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Musculoskeletal System

Reactive arthritis (ReA)

Inflammatory arthritis that manifests several days to weeks after a gastrointestinal/genitourinary infection.

Inflammatory arthritis that manifests several days to weeks after a gastrointestinal/genitourinary infection.

Reactive Arthritis falls within the subclass of seronegative spondyloarthropathies that affect the axial skeleton. Other members of that group:

  • Ankylosing spondylitis
  • Psoriatic arthritis

History:

Hans Conrad Julius Reiter
Hans Conrad Julius Reiter was a German Nazi physician and war criminal who conducted medical experiments at the Buchenwald concentration camp. He wrote a book on “racial hygiene” called Deutsches Gold, Gesundes Leben – Frohes Schaffen.

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.


Etiopathogenesis

The disorder is due to an aberrant autoimmune response to the gastrointestinal/genitourinary infection caused by salmonella, shigella, campylobacter, or chlamydia.

Genitourinary infections (2-4% incidence):

For sexually acquired reactive arthritis, there is a history of sexual intercourse, usually with a new partner, within 3 months of arthritis symptoms. Genital symptoms precede arthritis by about 2 weeks on average. It may include dysuria, discharge, testicular pain in men, and intermenstrual or postcoital bleeding, or deep pelvic pain apart from vaginal discharge in women.
  • Chlamydia trachomatis
  • Neisseria gonorrhea
  • Mycoplasma hominis
  • Ureaplasma urealyticum

Gastrointestinal (GI) infections (0-15% incidence):

These symptoms manifest several days to weeks after the initial infection. Diarrhea or other symptoms caused by the offending agents are usually resolved by the time the patient develops arthritis.
  • Salmonella enteritidis
  • Shigella flexneri, S. disenteriae
  • Yersinia enterocolitica
  • Campylobacter jejuni
  • Clostridium difficile

Immune-mediated syndrome:

Reactive arthritis is an immune-mediated syndrome triggered by a recent infection: T lymphocytes are induced by bacterial fragments (lipopolysaccharide and nucleic acids) which then attack the synovium and other self-antigens through molecular mimicry. Anti-bacterial cytokine response is also impaired, resulting in the decreased elimination of the bacteria.
Reactive Arthritis

Presentation

Classic triad:

Majority of patients do not present with the classic triad.
  1. Arthritis
  2. Urethritis
  3. Conjunctivitis

Classical findings:

Two or more of the above features plus involvement of the skeletal system establishes the diagnosis.
  • 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
Swollen “sausage” toe
Swollen “sausage” toe (top) and inflamed ankle (bottom) in a patient with postdysentery reactive arthritis on initial presentation. | BARTH, W., & SEGAL, K. (1999). Reactive Arthritis (Reiter’s Syndrome). American Family Physician, 60(2), 499-503. Retrieved from https://www.aafp.org/pubs/afp/issues/1999/0801/p499.html

Articular manifestations:

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 the 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.
Reactive arthritis after COVID-19
A previously healthy 53-year-old man was hospitalised for 12 days due to COVID-19 with shortness of breath. A few days after discharge from hospital, the patient developed fever and severe pain in several joints in the lower extremities. The pain was so severe that the patient was unable to stand on his feet. Synovial fluid from the right-side knee contained a high number of polynuclear cells and a few mononuclear cells. Microscopy, culture and PCR tests for bacterial infection were all negative. Furthermore, the patient tested negative for rheumatoid factor, anti-cyclic citrullinated peptide and human leukocyte antigen (HLA)-B27. Thus, the condition was compatible with reactive arthritis. The condition improved markedly after a few days’ treatment with non-steroid anti-inflammatory drugs and prednisolone. | Hønge BL, Hermansen MF, Storgaard MReactive arthritis after COVID-19BMJ Case Reports CP 2021;14:e241375.

Extra-articular manifestations:

  • Skeletal system: Enthesitis, dactylitis
  • Eye: Conjunctivitis (30% cases), 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 (rare): Carditis, aortic, conduction and valvular abnormalities
  • Nail changes: Onycholysis, subungual keratosis, or nail pits
  • Skin: Hyperkeratotic skin and erythematous dermatitis, pustular psoriasis on the sole (keratoderma blenorrhagica)
  • Mucosal: Geographic tongue, circinate balanitis, or oral ulceration.

Complications of ReA include:     

ReA can be self-limiting, recurrent, or continuous, and about 20-25% of the patients may progress to have chronic articular, ocular, and cardiac complications.
  • Recurrent arthritis (15-50%)    
  • Chronic arthritis or sacroiliitis 
  • Ankylosing spondylitis (30-50% if the patient is also HLA-B27–positive)    
  • Urethral stricture
  • Aortic root necrosis 
  • Cataracts
  • Cystoid macular edema

Diagnosis

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 diagnosing reactive arthritis.

American College of Rheumatology diagnostic criteria:

Diagnosis criteria of ReA issued during the fourth International Workshop on Reactive Arthritis, Berlin, Germany, in 1999

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

Microbiological tests:

Detect offending pathogens to confirm concomitant or preceding infections
  • Nucleic acid amplification tests (NAAT): Chlamydia trachomatis, Neisseria gonorrhea, Mycoplasma genitalium (urethritis)
  • Polymerase chain reaction (PCR): Chlamydia (joint)
  • Serological testing: Salmonella, Yersinia, and Campylobacter
  • Stool culture

Laboratory tests:

  • Acute phase reactants: Elevated ESR, CRP
  • Joint aspiration: Non-specific findings in synovial fluid, characteristic of inflammatory arthritis, with elevated WBC counts (2000-4000 WBC per ml), with neutrophil predominance
  • HLA-B27 (30-50% cases; not diagnostic): Correlates with severity of disease

Imaging:

Nonspecific inflammatory joint findings in the acute phase.
Reactive Arthritis radiography
Anteroposterior (AP) view of the forefoot ( A ) in reactive arthritis. There is involvement of the fourth toe with sausage-like soft tissue swelling. There is new bone formation around the proximal phalanx ( arrows ). There is erosive change involving the juxta-articular areas of PIP joint. Axial T1-weighted image of the forefoot ( B ) shows intermediate signal replacing fat in the subcutaneous fat and marrow of the fourth toe indicating edema. Axial fat-suppressed T1-image through the forefoot following intravenous contrast administration ( C ) shows intense enhancement of synovitis in the fourth MTP joint. | Reactive Arthritis. (2019). Retrieved 2 August 2022, from https://musculoskeletalkey.com/reactive-arthritis-4/

Management

Antibiotic therapy:

Treatment of the underlying concomitant infection, if present, should be initiated without delay. Patients who do not have an active infection do not benefit from antibiotic therapy.

The goal of therapy in reactive arthritis is to provide symptomatic relief and prevent chronic complications.

Acute ReA:

  • Non-steroidal anti-inflammatory (NSAIDs): Initial treatment of choice
  • Intra-articular glucocorticoids: Mono/oligoarthritis
  • Mechanical devices: Orthotics, insoles
  • Systemic use of glucocorticoids is limited to severe polyarthritis, cardiac and ocular manifestations.

Chronic ReA:

  • Disease-modifying antirheumatic drugs (DMARDs): Acute and chronic ReA
  • Immunosuppressants (indicated in NSAID failure): Methotrexate, azathioprine
  • Biologicals: Anti-TNF agents (e.g. infliximab, etanercept)

All patients should be urged to become physically active. Strengthening exercises are a key component of long-term therapy to prevent muscle wasting.

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