BOTTOM LINE

Inflammatory arthritis can occur in a significant minority of inflammatory bowel disease (IBD) patients, particularly those with large bowel and other extra-enteric IBD manifestations. Presentations of peripheral arthritis include acute/remitting/oligo-articular disease concordant with IBD flares, or chronic polyarticular inflammatory arthritis that may flare independently of IBD. Axial arthritis occurs more frequently in men and in HLA-B*27 positive patients. Choosing DMARDs that treat both IBD and inflammatory arthritis is ideal (ex: TNFi, JAKi, IL-23i), though not always clinically feasible. Enteropathic (IBD-related) Arthritis, Reactive Arthritis, and Psoriatic Arthritis can be conceptualized together as a spectrum of “Peripheral Spondyloarthropathy”.
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EPIDEMIOLOGY

—General Population

• IBD prevalence: 0.5% general population in Western countries

—IBD Population (Crohn’s Disease and Ulcerative Colitis)

• Pooled Prevalence of inflammatory arthritis in IBD Population
  • Peripheral arthritis: 13%
  • Sacroiliitis: 10%
  • Axial spondyloarthritis: 3%
• 5-year cumulative incidence of Inflammatory Arthritis in IBD Population
  • Crohn’s Disease:
    • Axial spondyloarthritis: 2%
    • Peripheral inflammatory arthritis: 0.9%
  • Ulcerative colitis:
    • Axial spondyloarthritis: 3%
    • Peripheral inflammatory arthritis: 5%
• Risk factors for Inflammatory Arthritis in IBD Population
  • Colonic involvement of IBD
  • Perianal disease
  • Other extra-intestinal manifestations
    • ex: erythema nodosum, stomatitis, uveitis, pyoderma gangrenosum
• Timing of inflammatory arthritis in IBD
  • Onset of inflammatory arthritis is more common in the first few years of bowel disease, but can also onset at any time over course of IBD
  • Arthritis precedes IBD  in 30% of cases
  • Arthritis flares with colitis 60-80% of the time.

—Spondyloarthritis (SpA) Population

• Within SpA Population
  • 30-42% have endoscopic (macroscopic) gastrointestinal inflammation
  • 46-58% have histologic (microscopic) gastrointestinal inflammation
    • Severity of microscopic inflammation in bowel is correlated with the severity of bone marrow edema in sacroiliac joints on MRI
  • Risk of IBD
    • 1-4X risk of IBD in SpA patients versus general population
    • 4-8% lifetime risk of IBD in SpA patients
    • In PsA population, IBD is more common in severe PsA and in Axial more than Peripheral-only PsA

CLINICAL FEATURES

—Peripheral arthritis

“Type 1” and “Type 2” inflammatory arthritis is not terminology used by rheumatologists, but may be referred to historically. Both are considered peripheral spondyloarthropathies without differentiation.

• TYPE 1
  • ~5% of IBD, more often associated with flares of IBD
  • Acute, oligo-articular large joint, self-limited, nonerosive.
  • Knee involvement is most common
• TYPE 2
  • ~3-4% of IBD, not associated with IBD flares
  • Chronic, polyarticular symmetrical, sometimes migratory, nonerosive
  • MCPs common; can also involve knees, ankles, shoulders, elbows, wrists, PIPs, MTPs

—Enthesitis/dactylitis

• Enthesitis:
  • 2-4 % of IBD patients
  • Inflammation at insertion of tendon/ligament to bone
  • Can lead to new bone formation at entheses (enthesophyte/bone spur)
  • Examples: elbow epicondylitis, Achilles enthesitis, plantar fasciitis, patellar tendon, iliac crest, supraspinatus insertions, greater trochanters
• Dactylitis:
  • 2-4% of IBD patients
  • Relatively uniform swelling of entire finger or toe (“sausage digit”)
  • Due to synovitis, osteitis, and flexor tenosynovitis

—Axial arthritis

• M > F (3:1)
  • Higher risk if HLA-B*27 positive
• Inflammatory back pain 5-30%
  • Onset of axial spondyloarthritis may precede clinical IBD
  • May not flare concordantly with IBD activity
• Sacroiliitis 2-35%
  • Can be symptomatic or asymptomatic, uni- or bilateral radiographic sacroiliitis
  • Prevalence increases with IBD duration; often picked up incidentally in abdominal CTs ordered to assess IBD

—Other extra-enteric features

• MSK
  • Osteoporosis, avascular necrosis (from steroid exposure)
• Cutaneous
  • Pyoderma gangrenosum
  • Apthous stomatitis
  • Erythema nodosum — more associated with “Type 1” inflammatory arthritis
  • Neutrophilic dermatoses, metastatic cutaneous Crohn’s disease, cutaneous vasculitis
• Ocular
  • Uveitis; episcleritis, scleromalacia, corneal ulcers.
  • More common in Crohn’s disease
• Hepato-biliary
  • PSC, autoimmune hepatitis, fatty liver disease, cholelithiasis

INVESTIGATIONS

Bloodwork

• CBC:
  • May see leukocytosis, thrombocytosis related to inflammation
• ALT:
  • May be elevated: liver steatosis, autoimmune hepatitis, drug toxicity (ex: methotrexate)
• CRP:
  • Often elevated, due to either/both of inflammatory arthritis or colitis
• RF, ANA:
  • Negative, no association
  • May consider ordering to evaluate differential diagnosis
  • Presence of detectable ANA can be seen after initiation of biological treatment for IBD
• pANCA (not routinely measured):
  • Ulcerative colitis: ~60-80%
  • Crohn’s: ~20%
• ASCA – anti Saccharomyces cerevisiae antibody (not routinely measured):
  • Crohn’s: ~50-70%
  • Rarely found in ulcerative colitis
• HLA-B*27:
  • In IBD population:
    • HLA-B27 prevalence reported ~30%
    • HLA-B27 positivity indicates higher risk of axial spondyloarthritis in an IBD patient

Synovial Fluid

• Synovial fluid is inflammatory: >2,000 WBC/µL.
  • Consider sending for culture if clinical suspicion for septic arthritis (ex: very acute red/warm monoarthritis)

Imaging

• X-rays, CT-abdomen/pelvis: may show sacroiliitis (2-35%), sometimes detected incidentally when imaging for complications of IBD
• 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 characteristics: 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)

DIAGNOSIS

In patients with known IBD, the clinical diagnosis of Enteropathic Arthritis should be suspected in patients presenting with inflammatory back pain or spontaneous joint swelling. Review should detect other extra-enteric features like erythema nodosum and uveitis.  Elevated CRP may support diagnosis of an enteropathic arthritis, though can also be elevated due to active IBD. If axial arthritis is suspected, x-ray and/or MRI of SI joint may reveal sacroiliitis.

Conversely, patients with an undifferentiated SpA presenting with unexplained weight loss, anemia, abdominal pain, and diarrhea should be investigated for underlying inflammatory bowel disease. A fecal calprotectin is a highly sensitive test for IBD and can help triage referral to gastroenterology. If fecal calprotectin is normal, IBD is highly unlikely. If elevated, the patient should be referred for consideration of endoscopy. Of note, NSAIDs should be held for two weeks prior to fecal calprotectin specimen collection to avoid false positives.

—“Red Flags”

Red flags for IBD in the Spondyloarthritis patient

• Chronic diarrhea (>3 months) with unexplained fever and/or weight loss >5%
• Nocturnal bowel movements
• Perianal fistula or abscess
• Rectal bleeding
• Recurrent abdominal pain
• Other: unexplained anemia, family history of IBD

Red flags for Spondyloarthritis in the IBD patient

• Chronic inflammatory low back pain
• Dactylitis, enthesitis
• Joint swelling
• Other: psoriasis, uveitis, family history of SpA, recurrent apthous ulcers, chest wall pain

TREATMENT

—General Principles

• Sometimes, the patient’s immunotherapy may not be efficacious to treat all tissue domains, leading to discordant disease activity between colitis and arthritis (i.e.: active inflammatory arthritis but quiescent IBD, or vice versa).
• It is preferable to choose therapies that are efficacious for both IBD and inflammatory arthritis, though this is not absolutely mandatory nor is it always feasible.
• Therapies that may be beneficial for both IBD and inflammatory arthritis include
  • csDMARDs: methotrexate, sulfasalazine, azathioprine (peripheral, not axial SpA)
  • tsDMARDs: JAKi (Upadacitinib, tofacitinib; N.B.: higher doses required in IBD)
  • bDMARDs: TNFi, IL-23i
• Choice of treatment should be guided by whichever tissue manifestation is most active (and the patient’s preferences), for example:
  • If IBD is active but inflammatory arthritis is quiescent, intestinal-specific therapy could be a reasonable choice for IBD treatment, if no other therapy is appropriate:
    • Anti-integrin (vedolizumab) for Crohn’s or ulcerative colitis
    • S1P receptor modulator (ozanimob and etrasimod) for ulcerative colitis only
  • If IBD is quiescent, but psoriasis and inflammatory arthritis are flaring, an IL-17 inhibitor could be considered only if no other therapy is appropriate (ie. not TNFi, JAKi, IL-23i, or csDMARD)
• Numerous reports exist of combination therapy, though this is not done routinely
  • Ex: combination Vedolizumab + JAKi, or +TNFi

Coordinated interdisciplinary care is necessary between rheumatology/gastroenterology in a shared care model, while respecting patient’s preferences.

—Peripheral arthritis

• Initial Treatment: csDMARDs
  • Sulfasalazine, methotrexate, azathioprine (for mild peripheral SpA and mild Crohn’s; methotrexate and azathioprine are not efficacious for ulcerative colitis)
  • If no improvement in 3-6 months, consider combination csDMARD or b/ts-DMARD
  • Limited symptomatic treatment
    • NSAIDs for 2-4 weeks (if IBD is in remission, in a shared decision with gastroenterologist, concern for exacerbating GI mucosal inflammation)
    • Local or short-course of systemic steroids
• Subsequent Treatment: b/ts-DMARDs
  • TNF inhibitors (adalimumab, certolizumab, golimumab, infliximab)
  • JAK inhibitors (tofacitinib, upadacitinib; IBD typically requires a higher dose of JAKi compared to rheumatologic indications)
  • IL-23 inhibitors (risankizumab, guselkumab)
  • Il-12/23 inhibitor (ustekinumab)
  • If primary non-response to first b/ts-DMARD, could switch to different mechanism

—Axial Arthritis

• Initial Treatment
  • NSAIDs for 2-4 weeks (if IBD is in remission, in a shared decision with gastroenterologist; concern for exacerbating GI mucosal inflammation)
• Subsequent Treatment
  • bDMARDs or tsDMARDs (listed in no particular order) efficacious/approved for both IBD and inflammatory arthritis:
    • TNF inhibitors (adalimumab, certolizumab, golimumab, infliximab)
    • JAK inhibitors (tofacitinib, upadacitinib; IBD typically requires a higher dose of JAKi compared to rheumatologic indications)
    • If primary non-response to first b/ts-DMARD, could switch to different mechanism or dose-optimizing TNF, if patient is on TNF
  • Local corticosteroid to SI joint for refractory isolated sacroiliitis may be considered

√ indicates use for particular disease

1. Whether IL-17i can truly exacerbate IBD is controversial. NSAIDs or IL-17i may be used if IBD is stable; liaise with gastroenterologist if considering use.

2. JAK inhibitors approved for IBD in Canada: Upadactinib (UC and Crohn’s); Tofacitinib (UC only). IBD typically requires a higher dose of JAKi compared to rheumatologic indications

3. TNF inhibitors approved for IBD in Canada: Adalimumab, Certolizumab (Crohn’s, considered weaker acting), infliximab, golimumab (UC only)

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