BOTTOM LINE

Reactive arthritis (ReA) is an inflammatory mono/oligo-articular lower-extremity predominant spondyloarthritis typically preceded by a mucosal infection (often gastrointestinal or genitourinary) 1-4 weeks prior. Patients may also present with other features of peripheral spondyloarthritis, such as enthesitis, dactylitis, and inflammatory back pain. HLA-B*27 positive patients tend to have worse prognosis and are more likely to present with axial spondyloarthritis and extra-articular manifestations (ex: conjunctivitis, uveitis, urethritis, and mucositis). Most patients achieve remission within 6-12 months, but 10-30% of patients develop chronic spondyloarthropathy. Reactive Arthritis, Enteropathic (IBD-related) arthritis, and Psoriatic Arthritis can be conceptualized together as a spectrum of “Peripheral Spondyloarthropathy”.
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EPIDEMIOLOGY

• Varied definitions of ReA, epidemiologic methods, population changes over time; overall incidence is felt to be declining
  • Incidence: 1-1.5% after enterogenic infection, 0.6-30% after chlamydial infection
  • Prevalence worldwide: 1/1000
• Sex:
  • Urogenic ReA: M > F
  • Enterogenic ReA: F=M     
• Age: 20-40 years.
• Rare in children and less prevalent in patients of African descent.

CLINICAL FEATURES

Historically called “Reiter’s Syndrome”: triad of conjunctivitis, nongonococcal urethritis, and inflammatory arthritis following dysentery. Only 2/3 of ReA patients have all 3 features of this triad.

—Preceding infection

• Mucosal infection 1-4 weeks beforehand, usually enterogenic or urogenic
  • Urogenic:
    • Chlamydia trachomatis, Ureaplasma urealyticum
    • Also: intravesical BCG therapy for bladder cancer
    • Enterogenic:
      • Salmonella, Shigella, Campylobacter, Yersina, C. difficile, E. coli
    • Less common:
      • Chlamydia pneumoniae, E. coli, HIV
• Causal organisms are often not detected and seem to be changing over time

—Musculoskeletal

• Peripheral inflammatory arthritis
  • Asymmetric oligoarticular lower-extremity predominant arthritis often including the knee
  • Less common:
    • Mono- or polyarticular disease
    • Upper extremity involvement
  • Enthesitis
    • Inflammation at insertion of tendon/ligament to bone
    • Examples: elbow epicondylitis, Achilles enthesitis, plantar fasciitis, patellar tendon, iliac crest, supraspinatus insertions, greater trochanters
  • Dactylitis
    • Relatively uniform swelling of entire finger or toe (“sausage digit”)
    • Due to synovitis, osteitis, and flexor tenosynovitis
• Axial inflammatory arthritis:
  • Inflammatory arthritis of spine, SI joints, costochondral and sternoclavicular joint
  • Can present as “inflammatory back pain” or chest wall pain

—Extra-articular

• Ocular
  • Sterile conjunctivitis (51%)
  • Anterior uveitis: acute unilateral uveitis, associated with HLA-B*27 positivity
• Cardiac:
  • Rare but reported aortitis, aortic regurgitation, pericarditis
• Gastrointestinal:
  • Ileitis/colitis: Sterile or infectious colitis
• Renal:
  • IgA nephropathy (rare)
• Genitourinary:
  • Circinate Balanitis (10-40%): painless erythematous ulcerating lesions on glans penis and urethral meatus; associated with chlamydia
  • Urethritis: infectious or sterile
  • Prostatitis
  • Hemorrhagic cystitis
  • Salpingitis, vulvovaginitis
• Cutaneous
  • Painless mucosal ulcers (up to 60%)
  • Keratoderma Blennorrhagica (20%): hyperkeratotic skin lesions soles and palms looking like pustular psoriasis; remember to order a VDRL
  • Erythema nodosum
  • Nail changes: looks like nail psoriasis (hyperkeratotic changes)
• Other:
  • Thrombophlebitis, livedo reticularis, cranial or peripheral neuropathy

HLA-B*27 positivity increases risk of axial spondyloarthritis, ocular involvement, and other extra-articular manifestations in ReA

INVESTIGATIONS

—Bloodwork

• CBC:
  • May have leukocytosis, thrombocytosis (due to systemic inflammation)
• CRP:
  • Usually elevated; non-specific
• Auto-antibodies (ex: RF, ACPA, ANA):
  • Negative; no association
  • May consider ordering to evaluate differential diagnosis
• HLA-B*27:
  • HLA B*27 prevalence ~30-50%

—Fluids, Cultures

• Synovial Fluid:
  • Inflammatory, i.e.: 2000-50,000 WBC/mm³ predominantly neutrophils
  • Culture negative
• Urine:
  • May see pyuria, microhematuria, bacteriuria, depending on presence of infectious or sterile urethritis
• Infectious:
  • Stool culture:
    • Diarrhea usually resolved before onset of arthritis and hence cultures are not often performed
  • If active diarrhea
    • May consider ordering culture or immunoassay for Salmonella, Shigella, Campylobacter, Yersina
    • Serologic testing for past infection is not normally performed
  • Depending on clinical suspicion:
    • Urine PCR or genital swab for Chlamydia trachomatis

—Imaging: X-rays

• Acutely:
  • No specific or sensitive features, may see soft tissue swelling
• Chronically: may see classic radiographic findings seen in spondyloarthropathies
  • “Fluffy” periostitis
  • New bone growth at site of enthesitis, bulky syndesmophytes
  • Ankylosis
  • Concurrent Erosions alongside New Bone Formation in the same joint
  • Erosions characeristics: marginal/nonmarginal, eccentric, DIP involvement, pencil-in-cup, located at entheses
  • Sacroiliac and spondylitis involvement
  • Polyarticular unidigit: MCP, PIP, and DIP in the same finger
  • Lack of juxta-articular osteoporosis (juxtra-articular osteoporosis is seen in early RA)

—Other

• As indicated, depending on clinical suspicion and need
  • ECG: benign ECG changes may be rarely observed, suggesting sub-clinical carditis
  • Colonoscopy: may reveal ileitis/colitis

DIAGNOSIS

The clinical diagnosis of ReA can be made in a patient with history of preceding gastrointestinal/genitourinary infection 1-4 weeks before the onset of axial or peripheral lower-limb predominant oligoarticular inflammatory arthritis with possible extra-articular manifestations like conjunctivitis, uveitis, sterile urethritis, and painless mucosal ulcers. Elevated and inflammatory markers and inflammatory synovial fluid may support the diagnosis; HLA-B*27 positivity suggests higher risk of axial spondyloarthritis, ocular involvement, and other extra-articular features in ReA.

Differential Diagnosis

• Infectious
  • Septic arthritis
  • Disseminated gonococcal infection
  • Poststreptococcal arthritis
  • Whipple’s Disease
• Gastrointestinal
  • Inflammatory bowel disease (Crohn’s, ulcerative colitis)
• Rheumatological
  • Behcets Disease
  • Crystalline arthropathy
  • Enteropathic arthritis and other Spondyloarthropathies
  • Lyme disease

TREATMENT

Infection

• Long-term antibiotics are not used treat inflammatory arthritis
• Enteric infection:
  • Antibiotics not indicated for uncomplicated infections; some may require treatment depending on organism (ex: C. difficile)
• Genitourinary infection:
  • Chlamydial infections should be given standard treatment
    (ex: azithromycin 1g POx1 or doxycycline 100mg BID x 7 days for patient and partner)

Inflammatory arthritis

• Acute:
  • Glucocorticoids
    • Intra-articular or cautious short term oral systemic glucocorticoid may be considered for active peripheral arthritis
    • Not for axial disease.
    • Glucocorticoid injections may be considered for some enthesitis sites (lateral epicondyle, greater trochanter) but should be avoided in others (Achilles).
  • NSAIDs
    • Short term NSAIDs (particularly for axial disease) as needed, use with caution, consider cardiovascular, gastrointestinal, and renal risk
• Chronic:
  • Consider DMARD therapy if >3-6 months of persistent inflammatory arthritis despite NSAIDS and if prednisone >5-7.5mg/day
    • csDMARDs:
      • Methotrexate, sulfasalazine, or leflunomide as mono- or combination therapy
      • If not effective by 3 months of therapy, can consider bDMARDs
    • bDMARDs:
      • TNF-inhibitors
      • Other bDMARDs have been reportedly used, including tocilizumab and secukinumab

Extra–articular manifestations

• Uveitis, conjunctivitis:
  • Treat in conjunction with opthalmology/optometry
  • May require topical steroids
• Skin lesions, mucositis:
  • Topical steroids

PROGNOSIS

• Most remit in 6-12 months
• 10-30% may progress to become a chronic SpA
• Patients with classic trial of arthritis, urethritis, and conjunctivitis are more likely to have recurrent and/or chronic ReA
• HLA-B27 positivity may predict development of chronic SpA

REFERENCES

Barber, C. E., Kim, J., Inman, R. D., Esdaile, J. M., & James, M. T. (2013). Antibiotics for treatment of reactive arthritis: a systematic review and metaanalysis. The Journal of rheumatology, 40(6), 916–928. https://doi.org/10.3899/jrheum.121192

Bentaleb, I., Abdelghani, K. B., Rostom, S., Amine, B., Laatar, A., & Bahiri, R. (2020). Reactive Arthritis: Update. Current clinical microbiology reports, 7(4), 124–132. https://doi.org/10.1007/s40588-020-00152-6

Carter, J. D., & Hudson, A. P. (2009). Reactive arthritis: clinical aspects and medical management. Rheumatic diseases clinics of North America, 35(1), 21–44. https://doi.org/10.1016/j.rdc.2009.03.010

Colmegna, I., Cuchacovich, R., & Espinoza, L. R. (2004). HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations. Clinical microbiology reviews, 17(2), 348–369. https://doi.org/10.1128/CMR.17.2.348-369.2004

Courcoul, A., Brinster, A., Decullier, E., Larbre, J. P., Piperno, M., Pradat, E., Tebib, J. G., Wendling, D., & Coury, F. (2018). A bicentre retrospective study of features and outcomes of patients with reactive arthritis. Joint bone spine, 85(2), 201–205. https://doi.org/10.1016/j.jbspin.2017.01.013

García-Kutzbach, A., Chacón-Súchite, J., García-Ferrer, H., & Iraheta, I. (2018). Reactive arthritis: update 2018. Clinical rheumatology, 37(4), 869–874. https://doi.org/10.1007/s10067-018-4022-5

Hannu T. (2011). Reactive arthritis. Best practice & research. Clinical rheumatology, 25(3), 347–357. https://doi.org/10.1016/j.berh.2011.01.018

Hayes KM, Hayes RJP, Turk MA, Pope JE. Evolving patterns of reactive arthritis. Clin Rheumatol. 2019 Aug;38(8):2083-2088. doi: 10.1007/s10067-019-04522-4. Epub 2019 Mar 27. PMID: 30919146.

Schmitt S. K. (2017). Reactive Arthritis. Infectious disease clinics of North America, 31(2), 265–277. https://doi.org/10.1016/j.idc.2017.01.002

Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev. 2014 Apr-May;13(4-5):546-9. doi: 10.1016/j.autrev.2014.01.005. Epub 2014 Jan 10. PMID: 24418301.

Wendling D, Prati C, Chouk M, Verhoeven F. Reactive Arthritis: Treatment Challenges and Future Perspectives. Curr Rheumatol Rep. 2020 May 26;22(7):29. doi: 10.1007/s11926-020-00904-9. PMID: 32458153.