Enteropathic arthritis (EA) is an inflammatory joint disease associated with inflammatory bowel diseases (IBD) such as Crohn disease (CD), ulcerative colitis (UC), and microscopic colitis. Less frequently, EA is associated with other GI disorders, including Whipple disease, celiac disease, and bowel-associated dermatitis-arthritis syndrome related to bypass surgery or intestinal disease. EA is included in the family of spondyloarthropathies (SpA), which have features of peripheral inflammatory arthritis, axial spondylitis and sacroiliitis, enthesitis, dactylitis, uveitis, and rashes.¹ Arthritis is the most common extraintestinal manifestation of IBD, with a prevalence between 2% and 26% according to both retrospective and prospective studies. Joint involvement in EA is classically divided into two patterns (Table 1): (1) Peripheral arthritis and (2) axial involvement, including sacroiliitis with or without spondylitis, similar to idiopathic ankylosing spondylitis (AS).

IBD-related spondyloarthropathy

Enteroarthritis

Arthritis associated with gastrointestinal disease

Peripheral arthritis occurs in 7% to 20% of patients with IBD in most studies and is slightly more common in CD than in UC. Spinal involvement occurs in 5% to 12% of cases and may be the only articular manifestation. However, it can also be accompanied by peripheral arthritis.¹

• Two types of joint involvement in IBD: Peripheral and/or axial. Peripheral: Affects peripheral joints, predominantly lower limb joints. Axial: Affects the spine in the form of sacroiliitis with or without spondylitis; can be similar to AS or other idiopathic SpA (e.g., psoriatic arthritis, reactive arthritis, undifferentiated SpA).^1,2
• Axial involvement is found more commonly in CD than in UC. Axial disease is independent of IBD activity. Can have asymptomatic sacroiliitis.¹
• Peripheral arthritis is the most frequent extraintestinal finding in both CD and UC. Peripheral and spinal disease equally affect both sexes² (Table 2).
• Type 1 peripheral arthropathy (pauciarticular, fewer than five joints): Usually acute and self-limited asymmetric inflammatory arthritis; commonly affects large joints of legs, such as the knee; occurs early in the course of IBD and commonly parallels the disease activity or flares of IBD, generally self-limiting.²
• Type 2 peripheral arthropathy (polyarticular, five or more joints): Affects mainly the metacarpophalangeal, proximal interphalangeal, knee, and ankle joints; bilateral and symmetric; may be migratory, nonerosive. Symptoms may take a more chronic course, independent of IBD activity.²
• Main complaints are inflammatory back pain, buttock pain, joint pain, and swelling (with prolonged morning stiffness and fatigue); symptoms worsen with rest or inactivity and improve with exercise.^4,5
• Examination reveals evidence of synovitis, progressive limitation of spinal mobility.^4,5
• Periarticular and other extraintestinal manifestations include enthesitis (inflammation of tendon insertion sites into bone such as Achilles or plantar fascia), dactylitis (flexor tenosynovitis of a finger or toe causing sausage-like swelling of digit), uveitis, and psoriasis.^1,2
• Uveitis in IBD is more often bilateral and more prone to chronicity.
• Erythema nodosum, pyoderma gangrenosum can be seen in IBD as skin lesions.^4-6

Although the exact mechanism behind EA is not well understood, the pathogenesis of joint disease likely involves a combination of abnormal bowel permeability, as well as immunologic and genetic influences. In genetically predisposed individuals with intestinal disease, the co-occurrence of joint inflammation provides important support to the theory that dysbiosis in the gut microbiome can link colitis to the development of EA. One theory suggests that HLA-B27-expressing macrophages exposed to specific bacterial antigens may activate CD4+ T cells, leading to their migration from gut to joint and the development of arthritis.²

• Hypertrophic osteoarthropathy
• Osteonecrosis (avascular necrosis)
• Septic arthritis
• Other idiopathic seronegative SPAs (e.g., reactive arthritis, psoriatic arthritis, AS, Whipple disease, Adamantiades-Behçet disease, intestinal bypass, gluten-sensitive enteropathy, and parasitic infections)
• Rheumatoid arthritis

Diagnosis mainly relies on clinical features and imaging data. There is no gold standard for diagnosis.

• Laboratory testing: Markers of inflammation such as sedimentation rate and C-reactive protein (CRP) may reflect underlying disease activity of bowel disease and thus may not be useful to track for EA activity. CBC can reveal leukocytosis, anemia, and thrombocytosis suggestive of inflammatory response.
• Synovial fluid is nonspecific; shows mild to marked inflammation: White blood cell count at 1500 to 50,000/mm³.
• Serologic tests for rheumatoid arthritis are negative (rheumatoid factor, cyclic-citrullinated peptide antibodies), and lupus-related antinuclear antibodies are usually absent.
• Tests for other intestinal diseases based on clinical suspicion: Whipple diagnosis is based on histology with periodic acid-Schiff (PAS)-positive cells, serology for T. whipplei and culture; celiac disease immunoglobulin A (IgA) antitissue transglutaminase and antiendomysial antibodies along with diagnostic villous atrophy on small bowel biopsy; microscopic colitis diagnosed only through histology from colonoscopy showing collagenous colitis or lymphocytic colitis.
• Calprotectin measured in the serum or in the stools has been used to identify subclinical bowel inflammation in patients with SpA. Individuals who had both CRP and calprotectin elevated had an increased frequency of bowel inflammation compared to patients who had low levels of these proteins.

• Plain x-ray of the spine and pelvis may appear normal in early disease but with progression may show evidence of sacroiliitis, spondylitis, or ankyloses.⁴
• X-ray of peripheral joints may show soft tissue swelling, periostitis, or joint effusion.
• MRI may be used to assess early changes of spondyloarthritis when plain x-rays are negative. MRI is the most sensitive method of detecting sacroiliitis in IBD patients.⁴
• Musculoskeletal ultrasonography is a noninvasive, safe, and easily reproducible means of detecting early pathologic changes in SpA patients. It can identify characteristic features of enthesitis, bone erosions, synovitis, bursitis, and tenosynovitis.⁴

• Rest, physical therapy, and exercise such as swimming⁷

• There has been concern that NSAIDs exacerbate IBD and that NSAID-related adverse events such as ulcers and GI bleeding may mimic IBD flares. Cyclooxygenase-2 inhibitors may be preferred to traditional NSAIDs, but similar concerns and cautions apply.⁷
• Intraarticular steroid injections may help treat joint synovitis.^2,7
• Systemic steroids can help reduce polyarticular joint and IBD activity but should be used at the lowest effective dose and ideally for only short courses. Intermittent pulsing corticosteroid therapy at large doses may be considered in moderate-to-severe nonresponsive cases of IBD.⁷

• Immunomodulatory agents such as sulfasalazine, azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine can be used to treat active IBD, peripheral arthritis, and associated skin conditions. Peripheral joint disease responds better than axial disease to these agents. Tumor necrosis factor (TNF) inhibitors, particularly infliximab, adalimumab, and certolizumab, are useful to treat both arthritis (axial or peripheral) and severe, refractory IBD. Golimumab is also in use for refractory IBD and for arthritis. Etanercept is not effective to control IBD.^2,7 Nonbiologic and biologic disease-modifying antirheumatic drug treatment options are summarized in Table 3.
• The axial disease associated with IBD is treated similar to other SpAs. Medications approved for other SpAs, such as ustekinumab (anti-IL12/23), secukinumab (anti-IL-17A), ixekizumab (anti-IL-17), and Janus kinase (JAK) inhibitors, may be effective therapies for EA, though not all have clear efficacy in IBD. Anti-IL-17 is usually avoided with IBD, given possible worsening of IBD. Ustekinumab is approved to treat CD. Tofacitinib (JAKi) is approved to treat UC.
• The choice of biologic requires the consideration of extraarticular and extraintestinal features such as skin disease or uveitis. The latter can be treated with infliximab or adalimumab, both of which also treat IBD.^2,7
• For highly active IBD, particularly UC, colectomy has been found to ameliorate peripheral joint inflammatory disease but does not influence axial involvement.^2,7
• Interdisciplinary approach and active cooperation between rheumatologist and gastroenterologist through combined clinics, for example, are essential.

Rheumatology and gastroenterology

Ankylosing Spondylitis (Related Key Topic)

Crohn Disease (Related Key Topic)

Psoriatic Arthritis (Related Key Topic)

Spondyloarthropathies (Related Key Topic)

Ulcerative Colitis (Related Key Topic)