# Reactive Arthritis and Enteropathic Arthritis

## Introduction

Reactive arthritis and enteropathic arthritis are forms of spondyloarthritis triggered by extra-articular infections or associated with inflammatory bowel disease, respectively. Reactive arthritis is a sterile inflammatory arthritis occurring after a genitourinary or gastrointestinal infection, while enteropathic arthritis encompasses the peripheral and axial articular manifestations associated with Crohn's disease or ulcerative colitis. Both conditions share the common features of the spondyloarthritis family, including HLA-B27 association, enthesitis, asymmetric oligoarthritis, and potential for axial involvement.

## Reactive Arthritis

### Epidemiology

The incidence of reactive arthritis ranges from 0.6 to 27 per 100,000 and varies substantially depending on the triggering pathogen and the population studied. The male-to-female ratio differs by trigger: post-urogenital reactive arthritis shows a striking 9 to 1 male predominance, while post-enteric disease has an equal gender distribution. Peak onset occurs between 20 and 40 years of age. HLA-B27 is positive in 50 to 80 percent and influences disease severity, chronicity, and the development of axial involvement.

### Triggering Organisms

Genitourinary triggers include Chlamydia trachomatis, the most common urogenital trigger, as well as Mycoplasma genitalium and Ureaplasma urealyticum. Gastrointestinal triggers include Salmonella species (enteritidis and typhimurium), Shigella flexneri, Yersinia enterocolitica, Campylobacter jejuni, and Clostridioides difficile. Neisseria gonorrhoeae is notably not a classic trigger for reactive arthritis but rather causes septic arthritis directly. The latency period between infection and arthritis onset is typically 1 to 4 weeks.

### Pathogenesis

Molecular mimicry between microbial peptides and self-antigens presented by HLA-B27 may drive the autoimmune response. Persistent microbial antigens, particularly from Chlamydia trachomatis, which can remain intracellularly in joints in a metabolically active but non-cultivable state, may perpetuate inflammation. An aberrant immune response with Th17/IL-17 pathway activation and impaired Th1-mediated clearance of intracellular pathogens contributes to disease chronicity.

### Clinical Features

The classic triad of reactive arthritis, colloquially summarized as "can't see, can't pee, can't climb a tree," encompasses arthritis, urethritis, and conjunctivitis, though the complete triad is present in fewer than 30 percent of cases. The arthritis is characteristically an asymmetric oligoarthritis predominating in the lower extremities, involving the knees, ankles, and feet, with onset 1 to 4 weeks after infection. Enthesitis, particularly of the Achilles tendon and plantar fascia, is common, and dactylitis occurs frequently. Urogenital manifestations include urethritis (which is sterile in post-enteric reactive arthritis), cervicitis, and circinate balanitis, which presents as painless shallow ulcers on the glans penis. Ocular involvement includes conjunctivitis, the most common ocular finding, which is typically bilateral and mild, and anterior uveitis, which is less common but more serious. Mucocutaneous manifestations include keratoderma blennorrhagicum, hyperkeratotic pustular lesions on the palms and soles that are histologically identical to pustular psoriasis, and painless oral ulcers. Axial involvement with unilateral sacroiliitis and inflammatory back pain is more common in HLA-B27-positive patients.

### Diagnosis

The diagnosis is clinical, as no definitive diagnostic test exists. Evidence of a preceding infection should be sought through urethral or cervical NAAT for Chlamydia, stool culture, and serologic testing for Yersinia and Chlamydia. HLA-B27 is supportive but not required. Synovial fluid is inflammatory with 2,000 to 50,000 WBCs and neutrophilic predominance, sterile culture, and possibly positive PCR for Chlamydia DNA. Imaging may demonstrate enthesitis on ultrasound or MRI, sacroiliitis on MRI, and periostitis on radiographs. Septic arthritis, crystalline arthropathy, and other SpA subtypes should be excluded.

### Management

For post-Chlamydia reactive arthritis, active infection should be treated with doxycycline 100 milligrams twice daily for 7 days or azithromycin 1 gram as a single dose, and sexual partners should be screened and treated. The TARA trial evaluated prolonged antibiotics (6 months of doxycycline plus rifampin versus placebo) for chronic Chlamydia-induced reactive arthritis, showing some benefit that has not been universally adopted. Post-enteric reactive arthritis does not benefit from antibiotics, as the triggering infection has typically cleared. NSAIDs are the first-line therapy for arthritis symptoms. Intra-articular glucocorticoids are appropriate for monoarticular or oligoarticular involvement. csDMARDs, particularly sulfasalazine at 2 to 3 grams daily, are indicated for persistent peripheral arthritis beyond 3 to 6 months, with methotrexate reserved for refractory cases. TNF inhibitors may be used for chronic, refractory reactive arthritis, though RCT data are limited.

### Prognosis

The disease is self-limited in the majority of patients, with 50 to 60 percent resolving within 6 to 12 months. A chronic course developing lasting more than 6 months occurs in 15 to 30 percent, with HLA-B27-positive patients having a worse prognosis. Recurrence rates range from 15 to 50 percent, especially with re-exposure to the triggering organism. Progression to ankylosing spondylitis occurs in 10 to 20 percent of HLA-B27-positive patients over 10 to 20 years.

<image>A clinical presentation diagram of reactive arthritis showing the classic triad and associated features on a male figure. Highlight: (1) Eyes: Conjunctivitis (bilateral conjunctival injection) and anterior uveitis (red eye with circumcorneal injection). (2) Genitourinary: Circinate balanitis (shallow painless ulcers on the glans penis). (3) Lower extremity: Asymmetric oligoarthritis of knee (swollen, effusion) and ankle, dactylitis of a toe, Achilles enthesitis. (4) Feet: Keratoderma blennorrhagicum showing hyperkeratotic, pustular lesions on the soles bilaterally. (5) Mouth: Painless oral ulcers on the palate. (6) Spine: Unilateral sacroiliitis. Include a timeline arrow showing "Infection (GU or GI)" → "1-4 week latency" → "Arthritis onset." Label all findings.</image>

## Enteropathic Arthritis

### Epidemiology

Peripheral arthritis affects 5 to 20 percent of IBD patients, while axial disease meeting ankylosing spondylitis criteria occurs in 3 to 10 percent, with sacroiliitis detectable on imaging in up to 30 percent. Both Crohn's disease and ulcerative colitis can be affected, and arthritis may precede gastrointestinal symptoms in 10 to 15 percent of cases.

### Classification of Joint Involvement

#### Type 1 (Pauciarticular)

Type 1 enteropathic arthritis involves fewer than 5 joints, predominantly large joints such as knees and ankles, in an asymmetric distribution. Episodes are acute and self-limited, typically resolving within 10 weeks, and critically, the arthritis parallels IBD activity, flaring with bowel disease exacerbations. It is non-erosive and non-deforming, with a weak HLA-B27 association but an association with HLA-DRB1*0103.

#### Type 2 (Polyarticular)

Type 2 enteropathic arthritis involves 5 or more joints, with small joints predominating. The course is chronic and persistent, does not correlate with IBD activity, and may persist even after colectomy in ulcerative colitis. It runs independently of bowel disease activity and is associated with HLA-B44.

| Feature | Type 1 (Pauciarticular) | Type 2 (Polyarticular) | Axial Disease |
|---------|------------------------|----------------------|---------------|
| Joint count | <5 joints | ≥5 joints | Sacroiliac joints, spine |
| Joint size | Large (knees, ankles) | Small joints predominate | Axial skeleton |
| Distribution | Asymmetric | Symmetric | Unilateral or bilateral SI |
| Duration | Acute, self-limited (<10 weeks) | Chronic, persistent | Chronic |
| Relation to IBD activity | **Parallels** IBD flares | **Independent** of IBD | **Independent** of IBD |
| Erosive | No | No | Possible (syndesmophytes) |
| HLA association | HLA-DRB1*0103 | HLA-B44 | HLA-B27 (50-70%) |
| Effect of colectomy | Improves | May persist | May worsen |
| Treatment priority | Control IBD | csDMARDs, TNFi | NSAIDs (caution), TNFi |

#### Axial Disease

Axial disease in IBD may present as sacroiliitis, which can be unilateral or bilateral and is often asymptomatic, or as ankylosing spondylitis that is clinically indistinguishable from primary AS. Axial disease runs independently of bowel disease and may worsen after colectomy. HLA-B27 is positive in 50 to 70 percent, lower than in primary AS.

### Extra-intestinal Manifestations Overlap

Erythema nodosum presents as tender, erythematous nodules on the shins and parallels IBD activity. Pyoderma gangrenosum produces painful undermined ulcers with pathergy. Oral aphthous ulcers, uveitis (which may be bilateral, chronic, or posterior, differing from typical SpA-related uveitis), primary sclerosing cholangitis, and venous thromboembolism during active IBD are additional extra-intestinal manifestations.

### Management of Enteropathic Arthritis

For Type 1 pauciarticular disease, treatment of the underlying IBD is paramount, as peripheral arthritis improves with bowel disease control. NSAIDs should be used cautiously as they may exacerbate IBD, with COX-2 selective agents being potentially safer. Intra-articular glucocorticoid injections and sulfasalazine, which benefits both bowel and joint disease, are useful. For Type 2 polyarticular disease, which is less responsive to IBD treatment, sulfasalazine and methotrexate are employed, and TNF inhibitors (infliximab and adalimumab preferred) are effective for both IBD and arthritis. For axial disease, management follows axial SpA guidelines with the critical caveat that NSAIDs should be used with caution, TNF inhibitors are first-line biologics (infliximab and adalimumab, never etanercept as it is ineffective for IBD), IL-17 inhibitors are contraindicated with active IBD as they may worsen Crohn's disease, and JAK inhibitors including tofacitinib (approved for UC) and upadacitinib (approved for UC and Crohn's) offer therapeutic options.

### NSAID Use in IBD

Traditional NSAIDs may trigger IBD flares in 20 to 30 percent of patients, though short courses of less than 2 weeks appear safer. The CRAMP trial suggested that short-term celecoxib was safe in quiescent IBD, though caution remains warranted. Individual risk assessment is essential, and NSAIDs should be avoided if possible in active IBD.

<image>A comparison table-style diagram of Type 1 vs Type 2 enteropathic arthritis and axial disease in IBD. Three columns: Type 1 (Pauciarticular), Type 2 (Polyarticular), and Axial. For each, show: number of joints affected (illustrated on a human figure with highlighted joints), relationship to IBD activity (parallel vs independent), duration (self-limited vs chronic), HLA association, and treatment approach. Below the table, show a treatment algorithm starting with IBD control, then NSAIDs (with caution symbol), csDMARDs, and biologics (highlighting infliximab and adalimumab as preferred, with red X on etanercept for IBD and IL-17i for Crohn's). Include symbols for "correlates with IBD activity" (linked chains) and "independent of IBD activity" (broken chains).</image>

## Other Infection-Related Arthritides

### Post-streptococcal Reactive Arthritis

Post-streptococcal reactive arthritis follows Group A streptococcal pharyngitis but does not meet Jones criteria for acute rheumatic fever. Unlike the migratory arthritis of rheumatic fever, it is non-migratory and may be additive with axial involvement. Duration is typically 2 to 3 months with the possibility of recurrence. The role of antibiotic prophylaxis is controversial, though some experts recommend penicillin prophylaxis for 1 to 2 years.

### Viral Arthritis

Parvovirus B19 causes a symmetric polyarthritis resembling RA that is self-limited, diagnosed by positive IgM anti-parvovirus antibodies. Hepatitis B can cause a PAN-like vasculitis or polyarthritis during the acute or prodromal phase. Hepatitis C is associated with cryoglobulinemic vasculitis and RF-positive polyarthritis. Chikungunya and Zika viruses cause symmetric polyarthritis that can become chronic. HIV produces various patterns including reactive arthritis, PsA, and diffuse infiltrative lymphocytosis syndrome.

## Key Clinical Pearls

- Keratoderma blennorrhagicum (ReA) is histologically identical to pustular psoriasis - reinforcing the SpA spectrum concept
- Post-enteric ReA does not benefit from antibiotics, whereas Chlamydia-induced ReA may benefit from prolonged antibiotic therapy
- Type 1 (pauciarticular) enteropathic arthritis parallels IBD activity; Type 2 (polyarticular) runs independently
- Etanercept and IL-17 inhibitors should be avoided in patients with IBD-associated arthritis
- NSAIDs should be used cautiously in IBD; COX-2 selective agents may be safer for short-term use
- Always aspirate acutely swollen joints in ReA to exclude septic arthritis, especially if febrile

## References
1. Carter JD, et al. Combination antibiotics for the treatment of Chlamydia-induced reactive arthritis (TARA trial). Arthritis Rheum. 2010;62(5):1298-1307.
2. Orchard TR, et al. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut. 1998;42(3):387-391.
3. Peluso R, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013;2013:631408.
4. Ajene AN, et al. Reactive arthritis: Update on diagnosis, management and prevention. J Rheumatol. 2013;40(12):2093-2095.
5. Sandborn WJ, et al. Safety of celecoxib in patients with ulcerative colitis in remission (CRAMP). Clin Gastroenterol Hepatol. 2006;4(2):203-211.