INTRODUCTION — Reactive arthritis is conventionally defined as an arthritis that arises following an infection, although the pathogens cannot be cultured from the affected joints. It is generally regarded as a form of spondyloarthritis (SpA).
The definition, clinical features, approach to diagnosis and differential diagnosis, and management of reactive arthritis will be reviewed here. Mechanisms that may play a role in reactive arthritis and in other spondyloarthritides are discussed separately. (See "Pathogenesis of spondyloarthritis".)
DEFINITION — The term "reactive arthritis" was introduced in 1969 as "an arthritis which developed soon after or during an infection elsewhere in the body, but in which the microorganisms cannot be recovered from the joint" . The original definition did not specify the pathogens that were accepted as causes of reactive arthritis, and, in 1999, a panel of experts determined a specific list of gastrointestinal and urogenital pathogens that could be considered causative . These included Chlamydia trachomatis, Yersinia, Salmonella, Shigella, and Campylobacter . Escherichia coli, Clostridioides difficile, and Chlamydia pneumoniae have since been added to the list [3-7]. Reactive arthritis triggered by a sexually transmitted infection is also referred to as sexually acquired reactive arthritis (SARA) .
Additional causative pathogens, alternative terms, and diagnostic and therapeutic strategies for reactive arthritis have subsequently been proposed [9,10]. However, none of the newer diagnostic or therapeutic approaches or alternate names has been adequately validated. Another problem is that many of the studies generating these approaches involved patients seen in rheumatology clinics or followed outbreaks of disease after exposure to a common pathogen; such patients are not likely to be representative of the affected patients in the general community. Thus, the definition of reactive arthritis is still evolving.
Two major clinical features that characterize reactive arthritis were identified :
●An interval ranging from several days to weeks between the antecedent infection and arthritis
●A typically mono- or oligoarticular pattern of the arthritis, often involving the lower extremities, and sometimes associated with dactylitis and enthesitis
By convention, reactive arthritis of more than six months' duration was regarded as being chronic instead of acute.
The term "reactive arthritis" has sometimes been used historically to refer to the clinical triad of postinfectious arthritis, urethritis, and conjunctivitis, which was formerly called Reiter syndrome [11,12]. However, these patients represent only a subset of patients with reactive arthritis [11,13].
Patients suspected of having reactive arthritis whose features initially or subsequently satisfy the Assessment of SpondyloArthritis International Society (ASAS) criteria for spondyloarthritis (SpA) are also considered as having a form of SpA. Indeed, a preceding episode of genital or gastrointestinal infection is included among the ASAS criteria that may not only support a classification of SpA, but also the inclusion of a patient with reactive arthritis in this group. The ASAS criteria for SpA divide SpA patients into an axial and a peripheral group depending on whether the features are predominantly axial or peripheral. Patients with reactive arthritis can be classified to either of these groups [14,15].
EPIDEMIOLOGY — Reactive arthritis is a relatively rare disease that typically occurs in young adults, affecting both males and females. Studies of the prevalence and annual incidence of reactive arthritis are highly heterogeneous with respect to the size of the cohort, collection of data, the definition of reactive arthritis, and the identification of the inducing pathogens. In a US population-based study in Oregon and Minnesota, the incidence of reactive arthritis following documented enteric bacterial infections ranged from 0.6 to 3.1 cases per 100,000, depending upon the organism . An analysis of the data in a 2013 systematic review found that the incidence of reactive arthritis following infection with Campylobacter, Salmonella, and Shigella, was estimated as 9, 12, and 12 per 1000 patients, respectively . The rate of chlamydia-induced arthritis has been estimated to be 4 to 15 percent, although most of the infections are asymptomatic . Globally, the annual incidence of reactive arthritis has been reported between 0.6 to 27 per 100,000, and the prevalence is estimated to be 30 to 40 per 100,000 adults [3,4,6,19]. Two publications in 2019 have suggested that the frequency of reactive arthritis has been diminishing [20,21].
Among patients with any of the spondyloarthritis (SpA) variants seen by rheumatologists, those with reactive arthritis are a small minority. This was illustrated by two registry-based studies from Spain in which 1.2 to 1.4 percent of all patients with SpA had been diagnosed with reactive arthritis [22,23].
Most cases of reactive arthritis appear sporadically, but outbreaks may follow single-source infections. In such outbreaks, the proportion of infected subjects who developed subsequent reactive arthritis has ranged from 0 to 21 percent [6,19].
The causative pathogens, incidence, and prevalence of reactive arthritis depend upon the geographic region. In general, among the pathogens, Chlamydia is probably the most endemic. A 2016 systematic review could identify only three studies of low to moderate quality reporting an incidence of sexually acquired reactive arthritis (SARA) of 3 to 8 percent among patients with a chlamydia infection . A Japanese study reported that only one of 123 patients with clinical chlamydial infections developed arthritis . Some epidemiologic studies include cases in which the preceding enterobacterial and chlamydial infections were silent .
CLINICAL MANIFESTATIONS — The onset of reactive arthritis is usually acute. Patients typically present with an asymmetric oligoarthritis, usually one to four weeks following the inciting infection [2,6,9,10,27].The extent of the interval between infection and the onset of arthritis considered consistent with a reactive arthritis by expert consensus is a minimum of several days and a maximum of several weeks . In at least half of patients, all symptoms resolve in less than six months ; in most patients, symptoms resolve within one year. The several types of clinical manifestations of reactive arthritis include:
●Symptoms of preceding enteric or genitourinary infection (see 'Preceding infection' below)
●Axial and/or peripheral musculoskeletal signs and symptoms (see 'Musculoskeletal signs and symptoms' below)
●Extraarticular signs and symptoms (see 'Extraarticular signs and symptoms' below)
Other than those symptoms due to the infection that has triggered the arthritis, the articular and extraarticular manifestations are similar regardless of the particular enteric or genitourinary organism or species of organism causing the disorder .
Preceding infection — The characteristic symptoms of the enteric or genitourinary infections that can cause reactive arthritis are diarrhea or urethritis. Patients with arthritis induced by enteric bacteria can also develop aseptic urethritis. Many patients have been described in whom the preceding infections are clinically silent and detectable only by laboratory testing [26,27,30]. There are no data to indicate whether the disease course or prognosis of reactive arthritis differs between patients with or without an antecedent infection that is symptomatic. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Causes of acute infectious diarrhea and other foodborne illnesses in resource-rich settings" and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections".)
The enteric bacteria commonly associated with reactive arthritis include:
●Salmonella of various serovars
●Shigella, especially Shigella flexneri, but also Shigella dysenteriae and Shigella sonnei
●Yersinia, including Yersinia enterocolitica 0:3 and 0:9 and Yersinia pseudotuberculosis
●Campylobacter, especially Campylobacter jejuni
The genital pathogen commonly accepted to be the cause of reactive arthritis is Chlamydia trachomatis.
Other bacteria also reported to cause reactive arthritis include Chlamydia pneumoniae, Escherichia coli, Ureaplasma urealyticum, and Mycoplasma genitalium. Intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer has also been identified as a rare cause of reactive arthritis. (See 'Differential diagnosis' below and "Infectious complications of intravesical BCG immunotherapy".)
Reactive arthritis has also been reported in patients with human immunodeficiency virus (HIV) infection, in which it is generally thought to be related to other infections to which patients have been exposed, rather than to HIV itself [31,32]. An association between reactive arthritis and human leukocyte antigen (HLA)-B27 has been noted in White HIV-infected patients in the United States, but not in patients from sub-Saharan Africa, where the prevalence of HLA-B27 is much lower [33,34]. At least 16 cases have been described following infection with coronavirus disease 2019 (COVID-19) .
Although a large variety of pathogens, including streptococcus, have been described that may induce musculoskeletal symptoms, an arthritis is conventionally considered to be a reactive arthritis only if some of the typical musculoskeletal features occur (see 'Musculoskeletal signs and symptoms' below). Not infrequently, patients do not volunteer the history of infection until asked about this specifically, since most patients are not aware that the infections can be related to arthritis.
Musculoskeletal signs and symptoms — The musculoskeletal features of reactive arthritis include four major manifestations: arthritis, enthesitis, dactylitis, and back pain [35,36].
●Peripheral arthritis – The typical picture of peripheral arthritis, seen in rheumatology clinics, is an acute-onset asymmetric oligoarthritis, often affecting the lower extremities, especially the knees  (picture 1). However, about 50 percent of patients have arthritis in the upper extremities, and some have polyarthritis in the small joints . By convention, the minority of patients with arthritis that does not resolve within six months is defined as having chronic reactive arthritis.
●Enthesitis – The enthesis is the site of insertion of ligaments, tendons, joint capsule, or fascia to bone; enthesitis (or enthesopathy), the term for inflammation around the enthesis, can occur in patients with reactive arthritis and other forms of spondyloarthritis (SpA). Swelling at the heels is among the most characteristic symptom of enthesitis. Common sites of heel involvement are at the insertions of the Achilles tendon and of the plantar fascia on the calcaneus. Pain, swelling, and local tenderness are suggestive clinical features. Estimates of the frequency of enthesitis in patients with reactive arthritis have ranged from 20 to 90 percent [16,35,38-40].
In one study in the US of patients with documented enteric infections and a symptom of reactive arthritis, enthesitis was more common than arthritis or inflammatory back pain, occurring in 89 percent of patients [16,35].
Enthesitis is discussed in more detail elsewhere. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Enthesitis' and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults", section on 'Musculoskeletal features'.)
●Dactylitis – Some patients also develop dactylitis, which typically presents as sausage digits (picture 2) . The frequency of dactylitis in patients with chlamydia-induced reactive arthritis may be as high as 40 percent . (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults", section on 'Musculoskeletal features'.)
●Axial, especially low back pain – Inflammatory low back pain is frequent as an accompanying symptom, but seldom as the only presenting symptom [16,36]. Inflammation in the spine or at the sacroiliac joints may be seen . (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Low back pain and neck pain'.)
Extraarticular signs and symptoms — Extraarticular involvement in reactive arthritis is associated with a variety of manifestations, which may be present during the acute or chronic phase of illness [4,27]. The relative frequency of each of these manifestations has not been well-analyzed. In one European cohort of 186 patients enrolled in a clinical trial, the frequencies of eye and skin involvement were approximately 20 and 15 percent, respectively .
Extraarticular manifestations include:
●Ocular symptoms, such as conjunctivitis, and less frequently, anterior uveitis (picture 3), episcleritis, and keratitis. In one report, a third of those with conjunctivitis were found to have detectable chlamydia in scrapings off the conjunctiva .
●Genitourinary tract symptoms, such as dysuria, pelvic pain, urethritis, cervicitis, prostatitis, salpingo-oophoritis, or cystitis. Urethritis can occur even when the arthritis is induced by enterobacteriaceae .
●Gastrointestinal symptoms, such as diarrhea.
●Cutaneous eruptions and other skin changes, such as keratoderma blennorrhagica (hyperkeratotic skin lesions on soles and palms resembling pustular psoriasis) (picture 6) and, uncommonly, erythema nodosum (picture 7). (See "Neutrophilic dermatoses", section on 'Reactive arthritis'.)
●Genital lesions such as circinate balanitis (painless erythematous lesions with small, shallow ulcers on the glans penis and urethral meatus) (picture 10).
None of the mucocutaneous or other manifestations are specific for reactive arthritis .
LABORATORY AND IMAGING FINDINGS — Several types of findings may be present, including:
●Evidence of antecedent or concomitant infection
●Elevated acute phase reactants
●Positive testing for human leukocyte antigen (HLA)-B27
●Imaging abnormalities consistent with enthesitis or arthritis
Antecedent or concomitant infection — Laboratory tests, such as stool cultures to test for Salmonella, Shigella, Campylobacter, and Yersinia, can sometimes confirm a preceding or concomitant infection with one of the pathogens that classically induce reactive arthritis. However, by the time patients develop arthritis, the diarrhea has usually resolved, and the pathogens may no longer be retrievable. Urine and genital swab testing can sometimes detect Chlamydial trachomatis infection using nucleic acid amplification techniques. (See 'Chronic chlamydia-related arthritis' below and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Nucleic acid amplification testing (test of choice)'.)
Serologic testing is used primarily in epidemiologic studies to test for preceding infections but is generally not useful in clinical practice [9,49,50]. Infections by Yersinia, Salmonella, Campylobacter, and Chlamydia trachomatis cause strong antibody responses, and the triggering enteric infections can still be identified by serology in more than 50 percent of Yersinia- or Salmonella-infected patients, if such testing is performed . In communities in which these infections are endemic and often clinically silent, serologic testing is not specific for recent episodes of infection.
Acute inflammatory changes — Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be elevated. In many patients, however, these studies may be normal; elevations in acute phase reactants were found in less than half of patients diagnosed with reactive arthritis in one study .
Genetic predisposition — The prevalence of HLA-B27, which is increased in patients with the various forms of spondyloarthritis (SpA), including reactive arthritis, is generally estimated at 30 to 50 percent in patients with reactive arthritis, although values range widely [6,27]. In hospital-based studies with more severely affected patients, frequencies as high as 60 to 80 percent have been reported ; however, estimates in population-based studies and analyses of disease outbreaks are generally much lower and occasionally have shown no increase in HLA-B27 prevalence compared with the general population . (See "Pathogenesis of spondyloarthritis".)
Inflammatory synovitis — The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts, predominantly neutrophils. White blood cell (WBC) counts are typically between 2000 and 64,000 WBC per mm3 . (See "Synovial fluid analysis" and "Monoarthritis in adults: Etiology and evaluation".)
Imaging abnormalities — There are no specific findings on plain radiographs that can establish a diagnosis of reactive arthritis. Changes are usually limited to those associated with joint swelling if inflammatory arthritis is present. Patients with concurrent or past heel pain may show calcaneal spurs, but such findings are nonspecific and can be seen in other forms of arthritis and in asymptomatic individuals .
Radiographic sacroiliitis, a feature of axial SpA, has been reported . In patients with chronic joint disease, imaging studies such as ultrasonography and magnetic resonance imaging (MRI) can also identify changes consistent with peripheral synovitis, enthesitis, or sacroiliitis. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Musculoskeletal imaging'.)
DIAGNOSIS — The diagnosis of reactive arthritis is a clinical diagnosis based upon the pattern of findings and exclusion of other diseases. There is no single definitive diagnostic test, nor are there validated diagnostic criteria. The diagnosis can generally be suspected in patients who exhibit all three of the following:
●Characteristic musculoskeletal findings – Such findings include a combination of oligoarthritis of peripheral joints, most often with asymmetric involvement of the lower extremity, enthesitis, dactylitis, or inflammatory back pain. (See 'Musculoskeletal signs and symptoms' above and 'Inflammatory synovitis' above and 'Imaging abnormalities' above.)
●Evidence of preceding extraarticular infection – The presence of a preceding extraarticular infection may be indicated simply by a history of urethritis or diarrhea. In the case of urethritis, or suspected silent urethritis, chlamydia can usually be identified, if present, by nucleic acid amplification. Stool cultures are usually not done in patients in whom the preceding episode of diarrhea has resolved. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Nucleic acid amplification testing (test of choice)'.)
Inability to identify the causative pathogen does not exclude the diagnosis of reactive arthritis. Even in well-controlled studies, pathogens can be identified in only about 50 percent of the patients. In those cases, the diagnosis of infections would depend entirely upon the history. (See 'Preceding infection' above and 'Antecedent or concomitant infection' above.)
●A lack of convincing evidence for another more likely cause of oligoarthritis, monoarthritis, or enthesitis – It is particularly important for diagnosis of reactive arthritis to exclude another more likely cause of the patient's condition. Similar musculoskeletal findings may occur in patients with other disorders, such as other forms of spondyloarthritis (SpA); traumatic arthritis, crystal-induced arthritis; other forms of inflammatory polyarthritis, such as psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus; septic arthritis; poststreptococcal arthritis; arthritis associated with inflammatory bowel disease; or viral or Lyme arthritis. These alternative diagnoses can usually be excluded based upon the history, physical examination, and laboratory examination. (See 'Diagnostic evaluation' below and 'Differential diagnosis' below.)
Algorithms derived from analysis of available cross-sectional data in the literature provide support for the above criteria; although the probabilities described below are estimates, given the lack of a definitive diagnostic test for reactive arthritis :
●In patients with new onset of arthritis in a pattern characteristic of reactive arthritis (see 'Musculoskeletal signs and symptoms' above), in whom alternative diagnoses have been excluded (see 'Differential diagnosis' below), the probability of reactive arthritis has been estimated to be about 40 percent.
●In a patient with a typical musculoskeletal presentation, in whom other diagnoses have been excluded, plus symptomatic enteritis with a positive stool culture for bacteria associated with reactive arthritis, the probability of reactive arthritis is high.
●In a patient with a typical musculoskeletal presentation, in whom other diagnoses have been excluded, plus a history of proven symptomatic preceding infection by Chlamydia trachomatis, the probability of reactive arthritis is very high (increased to about 90 percent). If the patient does not have a symptomatic Chlamydia trachomatis infection but Chlamydia trachomatis can be detected in the urine, the probability is roughly 60 percent.
The diagnostic values of inflammatory spinal pain and extraarticular features, including conjunctivitis, balanitis, and keratoderma blennorrhagica, have not been systematically evaluated in longitudinal studies. (See 'Extraarticular signs and symptoms' above.)
Diagnostic evaluation — The diagnostic evaluation in a patient suspected of reactive arthritis depends upon the presenting symptoms and likely infectious etiology. In most patients, we do the following:
●A thorough history and physical examination. The history is directed, in particular, at distinguishing musculoskeletal manifestations characteristic of reactive arthritis from those suggesting an alternative diagnosis and at determining whether there are symptoms to indicate a preceding or concomitant infection, especially diarrhea or urethritis. (See 'Musculoskeletal signs and symptoms' above and 'Preceding infection' above and 'Extraarticular signs and symptoms' above and 'Differential diagnosis' below.)
The physical examination should include a detailed examination of the joints, including the heels, digits, and spine, as well as the rest of the joint examination. The general examination should aim at excluding other systemic or localized arthritic disorders (eg, examination of the skin and nails to exclude psoriatic arthritis). (See 'Musculoskeletal signs and symptoms' above and 'Differential diagnosis' below.)
●Plain radiographs of affected joints and entheses, if necessary to exclude other causes of joint pain, including other forms of arthritis and stress fractures. Plain radiographs of sacroiliac joints are performed in patients suspected of sacroiliitis. MRI of the sacroiliac joints is performed in patients in whom radiographs of the sacroiliac joints are normal but with high suspicion of sacroiliitis.
We perform the following studies, depending upon the history and findings:
●In patients with a joint effusion, we perform arthrocentesis and examination of the synovial fluid, including total and differential white blood cell counts, crystal search, and examination for bacteria by Gram stain and culture to exclude septic arthritis. Techniques such as polymerase chain reaction (PCR) testing for pathogens in the synovial fluid or tissue are not indicated in the routine clinical evaluation and management of reactive arthritis. (See 'Inflammatory synovitis' above and "Joint aspiration or injection in adults: Technique and indications" and "Synovial fluid analysis".)
●In patients with ongoing active diarrhea, we obtain stool cultures to test for Salmonella, Shigella, Campylobacter, and Yersinia. Serologic testing for enteric pathogens is generally not indicated because of the limited specificity of such testing . (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Clinical manifestations and diagnosis of Yersinia infections", section on 'Diagnosis' and "Causes of acute infectious diarrhea and other foodborne illnesses in resource-rich settings", section on 'Inflammatory diarrhea'.)
●In patients suspected of infection with Chlamydia trachomatis and in patients with neither gastrointestinal nor genitourinary symptoms, we may obtain a first-catch urine sample (first portion of the urine specimen) or a vaginal swab, which may be self-administered by the patient or obtained by the clinician, for testing for chlamydia using nucleic acid amplification techniques. Testing for chlamydia is described in detail separately. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Test performance'.)
Additional testing which may further increase or decrease support for the diagnosis, but which alone is not diagnostic or exclusionary, includes the following:
●Routine laboratory testing – We obtain a complete blood count and differential, acute phase reactants, renal and liver chemistries, and urinalysis to obtain supportive evidence of acute inflammation and to exclude other systemic disorders. (See 'Acute inflammatory changes' above.)
●Testing for human leukocyte antigen (HLA)-B27 – We obtain HLA-B27 testing in patients with an intermediate likelihood of reactive arthritis. The prevalence of HLA-B27 in patients with reactive arthritis is generally estimated at 30 to 50 percent. Thus, a positive test would increase the likelihood of reactive arthritis being the correct diagnosis, rather than a different form of arthritis, other than another type of SpA. A negative HLA-B27 test does not exclude reactive arthritis.
●Serologic testing for rheumatoid arthritis – Rheumatoid factor and anticyclic citrullinated peptide antibody testing are obtained only in patients with polyarthritis suspected of possible rheumatoid arthritis. At least one of these antibodies is present in over 70 to 80 percent of patients with rheumatoid arthritis, but both are usually absent in patients with reactive arthritis. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)
DIFFERENTIAL DIAGNOSIS — Acute inflammatory monoarthritis or oligoarthritis may occur in a variety of disorders. Particularly important and/or common causes of arthritis to differentiate from reactive arthritis include crystal-induced inflammation, which is diagnosed by the history and identification of crystals (typically monosodium urate or calcium pyrophosphate) upon examination of the joint fluid, and bacterial infection (eg, septic arthritis and Lyme disease, which are identified by joint fluid examination and culture and by serologic testing of patients potentially exposed while in an endemic area, respectively). The general approaches to the evaluation of acute monoarthritis and polyarthritis are discussed separately. (See "Monoarthritis in adults: Etiology and evaluation" and "Synovial fluid analysis" and "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease" and "Evaluation of the adult with polyarticular pain" and "Diagnosis of Lyme disease".)
The differential diagnosis of reactive arthritis can be guided, in part, by the pattern of symptoms and findings that are associated with the arthritis and that may suggest a related infectious or other systemic disorder. The following conditions should also be considered in the differential diagnosis:
●Monoarthritis – Common causes of acute monoarthritis such as traumatic arthritis, gout flares, septic arthritis, and Lyme arthritis should be considered. The evaluation and differential diagnosis of monoarthritis are described in detail separately. (See "Monoarthritis in adults: Etiology and evaluation".)
●Diarrhea and arthritis – Various systemic conditions affecting the gastrointestinal tract and some infectious disorders may cause diarrhea in association with chronic or self-limited arthritis, features that may suggest reactive arthritis. Enteroviral infection-associated arthritis may represent a substantial number of cases of nonspecific, self-limited inflammatory joint disease; although arthritis is an uncommon manifestation of enterovirus infection, viral gastroenteritis is relatively common. Additional symptoms suggestive of a viral etiology include the presence of myalgias, an evanescent rash, and constitutional symptoms such as fever. Both large and small joints may be involved. Sore throat, pleuritic pain, and myocarditis are other features suggestive of enteroviral infection .
Inflammatory bowel diseases (eg, Crohn disease and ulcerative colitis), Behçet syndrome, celiac (sprue) disease, Whipple's disease, parasitic infections, and intestinal bypass surgery may cause diarrhea and arthritis. These conditions can usually be differentiated from reactive arthritis by the history, including the chronicity of the gastrointestinal symptoms and other features suggesting the alternative diagnosis; by physical examination; and, as indicated clinically, by serology, biopsy, or culture. These conditions are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)
●Genitourinary symptoms/disorders and arthritis – Disseminated gonococcal infection (DGI) is the primary cause to consider when urethral, uterine, cervical, or tuboovarian inflammation occurs in a patient with arthritis. The presence of a rash and tenosynovitis are suggestive. However, purulent arthritis due to gonococcal infection can occur in the absence of these findings. Culture of synovial fluid, the urethra, and other potentially infected mucosal sites is helpful in the diagnosis or exclusion of DGI or gonococcal arthritis. Nucleic acid amplification testing may be substituted for culture of genitourinary sites when it is available. The clinical manifestations and diagnosis of gonococcal infection and DGI are discussed in detail separately. (See "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents" and "Disseminated gonococcal infection".)
Arthritis and arthralgias are a rare complication of intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer, occurring in 1 to 2 percent of patients treated . Affected patients commonly experience polyarthritis or oligoarthritis, predominantly of the lower extremities, within two weeks after instilling BCG. Approximately 20 percent of reported patients complain of axial pain compatible with spondyloarthritis (SpA), and over one-half of patients are human leukocyte antigen (HLA)-B27-positive. Associated genitourinary symptoms include cystitis, fever, and hematuria . (See "Infectious complications of intravesical BCG immunotherapy".)
●Arthritis/SpA/enthesitis without preceding infectious symptoms – Other members of the SpA family, especially peripheral SpA related or unrelated to psoriasis or inflammatory bowel disease (undifferentiated SpA), may present with arthritis and sometimes enthesitis, which are indistinguishable from the musculoskeletal manifestations of reactive arthritis. Such conditions are distinguished from reactive arthritis by the lack of history and laboratory findings to suggest recent infection with the organisms associated with reactive arthritis. (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults".)
●Poststreptococcal arthritis – Arthritis is a common manifestation in patients with acute rheumatic fever (ARF) following streptococcal pharyngitis. These patients typically lack features common to the spondyloarthritides (eg, enthesitis), and this condition is generally not considered to be a form of reactive arthritis. Other clinical and laboratory manifestations of rheumatic fever and evidence of recent streptococcal infection distinguish these patients from those with reactive arthritis. A "poststreptococcal reactive arthritis" has been described in adults who have arthritis but do not satisfy criteria for ARF . These issues are discussed in detail separately. (See "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Poststreptococcal reactive arthritis'.)
TREATMENT — There are several major aspects to management. In some patients, particularly those with genitourinary infection, treatment of the infection that triggered the arthritis is indicated; arthritis and associated periarticular conditions should be treated in patients with symptomatic joint disease. Additional interventions may also be required for the treatment of extraarticular manifestations. (See 'Treatment of the infection' below and 'Treatment of arthritis' below and 'Treatment of other clinical features' below.)
Treatment of the infection — Antibiotics are not used to treat the arthritis specifically but may be indicated for treatment of the underlying infection if there is evidence of ongoing genitourinary infection or carriage of potentially pathogenic organisms. A role for antibiotic therapy in the treatment of chronic arthritis has not been established. (See 'Chronic chlamydia-related arthritis' below.)
A systematic review and meta-analysis of randomized trials comparing antibiotic therapy with placebo or no antibiotics for treatment of reactive arthritis found that antibiotic treatment did not significantly reduce the likelihood of failing to achieve remission of the reactive arthritis; although results of the studies were very heterogeneous, trial design varied substantially, and many trials were at risk of bias . Rates of remission were able to be analyzed in 7 of the 12 trials included in the review, involving a total of 375 patients. Additionally, there were no significant effects of antibiotic therapy on pain, joint counts, or patient global assessment, but gastrointestinal side effects were nearly twice as likely in the patients receiving antibiotics.
Enteric infection — In general, antibiotics are not indicated for uncomplicated enteric infections, but some patients with active enteric infections may require treatment, depending upon their comorbidities and upon the specific organism. For example, therapy may be indicated in patients with severe gastrointestinal disease, in older adults, or in immunocompromised hosts. Treatment of enteric infections is discussed separately. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Travelers' diarrhea: Treatment and prevention".)
In patients with chronic reactive arthritis induced by enteric bacteria, the available evidence does not support the use of long-term antibiotics [35,38,61-64].
Genitourinary tract infection — In contrast with most patients with enteritis, patients with acute Chlamydia trachomatis infection of the genitourinary tract and their sexual partners should receive a standard antimicrobial treatment for chlamydial infection of the genital tract. Treatment regimens are presented elsewhere. (See "Treatment of Chlamydia trachomatis infection".)
Patients with a history of chlamydia-induced arthritis should be evaluated for recurrent genitourinary infection if arthritis or genitourinary symptoms recur and should be retreated with antibiotics if testing for chlamydia infection is positive. Antibiotic treatment of the infection might prevent relapses of arthritis in patients with recurrent genitourinary tract symptoms alone . It has not been proven whether prompt treatment of acute chlamydia infections prior to the development of reactive arthritis, in both patients and partners, may lower the probability of developing reactive arthritis.
The approach to the evaluation and treatment of persistent or recurrent genitourinary tract symptoms despite initial antibiotic therapy is discussed in detail separately. (See "Treatment of Chlamydia trachomatis infection", section on 'Persistent or recurrent symptoms'.)
Chronic chlamydia-related arthritis — We do not advise the routine use of long-term antibiotics to treat chronic reactive arthritis. Results are mixed in randomized trials of long-term therapy with single antibiotics, and most do not show benefit [38,61-64,66].
Treatment of arthritis — The treatment of arthritis with antiinflammatory and immunosuppressive agents can be divided into two stages: the treatment of acute reactive arthritis and the treatment of refractory (chronic) reactive arthritis, usually defined as disease of greater than six months' duration. (See 'Acute reactive arthritis' below and 'Chronic reactive arthritis' below.)
The initial treatment goal is symptomatic relief of the arthritis because the disease is self-limited in a substantial majority of patients, and joint injury with significant continued symptoms is infrequent. (See 'Prognosis' below.)
The approach to therapy is based upon both clinical experience in reactive arthritis and upon evidence of benefit for these therapies in other inflammatory arthritides, particularly other forms of spondyloarthritis (SpA), given the paucity of randomized trials and longitudinal observational studies in patients with reactive arthritis. (See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Treatment of psoriatic arthritis".)
In clinical practice, disease activity and the response to therapy are assessed by the swollen or tender joint counts, the intensity of pain and disability, the presence and severity of enthesitis, and global assessments by the clinician and patient. There are no specific validated indices for assessment of disease activity in reactive arthritis.
Acute reactive arthritis — In patients with acute reactive arthritis, we initiate treatment with nonsteroidal antiinflammatory drugs (NSAIDs), which are usually the principal form of therapy, and may administer intraarticular and/or systemic glucocorticoids in patients with disease resistant to NSAIDs. (See 'Initial therapy' below and 'Intraarticular glucocorticoids' below and 'Systemic glucocorticoids' below.)
Initial therapy — We suggest treatment with antiinflammatory doses of NSAIDs (eg, naproxen 500 mg twice daily, diclofenac 50 mg three times daily, or indomethacin 50 mg three to four times daily) for symptomatic therapy for most patients, unless contraindicated (eg, by a history of gastrointestinal bleeding, allergy, cardiovascular disease, or compromised renal status). Maximum antiinflammatory doses and continuous use may be necessary to control pain and inflammation. An adequate trial of a given NSAID is usually at least two weeks in duration. Individual responses vary, and more than one NSAID may need to be tried before identifying an effective agent. There is no evidence that NSAIDs shorten or otherwise affect the course of the disease.
NSAIDs are used initially as the major modality because treatment of the infection does not alleviate the signs or symptoms of arthritis, because the disease is most frequently self-limited, and because most patients will not require disease-modifying antirheumatic drugs (DMARDs) to control inflammation or to prevent erosive joint changes. The use of NSAIDs is based upon their ability to provide significant symptomatic relief in other forms of SpA and upon clinical experience with their use in reactive arthritis [6,27,67-69]; there have been few formal trials of NSAIDs in reactive arthritis [70,71]. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
Patients receiving NSAIDs should be cautioned regarding the risk of gastrointestinal, renal, hepatic, and cardiovascular adverse effects, including the risk of NSAID gastropathy and gastrointestinal bleeding. Complete blood counts, renal function, and hepatic aminotransferases should be measured after two months on a given agent and then every six months thereafter in patients continuing to require antiinflammatory dosing regimens of NSAIDs, depending upon the comorbidities present. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs".)
Inadequate response to NSAIDs — Intraarticular glucocorticoids can be administered in patients with persistent symptoms despite treatment with NSAIDs, and oral glucocorticoids may be of benefit in patients who do not respond to these therapies.
Intraarticular glucocorticoids — In patients with monoarthritis or oligoarthritis who do not respond adequately to NSAIDs, we suggest injection of major affected joints with intraarticular glucocorticoids. In our experience, intraarticular injection with triamcinolone acetonide (40 mg for a large joint, such as the knee, and lower doses for smaller joints), or an alternative agent in equivalent doses, is generally effective in reducing joint inflammation and in providing symptomatic relief similar to that seen in other forms of SpA or in rheumatoid arthritis. These may result in symptomatic relief sufficient to avoid the need for oral glucocorticoids or DMARD therapy and the side effects associated with use of these agents. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Intraarticular therapy'.)
There is no evidence in our experience, nor are there any reports, of a greater frequency of adverse events or of disease worsening associated with the use of intraarticular or systemic glucocorticoids, despite the infectious etiology of reactive arthritis and the detection of the causative microbes in the joints of some patients with reactive arthritis. This issue has not been systematically evaluated. Pain and swelling of the plantar fascia can also be relieved by local glucocorticoid injections. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Joint aspiration or injection in adults: Technique and indications" and "Joint aspiration or injection in adults: Complications".)
Systemic glucocorticoids — In patients who do not respond adequately to NSAIDs and intraarticular glucocorticoid injections or in those with a large number of involved joints, we suggest low to moderate doses of oral glucocorticoids (eg, a starting dose of prednisone 20 mg daily), which should be reduced gradually to the lowest dose required to control symptoms. In our experience, use of these agents for a limited period and in a tolerable dose range may preclude need for use of DMARD therapy. There are no randomized trials of systemic glucocorticoids in reactive arthritis. The use of glucocorticoids for inflammatory joint disease, the adverse effects of these agents, and strategies for the prevention of glucocorticoid-induced osteoporosis are described in detail elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Resistant to NSAIDs and glucocorticoids — Treatment with a DMARD is indicated in patients who do not respond adequately to initial therapies. The duration prior to beginning DMARDs depends upon the degree of disease activity and upon the relative risks and benefits of NSAIDs and glucocorticoids in a given patient, given the comorbidities that are present and the dose of glucocorticoids required to control symptoms. We generally use DMARDs in patients who have not responded adequately to at least two different NSAIDs over a total of four weeks and who require ongoing therapy with more than 7.5 mg of prednisone or equivalent for more than three to six months.
We usually prescribe sulfasalazine (SSZ; beginning with 500 to 1000 mg daily and titrating the dose to a maximum of 3 g daily). Methotrexate (MTX; up to 25 mg one day weekly) is an alternative to SSZ. Treatment with a tumor necrosis factor (TNF) blocker may be used in the rare patients who are resistant to NSAIDs and conventional synthetic (cs) DMARD therapy. This approach is based on the treatment of patients with peripheral SpA, which is discussed separately. (See "Treatment of peripheral spondyloarthritis", section on 'Resistant to initial therapy'.)
Chronic reactive arthritis — Some patients will develop refractory reactive arthritis, usually defined as disease lasting greater than six months or who are resistant to initial therapy for acute arthritis with NSAIDs and glucocorticoids.
Such patients have a similar clinical course and response to treatment as those with axial or peripheral SpA . Thus, our treatment approach is similar to those conditions and may include traditional DMARDs and in some cases, biologic agents. The use of these medications for reactive arthritis is based upon limited data and upon clinical experience. Multiple biologic agents have been approved by the FDA for the treatment of axial, but not peripheral, SpA, although these agents are effective for both phenotypes. The management of axial and peripheral SpA are discussed separately. (see "Treatment of peripheral spondyloarthritis" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults").
Treatment of other clinical features — Some extraarticular manifestations, including ocular involvement and mucous membrane and skin manifestations, require additional interventions. The management approaches are based upon the treatments used for these or for similar manifestations in patients with other disorders and upon clinical experience [72-74].
None of these interventions has been systematically evaluated in randomized trials or has been the subject of observational studies in patients with reactive arthritis, and most treatment studies of antiarthritic or antibiotic therapy for reactive arthritis and reviews of this disease do not discuss the effects of such therapies on these manifestations or the recommended approaches for their treatment. Extraarticular manifestations that may require treatment include the following:
●Ocular manifestations – Patients with eye pain, visual disturbance, or abnormal eye findings should be referred for ophthalmologic evaluation, as a slit-lamp examination may be required to determine if uveitis is present. The diagnosis and treatment of conjunctivitis and anterior uveitis are discussed separately. (See "Conjunctivitis" and "Uveitis: Etiology, clinical manifestations, and diagnosis" and "Uveitis: Treatment".)
●Skin and mucous membrane lesions – Patients with very mild skin involvement or oral ulcers may not require intervention . Symptomatic treatment may be sufficient in patients with oral mucosal ulcers, and topical steroids are effective in some patients . The treatment of oral mucosal ulcers is discussed in detail elsewhere. (See "Oral lesions", section on 'Erosive, ulcerative, and bullous lesions'.)
More symptomatic involvement with mild to moderate keratoderma blennorrhagica may benefit from the use of topical steroids, and some skin lesions can be treated with topical salicylates [27,73-75]. In general, treatment of these manifestations is very similar to the approach in patients with palmoplantar pustulosis from other causes. The treatment of circinate balanitis is discussed separately. (See "Neutrophilic dermatoses", section on 'Palmoplantar pustulosis' and "Balanitis in adults".)
Patients with more severe keratoderma blennorrhagica and pustular lesions who do not respond to topical medications may require systemic DMARDs, such as MTX or a TNF inhibitor [75,76]. Other treatments that may be of benefit in keratoderma blennorrhagica include topical vitamin D (calcipotriol/calcipotriene) in mild to moderate cases  and retinoids in patients with more severe involvement [73,78,79]. Therapy of these skin findings and of nail involvement is similar to that used in patients with psoriasis. (See "Treatment of psoriasis in adults".)
PROGNOSIS — The course of reactive arthritis varies considerably, probably depending upon the triggering pathogen and the genetic background of the host [6,9]. The typical disease duration is three to five months. Most patients either remit completely or have little active disease within 6 to 12 months after presentation, but 15 to 20 percent may experience more chronic persistent arthritis. After entering remission of peripheral joint arthritis, pain is occasionally still noted in the joints, at entheses, or in the spine. Representative results are illustrated by the following:
●A European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) study evaluated 152 patients with reactive arthritis who were enrolled within two months of the onset of arthritis . By the end of an additional 24 weeks of observation, almost all patients had very low disease activity as determined by clinician- and patient-global assessments.
●In other studies, reactive arthritis that lasted for more than one year occurred in 4 to 19 percent of patients in Finland whose arthritis was induced by Yersinia, Salmonella, Shigella, and Chlamydia [6,19]. It is difficult to know whether this proportion of patients who develop chronic disease can be generalized to other geographic regions.
●In a 2018 study in Guatemala 15 of 32 patients showed persistence of symptoms two years after onset .
Some patients with chronic reactive arthritis later develop features characteristic of another of the spondyloarthritides, eg, psoriatic arthritis, ankylosing spondylitis, or the arthritis associated with inflammatory bowel disease. Human leukocyte antigen (HLA)-B27 testing has been associated with a worse prognosis in some, but not all studies, with findings suggesting that patients who are HLA-B27-positive are more likely to develop a chronic spondyloarthropathy with radiographic changes [9,38,80]. Patients with the triad of postinfectious arthritis, urethritis, and conjunctivitis may also have a poorer prognosis [81,82].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Spondyloarthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Reactive arthritis (The Basics)")
●Beyond the Basics topic (see "Patient education: Reactive arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Reactive arthritis is a relatively rare disease even among rheumatology practices. It typically occurs in young adults, affecting both males and females. (See 'Epidemiology' above.)
●Definition – Reactive arthritis has been defined by consensus as a form of arthritis that is associated with a coexisting or recent antecedent extraarticular infection. Only certain enteric and genitourinary pathogens are conventionally accepted as capable of causing reactive arthritis. These include Chlamydia trachomatis, Yersinia, Salmonella, Shigella, Campylobacter, Clostridioides difficile, and Chlamydia pneumoniae. Various other bacterial and viral infections have been suggested as triggers for postinfectious arthritis but they are by convention not considered as "reactive arthritis." (See 'Definition' above and 'Preceding infection' above.)
●Musculoskeletal features – Musculoskeletal features of reactive arthritis typically develop one to four weeks following an acute infection with one of the triggering organisms. At least one of the following is seen in all patients with this condition: asymmetric oligoarthritis (often affecting the lower extremities) (picture 1), enthesitis, dactylitis, and inflammatory back pain. (See 'Musculoskeletal signs and symptoms' above.)
●Extramusculoskeletal features – Extraarticular nonmusculoskeletal manifestations occur in some patients, but none are specific for reactive arthritis. These include eye involvement, most often with conjunctivitis, but infrequently with anterior uveitis (picture 3); genitourinary tract symptoms; oral mucosal ulcers (picture 4); and cutaneous manifestations such as keratoderma blennorrhagica (picture 6), circinate balanitis (picture 10), and psoriasis-like nail changes (picture 9). (See 'Extraarticular signs and symptoms' above.)
●Laboratory and imaging findings – Laboratory findings may include evidence of the antecedent infection, elevated acute phase reactants, and findings of inflammatory joint fluid in patients with arthritis. Plain radiographs are generally nondiagnostic. (See 'Laboratory findings' above and 'Imaging abnormalities' above.)
●Diagnosis – The diagnosis is based upon the presence of characteristic musculoskeletal and other clinical features in a patient with a preceding or ongoing enteric or genitourinary infection, in whom other causes of arthritis have been excluded. There is no single definitive test for reactive arthritis. Laboratory testing to confirm infection if feasible may be helpful but is not required to make the diagnosis; such testing may include stool cultures in patients with ongoing gastrointestinal symptoms and testing for Chlamydia trachomatis with a vaginal swab or urine sample for nucleic acid amplification testing in patients with genitourinary symptoms and those without localizing symptoms of infection. Serologic testing for preceding infections is used primarily in epidemiologic studies but is generally not useful in clinical care. Human leukocyte antigen (HLA)-B27 testing may be useful in selected patients. (See 'Diagnostic evaluation' above and 'Antecedent or concomitant infection' above.)
●Differential diagnosis – It is mandatory to consider the various differential diagnoses before diagnosing a patient as having reactive arthritis. The differential diagnosis encompasses disorders that can cause acute mono- or oligoarthritis, particularly those associated with bowel diseases or genitourinary symptoms (eg, enterovirus infection, inflammatory bowel disease, and disseminated gonococcal infection), acute septic or crystal arthritis, undifferentiated spondyloarthritis (SpA), and other postinfectious arthritic disorders. (See 'Differential diagnosis' above.)
●Role of antibiotics – Antibiotic therapy should be used for treatment of active Chlamydia trachomatis infection, if present. In general, antibiotics are not indicated for uncomplicated enteric infections or for treatment of the arthritis itself. (See 'Genitourinary tract infection' above and 'Enteric infection' above and 'Treatment of the infection' above.)
•Initial therapy – We suggest treatment of arthritis in most patients initially with nonsteroidal antiinflammatory drugs (NSAIDs) in antiinflammatory doses (eg, naproxen 500 mg two to three times daily, diclofenac 50 mg three times daily, or indomethacin 50 mg three times daily), rather than starting a disease-modifying antirheumatic drugs (DMARD) upon diagnosis (Grade 2B). (See 'Initial therapy' above.)
•Inadequate response to initial NSAID therapy – In patients who do not respond adequately to NSAIDs, we suggest intraarticular glucocorticoids, rather than initiating therapy with daily oral glucocorticoids or a DMARD. (Grade 2C). (See 'Intraarticular glucocorticoids' above.)
•Inadequate response to NSAIDs and intraarticular glucocorticoids – In patients who do not respond adequately to NSAIDs and intraarticular glucocorticoid injections, we suggest low to moderate doses of systemic glucocorticoids, rather than initiating treatment with a DMARD. (Grade 2C). A typical dose would be prednisone, 20 mg daily, titrated to the lowest dose required to control symptoms (See 'Systemic glucocorticoids' above.)
•Refractory patients – In patients who have not responded adequately to NSAIDs over at least four weeks and who require ongoing therapy with more than 7.5 mg of prednisone or equivalent for more than three to six months we suggest a trial of a conventional synthetic (cs) DMARD, rather than continuing moderate to high dose glucocorticoids without a DMARD (Grade 2B). We usually prescribe sulfasalazine (SSZ; beginning with 500 to 1000 mg daily and titrating the dose to a maximum of 3 g daily). Methotrexate (MTX; up to 25 mg one day weekly) is an alternative to SSZ. Treatment with a tumor necrosis factor (TNF) blocker may be used in the rare patients who are resistant to NSAIDs and csDMARD therapy. (See 'Resistant to NSAIDs and glucocorticoids' above.)
•Chronic reactive arthritis – Some patients will develop chronic reactive arthritis, usually defined as disease lasting greater than six months or who are resistant to initial therapy for acute arthritis with NSAIDs and glucocorticoids. Such patients have a similar clinical course and response to treatment as those with axial or peripheral SpA and are treated similarly. (See "Treatment of peripheral spondyloarthritis" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
●Prognosis – The prognosis is good in the majority of patients, with spontaneous remission within 6 to 12 months of onset of arthritis. However, some patients have persistent but mild musculoskeletal symptoms, and others develop radiologic evidence of joint injury and evolve to a more chronic form of SpA. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Yu, MD, who contributed to earlier versions of this topic review.
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