination. They found that 4.1% of patients with urethral inflammation or infection had features of ReA. It is likely that the true incidence of ReA is higher than what is shown by the population-based studies because mild cases can go unrecognized. Pathophysiology Components of triggering bacteria including nucleic acids and protein have been identified in the synovium and in circulatory monocytes of patients diagnosed with ReA [14]. It is not clear how and in what form the bacterial components
reach the joint and whether there are viable bacteria in the joint. In one older Russian study, more than 60% of patients with ReA had positive joint culture results for Chlamydia trachomatis [15]. However, negative joint culture results are the norm in the majority of patients with ReA, making it unlikely that viable bacteria exist within the joint space. Rather, nonviable bacterial components are thought to cause proliferation of the synovial fluid mononuclear cells, and this inflammatory reaction is responsible for the manifestations of ReA [16]. Individuals who are class I major histocompatibility complex (MHC) glycoprotein HLA-B27 positive have a 50-fold increased risk of developing ReA. HLA-B27– positive patients with ReA are more likely to have severe, prolonged episodes and to have associated mucocutaneous disease, axial disease, carditis, and uveitis [2]. There is also an increased risk of developing radiologic sacroiliitis in these patients [17,18]. Several theories attempt to explain the association between HLA-B27 and ReA. The arthritogenic peptide hypothesis is the most frequently cited [4]. Some peptide antigens from chlamydia and yersinia can only be presented by HLA-B27. These peptides are stimulatory for CD8þ T-cells derived from patients with ReA. Thus, it is inferred that peptides presented to the T-cells by HLA-B27 may play a role in the pathogenesis and the severity of ReA. Another theory involves interferon- g (IFN-g) because it may have an important role in clearance of the bacteria associated with ReA. Bas et al [19] showed that for a subset of
P.S. Kim et al. / Journal of Adolescent Health 44 (2009) 309–315 Table 2 Etiologic microorganisms of reactive arthritis Probable Chlamydia trachomatis Shigella flexneri Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni Possible Neisseria gonorrhoeae Mycoplasma fermentans Mycoplasma genitalium Ureaplasma urealyticum Escherichia coli Cryptosporidium Entamoeba histolytica Giardia lamblia Brucella abortus Clostridia difficile Stretpococcus pyogenes Chlamydia pneumoniae Chlamydia psittaci
patients with chlamydia-induced ReA, synovial fluid concentration of IFN-g was significantly lower in the group that was HLA-B27 positive. Inadequate clearance of the bacteria could be related to the more severe and chronic arthritis seen in these patients. After a 2-year follow-up in this study of patients with ReA, two of 19 HLA-B27–positive patients with low synovial fluid levels of IFN-g had chronic arthritis whereas within 1 year all 15 patients who were HLA-B27 negative had complete resolution of arthritis. It appears that HLA-B27 is not the only predisposing immunologic factor for the development of ReA. Yin et al [20] found that the balance of interleukin (IL–10) and IL12 in the synovial fluid of joints is also important. IL-10 is responsible for the suppression of Th-1–like cytokines including IFN-g and tumor necrosis factor–a (TNF-a), whereas IL-12 enhances them. These cytokines are necessary for the elimination of bacteria associated with ReA. In patients with ReA, IL-10 is present at high amounts within the synovial fluid upon stimulation with bacterial antigens. This may contribute to the decreased clearance of the bacteria or their components from the joint and lead to ReA. These authors suggest future study to determine whether IL-12 could be a possible treatment for ReA. Clinical manifestations The latent period from infection to onset of symptoms can be anywhere from few days to 6 weeks, with an average of 4 weeks [4,21]. The typical pattern of ReA is an asymmetric, mono- or oligoarthritis, predominantly of the lower extremities including the knees, ankles, and feet. The severity of ReA depends on the population being studied. Patients hospitalized with ReA are more likely to be HLA-B27 positive, to
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have more severe arthritis in large joints including the knees and ankles, and to have increased inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ReA patients in population-based outpatient series tend to have less severe arthritis [4]. Predictors of more severe disease at presentation include arthritis of the hip, ESR >30, poor response to nonsteroidal inflammatory drugs (NSAIDS), lumbar spine stiffness, dactylitis, oligoarthritis, and onset at age less than 16 years [2]. Heel and foot involvement tends to be an important predictor of poor functional outcome and disability. ReA may last for several weeks to months. Joint pain, mild constitutional symptoms including fever, weight loss, and malaise, and other extra-articular manifestations usually resolve within 2 to 3 months. If symptoms last for more than 6 months, then the condition is classified as chronic ReA [21]. In addition to the peripheral arthritis, musculoskeletal symptoms may include inflammatory pain in cervical, thoracic, and lumbosacral spine. Radiographically verifiable sacroiliitis can occur in up to one-third of patients with urogenital ReA and in about one-tenth of patients with enteric ReA. The main symptom of sacroiliitis is often an acute low back pain radiating to the hips that is worse during the night and may also manifest as alternating buttock pain [4]. Sacroilitis is more common in those with severe, prolonged episodes of ReA. Enthesitis, inflammation occurring at the point of attachment of skeletal muscles to bone, is commonly seen in ReA. Enthesitis gives rise to localized pain, swelling, and tenderness. The plantar aponeurosis and Achilles’ tendon attachments to the calcaneum are most commonly seen, often causing heel pain and difficulty walking [2]. In adolescents, enthesitic points also may include the base of the fifth metatarsal, metatarsal heads, patellar tendon insertions, and the greater trochanter of the hip. Involvement of interphalangeal joints with digital tendonitis and multiple entheseal lesions probably is the cause of dactylitis or ‘‘sausage digits’’ also seen in ReA. Arthritis in the upper limbs and a mild polyarticular form of arthritis in the small joints has also been reported. In a recent study of 45 patients with ReA after a campylobacter infection, 36% had proximal interphalangeal joint involvement, 33% had metacarpophalangeal joint involvement, and 22% had wrist involvement [22]. The upper extremity arthritis tended to be so mild that patients did not seek medical attention for their symptoms. The genitourinary system may also be involved in both urogenital and enteric ReA as an extra-articular manifestation. These symptoms are distinct from the initial infectious urethritis in the case of urogenital ReA and include subsequent frequency, dysuria, urgency, and urethral discharge. In males, the prostate, urethra, and penis may be involved. Females may develop cervicitis, urethritis, salpingitis, or vulvovaginitis, but these may be asymptomatic. Severe glomerulonephritis and IgA nephropathy have been rarely associated with ReA [2].
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Conjunctivitis with mucopurulent discharge is the most common ophthalmologic symptom of ReA and may be found in up to 30% of patients. This usually occurs early in the course, often preceding the arthritis by a few days. It tends to be bilateral and mild and is often ignored. Symptoms include red eyes, crusting, and sterile ocular discharge. Signs and symptoms usually subside within 1–4 weeks but occasionally may progress to episcleritis, keratitis, or corneal ulceration. Anterior uveitis, photophobia, pain, and decreased vision rarely occur [2]. Dermatologic manifestations include balanitis circinata and keratoderma blennorrhagica. Balanitis circinata consists of small, shallow, painless sores or ulcers at the end of the penis and is found in 20–40% of males affected with ReA. These are usually moist on uncircumcised patients but may harden and crust on circumcised patients and lead to pain or scarring. Keratoderma blennorrhagica, which affects 5–10% of patients, is highly characteristic of ReA. These lesions begin as pustules, which become hyperkeratotic and scaly and may coalesce into larger psoriatic-like plaques. These are generally found on the sole, palm, toe, scrotum, trunk, or scalp. Other stigmata include oral ulcers, rashes or nail changes similar to psoriasis including pitting and thickening [2]. Clinically apparent involvement of the cardiovascular system is rare. Transient conduction abnormalities, including heart block on the electrocardiogram are not uncommon but are generally of little significance. Proximal aortitis affects 1– 2% of patients, particularly those with severe or recurrent disease. This may cause secondary aortic regurgitation and eventually warrant aortic valve replacement to avoid heart failure. Aneurysmal aortic dilatation, myocarditis, and pericarditis have been reported, but these are exceedingly rare [2,23].
Differential diagnosis It is necessary to exclude other causes of acute mono- or oligoarthritis. Some viruses including parvovirus B19, hepatitis B and C viruses, and human immunodeficiency virus rarely may cause virally associated arthritis. However, these usually mimic rheumatoid arthritis and have a symmetric and oligoarticular pattern of arthritis that is different from ReA [24]. Bacterial infection or trauma should also be considered. Disseminated gonococcal infection (DGI) can cause arthritis and arthralgia. Recent symptomatic genital infection is uncommon, and an asymptomatic mucosal infection is thought to be the primary event [25]. Patients may have joint pain involving fingers, wrists, knees, ankles, or toes and transient pustular or vesicular skin lesions. Results of cultures or nucleic acid amplification test (NAAT) of the urethra, cervix, or rectum are more likely to be positive than blood or synovial fluid cultures. These tests are important to rule out disseminated gonococcal infection in certain patients.
Clinically, the arthritis associated with DGI quickly resolves with appropriate antibiotics. Other possible diseases that can cause diarrhea and arthritis include inflammatory bowel disease, celiac sprue, Whipple’s and Behc¸et’s disease. Pseudomembranous colitis, intestinal bypass surgery, and enteroviral infection may also cause similar symptoms but are rare in the adolescent population. Diagnosis Diagnosis of ReA is based on a clinical algorithm developed from observational data in Germany and Scandinavia [26]. The first criterion is having mono- or oligoarthritis of the lower extremities. The second criterion is exclusion of other diagnoses including septic or traumatic arthritis and the other rarer conditions. If both criteria are present, then the probability of ReA is 40%. Evidence of a previous infection can be found in approximately 60% of patients with ReA and is regarded as being the most relevant criterion in diagnosing ReA [4,26]. If there is a history of symptomatic preceding infection with Chlamydia trachomatis, then the probability of ReA increases to 90%. If bacteria associated with ReA can be cultured from the stool, then the probability of ReA increases to 70%. It is also important to keep in mind that some predisposing infections may be asymptomatic, especially chlamydia. The recommendation is to search for chlamydia in urine, urethra, or cervix if there is any suspicion of ReA regardless of symptoms. If the patient either has or recently has had diarrhea associated with ReA, then a stool culture to look for causative enteric infections would be appropriate [2,21]. Serologic testing for various enteric pathogens is not very useful because it may not be specific for a recent infection. There are no internationally validated standard serologic techniques or thresholds for this type of testing [26,27]. A clinical diagnostic pathway is depicted in Figure 1 [2,26,28]. Nonspecific laboratory findings initially include an elevated ESR and CRP acutely, which usually return to normal in the chronic stage of the disease. Patients can develop neutrophilic leukocytosis for acute cases of ReA and mild normocytic anemia for chronic cases. Both RF and antinuclear antibody (ANA) should be measured to exclude other causes of arthritis. A Gram stain and culture of the synovial fluid may be important to exclude septic arthritis, especially if the case involves a monoarticular arthritis with constitutional symptoms. A positive HLAB27 result increases the likelihood of ReA, but this is neither sensitive nor specific for the condition [26]. Finally, an HIV test should be considered because ReA has a higher prevalence in the HIV-positive population. ReA has been reported in up to 11% of HIV-infected patients, and the symptoms tend to be more severe [2]. Radiographs of the affected site are usually normal, and imaging studies do not have to be performed for the diagnosis of ReA if clinical suspicion is high. However, in less clear
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Diagnostic Algorithm for Adolescents with Suspected Reactive Arthritis
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Arthritis (2 of 3 features) - Asymmetric - Mono or oligo arthritis - Lower limbs
Rule out other diagnoses - Check ESR, CBC, CRP, RF, ANA - Synovial fluid analysis - Plain X-ray
Other diagnosis found
Other diagnoses ruled out
Symptomatic infection 3 days to 6 weeks prior to arthritic symptoms - Enteritis: diarrhea for one or more days - Urethritis: dysuria / discharge for one or more days
No symptomatic infection
Test for Chlamydia trachomatis
No evidence of infection
Positive for infection - Nucleic Acid Amplification Test (NAAT) - Urine / Urethra - Cervix - Synovial fluid
Possible Reactive Arthritis (~40% chance)
No evidence of triggering infection
Probable Reactive Arthritis (40-70% chance)
Evidence of triggering infection: - Chlamydia trachomatis - Urine, urethral/cervical NAAT - Synovial fluid NAAT positive for chlamydia - Reactive arthritis associated enterobacteria - Positive stool culture - +/- Serologic studies
Definite Reactive Arthritis (70 – 90% chance)
Figure 1. Diagnostic algorithm for adolescents with suspected reactive arthritis.
cases of ReA, plain radiographs may be used to rule out other diagnoses such as osteoarthritis. Also, plain radiographs may occasionally show nonspecific changes such as periarticular osteopenia and soft tissue swelling in acute ReA and joint erosions may develop with recurrent or chronic disease [2]. Ultrasound of the entheseal insertions is more accurate than clinical examination in diagnosing enthesopathy, periosteal reaction, and tendinosis but is of limited availability. Scintigraphy can show joint inflammation and is useful for demonstrating enthesitis and sacroiliac inflammation. However, scintigraphy subjects a patient to a significant radiation exposure and is of low specificity; therefore it is rarely used. Magnetic resonance imaging (MRI) is also very sensitive for sacroiliac and spinal inflammation. Unfortunately, however, there are no guidelines on how to use and interpret the newer imaging techniques [4]. Treatment The goals of treatment are to decrease pain and inflammation, minimize disability, and prevent relapse or progression to chronic disease. As a screen for extra-articular involvement, an electrocardiogram, echocardiogram, and ophthalmologic referral is recommended, especially in chronic cases of ReA. Because there is a significant risk of some patients developing chronic disease, a rheumatologist should be consulted as soon as the diagnosis of ReA is made.
General treatment of acute joint inflammation includes local cold treatment and avoidance of overuse. For those with enthesitis, orthotics such as insoles or heel support may limit pain and increase mobility. Short periods of non–weightbearing status may reduce inflammation and decrease the pressure of the body’s weight on painful joints. Gentle range-of-motion and strengthening exercises are important to prevent muscle atrophy. To assess the response to treatment, the number of swollen or tender joints, the intensity of joint pain, and the presence or severity of enthesitis can be measured. Medical treatment of ReA starts with NSAIDs, most commonly ibuprofen, indomethacin, or naproxen. These do not affect the course of the disease but provide symptom relief and may facilitate physical therapy. NSAIDs should be continued for at least 2–4 weeks before advancing to more potent medications or interventions. Intraarticular glucocorticoid injection may be beneficial for mono- or oligoarticular disease and for enthesopathy but should be used with caution in the pediatric population. The Achilles tendon should not be injected directly; the inflamed bursa, if present, should be injected instead. Challenging sites should be injected using ultrasound guidance if possible. Systemic corticosteroids are indicated only if patients are bedridden secondary to severe polyarthritis or if significant atrioventricular conduction disturbances are present [4]. For adolescents, it is important to note that systemic corticosteroids should be of short
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duration because of increased toxicity, especially in the peripubertal stage. If the above methods fail to relieve the pain, then the next step would be a trial of disease modifying antirheumatic drugs (DMARDs). Among the DMARDs, usually the firstline medication is methotrexate or sulfasalazine, which is generally continued until the patient enters remission [29]. If the disease persists, anti-TNF agents may be used. An HIV test should be obtained before starting this treatment. Etanercept, a soluble TNF-a receptor immunoglobulin fusion protein, is the main agent to use in this class. In one study of patients with undifferentiated spondyloarthritis, a small subset of seven patients who satisfied the author’s criteria for ReA were treated with etanercept for 6 months and appeared to have a therapeutic benefit [30]. Antibiotic use is warranted if there is evidence of pathogenic organisms. Active genitourinary infections should be treated with appropriate antibiotics. For acute Chlamydia trachomatis infection, patients and sexual partners should receive the current recommended regimen for treatment to eradicate infection and prevent other late complications [4,31]. Prompt treatment of acute chlamydia infection in both patients and partners may lower the probability of developing ReA. For uncomplicated enteric infections, the benefits of antibiotic use are less clear. Generally antibiotics are not indicated unless the disease is severe or the patient is elderly or immunocompromised [2]. Although components of the triggering microbes can be demonstrated at the site of inflammation, there is no evidence for using long-term antibiotics in the treatment of ReA. Early studies with minocycline [32] and lymecycline [33] suggested a beneficial effect on long-term antibiotics, however randomized, controlled trials involving ciprofloxacin [34], azithromycin [35], and doxycycline [36] found that these antibiotics did not provide any significant benefit compared with placebo in the resolution of ReA. It is hypothesized that the initial favorable effect of minocycline and lymecycline may have been due to nonantibacterial features of those drugs such as immunosuppressive and anti-inflammatory effects [1]. Prognosis The prognosis of ReA varies, depending on the triggering pathogen and on the genetic background of the host. Usually, patients achieve full recovery by 2–6 months [35]. However, chronic arthritis (i.e., arthritis symptoms lasting more than 6 months) is observed in 4–19% of patients. Leirisalo-Repo et al [4] evaluated ReA induced by yersinia, salmonella, shigella, and chlamydia in Finland. Chronic arthritis occurred in 4% of patients with yersinia-induced arthritis, 17% of patients with chlamydia-induced arthritis, and 19% of patients with arthritis caused by salmonella or shigella. Over a 20-year follow-up, chronic relapsing ReA was found in 16–18% of patients in the group with ReA induced by salmonella, shigella, or chlamydia compared with 2% of
patients with ReA induced by yersinia. Data from multiple studies including patients of all ages demonstrate that sacroiliitis occurs in 14–49% and ankylosing spondylitis in 12– 26% when patients with ReA are followed for up to 20 years. There is increased risk of sacroiliitis and ankylosing spondylitis if patients are HLA-B27 positive or if the ReA was chlamydia induced [37]. Conclusion In summary, ReA is caused by a preceding infection. It is currently unclear how arthritis is caused by this infection, but it appears to be immunologically mediated. A better understanding of the pathogenesis of the disease should facilitate treatment and prevention of long-term complications. Treatment is currently focused on anti-inflammatory and immunomodulatory methods but often falls short of complete success. Long-term antibiotics do not appear to be beneficial. Future directions include the use of other immunomodulators or different antibiotics as treatment, establishing a clearer picture of the pathogenesis of ReA, and determining clearer diagnostic guidelines. Acknowledgment This work was supported in part by grant HRSA/MCHB T71MC000008. References [1] Toivanen A. Bacteria-triggered reactive arthritis: Implications for antibacterial treatment. Drugs 2001;61:343–51. [2] Hamadulay S, Glynne S, Keat A. When is arthritis reactive? Postgrad Med J 2006;82:446–53. [3] Panush R, Wallace D, Dorff R, et al. Retraction of the suggestion to use the term ‘‘Reiter’s syndrome’’ sixty-five years later: The legacy of Reiter, a war criminal, should not be eponymic honor but rather condemnation. Arthritis Rheum 2007;56:693. [4] Leirisalo-Repo M, Sieper J. Reactive arthritis: Epidemiology, clinical features, and treatment. In: Weisman M, van der Heijde D, Reveille J, eds. Ankylosing Spondylitis and the Spondyloarthropathies. Philadelphia: Mosby Elsevier, 2006:53–64. [5] Orchard T, Jewell D. Articular and ocular complications of inflammatory bowel disease. In: Targan S, Shanahan F, Karp L, eds. Inflammatory Bowel Disease: From Bench to Bedside. 2nd Edition. Dordrecht: Kluwer: Academic Publishers, 2003:747–56. [6] Palm O, Moum B, Jahnsen J, et al. The prevalence and incidence of peripheral arthritis in patients with inflammatory bowel disease, a prospective population-based study. Rheumatology 2001; 40:1256–61. [7] Passo M, Fitzgerald J, Brandt K. Arthritis associated with inflammatory bowel disease in children. Relationship of joint disease to activity and severity of bowel lesion. Dig Dis Sci 1986;31:492–7. [8] Petty R, Southwood T, Manners P, et al. International League of Associations for Rheumatology Classification of Juvenlie Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol 2004; 31:390–2. [9] Bas S, Scieux C, Vischer T. Male sex predominance in Chlamydia trachomatis sexually acquired reactive arthritis: Are women more protected by anti-chlamydia antibodies? Ann Rheum Dis 2001;60:605–11. [10] Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007; 369:767–78.
P.S. Kim et al. / Journal of Adolescent Health 44 (2009) 309–315 [11] Hannu T, Mattila L, Siitonen A, et al. Reactive arthritis attributable to Shigella infection: A clinical and epidemiological nationwide study. Ann Rheum Dis 2005;64:594–8. [12] Dworkin M, Shoemaker P, Goldoft M, et al. Reactive arthritis and Reiter’s syndrome following an outbreak of gastroenteritis caused by Salmonella enteritidis. Clinical Infectious Diseases 2001;33:1010–4. [13] Rich E, Hook E, Alarcon G, et al. Reactive arthritis in patients attending an urban sexually transmitted diseases clinic. Arthritis Rheum 1996; 39:1172–7. [14] Singh R, Shasany K, Aggarwal A, et al. Low molecular weight proteins of outer membrane of Salmonella typhimurium are immunogenic in Salmonella induced reactive arthritis revealed by proteomics. Clin Exp Immunol 2007;148:486–93. [15] Hughes R, Keat A. Reiter’s syndrome and reactive arthritis: A current view. Seminars in Arthritis and Rheumatism 1994;24:190–210. [16] Pacheco-Tena C, Alvarado de la Barrera C, Lopez-Vidal Y, et al. Bacterial DNA in synovial fluid cells of patients with juvenile onset spondyloarthropathies. Rheumatology 2001;40:920–7. [17] Ekman P, Kirveskari J, Granfors K. Modification of disease outcome in Salmonella-infected patients by HLA-B27. Arthritis Rheum 2000; 43:1527–34. [18] Leirisalo-Repo M, Helenius P, Hannu T, et al. Long term prognosis of reactive salmonella arthritis. Ann Rheum Dis 1997;56:516–20. [19] Bas S, Kvien T, Buchs N, et al. Lower level of synovial fluid interferong in HLA-B27-positive than in HLA-B27-negative patients with Chlamydia trachomatis reactive arthritis. Rheumatology 2003;42:461–7. [20] Yin Z, Braun J, Neure L, et al. Crucial role of interleukin-10 / interleukin-12 balance in the regulation of the type 2 T-helper cytokine response in reactive arthritis. Arthritis Rheum 1997;40:1788–97. [21] Braun J, Kingsley G, van der Heijde D, et al. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th international workshop on reactive arthritis, Berlin, Germany, July 3–6, 1999. J Rheumatol 2000;27:2185–92. [22] Hannu T, Mattila L, Rautelin H, et al. Campylobacter-triggered reactive arthritis: A population-based study. Rheumatology 2002; 41:312–8. [23] Novaro G, Erim T, Pinski S. Spondyloarthropathy-associated aortitis and massive thickening of the aortic-mitral curtain: Diagnosis by echocardiography. Cardiology 2006;106:98–101.
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[24] Vassilopoulos D, Calabrese L. Virally associated arthritis 2008: Clinical, epidemiologic, and pathophysiologic considerations. Arthritis Res Ther 2008;10:215–22. [25] O’Brien J, Goldenberg D, Rice P. Disseminated gonococcal infection: A prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine 1983;62:395–406. [26] Sieper J, Rudwaleit M, Braun J, et al. Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002;46:319–27. [27] Fendler C, Laitko S, Sorensen H, et al. Frequency of triggering bacteria in patients with reactive arthritis and undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis. Ann Rheum Dis 2001;60:337–43. [28] Kobayashi S, Kida I. Reactive arthritis: Recent advances and clinical manifestations. Internal Medicine 2005;44:408–12. [29] Clegg D, Reda D, Weisman M, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome): A Department of Veterans Affairs cooperative study. Arthritis Rheum 1996;39:2021–7. [30] Flagg S, Meador R, Hsia E, et al. Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: An open-label trial. Arthritis Rheum 2005;53:613–7. [31] Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR 2006;55:38–42. [32] Panayi G, Clark B. Minocycline in the treatment of patients with Reiter’s syndrome. Clin Exp Rheumatol 1989;7:100–1. [33] Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 1991;34:6–14. [34] Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of three month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis 2000;59:565–70. [35] Kvien T, Gaston J, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113–9. [36] Smieja M, MacPherson D, Kean W, et al. Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis. Ann Rheum Dis 2001;60:1088–94. [37] Leirisalo-Repo M. Prognosis, course of disease, and treatment of the spondylarthropaties. Rheum Dis Clin North Am 1998;24:737–51.
Review article
Reactive Arthritis: A Review Paul S. Kim M.D.,a,*, Thomas L. Klausmeier, M.D.b, and Donald P. Orr, M.D.a a
Section of Adolescent Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana Section of Pediatric Rheumatology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana Manuscript received June 23, 2008; manuscript accepted December 4, 2008
b
Abstract
This review article summarizes the available literature on adolescent reactive arthritis. A review of the pathophysiology, diagnosis, and treatment guidelines will be helpful to better diagnose and treat reactive arthritis. Ó 2009 Society for Adolescent Medicine. All rights reserved.
Keywords:
Adolescent; Reactive arthritis; Reiter syndrome; Arthritis; Spondyloarthritis; Enthesitis-related arthritis
Joint symptoms are common among adolescents. Most often the symptoms are related to trauma or overuse, are transient, and are not serious; however arthritis must be included in the differential diagnosis. Reactive arthritis (ReA) is one of the types known to primarily affect young men. Because it can be a complication of sexually transmitted infections, ReA is an important topic in adolescent medicine. Although the disease is usually self-limiting, patients with ReA may experience relapses, develop chronic arthritis or ankylosing spondylitis, and experience cardiac or other complications [1,2]. This article reviews current literature to enable adolescent practitioners to better identify and treat this disease. The condition known as ReA was described by Hans Reiter in 1916 and was known as Reiter Syndrome. The classic triad of Reiter Syndrome consists of postinfectious arthritis, nongonococcal urethritis, and conjunctivitis. However, Hans Reiter was held accountable for war crimes during the Second World War, and in 2003 the term ‘‘Reiter Syndrome’’ was replaced with ‘‘reactive arthritis’’ [3]. ReA is classified as a type of spondyloarthritis. This group of joint diseases features mono- or oligoarthritis, often associated with extra-articular inflammatory manifestations involving the musculoskeletal, ophthalmologic, dermatologic, and genitourinary systems. These were previously referred to as seronegative spondyloarthritides because the rheumatoid factor (RF) is usually negative. The diagnostic subgroups of the spondyloarthritis family and its classifica-
*Address correspondence to: Paul S. Kim, M.D., Department of Pediatrics, Indiana University School of Medicine, 410 W 10th Street, Room 1001, Indianapolis, IN 46202. E-mail address: [email protected]
tion criteria are listed in Table 1 [2,4–7]. This entire group has a strong association with genetic marker human leukocyte antigen B27 (HLA-B27) and a tendency for familial aggregation. Undifferentiated arthritis describes those patients whose clinical features do not fit exactly in any one of the categories within the spondyloarthritis family. Of note, for children and adolescents less than 16 years of age, the International League of Associations for Rheumatology recently proposed to classify childhood reactive arthritis under the umbrella of Juvenile Idiopathic Arthritis (JIA) [8], as enthesitis-related arthritis (ERA). However, the authors state that before this is used in the clinical setting, this classification scheme requires validation. Despite the proposed difference in classification for reactive arthritis patients in relation to their age, these are essentially the same disease processes. In this article we will use the adult classification system. Epidemiology ReA occurs worldwide and predominantly occurs in adults aged 20–40 years. It begins with an enteric, urogenital, or possibly an upper respiratory tract infection by a triggering microorganism (Table 2) [2]. The male:female ratio is 3:1. Women often have less severe disease than men. Bas et al [9] postulates that the male predominance of urogenital ReA may be due to a less potent antibody production in response to chlamydial infection in men compared with women, which may lead to systemic dissemination of the organisms to the joints. ReA occurs in 1–4% of patients a few days to 6 weeks after infection of the urogenital or enteric tract, and 30– 70% of these patients are positive for HLA-B27 [4]. It is important to note that the arthritic symptoms may be present
1054-139X/09/$ – see front matter Ó 2009 Society for Adolescent Medicine. All rights reserved. doi:10.1016/j.jadohealth.2008.12.007
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Table 1 The spondyloarthropathy family—classification criteria Reactive arthritis
Enteropathic arthritis
Ankylosing spondylitis
Psoriatic Arthritis
Arthritis pattern Asymmetric mono or oligoarthritis, often of lower extremities
Diagnosis Preceding infection; Laboratory tests: CBC, ESR, CRP, RF, ANA, HLAB27; Imaging: X-ray
Large joints affected: hip, knee, wrists in 10-20% of patients; Arthritic symptoms correlates to disease activity Inflammatory back pain; SI joint tenderness; Limited spinal / chest mobility
Compatible symptoms; Colonoscopy / biopsy; Laboratory tests: CBC, ESR, CRP, ASCA, atypical p-ANCA
Inflammatory, asymmetric oligoarthritis; Distal joints can be affected
Inflammatory arthritis, enthesitis or back pain; Skin lesions; Nail lesions; RF negative; Juxtaarticular bone formation on X-ray
Compatible symptoms; Imaging: evidence of sacroiliitis; Modified Schober testa; Chest expansion testb; Laboratory tests: HLA-B27, CRP
Other/Extra-articular Sx May also have ophthalmologic, musculoskeletal, genitourinary, dermatologic, or cardiovascular signs and symptoms May cause growth failure and delayed puberty
Positive family history provides support of diagnosis; May affect extraspinal structures such as peripheral joints, enthesis, eyes or aorta, especially in cases of juvenile ankylosing spondylitis Different presentations possible: asymmetric oligoarthritis, symmetric polyarthritis, arthritis mutilans, spondyloarthropathy
ANA ¼ antinuclear antibody; ASCA ¼ anti–Saccharomyces cerevisiae mannan antibodies test; CBC ¼ complete blood count; CRP ¼ C-reactive protein; ESR ¼ erythrocyte sedimentation rate; HLA-B27 ¼ hHHuman leukocyte antigen B27; p-ANCA ¼ perinuclear staining antineutrophil cytoplasmic antibodies; RF ¼ rheumatoid factor; SI ¼ sacroiliac. a Modified Schober test: With the patient standing erect, the position of the fifth lumbar spinous process is marked; additional marks are made 10 cm above and 5 cm below in the midline. The patient then bends forward maximally, and the distance between the upper and lower marks is measured. Persons with normal spinal mobility have increase in measured distance of 5 cm. Of note, adolescents may have increased normal range because of hypermobility. b Chest expansion test: Measured at the level of the fourth intercostal space. Arms should be elevated above and hands folded behind the head. The patient is instructed to exert maximal forced expiration followed by maximal inspiration. The expansion is usually 5 cm or more. An expansion of less than 2.5 cm is abnormal.
before the full resolution of the initial infection. The prevalence in adolescents and young adults varies widely by country and is difficult to accurately estimate because of differences in classification between adults and children and lack of national registries. Ravelli and Martini estimate that ERA accounts for 3–11% of those diagnosed with JIA [10]. Among adult populations, the prevalence is estimated to be 30–40 per 100,000 persons [4]. The incidence of ReA is related to the population prevalence of HLA-B27 and the incidence of urethritis, cervicitis, and infectious diarrhea caused by a predisposing organism. In Europe, the incidence of ReA is estimated to be 10–30 per 100,000 persons [4]. Some studies have shown the incidence of the enteric type to be as high as 7% after shigella [11] and 29% after Salmonella enteritidis [12]. Rich et al [13] examined the incidence of urogenital ReA in an urban STD clinic in Alabama using a survey and confirmatory physical examination. They found that 4.1% of patients with urethral inflammation or infection had features of ReA. It is likely that the true incidence of ReA is higher than what is shown by the population-based studies because mild cases can go unrecognized. Pathophysiology Components of triggering bacteria including nucleic acids and protein have been identified in the synovium and in circulatory monocytes of patients diagnosed with ReA [14]. It is not clear how and in what form the bacterial components
reach the joint and whether there are viable bacteria in the joint. In one older Russian study, more than 60% of patients with ReA had positive joint culture results for Chlamydia trachomatis [15]. However, negative joint culture results are the norm in the majority of patients with ReA, making it unlikely that viable bacteria exist within the joint space. Rather, nonviable bacterial components are thought to cause proliferation of the synovial fluid mononuclear cells, and this inflammatory reaction is responsible for the manifestations of ReA [16]. Individuals who are class I major histocompatibility complex (MHC) glycoprotein HLA-B27 positive have a 50-fold increased risk of developing ReA. HLA-B27– positive patients with ReA are more likely to have severe, prolonged episodes and to have associated mucocutaneous disease, axial disease, carditis, and uveitis [2]. There is also an increased risk of developing radiologic sacroiliitis in these patients [17,18]. Several theories attempt to explain the association between HLA-B27 and ReA. The arthritogenic peptide hypothesis is the most frequently cited [4]. Some peptide antigens from chlamydia and yersinia can only be presented by HLA-B27. These peptides are stimulatory for CD8þ T-cells derived from patients with ReA. Thus, it is inferred that peptides presented to the T-cells by HLA-B27 may play a role in the pathogenesis and the severity of ReA. Another theory involves interferon- g (IFN-g) because it may have an important role in clearance of the bacteria associated with ReA. Bas et al [19] showed that for a subset of
P.S. Kim et al. / Journal of Adolescent Health 44 (2009) 309–315 Table 2 Etiologic microorganisms of reactive arthritis Probable Chlamydia trachomatis Shigella flexneri Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni Possible Neisseria gonorrhoeae Mycoplasma fermentans Mycoplasma genitalium Ureaplasma urealyticum Escherichia coli Cryptosporidium Entamoeba histolytica Giardia lamblia Brucella abortus Clostridia difficile Stretpococcus pyogenes Chlamydia pneumoniae Chlamydia psittaci
patients with chlamydia-induced ReA, synovial fluid concentration of IFN-g was significantly lower in the group that was HLA-B27 positive. Inadequate clearance of the bacteria could be related to the more severe and chronic arthritis seen in these patients. After a 2-year follow-up in this study of patients with ReA, two of 19 HLA-B27–positive patients with low synovial fluid levels of IFN-g had chronic arthritis whereas within 1 year all 15 patients who were HLA-B27 negative had complete resolution of arthritis. It appears that HLA-B27 is not the only predisposing immunologic factor for the development of ReA. Yin et al [20] found that the balance of interleukin (IL–10) and IL12 in the synovial fluid of joints is also important. IL-10 is responsible for the suppression of Th-1–like cytokines including IFN-g and tumor necrosis factor–a (TNF-a), whereas IL-12 enhances them. These cytokines are necessary for the elimination of bacteria associated with ReA. In patients with ReA, IL-10 is present at high amounts within the synovial fluid upon stimulation with bacterial antigens. This may contribute to the decreased clearance of the bacteria or their components from the joint and lead to ReA. These authors suggest future study to determine whether IL-12 could be a possible treatment for ReA. Clinical manifestations The latent period from infection to onset of symptoms can be anywhere from few days to 6 weeks, with an average of 4 weeks [4,21]. The typical pattern of ReA is an asymmetric, mono- or oligoarthritis, predominantly of the lower extremities including the knees, ankles, and feet. The severity of ReA depends on the population being studied. Patients hospitalized with ReA are more likely to be HLA-B27 positive, to
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have more severe arthritis in large joints including the knees and ankles, and to have increased inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ReA patients in population-based outpatient series tend to have less severe arthritis [4]. Predictors of more severe disease at presentation include arthritis of the hip, ESR >30, poor response to nonsteroidal inflammatory drugs (NSAIDS), lumbar spine stiffness, dactylitis, oligoarthritis, and onset at age less than 16 years [2]. Heel and foot involvement tends to be an important predictor of poor functional outcome and disability. ReA may last for several weeks to months. Joint pain, mild constitutional symptoms including fever, weight loss, and malaise, and other extra-articular manifestations usually resolve within 2 to 3 months. If symptoms last for more than 6 months, then the condition is classified as chronic ReA [21]. In addition to the peripheral arthritis, musculoskeletal symptoms may include inflammatory pain in cervical, thoracic, and lumbosacral spine. Radiographically verifiable sacroiliitis can occur in up to one-third of patients with urogenital ReA and in about one-tenth of patients with enteric ReA. The main symptom of sacroiliitis is often an acute low back pain radiating to the hips that is worse during the night and may also manifest as alternating buttock pain [4]. Sacroilitis is more common in those with severe, prolonged episodes of ReA. Enthesitis, inflammation occurring at the point of attachment of skeletal muscles to bone, is commonly seen in ReA. Enthesitis gives rise to localized pain, swelling, and tenderness. The plantar aponeurosis and Achilles’ tendon attachments to the calcaneum are most commonly seen, often causing heel pain and difficulty walking [2]. In adolescents, enthesitic points also may include the base of the fifth metatarsal, metatarsal heads, patellar tendon insertions, and the greater trochanter of the hip. Involvement of interphalangeal joints with digital tendonitis and multiple entheseal lesions probably is the cause of dactylitis or ‘‘sausage digits’’ also seen in ReA. Arthritis in the upper limbs and a mild polyarticular form of arthritis in the small joints has also been reported. In a recent study of 45 patients with ReA after a campylobacter infection, 36% had proximal interphalangeal joint involvement, 33% had metacarpophalangeal joint involvement, and 22% had wrist involvement [22]. The upper extremity arthritis tended to be so mild that patients did not seek medical attention for their symptoms. The genitourinary system may also be involved in both urogenital and enteric ReA as an extra-articular manifestation. These symptoms are distinct from the initial infectious urethritis in the case of urogenital ReA and include subsequent frequency, dysuria, urgency, and urethral discharge. In males, the prostate, urethra, and penis may be involved. Females may develop cervicitis, urethritis, salpingitis, or vulvovaginitis, but these may be asymptomatic. Severe glomerulonephritis and IgA nephropathy have been rarely associated with ReA [2].
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Conjunctivitis with mucopurulent discharge is the most common ophthalmologic symptom of ReA and may be found in up to 30% of patients. This usually occurs early in the course, often preceding the arthritis by a few days. It tends to be bilateral and mild and is often ignored. Symptoms include red eyes, crusting, and sterile ocular discharge. Signs and symptoms usually subside within 1–4 weeks but occasionally may progress to episcleritis, keratitis, or corneal ulceration. Anterior uveitis, photophobia, pain, and decreased vision rarely occur [2]. Dermatologic manifestations include balanitis circinata and keratoderma blennorrhagica. Balanitis circinata consists of small, shallow, painless sores or ulcers at the end of the penis and is found in 20–40% of males affected with ReA. These are usually moist on uncircumcised patients but may harden and crust on circumcised patients and lead to pain or scarring. Keratoderma blennorrhagica, which affects 5–10% of patients, is highly characteristic of ReA. These lesions begin as pustules, which become hyperkeratotic and scaly and may coalesce into larger psoriatic-like plaques. These are generally found on the sole, palm, toe, scrotum, trunk, or scalp. Other stigmata include oral ulcers, rashes or nail changes similar to psoriasis including pitting and thickening [2]. Clinically apparent involvement of the cardiovascular system is rare. Transient conduction abnormalities, including heart block on the electrocardiogram are not uncommon but are generally of little significance. Proximal aortitis affects 1– 2% of patients, particularly those with severe or recurrent disease. This may cause secondary aortic regurgitation and eventually warrant aortic valve replacement to avoid heart failure. Aneurysmal aortic dilatation, myocarditis, and pericarditis have been reported, but these are exceedingly rare [2,23].
Differential diagnosis It is necessary to exclude other causes of acute mono- or oligoarthritis. Some viruses including parvovirus B19, hepatitis B and C viruses, and human immunodeficiency virus rarely may cause virally associated arthritis. However, these usually mimic rheumatoid arthritis and have a symmetric and oligoarticular pattern of arthritis that is different from ReA [24]. Bacterial infection or trauma should also be considered. Disseminated gonococcal infection (DGI) can cause arthritis and arthralgia. Recent symptomatic genital infection is uncommon, and an asymptomatic mucosal infection is thought to be the primary event [25]. Patients may have joint pain involving fingers, wrists, knees, ankles, or toes and transient pustular or vesicular skin lesions. Results of cultures or nucleic acid amplification test (NAAT) of the urethra, cervix, or rectum are more likely to be positive than blood or synovial fluid cultures. These tests are important to rule out disseminated gonococcal infection in certain patients.
Clinically, the arthritis associated with DGI quickly resolves with appropriate antibiotics. Other possible diseases that can cause diarrhea and arthritis include inflammatory bowel disease, celiac sprue, Whipple’s and Behc¸et’s disease. Pseudomembranous colitis, intestinal bypass surgery, and enteroviral infection may also cause similar symptoms but are rare in the adolescent population. Diagnosis Diagnosis of ReA is based on a clinical algorithm developed from observational data in Germany and Scandinavia [26]. The first criterion is having mono- or oligoarthritis of the lower extremities. The second criterion is exclusion of other diagnoses including septic or traumatic arthritis and the other rarer conditions. If both criteria are present, then the probability of ReA is 40%. Evidence of a previous infection can be found in approximately 60% of patients with ReA and is regarded as being the most relevant criterion in diagnosing ReA [4,26]. If there is a history of symptomatic preceding infection with Chlamydia trachomatis, then the probability of ReA increases to 90%. If bacteria associated with ReA can be cultured from the stool, then the probability of ReA increases to 70%. It is also important to keep in mind that some predisposing infections may be asymptomatic, especially chlamydia. The recommendation is to search for chlamydia in urine, urethra, or cervix if there is any suspicion of ReA regardless of symptoms. If the patient either has or recently has had diarrhea associated with ReA, then a stool culture to look for causative enteric infections would be appropriate [2,21]. Serologic testing for various enteric pathogens is not very useful because it may not be specific for a recent infection. There are no internationally validated standard serologic techniques or thresholds for this type of testing [26,27]. A clinical diagnostic pathway is depicted in Figure 1 [2,26,28]. Nonspecific laboratory findings initially include an elevated ESR and CRP acutely, which usually return to normal in the chronic stage of the disease. Patients can develop neutrophilic leukocytosis for acute cases of ReA and mild normocytic anemia for chronic cases. Both RF and antinuclear antibody (ANA) should be measured to exclude other causes of arthritis. A Gram stain and culture of the synovial fluid may be important to exclude septic arthritis, especially if the case involves a monoarticular arthritis with constitutional symptoms. A positive HLAB27 result increases the likelihood of ReA, but this is neither sensitive nor specific for the condition [26]. Finally, an HIV test should be considered because ReA has a higher prevalence in the HIV-positive population. ReA has been reported in up to 11% of HIV-infected patients, and the symptoms tend to be more severe [2]. Radiographs of the affected site are usually normal, and imaging studies do not have to be performed for the diagnosis of ReA if clinical suspicion is high. However, in less clear
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Diagnostic Algorithm for Adolescents with Suspected Reactive Arthritis
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Arthritis (2 of 3 features) - Asymmetric - Mono or oligo arthritis - Lower limbs
Rule out other diagnoses - Check ESR, CBC, CRP, RF, ANA - Synovial fluid analysis - Plain X-ray
Other diagnosis found
Other diagnoses ruled out
Symptomatic infection 3 days to 6 weeks prior to arthritic symptoms - Enteritis: diarrhea for one or more days - Urethritis: dysuria / discharge for one or more days
No symptomatic infection
Test for Chlamydia trachomatis
No evidence of infection
Positive for infection - Nucleic Acid Amplification Test (NAAT) - Urine / Urethra - Cervix - Synovial fluid
Possible Reactive Arthritis (~40% chance)
No evidence of triggering infection
Probable Reactive Arthritis (40-70% chance)
Evidence of triggering infection: - Chlamydia trachomatis - Urine, urethral/cervical NAAT - Synovial fluid NAAT positive for chlamydia - Reactive arthritis associated enterobacteria - Positive stool culture - +/- Serologic studies
Definite Reactive Arthritis (70 – 90% chance)
Figure 1. Diagnostic algorithm for adolescents with suspected reactive arthritis.
cases of ReA, plain radiographs may be used to rule out other diagnoses such as osteoarthritis. Also, plain radiographs may occasionally show nonspecific changes such as periarticular osteopenia and soft tissue swelling in acute ReA and joint erosions may develop with recurrent or chronic disease [2]. Ultrasound of the entheseal insertions is more accurate than clinical examination in diagnosing enthesopathy, periosteal reaction, and tendinosis but is of limited availability. Scintigraphy can show joint inflammation and is useful for demonstrating enthesitis and sacroiliac inflammation. However, scintigraphy subjects a patient to a significant radiation exposure and is of low specificity; therefore it is rarely used. Magnetic resonance imaging (MRI) is also very sensitive for sacroiliac and spinal inflammation. Unfortunately, however, there are no guidelines on how to use and interpret the newer imaging techniques [4]. Treatment The goals of treatment are to decrease pain and inflammation, minimize disability, and prevent relapse or progression to chronic disease. As a screen for extra-articular involvement, an electrocardiogram, echocardiogram, and ophthalmologic referral is recommended, especially in chronic cases of ReA. Because there is a significant risk of some patients developing chronic disease, a rheumatologist should be consulted as soon as the diagnosis of ReA is made.
General treatment of acute joint inflammation includes local cold treatment and avoidance of overuse. For those with enthesitis, orthotics such as insoles or heel support may limit pain and increase mobility. Short periods of non–weightbearing status may reduce inflammation and decrease the pressure of the body’s weight on painful joints. Gentle range-of-motion and strengthening exercises are important to prevent muscle atrophy. To assess the response to treatment, the number of swollen or tender joints, the intensity of joint pain, and the presence or severity of enthesitis can be measured. Medical treatment of ReA starts with NSAIDs, most commonly ibuprofen, indomethacin, or naproxen. These do not affect the course of the disease but provide symptom relief and may facilitate physical therapy. NSAIDs should be continued for at least 2–4 weeks before advancing to more potent medications or interventions. Intraarticular glucocorticoid injection may be beneficial for mono- or oligoarticular disease and for enthesopathy but should be used with caution in the pediatric population. The Achilles tendon should not be injected directly; the inflamed bursa, if present, should be injected instead. Challenging sites should be injected using ultrasound guidance if possible. Systemic corticosteroids are indicated only if patients are bedridden secondary to severe polyarthritis or if significant atrioventricular conduction disturbances are present [4]. For adolescents, it is important to note that systemic corticosteroids should be of short
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duration because of increased toxicity, especially in the peripubertal stage. If the above methods fail to relieve the pain, then the next step would be a trial of disease modifying antirheumatic drugs (DMARDs). Among the DMARDs, usually the firstline medication is methotrexate or sulfasalazine, which is generally continued until the patient enters remission [29]. If the disease persists, anti-TNF agents may be used. An HIV test should be obtained before starting this treatment. Etanercept, a soluble TNF-a receptor immunoglobulin fusion protein, is the main agent to use in this class. In one study of patients with undifferentiated spondyloarthritis, a small subset of seven patients who satisfied the author’s criteria for ReA were treated with etanercept for 6 months and appeared to have a therapeutic benefit [30]. Antibiotic use is warranted if there is evidence of pathogenic organisms. Active genitourinary infections should be treated with appropriate antibiotics. For acute Chlamydia trachomatis infection, patients and sexual partners should receive the current recommended regimen for treatment to eradicate infection and prevent other late complications [4,31]. Prompt treatment of acute chlamydia infection in both patients and partners may lower the probability of developing ReA. For uncomplicated enteric infections, the benefits of antibiotic use are less clear. Generally antibiotics are not indicated unless the disease is severe or the patient is elderly or immunocompromised [2]. Although components of the triggering microbes can be demonstrated at the site of inflammation, there is no evidence for using long-term antibiotics in the treatment of ReA. Early studies with minocycline [32] and lymecycline [33] suggested a beneficial effect on long-term antibiotics, however randomized, controlled trials involving ciprofloxacin [34], azithromycin [35], and doxycycline [36] found that these antibiotics did not provide any significant benefit compared with placebo in the resolution of ReA. It is hypothesized that the initial favorable effect of minocycline and lymecycline may have been due to nonantibacterial features of those drugs such as immunosuppressive and anti-inflammatory effects [1]. Prognosis The prognosis of ReA varies, depending on the triggering pathogen and on the genetic background of the host. Usually, patients achieve full recovery by 2–6 months [35]. However, chronic arthritis (i.e., arthritis symptoms lasting more than 6 months) is observed in 4–19% of patients. Leirisalo-Repo et al [4] evaluated ReA induced by yersinia, salmonella, shigella, and chlamydia in Finland. Chronic arthritis occurred in 4% of patients with yersinia-induced arthritis, 17% of patients with chlamydia-induced arthritis, and 19% of patients with arthritis caused by salmonella or shigella. Over a 20-year follow-up, chronic relapsing ReA was found in 16–18% of patients in the group with ReA induced by salmonella, shigella, or chlamydia compared with 2% of
patients with ReA induced by yersinia. Data from multiple studies including patients of all ages demonstrate that sacroiliitis occurs in 14–49% and ankylosing spondylitis in 12– 26% when patients with ReA are followed for up to 20 years. There is increased risk of sacroiliitis and ankylosing spondylitis if patients are HLA-B27 positive or if the ReA was chlamydia induced [37]. Conclusion In summary, ReA is caused by a preceding infection. It is currently unclear how arthritis is caused by this infection, but it appears to be immunologically mediated. A better understanding of the pathogenesis of the disease should facilitate treatment and prevention of long-term complications. Treatment is currently focused on anti-inflammatory and immunomodulatory methods but often falls short of complete success. Long-term antibiotics do not appear to be beneficial. Future directions include the use of other immunomodulators or different antibiotics as treatment, establishing a clearer picture of the pathogenesis of ReA, and determining clearer diagnostic guidelines. Acknowledgment This work was supported in part by grant HRSA/MCHB T71MC000008. References [1] Toivanen A. Bacteria-triggered reactive arthritis: Implications for antibacterial treatment. Drugs 2001;61:343–51. [2] Hamadulay S, Glynne S, Keat A. When is arthritis reactive? Postgrad Med J 2006;82:446–53. [3] Panush R, Wallace D, Dorff R, et al. Retraction of the suggestion to use the term ‘‘Reiter’s syndrome’’ sixty-five years later: The legacy of Reiter, a war criminal, should not be eponymic honor but rather condemnation. Arthritis Rheum 2007;56:693. [4] Leirisalo-Repo M, Sieper J. Reactive arthritis: Epidemiology, clinical features, and treatment. In: Weisman M, van der Heijde D, Reveille J, eds. Ankylosing Spondylitis and the Spondyloarthropathies. Philadelphia: Mosby Elsevier, 2006:53–64. [5] Orchard T, Jewell D. Articular and ocular complications of inflammatory bowel disease. In: Targan S, Shanahan F, Karp L, eds. Inflammatory Bowel Disease: From Bench to Bedside. 2nd Edition. Dordrecht: Kluwer: Academic Publishers, 2003:747–56. [6] Palm O, Moum B, Jahnsen J, et al. The prevalence and incidence of peripheral arthritis in patients with inflammatory bowel disease, a prospective population-based study. Rheumatology 2001; 40:1256–61. [7] Passo M, Fitzgerald J, Brandt K. Arthritis associated with inflammatory bowel disease in children. Relationship of joint disease to activity and severity of bowel lesion. Dig Dis Sci 1986;31:492–7. [8] Petty R, Southwood T, Manners P, et al. International League of Associations for Rheumatology Classification of Juvenlie Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol 2004; 31:390–2. [9] Bas S, Scieux C, Vischer T. Male sex predominance in Chlamydia trachomatis sexually acquired reactive arthritis: Are women more protected by anti-chlamydia antibodies? Ann Rheum Dis 2001;60:605–11. [10] Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007; 369:767–78.
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