Reactive Arthritis – Causes, Symptoms, Diagnosis, Treatment

Reactive Arthritis (ReA) is inflammatory arthritis which manifests after several days to weeks after a gastrointestinal or genitourinary infection. It is also described as a classic triad of arthritis, urethritis and, conjunctivitis. However, a majority of patients do not present with the classic triad. It was previously called “Reiter syndrome”, named after Hans Reiter, who first described this syndrome. The name, Reiter syndrome was dismissed because it is believed that Hans Reiter was a member of The National Socialist German Workers’ Party or the “Nazis” and the director of the Kaiser Wilhelm Institute of Experimental Therapy under whose leadership the war prisoners were subject to many inhumane experiments. Today, it is believed that the disorder is due to an aberrant autoimmune response to the gastrointestinal infection caused by salmonella, shigella, campylobacter or chlamydia.[rx][rx][rx]

Reactive arthritis is known to be triggered by a bacterial infection, particularly of the

• Genitourinary (Chlamydia trachomatis, Neisseria gonorrhea, Mycoplasma hominis, and Ureaplasma urealyticum) or gastrointestinal (GI) tract (Salmonella enteritidis, Shigella flexneri, and dysenteries, Yersinia enterocolitica, Campylobacter jejuni, Clostridium difficile).
• The incidence is about 2% to 4% after a urogenital infection mainly with chlamydia trachomatis and varies from 0% to 15% after gastrointestinal infections with Salmonella, Shigella, Campylobacter, or Yersinia.
• This might be affected by the epidemiological, environmental factors, the pathogenicity of the bacteria, and differences in the study designs. The enteric ReA occurs commonly following enteric infections. However, chlamydia associated ReA is endemic, especially in developed countries.[rx][rx]
• Typically, reactive arthritis is caused by a sexually transmitted infection (STI), such as chlamydia, or an infection of the bowel, such as food poisoning. You may also develop reactive arthritis if you, or someone close to you, has recently had glandular fever or slapped cheek syndrome.
• The body’s immune system seems to overreact to the infection and starts attacking healthy tissue, causing it to become inflamed. But the exact reason for this is unknown.

Rare cases have been reported after the administration of the Bacillus Calmette Guerin vaccine (BCG) treatment for bladder cancer.[rx]

Pathophysiology

Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that when the invasive bacteria reach the systemic circulation, T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids. These activated cytotoxic-T cells then attack the synovium and other self-antigens through molecular mimicry. This is supported by the evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA, and bacterial degradation products in the synovial tissue and fluid. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in the decreased elimination of the bacteria. It is, however, unclear why such localization of inflammation occurs.

The prevalence of HLA-B27 in reactive arthritis is estimated at 30% to 50% in patients with reactive arthritis, although values range widely. In hospital-based studies with more severely affected patients, frequencies as high as 60% to 80% have been reported. HLA-B27 should not be used as a diagnostic tool for a diagnosis of acute ReA. The presence of HLA-B27 is believed to potentiate reactive arthritis by presenting bacterial antigens to T cells, altering self-tolerance of the host immune system, increased TNF-alpha production, promoting the invasion of microbes in the gut, and delayed clearance of causative organisms.[rx]

Symptoms of Reactive Arthritis

Reactive arthritis may cause arthritis symptoms, such as joint pain and inflammation. It can also cause urinary tract symptoms and eye infection (conjunctivitis). Symptoms can last from 3 to 12 months. In a small number of people, the symptoms may turn into chronic disease. Symptoms can happen a bit differently in each person, and may include:

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The signs and symptoms of reactive arthritis generally start one to four weeks after exposure to a triggering infection. They might include:

• Because common systems involved include the eye, the urinary system, and the hands and feet, one clinical mnemonic in reactive arthritis is “Can’t see, can’t pee, can’t climb a tree.”^[rx]
• The classic triad consists of:
  • Conjunctivitis
  • Nongonococcal urethritis
  • Asymmetric oligoarthritis
• Symptoms generally appear within 1–3 weeks but can range from 4 to 35 days from the onset of the inciting episode of the disease.
• The classical presentation of the syndrome starts with urinary symptoms such as burning pain on urination (dysuria) or an increased frequency of urination. Other urogenital problems may arise such as prostatitis in men and cervicitis, salpingitis and/or vulvovaginitis in women.
• It presents with monoarthritis affecting the large joints such as the knees and sacroiliac spine causing pain and swelling. Asymmetrical inflammatory arthritis of interphalangeal joints may be present but with relative sparing of small joints such as the wrist and hand.
• The patient can have enthesitis presenting as heel pain, Achilles tendonitis or plantar fasciitis, along with balanitis circinata (circinate balanitis), which involves penile lesions present in roughly 20 to 40 percent of the men with the disease.
• A small percentage of men and women develop small hard nodules called keratoderma blennorrhagicum on the soles of the feet and, less commonly, on the palms of the hands or elsewhere. The presence of keratoderma blennorrhagica is diagnostic of reactive arthritis in the absence of the classical triad. Subcutaneous nodules are also a feature of this disease.
• Ocular involvement (mild bilateral conjunctivitis) occurs in about 50% of men with urogenital reactive arthritis syndrome and about 75% of men with enteric reactive arthritis syndrome. Conjunctivitis and uveitis can include redness of the eyes, eye pain and irritation, or blurred vision. Eye involvement typically occurs early in the course of reactive arthritis, and symptoms may come and go.
• Dactylitis, or “sausage digit”, diffuse swelling of a solitary finger or toe, is a distinctive feature of reactive arthritis and other peripheral spondylarthritides but can also be seen in polyarticular gout and sarcoidosis.
• Mucocutaneous lesions can be present. Common findings include oral ulcers that come and go. In some cases, these ulcers are painless and go unnoticed. In the oral cavity, the patients may suffer from recurrent aphthous stomatitis, geographic tongue, and migratory stomatitis in higher prevalence than the general population.^[rx]
• Some patients suffer serious gastrointestinal problems similar to those of Crohn’s disease.
• About 10 percent of people with reactive arthritis, especially those with a prolonged course of the disease, will develop cardiac manifestations, including aortic regurgitation and pericarditis. Reactive arthritis has been described as a precursor of other joint conditions, including ankylosing spondylitis.
• Pain and stiffness – The joint pain associated with reactive arthritis most commonly occur in your knees, ankles, and feet. You also might have pain in your heels, low back, or buttocks.
• Eye inflammation – Many people who have reactive arthritis also develop eye inflammation (conjunctivitis).
• Urinary problems – Increased frequency and discomfort during urination may occur, as can inflammation of the prostate gland or cervix.
• Inflammation of soft tissue where it enters bone (enthesitis) – This might include muscles, tendons and ligaments.
• Swollen toes or fingers – In some cases, your toes or fingers might become so swollen that they resemble sausages.
• Skin problems – Reactive arthritis can affect your skin a variety of ways, including a rash on your soles and palms and mouth sores.
• Low back pain – The pain tends to be worse at night or in the morning.

Symptoms By Specific Organ

Diagnosis of Reactive Arthritis

The physical exam may reveal

• Sausage shaped finger, toe or heel pain
• Asymmetric oligoarthritis- usually of the lower extremities
• Conjunctivitis or iritis
• Acute diarrhea or cervicitis within 4 weeks of the onset of arthritis
• Urethritis or genital ulcers

Two or more of the above features plus involvement of the skeletal system establishes the diagnosis.

Joint and entheses

Patients typically present with acute onset oligo-arthritis, mainly involving the lower extremities, sacroiliac joint, and the lumbar spine. Not more than 6 large joints are affected at a time and knee and ankle are the most commonly affected. Joint pain is classically nocturnal with early morning stiffness.  Involvement is asymmetric and affects the weight-bearing joint. The joints are often warm, painful and swollen. Tendinitis is a common feature of the disease. About 30% of patients suffer from associated enthesitis in the form of plantar fasciitis or Achilles tendinitis.[rx]

Extra-articular manifestations

Extra-articular manifestations may involve the skeletal system (enthesitis, dactylitis), eye (conjunctivitis, anterior uveitis episcleritis, and keratitis), genitourinary (urethritis, cervicitis, prostatitis, salpingo-oophoritis, cystitis or circinate balanitis), mucosal and skin involvement (mucosal ulcers, keratoderma blennorrhagica and erythema nodosum), cardiac (carditis, aortic, conduction and valvular abnormalities), and nail changes (onycholysis, subungual keratosis, or nail pits) also are seen

Skin and mucocutaneous changes are common and may include hyperkeratotic skin and erythematous dermatitis. Nail dystrophy is common. Other involvements include pustular psoriasis on the sole ( keratoderma menorrhagia), geographic tongue, circinate balanitis, or oral ulceration.

Eye involvement is common and may include conjunctivitis (30%) or uveitis. In patients with visual symptoms, recognition of uveitis is of paramount importance as it can rapidly lead to visual loss.

Rare cases can involve the cardiovascular system causing conduction abnormalities in early-stage and aortic regurgitation when advanced. Myelopathy, as well as non-specific gastrointestinal features of diarrhea and colitis, can also persist.[rx]

Evaluation

Reactive Arthritis falls within the subclass of seronegative spondyloarthropathies that affect the axial skeleton. Other members of that group are Ankylosing spondylitis and Psoriatic arthritis. Joint involvement is oligoarticular and asymmetrical.

American College of Rheumatology came up with diagnostic guidelines for Reactive arthritis in 1999. The criteria were divided into

MAJOR

• Asymmetric oligo or monoarthritis involving lower extremities
• Either enteritis or urethritis symptoms preceding the onset of arthritis by a time interval of 3 days to 6 weeks

MINOR

• Presence of a triggering infection as evidenced by culture positivity
• Presence of persistent synovial involvement

A combination of genitourinary symptoms, metatarsophalangeal joint involvement, elevated C reactive protein and Positive HLA- B27 renders a 69% sensitivity and 93.5% specificity to the diagnosis of reactive arthritis.[rx]

• Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or
• C-reactive protein (CRP) may be elevated.
• Joint aspiration must be performed when possible to rule out other arthritis. Aspiration of the joint is often done to rule out septic arthritis and crystalline arthritis.
• The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts (typically 2000 to 4000 WBC per ml), with neutrophil predominance.
• HLA B 27 can be measured as it correlates with the severity of the disease but is not diagnostic. It is also important in the localization of arthritis. Sacroiliitis occurs more commonly in HLA B 27 positive patients [15]

Blood tests

Your doctor might recommend that a sample of your blood be tested for:

• Evidence of past or current infection
• Signs of inflammation
• Antibodies associated with other types of arthritis
• A genetic marker linked to reactive arthritis

Joint fluid tests

Your doctor might use a needle to withdraw a sample of fluid from within an affected joint. This fluid will be tested for:

• White blood cell count – An increased number of white blood cells might indicate inflammation or an infection.
• Infections – Bacteria in your joint fluid might indicate septic arthritis, which can result in severe joint damage.
• Crystals – Uric acid crystals in your joint fluid might indicate gout. This very painful type of arthritis often affects the big toe.

Imaging tests

X-rays of your low back, pelvis and joints can indicate whether you have any of the characteristic signs of reactive arthritis. X-rays can also rule out other types of arthritis.

Plain radiographs may reveal nonspecific inflammatory joint findings, in the acute phase. Ultrasonography or magnetic resonance imaging (MRI) can be used to diagnose peripheral synovitis, enthesitis, or sacroiliitis. Scintigraphy can reveal early stages of enthesitis.

Treatment 0f Reactive Arthritis

The main goal of treatment is to identify and eradicate the underlying infectious source with the appropriate antibiotics if still present. Otherwise, treatment is symptomatic for each problem. Nonspecific urethritis may be treated with a short course of tetracycline. Analgesics, particularly NSAIDs, are used. Steroids, sulfasalazine and immunosuppressants may be needed for patients with severe reactive symptoms that do not respond to any other treatment. Local corticosteroids are useful in the case of iritis.

• https://www.ncbi.nlm.nih.gov/books/NBK531507/
• https://pubmed.ncbi.nlm.nih.gov/29455267/
• https://www.ncbi.nlm.nih.gov/books/NBK459356/
• https://en.wikipedia.org/wiki/Reactive_arthritis
• https://rarediseases.org/organizations/arthritis-society/
• https://www.health.harvard.edu/pain/reactive-arthritis-a-to-z
• https://www.arthritis.org/diseases/reactive-arthritis
• https://www.cedars-sinai.org/health-library/diseases-and-conditions/r/reactive-arthritis-reiters-syndrome.html
• https://www.nhs.uk/conditions/reactive-arthritis/symptoms/
• https://www.versusarthritis.org/about-arthritis/conditions/reactive-arthritis/
• https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Reactive-Arthritis
• https://www.mayoclinic.org/diseases-conditions/reactive-arthritis/diagnosis-treatment/drc-20354843