Reactive arthritis

What is reactive arthritis?

Reactive arthritis is a form of seronegative spondyloarthritis clinically associated with inflammatory back pain, additive or migratory oligoarthritis and extra-articular symptoms that typically follow a gastrointestinal or urogenital infection by a minimum of 1 to a maximum of 3-6 weeks.¹

The presence of large joint oligoarthritis, urogenital tract infection and uveitis characterises a syndrome (formerly named after Reiter, the doctor who first described it as a clinical subtype of reactive arthritis.)¹ Reactive arthritis which accompanies a sexually transmitted infection (which includes Reiter's syndrome) is now encompassed in the term 'sexually acquired reactive arthritis' (SARA).

There appears to be a strong association with HLA B27 (~75%) and the seronegative arthropathies. The syndrome is sometimes subdivided into two subgroups:

• Post-enteric: the three most commonly associated enteric pathogens are Campylobacter, Salmonella and Shigella species.²

• Post-venereal: following Chlamydia trachomatis infection or with human immunodeficiency virus (HIV).

How common is reactive arthritis? (Epidemiology)

• Usually reactive arthritis affects the young population, particularly between 18 and 40 years old, with peak between the age of 20 to 29 years. Reactive arthritis can occur in children but the prevalence of juvenile reactive arthritis is very low. Reactive arthritis is more common in white patients, as the presence of the HLA-B27 gene is higher in them than in patients of other ethnicities.³

• C. trachomatis and Chlamydia pneumoniae are the most frequent causative pathogens.⁴ A recent decrease in the incidence of chlamydia-related SARA has been documented, which may reflect a response to early recognition and treatment strategies.

• Up to 16% of cases are associated with Neisseria gonorrhoeae.

• Non-travel-related outbreaks of Shigella-associated reactive arthritis suggest a possible sexually-transmitted route.

• Reactive arthritis may be associated with tuberculosis (Poncet's disease).⁵

• Arthritis may also occur after infection with atypical organisms such as Clostridium difficile and Giardia lamblia.⁶

• Post-COVID sacroiliitis has been reported.⁷

Symptoms of reactive arthritis (presentation)⁸

• Reactive arthritis usually develops 2-4 weeks after a genitourinary or gastrointestinal infection. About 10% of patients do not have a preceding symptomatic infection.

• The onset is most often acute, with malaise, fatigue and fever.

• An asymmetrical - predominantly lower-extremity - oligoarthritis (usually no more than six joints) is the major presenting symptom.

• Low back pain often occurs.

• Heel pain is common because of inflammation of the Achilles or plantar aponeurosis insertions on the calcaneus.

• The complete triad of urethritis, conjunctivitis and arthritis may occur.

• Skin (eg, erythema nodosum, circinate balanitis), nails (dystrophic changes) and mucous membranes (mouth ulcers) may all be affected.

• Other features include:

  • Eyes: uveitis, episcleritis, keratitis, and corneal ulcerations.

  • Gastrointestinal: some patients have intermittent bouts of abdominal pain and diarrhoea - and show lesions on colonoscopy, similar in appearance to inflammatory bowel disease.

  • Cardiovascular: aortitis with or without aortic regurgitation (2%), conduction defects.

Differential diagnosis

• Ankylosing spondylitis and undifferentiated spondyloarthropathy.

• Gonococcal arthritis.

• Gout.

• Inflammatory bowel disease.

• Psoriatic arthritis.

• Rheumatic fever.

• Rheumatoid arthritis.

• Septic arthritis.

Diagnosing reactive arthritis (investigations)⁹

Once arthritis is observed, microbial tests and blood or synovial fluid cultures are negative, and only serum antibodies are detected.¹

• ESR and CRP are usually very high.

• FBC: normocytic normochromic anaemia, mild leukocytosis and thrombocytosis during the acute phase.

• In men:

  • Urine nucleic acid amplification test (NAAT) for C. trachomatis and N. gonorrhoeae.

  • Urethral Gram-stained smear (if urethral symptoms).

  • Urethral culture and sensitivity testing for N. gonorrhoeae.

• In women:

  • Vulvovaginal NAAT for C. trachomatis and N. gonorrhoeae.

  • Endocervical culture and sensitivity testing for N. gonorrhoeae (if microscopy or NAAT positive).

• In both sexes:

  • Pharyngeal and rectal NAAT samples for C. trachomatis and N. gonorrhoeae where indicated by the sexual history.

  • Screening for HIV and syphilis.

  • Screening for hepatitis B and C based on risk factors in the sexual history.

  • M. genitalium is an uncommon cause of SARA but a NAAT test (urine in men/vulvovaginal sample in women) should be considered for completeness.

• The British Association for Sexual Health and HIV (BASHH) has produced standards for trans and non-binary people.¹⁰

• HLA-B27 is positive in the majority of those affected. Rheumatoid factor and antinuclear antibodies are absent.

• Joint aspiration may be required to rule out septic or crystalline arthritis. Synovial fluid analysis in patients with reactive arthritis shows a high white blood cell count (mostly polymorphonuclear leukocytes in acute phase).

• Refer to a sexual health clinic for further genitourinary investigation in sexually active patients.

• Serology for other possible infectious triggers - eg, HIV, Yersinia, Campylobacter, Salmonella and Shigella species.¹¹

• A tuberculin skin test should be performed in a patient from an endemic population.

• X-rays: normal in early stages of disease. In advanced or long-term disease, they may show periosteal reaction and proliferation at sites of tendon insertion, plantar spurs, marginal erosions with adjacent bone proliferation in the hands and feet and, less often, features of sacroiliitis and ankylosing spondylitis.

• Ultrasonography or MRI may be helpful in diagnosing peripheral synovitis, enthesitis, or sacroiliitis. Scintigraphy can detect the early stages of enthesitis.

• ECG: in patients with prolonged disease to assess for conduction disturbances.

Management of reactive arthritis

• In the acute phase, rest affected joints, aspirate synovial effusions.

• Physiotherapy.

• Non-steroidal anti-inflammatory drugs (NSAIDs).

• Corticosteroids:

  • These can be used as either intra-articular injections or systemic therapy. Joint injections can help avoid the use of other systemic therapy. Sacroiliac joints can be injected, usually under fluoroscopic guidance.

  • Systemic corticosteroids are usually reserved for patients non-responsive to NSAIDs, who have severe polyarthritis, or cardiac or ocular manifestations.⁸

• Antibiotics to treat an identified causative organism. The duration of treatment is controversial. BASHH recommends treating any identified genital infection but does not recommend lengthy courses of antibiotics. Other authorities recommend antibiotic treatment of proven infection for 3-6 months, based on evidence that such an approach is linked to an increase in the duration of remission.⁸

• Disease-modifying antirheumatic drugs (DMARDS):

  • Clinical experience with DMARDs in reactive arthritis is limited.

  • Sulfasalazine has been shown to be beneficial in some patients.

  • Experiences with other DMARDs (eg, methotrexate) have been anecdotally reported and they may be used in patients unresponsive to standard treatments (NSAIDs and physiotherapy).

  • There is insufficient evidence for the treatment of refractory reactive arthritis with biological agents, although biological agents against cytokines have been developed.¹²

  • In more aggressive cases, or when reactive arthritis evolves towards ankylosing spondylitis, TNF alpha-blockers may represent an effective choice.

Prognosis⁸

• Reactive arthritis is usually self-limiting with resolution of symptoms by 3-5 months. Symptoms lasting more than six months suggest chronicity.

• The presence of hip involvement, unresponsiveness to NSAIDs, and ESR greater than 30 portend a worse outcome.

• There is a high incidence of recurrence, especially in those who are HLA-B27-positive.

• Recurrence of disease may be triggered by a new infection or other stress factor.