Reactive arthritis: causes, symptoms, diagnosis, treatment, and prognosis

Reactive arthritis (ReA) is an arthritis induced by infections, especially gastrointestinal or genitourinary infections.

Reactive arthritis is associated with human leukocyte antigen (HLA)-B27, the involvement is asymmetric and mainly in the lower joints, and the spine may be involved, thus reactive arthritis is a spondyloarthropathy.

Reactive arthritis can be divided into sexually transmitted reactive arthritis and intestinal reactive arthritis. The former is mainly seen in males aged 20 - 40 years and occurs after genitourinary infections with chlamydia or mycoplasma. The incidence of males and females in the latter is basically identical. Most intestinal bacteria, including Shigella, Salmonella, Yersinia, and Campylobacter, are Gram-negative.


Causes

The onset of reactive arthritis is related to infections, genetic markers, and immune disorders. Numbers of the patient’s relatives with sacroiliitis, ankylosing spondylitis, and psoriasis are higher than normal population. Common pathogenic microorganisms include intestinal, genitourinary, pharyngeal, and respiratory bacterial flora, viruses, chlamydia, and protozoa, mostly Gram-negative. Studies have found that DNA and RNA of Chlamydia trachomatis and antigenic components of Shigella can be detected in the synovium and synovial leukocytes of many patients with reactive arthritis. Chlamydia heat shock protein (HSP), Yersinia heat shock protein-60, and polypeptide fragments can induce T cell proliferation in patients with reactive arthritis, suggesting that T cells in the peripheral blood induced by antigenic components of the bacteria may cause the disease. Group B hemolytic streptococcal infection is another common cause of reactive arthritis.

Reactive arthritis caused by intestinal and genitourinary infections is mostly related to the susceptibility gene HLA-B27, whereas reactive arthritis caused by streptococcus, viruses, and spirochaete is generally not associated with HLA-B27.

HLA-B51, B60, B39, and B7 may increase susceptibility to reactive arthritis. HLA-B60 and HLA-B27 have synergistic effects in the pathogenesis of reactive arthritis, and HLA-B39 and HLA-B7 can be found in HLA-B27 negative patients and may be directly involved in the pathogenesis of reactive arthritis.


Signs and Symptoms

Systemic symptoms

Systemic symptoms are often prominent, and fever, weight loss, fatigue, and sweating occur several weeks after infection. Moderate to high fever with 1 to 2 peaks per day is mostly not affected by antipyretics, persisting for 10 - 40 days. The symptoms can be relieved spontaneously.

Arthritis

The initial symptom is usually acute arthritis. Typical arthritis occurs 1 - 6 weeks after urinary or intestinal infection. Acute onset, mostly monarthritis or pauciarthritis, asymmetry, and dactylitis with periarthritis are present. Arthritis usually lasts for 1 - 3 months, and can persist for more than 6 months in few patients. Lower large joints, such as knee joints and ankle joints, are mainly involved, and small joints, such as shoulder joints, wrist joints, elbow joints, hip joints, hand joints, and foot joints, can also be affected. The involved joints are hot, swollen, severely painful, and tender. The knee joint often has obvious swelling and a lot of effusion. Back discomfort often radiates to the hips and thighs. The symptoms are aggravated during bed rest or inaction. The typical manifestation of tendinopathy is achilles tendonitis. The symptoms usually resolve within 3 - 4 months and can recover completely on the first episode. However, there is a tendency to relapse, and some patients may develop joint deformities, ankylosis, sacroiliitis, or spondylitis during recurrent episodes.

Genitourinary inflammation

Typical patients develop aseptic urethritis 7 - 14 days after sexual contact or dysentery. Male patients have frequent urination, urethral burning sensation, and red and swollen urethral orifice with clear myxoid secretions. Hemorrhagic cystitis or prostatitis may also occur and can be relieved spontaneously. Circinate balanitis with painless, superficial ulcers is seen in 20% - 40% of male patients. The occurrence of balanitis is not associated with the presence or severity of urethritis. Balanitis usually heals in few days or weeks, and very few can last for months. Female patients may have asymptomatic or mild cystitis and cervicitis, with a small amount of vaginal discharge or dysuria.

Cutaneous and mucosal manifestations

Cutaneous and mucosal symptoms can occur in over 50% of patients. Keratoderma blennorrhagicum is excessive keratosis of the diseased skin and is seen in 10% - 30% of patients, usually on the soles and palms, as well as perionychium, scrotum, penis, trunk, and scalp. Clear vesicles on the base of erythema occur initially, developing into macules, papules, and keratinized nodules, difficult to differentiate from pustular psoriasis clinically and histopathologically. Keratosis of nails is also seen in about 6% - 12% of patients. Transient superficial ulcers, mostly in the hard and soft palate, gums, tongue, and buccal mucosa, can occur in 5% - 15% of patients. Initial vesicles gradually develop into superficial, sometimes fused ulcers, mostly painless. Erythema nodosum is a clinical manifestation of Yersinia infection, mainly in females, patients with negative HLA-B27, and patients without gastrointestinal symptoms.

Ocular symptoms

Conjunctivitis can occur in 1/3 of patients with reactive arthritis, usually with mild symptoms, with arthritis, unilaterally or bilaterally, with sterile secretions. Spontaneous remission can occur in 1 - 4 weeks, but easy to relapse. 5% of patients develop acute anterior uveitis, manifested by pain, redness, and photophobia, and the prognosis is generally good. However, if untreated, 11% of patients may develop blindness. Keratitis, keratohelcosis, episcleritis, optic neuritis, retrobulbar neuritis, and anterior chamber hemorrhage can also be seen in persistent or chronic patients.

Cardiac manifestation

Cardiac manifestations include aortic lesions and conduction abnormalities. Aortic annulus and ascending aorta are usually involved. In few patients, aortic valve insufficiency eventually occurs due to aortic medial lesions and aortic root expansion. Electrocardiogram abnormalities can occur in 5% - 14% of patients. Most patients with chronic diseases more than 10 years report a first degree atrioventricular block, which may progress to a second degree or complete atrioventricular block. Studies have suggested that about 6% of patients with reactive arthritis after streptococcal infection may develop carditis.

Others

Proteinuria, microscopic hematuria, or sterile pyuria can be seen in about 50% of sexually transmitted reactive arthritis, which is often asymptomatic. Glomerulonephritis and IgA nephropathy can be seen in a small number of patients. Severe systemic necrotizing vasculitis, superficial thrombophlebitis, purpura, amyloidosis, cranial neuropathy, and peripheral neuropathy are also less common complications in patients with chronic diseases.


Diagnosis

In patients with acute, asymmetric arthritis in the lower extremities or toes, especially enthesopathy, or with a history of diarrhea or dysuria, reactive arthritis should be suspected.

Diagnostic considerations include:

  • Peripheral arthritis: asymmetric oligoarthritis in lower limbs
  • Prodromal infections: clinically typical diarrhea or urethritis before 4 weeks or laboratory results
  • Exclusion of other causes of monarthritis or oligoarthritis, such as spinal arthritis, infectious arthritis, Lyme disease, and streptococcal reactive arthritis
  • Positive HLA-B27

Other manifestations of reactive arthritis, such as conjunctivitis, uveitis, as well as lesions in skin, heart, and nervous system, or symptoms of typical spinal arthritis, such as inflammatory lower back pain, alternating hip pain, enthesopathy, and iris, are not essential for the definitive diagnosis of reactive arthritis.


Treatment

Non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac sodium, loxoprofen sodium, meloxicam, indomethacin, and celecoxib, can be administered.

After administration of non-steroidal anti-inflammatory drugs, if the symptoms persist for more than 3 months or joint lesions are present, slow-acting antirheumatic drugs, such as sulfasalazine, can be used.

For severe patients, immunosuppressants such as methotrexate and azathioprine can be selected.


Prognosis

The prognosis in most patients with reactive arthritis is good. After prompt treatment, patients can completely recover. Oligoarthritis on the first episode usually resolves within 3 - 6 months, and 75% of patients have complete remission in 2 years. 10% - 15% of patients can have a disease course of more than 2 years, and 1% of patients, especially those with keratoderma blennorrhagica, may have a poor prognosis. However, the disease has a tendency to relapse. Intestinal, genitourinary, and respiratory infections may be the direct inducers of recurrence.

Some patients may have recurrent peripheral arthritis, tendonitis, iritis, or other symptoms 3 - 4 years after the first episode. Hip joint involvement, persistent elevated erythrocyte sedimentation rate, and poor response to non-steroidal anti-inflammatory drugs suggest a poor prognosis. Some patients may develop peripheral or axial arthritis.