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Reactive Arthritis

Essentials

  • Reactive arthritis usually develops in response to an intestinal or sexually transmitted infection.
  • The majority of patients are HLA-B27 positive.
  • A sexually transmitted infection that precipitates reactive arthritis must always be treated with antimicrobials.
  • Other triggering microbes are usually not treated, if the patient is asymptomatic with respect to them.

Epidemiology

  • The annual incidence approximately 3 cases per 10 000 adults
  • The average age at disease onset is 20-30 years.
  • There is no sex predilection but symptoms are often more severe in men.
  • Pathogens considered certain to trigger reactive arthritis are Yersinia (picture 1), Salmonella, Shigella and Campylobacter. Uroarthritis is triggered by a chlamydial and gonococcal infection.
    • Other microbes, such as Borrelia, E. coli, Clostridioides difficile, Chlamydia pneumoniae, Staphylococcus and Streptococcus have been associated with reactive arthritis as well. With the exception of chlamydia, these are not equally clearly associated with HLA-B27 tissue type and hence the clinical picture may often be different.
  • There is no difference between the occurrence rates of enteroarthritis and uroarthritis.
  • At present, reactive arthritis that develops in response to Salmonella, Campylobacter or Chlamydia infection is the most common type. Reactive arthritis associated with Yersinia infection is now more rare. Check local epidemiology.
  • The synovial fluid is sterile in reactive arthritis, but Staphylococcus, Streptococcus, Salmonella, gonococci and Borrelia may also cause purulent arthritis.
  • In hospital-based studies, up to 80% of patients with reactive arthritis are HLA-B27 positive, but in population-based studies only 14-42%. HLA-B27 seems to be associated with more severe and prolonged course of the disease.

Clinical picture

  • Reactive arthritis often manifests about 1-4 weeks after the preceding infection.
    • The triggering infection is symptomatic (diarrhoea or abdominal pain) in many, but not all, patients with enteroarthritis. A genitourinary infection is often symptomatic in men, whereas asymptomatic or only mildly symptomatic in women.
    • Gonococcal infections often cause inflammatory joint symptoms, but the so-called postgonococcal arthritis is probably most often triggered by a concurrent Chlamydia infection.
  • Joint symptoms may range from mild joint pain to a severe polyarthritis.
  • The most typical clinical picture is a monoarthritis or oligoarthritis in a young adult, predominantly affecting the lower limbs.
  • The most common symptom is inflammation in any of the large joints of the lower limbs. However, inflammation of the joints of the upper limbs or inflammation of smaller joints is not an uncommon symptom either.
  • Severe disease may associated with recurring bouts of fever and a marked elevation of ESR and CRP levels.
    • The involvement of several joints, the patient's age and the lack of underlying diseases best distinguish the condition from septic arthritis.
  • Extra-articular manifestations are frequent.
    • Enthesites, such as inflammation or peritendinitis of the insertion of the achilles tendon or the plantar aponeurosis, in 30-50% of the cases
    • Symptomatic sacroiliitis in 20-30%
    • Urethritis (may in association with an intestinal infection be reactive, i.e. sterile)
    • Balanitis in 10-25% (circinate balanitis with annular lesions on the glans penis; picture 2)
    • Conjunctivitis in 10-35%
    • Iritis in 5%
    • ECG changes in 5-15%
    • Erythema nodosum (yersinia, salmonella) Erythema Nodosum.

Diagnosis

  • There are no official diagnostic criteria, which is why the criteria for spondylarthritis may be relied on.
  • The following tests should be performed at the first visit on all patients with arthritis if reactive arthritis is suspected:
    • synovial fluid analysis Investigation of Synovial Fluid
    • nucleic acid testing for faecal pathogens (Salmonella, Shigella, Campylobacter, Yersinia enterocolitica/pseudotuberculosis, Vibrio spp., Plesiomonas shigelloides, and E. coli strains that cause diarrhoea [EHEC, EAEC, EIEC, ETEC, EPEC]) and, if applicable, bacterial culture of positive findings
    • first-stream urine sample for nucleic acid testing of Chlamydia trachomatis and Neisseria gonorrhoeae
    • urinalysis, basic blood count with platelet count, ESR, CRP, plasma creatinine, ALT, ALP and ECG.
    • Concerning patients with genitourinary symptoms: see also articles on Chamydial urethritis and cervicitis Chlamydia and Gonorrhoea Gonorrhoea.
  • The following tests are indicated at the first visit or within 1-3 weeks if the clinical picture and patient history are compatible with reactive arthritis:
    • anti-Yersinia antibodies
    • anti-Salmonella antibodies
    • anti-Campylobacter antibodies
    • anti-Chlamydia antibodies (C. trachomatis, C. pneumoniae), if the PCR test is negative but an arthritis triggered by C. trachomatis or C. pneumoniae is suspected
    • anti-streptolysin if there is suspicion of rheumatic fever (in practice the disease is no longer encountered, and infections other than streptococcal may give false positive anti-streptolysin titres)
    • anti-staphylolysin (ASTA),anti-Borrelia antibodies, as deemed appropriate.
  • A chest x-ray should be taken to detect possible sarcoidosis.
  • In the early stage of the disease, radiographic findings of the joints are usually normal, but examination with ultrasound is useful in detecting early arthritis, tenosynovites and enthesites.
  • If the patient has back pain consistent with an inflammatory condition, an MRI of the lumbar spine and/or SI joints should be performed, as considered necessary.
  • ECG should be recorded without much hesitation due to possible coexistence of (usually asymptomatic) carditis.
  • HLA-B27 testing aids the diagnosis in borderline cases, but there is no necessity to do the test, if the clinical picture is obvious and there is no doubt about the triggering infection.
  • In differential diagnosis, crystal-induced arthritis Gout and Pseudogout, sarcoidosis Sarcoidosis and borrelia arthritis Lyme Borreliosis (LB) should be considered.

Treatment Combination Antibiotics as a Treatment for Chronic Chlamydia-Induced Reactive Arthritis

  • Treatment of the infection
    • A sexually transmitted infection must always be treated with antimicrobials.
      • Chlamydia: azithromycin 1,000 mg as a single dose. Alternatively doxycycline 100 mg twice daily; the duration of treatment in primary infection is 7 days.
    • Enteroarthritis can be managed with a short course of antimicrobials (7-14 days) if diarrhoea is still present and the stool culture is positive.
  • Somewhat conflicting data exist on the benefit of antimicrobial therapy lasting for several months as regards the arthritis becoming prolonged or chronic. It may be beneficial in Chlamydia-induced arthritis, but a long course of antimicrobials is not the routine practice.
  • Treatment of an acute phase of arthritis
  • If symptoms persist, the patient should be referred to a unit treating rheumatic diseases, where antirheumatic pharmacotherapy is usually started (usually sulfasalazine, methotrexate or even biological medication).

Prognosis

  • Reactive arthritis subsides in most cases within 6 months.
  • Approximately 15% of patients will develop chronic arthritis, more often in uroarthritis than in enteroarthritis.
  • Recurrent infections that activate the immune response, as well as HLA-B27 worsen the prognosis.

Prevention

  • The importance of avoiding infections with enteric bacteria or Chlamydia should be emphasised to a patient with a history of reactive arthritis.
    • When travelling, antimicrobial drugs can be considered if severe symptoms of a gastrointestinal infection should occur, but prophylactic antimicrobials to prevent gastrointestinal infections are not recommended Acute Diarrhoeal Disease in a Traveller.

    References

    • Lucchino B, Spinelli FR, Perricone C, et al. Reactive arthritis: current treatment challenges and future perspectives. Clin Exp Rheumatol 2019;37(6):1065-1076 [PubMed]
    • Schmitt SK. Reactive Arthritis. Infect Dis Clin North Am 2017;31(2):265-277 [PubMed]
    • Carter JD, Espinoza LR, Inman RD, et al. Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum 2010;62(5):1298-307. [PubMed]