Reactive arthritis

Reactive arthritis is one of the spondyloarthropathies that is defined as arthritis occurring after an infection.

Reactive arthritis (ReA) is one of the spondyloarthropathies that can cause peripheral arthritis (i.e. joint inflammation) or spondylitis (i.e. spinal inflammation) following an infection. It causes ’sterile’ inflammation because there is no actual infection in the joint.

ReA commonly occurs several weeks following infection by a variety of organisms that usually infect the urogenital or gastrointestinal tract. ReA was historically referred to as ‘Reiter’s syndrome’, which describes a clinical triad of arthritis, urethritis, and conjunctivitis. However, only a small proportion of patients present with this classical triad.

ReA is one of the SpAs that are a diverse group of conditions associated with the HLA-B27 gene.

ReA is one of the SpAs that are a diverse group of conditions characterised by chronic inflammation leading to pain, stiffness, and loss of mobility. They are often referred to as the ‘seronegative spondyloarthropathies’ and include:

• Ankylosing spondylitis
• Psoriatic arthritis
• Reactive arthritis (Reiter’s syndrome)
• IBD-associated spondyloarthropathy

NOTE: the ‘seronegative’ label refers to both the lack of rheumatoid factor positivity and the absence of specific antibodies for each disease.

The SpAs are associated with a multitude of musculoskeletal clinical features including:

• Spinal & sacroiliac joint inflammation
• Peripheral arthritis
• Dactylitis: inflammation of an entire digit
• Enthesitis: inflammation at a tendon insertion point
• Extra-articular manifestations: uveitis, psoriasis, bowel symptoms, cardio-pulmonary disease

Due to the predominant axial skeletal involvement, they may also be collectively termed ‘axial spondyloarthropathies’ (AxSpA).

Reactive arthritis most commonly affects young adults who have the HLA-B27 gene.

ReA is rare and usually occurs in young adults. It accounts for only a small proportion of all cases of spondyloarthropathies. It occurs in both sexes but is more common in men with a peak onset in the third decade of life. The male-to-female ratio may differ depending on the preceding infection (e.g. enteric vs. urogenital).

Reactive arthritis typically occurs 1-4 weeks after the initial infection.

ReA is suspected to occur in patients who are genetically predisposed following an infection. Like all SpAs, the major genetic contribution is the HLA-B27 gene that occurs in 30-50% of patients with ReA. HLA-B27 is one of the major histocompatibility complexes (MHC) that is involved in antigen recognition by the immune system.

Preceding infection

ReA most commonly occurs after a causative infection from the urogenital or gastrointestinal tract.

• Urogenital infections: commonly implicated microorganisms include Chlamydia spp., U. urealyticum, and N. gonorrhoeae
• Gastrointestinal infections: commonly implicated microorganisms include Campylobacter, Shigella, Salmonella, Yersinia, and C. difficile.

NOTE: mycobacterial infection is a rare cause of reactive arthritis known as Poncet’s disease.

Patients may have a clear history of preceding diarrhoea or urethritis indicating a prior or current infection of the gastrointestinal or urogenital tract, respectively. Others may have a clinically asymptomatic infection prior to the onset of joint symptoms that may occur in up to 10%.

Natural history

The presentation of ReA usually occurs 1-4 weeks following the initial infection that may be urogenital or gastrointestinal. Regardless of the site of infection or the causative organism, the pattern of arthritis and extra-articular manifestations is similar and can include:

• Peripheral arthritis
• Axial arthritis: inflammatory back pain
• Enthesitis and/or dactylitis
• Extra-articular manifestations: ocular symptoms (conjunctivitis, uveitis), oral symptoms (ulcers), gastrointestinal symptoms (diarrhoea), urogenital symptoms (pelvic pain, urethritis, prostatitis, dysuria), skin changes (keratoderma blennorrhagica)

NOTE: keratoderma blennorrhagica describes a thickening of the soles and palms that may mimic pustular psoriasis.

Up to 50% of patients have a self-limiting disease whereas the other 50% go on to have chronic reactive arthritis (symptoms > 6 months).

It is suspected that following infection there is a defective immune response with microbial antigens potentially cross-reacting with self-antigens in a process known as molecular mimicry. This leads to the immune system reacting to self-antigens as ‘foreign’ and initiating an autoimmune reaction.

The clinical presentation of ReA is typically an asymmetrical oligoathritis and/or axial involvement.

The clinical presentation of ReA varies but it typically causes joint pain, swelling, stiffness, and loss of mobility. Involvement of the peripheral joints typically leads to an asymmetrical oligoarthritis that commonly affects the knees. Involvement of the axial skeleton leads to inflammatory back pain with involvement of the spine and sacroiliac joints.

Musculoskeletal features

• Joint pain: typically an oligoarthritis involving weight-bearing joints (e.g. knees)
• Inflammatory back pain: worse with inactivity, improved with exercise
• Joint stiffness
• Joint swelling
• Loss of mobility
• Enthesitis: inflammation of the insertion of soft tissue to bone (e.g. tendons, ligaments, fascia). Commonly affects the heel due to insertion of the Achilles tendon or plantar fascia.
• Dactylitis: inflammation of an entire digit, often referred to as ‘sausage-shaped’

Extra-articular features

A variety of clinical features occurring outside of the joints are seen in ReA. These are collectively termed ‘extra-articular features’.

• Constitutional symptoms: fever, malaise, weight loss
• Eye involvement: conjunctivitis, keratitis, uveitis, and corneal ulceration may all be seen
• Skin involvement: erythema nodosum (reddened, raised, tender nodules), keratoderma blenorrhagica (skin lesions resembling psoriasis on the palms/soles), circinate balanitis (form of dermatitis on the glans penis)
• Oral aphthous ulcers
• Gastrointestinal: diarrhoea
• Urogenital: urethritis, prostatitis, cervicitis
• Cardiac (rare): aortitis, pericarditis

The diagnosis of ReA is a clinical diagnosis based on a typical history, examination findings and investigations.

The diagnosis of ReA is typically based on the characteristic presentation of asymmetric oligoarthritis, inflammatory back pain, enthesitis, and/or dactylitis in a patient with a preceding infection. However, only ~50% of cases will have an identifiable microorganism so the absence does not exclude the diagnosis.

When to suspect?

ReA typically presents as an asymmetric inflammatory oligoarthritis. Patients with a suspected new-onset inflammatory arthritis should be referred to a rheumatologist for further investigation.

The following features are suggestive of a peripheral SpA and should be referred to a rheumatologist:

• Dactylitis
• Enthesitis (without clear mechanical cause) that is
  • Persistent
  • Multiple sites
  • Associated with back pain, psoriasis, uveitis history, or preceding infection
• Family history: first degree relative with SpA or psoriasis

An axial SpA (i.e. ReA with axial involvement) should also be suspected in patients presenting with inflammatory back pain. For more information on referral in the context of back pain see our Ankylosing spondylitis notes.

Diagnostic criteria

There are no specific diagnostic criteria for ReA. Instead, a number of broad criteria can be used for patients with a suspected SpA that is axial (i.e. involvement of the spine and sacroiliac joints) or peripheral (i.e. arthritis affecting the limbs). These criteria can be used to confirm evidence of a SpA of which the subtype can then be deduced.

• Axial SpA
  • Assessment of Spondyloarthritis International Society (ASAS): axial
  • Modified New York
• Peripheral SpA
  • Assessment of Spondyloarthritis International Society (ASAS): peripheral

Differential diagnosis

Many musculoskeletal conditions may present with an oligoarthritis and it is important to consider these in any patient presenting with new mono- or oligoarthropathy:

• Septic arthritis
• Gout,
• Pseudogout
• Rheumatoid arthritis
• SLE
• Disseminated gonococcal infection
• Traumatic arthritis

It is particularly important to consider septic arthritis in patients presenting with a new hot, swollen joint because it can lead to the rapid destruction of the joint without urgent treatment. Therefore, if there is any suspicion of septic arthritis patients should be referred and assessed urgently. For more information see our Septic arthritis notes.

Any patient with a concerning hot swollen joint should undergo joint aspiration to exclude septic arthritis.

Investigations for ReA are guided by the symptoms and pattern of clinical presentation. Imaging is essential to investigate for peripheral arthritis or spinal/sacroiliac involvement and includes x-rays, MRI, and US.

Bedside tests

Patients with ReA typically have evidence of past or current infection. Therefore, investigations to look for an underlying microorganism that has precipitated the joint disease are essential. These can include:

• Urinalysis
• Mid-stream urine MC&S
• Stool cultures
• Genital swabs
• Nucleic amplification tests (e.g. chlamydia/gonorrhoea)

Bloods

Blood tests are important to assess for an inflammatory response and exclude a systemic disorder.

• FBC
• U&E
• LFT
• CRP
• Blood cultures – if febrile

HLA-B27 testing can be completed in indeterminate cases to help support the diagnosis. A negative test does not exclude a diagnosis of ReA and a positive test is supportive but not confirmative.

Imaging

Plain x-rays of affected joints should be requested and patients with back pain require pelvic/spinal x-rays. If x-rays are inconclusive or more information is needed then an MRI can be requested, particularly for patients with inflammatory back pain but normal sacroiliac joints on x-ray.

Joint aspiration

Any patient with suspected septic arthritis (hot, painful, swollen joint) needs to undergo joint aspiration for microscopy, culture, and sensitivity, and white cell count to exclude an infective cause. Additional tests including crystals should be completed to exclude a crystal arthropathy.

The treatments of choice for acute arthritis secondary to ReA are NSAIDs and/or steroids.

The management of ReA can be broadly divided into treatment of acute and chronic arthritis and treatment of the suspected precipitating infection. Non-pharmacological therapy is important at all stages including patient education and physiotherapy.

Treatment of precipitating infection

If there is evidence of an ongoing infection, treatment should be directed towards the microorganism. In general, patients with urogenital infections should be treated whereas enteric infections are usually self-limiting. However, treatment with antibiotics may be indicated in certain cases.

Acute treatment

The acute treatment of ReA usually centres on NSAIDs and/or steroids. It is important to consider any contraindications before the use of NSAIDs and the role of gastric protection (e.g. PPI). Typical choices include naproxen or ibuprofen. NSAIDs are first-line because most cases of ReA are self-limiting.

Patients with an incomplete response to NSAIDs, or with a large number of joints involved, may be treated with corticosteroids (e.g. prednisolone). A steroid joint injection can be considered for major affected joints. If patients do not respond to steroids then disease-modifying anti-rheumatic agents (DMARDs) can be considered (e.g. methotrexate).

Chronic treatment

Patients with chronic arthritis (symptoms > 6 months) or those who are refractory to NSAIDs and steroids should be treated with conventional DMARDs. Examples include methotrexate and sulfasalazine. Those refractory to conventional DMARDs may be treated with biologics (e.g. anti-TNF agents) and this may be more appropriate in patients with predominantly axial involvement.

The typical duration of ReA is 3-5 months.

ReA is usually a self-limiting illness but up to 20% may develop chronic arthritis. During follow-up, patients with chronic ReA may develop features typical of another SpA (e.g. ankylosing spondylitis). In general, patients with HLA-B27 or the characteristic Reiter’s triad are more likely to have a poorer prognosis with chronic SpA symptoms.