Enteropathic Arthritis  

Enteropathic Arthritis

• 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).

TABLE 1

Inflammatory Bowel Disease Classification Schema

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Characteristics	Type I	Type II
Distribution	Oligoarticular, asymmetric, migratory	Polyarticular, symmetric
Common joints involved	Knees, ankles	Metacarpophalangeal
Erosive disease	Rare	Can occur if progressive
Clinical course	Self-limiting	Persistent, often requires immunosuppressive therapy
Association with bowel disease	Flares are associated with bowel disease	Minimal association

Synonyms

• IBD-related spondyloarthropathy
• Enteroarthritis
• Arthritis associated with gastrointestinal disease

ICD-10CM CODES
M07.60	Enteropathic arthropathies, unspecified sites
M07.68	Enteropathic arthropathies, vertebra
M07.69	Enteropathic arthropathies, multiple sites
M07.611	Enteropathic arthropathies, right shoulder
M07.612	Enteropathic arthropathies, left shoulder
M07.619	Enteropathic arthropathies, unspecified shoulder
M07.621	Enteropathic arthropathies, right elbow
M07.622	Enteropathic arthropathies, left elbow
M07.629	Enteropathic arthropathies, unspecified elbow
M07.631	Enteropathic arthropathies, right wrist
M07.632	Enteropathic arthropathies, left wrist
M07.639	Enteropathic arthropathies, unspecified wrist
M07.641	Enteropathic arthropathies, right hand
M07.642	Enteropathic arthropathies, left hand
M07.649	Enteropathic arthropathies, unspecified hand
M07.651	Enteropathic arthropathies, right hip
M07.652	Enteropathic arthropathies, left hip
M07.659	Enteropathic arthropathies, unspecified hip
M07.661	Enteropathic arthropathies, right knee
M07.662	Enteropathic arthropathies, left knee
M07.669	Enteropathic arthropathies, unspecified knee
M07.671	Enteropathic arthropathies, right ankle and foot
M07.672	Enteropathic arthropathies, left ankle and foot
M07.679	Enteropathic arthropathies, unspecified ankle and foot

Epidemiology & Demographics

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

Predominant Sex & Age

Males and females are equally affected, although the male:female ratio of axial involvement has been shown to be 3:1. Inflammatory back pain usually presents before the age of 45 yr. Onset of peripheral arthritis is usually between 25 and 45 yr of age. ²

Risk Factors

• •Active large bowel disease ^1 , 2
• •Family history of IBD ^1 , 2
• •Appendectomy ^1 , 2
• •Cigarette smoking ^1 , 2
• •Genetics (HLA-B27) ^1 , 2
• •Extraintestinal manifestations such as erythema nodosum or pyoderma gangrenosum ^1 , 2

Genetics

• The presence of human leukocyte antigen-B27 (HLA-B27) is the strongest association with SpA, present in >90% of patients with AS. ² 
• Recent genome-wide association studies demonstrated a genetic overlap between IBD and SpA, implicating NOD2 (CARD15), ² interleukin-23 receptor (IL-23R), ^2 , 3 and IL-17 ^2 , 3 as susceptibility genes.

Physical Findings & Clinical Presentation

• •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 sexes ² ( Table 2 ).

TABLE 2

Enteropathic Arthritis

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Feature	Peripheral Arthritis	Sacroiliitis, Spondylitis
Crohn Disease
Frequency in CD	10%-20%	2%-7%
HLA-B27 associated	No	Yes
Pattern	Transient, symmetrical	Chronic
Course	Related to activity of CD	Unrelated to activity of CD
Effect of surgery	Remission of arthritis uncommon	No effect
Effect of anti-TNF therapy	Effective	Effective
Ulcerative Colitis
Frequency in UC	5%-10%	2%-7%
HLA-B27 associated	No	Yes
Pattern	Transient	Chronic
Course	More common in pancolitis than proctitis; related to activity of UC	Unrelated
Effect of surgery	Remission of arthritis	No effect

CD, Crohn disease; HLA, human leukocyte antigen; TNF, tumor necrosis factor; UC, ulcerative colitis.

• 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. ⁴⁵⁶

What causes Enteropathic Arthritis?

• 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

Differential Diagnosis

• •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

Workup

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

Laboratory Tests

• •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/mm ³ .
• •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.

Imaging Studies

• •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

Treatment

• •Effective treatment of underlying IBD is helpful in controlling the peripheral arthritis. The goal of treatment of EA is reducing inflammation to relieve suffering and prevent joint deformity and disability. ^2 , 7
• •When IBD and SpA coexist, treatment strategy should also address extraintestinal and extraarticular features such as enthesitis, dactylitis, uveitis, and psoriasis, with need for tailored consideration of certain limited biologic options. ⁷
• •Avoidance of NSAIDs in the treatment of axial symptoms because of controversial increased risk of exacerbation of intestinal disease. ⁷

Nonpharmacologic Therapy

• •Rest, physical therapy, and exercise such as swimming ⁷

Acute General Treatment

• •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

Chronic Treatment

• •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

TABLE 3

Nonbiologic and Biologic DMARD Treatment Options

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Drug Class	Therapies	Effective in SpA	Effective in IBD	Notes
Nonbiologic DMARD	Methotrexate	+	+	Often as combo therapy when used for IBD
	Azathioprine	−	+
	Sulfasalazine	+	+	Typically more beneficial for UC compared to CD
TNF inhibitor	Adalimumab	+	+	Subcutaneous
	Infliximab	+	+	Intravenous
	Etanercept	+	−	Not recommended in IBD-associated arthritis
IL 12/23 inhibitor	Ustekinumab	+	+	Crohn disease only Not effective for AxSpA
IL 17 inhibitor	Secukinumab	+	−	Rare reports of inducing IBD; Should generally not be used in patients with active IBD
	Ixekizumab	+	−
CTLA4-Ig	Abatacept	+	−	Not effective in IBD
JAK inhibitor	Tofacitinib	+	+	UC only Only phase II data available for AxSpA
IL-6 inhibitor	Tocilizumab	−	−	Associated with intestinal ulcers
α4β7 inhibitor	Vedolizumab	−	+	Gut specific; may see worsening of inflammatory arthritis after switching to vedolizumab

CD, Crohn disease; DMARD, disease-modifying antirheumatic drug; IBD, inflammatory bowel disease; IL, interleukin; SpA, spondyloarthritis; TNF, tumor necrosis factor; UC, ulcerative colitis.

• 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.

Referral

Rheumatology and gastroenterology

Pearls & Considerations

• •When a single joint is affected, consider joint aspiration to rule out septic arthritis. Signs of infection may be atypical in those receiving antiinflammatory or immunosuppressive medications.
• •Other extraintestinal manifestations of EA include skin and mucous membrane involvement, anterior uveitis, Hashimoto thyroiditis, genitourinary involvement (nephrolithiasis), aortic insufficiency, and cardiac conduction abnormalities. These are often seen in patients with prolonged disease activity and positive HLA-B27.

References

1.Gionchetti P., et al.: Inflammatory bowel diseases and spondyloarthropathies . J Rheumatol 2015; 93: pp. 21-23.

2.Peluso R., et al.: Enteropathic spondyloarthritis: from diagnosis to treatment . Clin Dev Immunol 2013; 2013:

3.Taams L.S., et al.: IL-17 in the immunopathogenesis of spondyloarthritis . Nat Rev Rheumatol 2018; 14 (8): pp. 453-466.

4.Atzeni F., et al.: Rheumatic manifestations in inflammatory bowel disease . Autoimmun Rev 2014; 13 (1): pp. 20-23.

5.Voulgari P.V.: Rheumatological manifestations in inflammatory bowel disease . Ann Gastroenterol 2011; 24: pp. 173-180.

6.Antonelli E., et al.: Dermatological manifestations in inflammatory bowel diseases . J Clin Med 2021; 10 (2): pp. 1-16.

7.Peluso R., et al.: Management of arthropathy in inflammatory bowel diseases . Ther Adv Chronic Dis 2015; 6 (2): pp. 65-77.