Continuing Education Activity

Arthritis is a recognized manifestation associated with several medical conditions, including inflammatory bowel disease, bacterial gut infections, gluten-sensitive enteropathy, parasitic infections, pseudomembranous colitis, Whipple disease, and following intestinal bypass surgery. Studies reveal connections between alterations in gut microflora and joint inflammation, particularly with enteropathic arthritis. Enteropathic arthritis can manifest as peripheral, axial, or a combination of both, ranging from subclinical inflammation on imaging to severe symptoms with functional limitations. Effective treatment should address both arthritic and bowel manifestations, with options such as nonsteroidal anti-inflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs, and biological agents. The advent of biological therapies has significantly improved outcomes for inflammatory bowel disease and associated arthropathies.

Within this activity, participants explore the etiology, pathophysiology, evaluation, and management of enteropathic arthritis, gaining essential knowledge and tools to enhance patient care and overall outcomes while navigating this complex condition. By engaging with the course content, learners deepen their understanding of the relationship between gut health and joint inflammation, as well as refine their skills in diagnosing and treating enteropathic arthritis effectively. Moreover, participation in this course fosters interprofessional collaboration and communication among healthcare teams, facilitating a holistic approach to patient care and optimizing treatment strategies through shared expertise and perspectives.

Objectives:

• Evaluate the impact of dysbiosis of the gut microbiome on the pathogenesis of enteropathic arthritis.

• Identify musculoskeletal symptoms suggestive of enteropathic arthritis in patients with gastrointestinal illnesses.

• Apply evidence-based guidelines for treating patients with enteropathic arthritis.

• Collaborate with multidisciplinary teams, including gastroenterologists, rheumatologists, and other specialists, to optimize patient care.

Introduction

Enteropathic arthritis refers to immune-driven rheumatologic conditions linked to gastrointestinal pathology, typically denoting the inflammatory spondyloarthropathies associated with inflammatory bowel disease (IBD) and reactive arthritis triggered by bacterial and parasitic infections. Psoriatic arthritis, ankylosing spondylitis, and undifferentiated spondyloarthropathy are other inflammatory spondyloarthropathies. 

Joint involvement is a common extraintestinal manifestation of IBD, which may precede the onset of intestinal manifestations. Spondyloarthritis manifests with axial involvement of the spine and sacroiliac joints, peripheral involvement, or a combination of both.[1][2][3] Patients with other gastrointestinal illnesses such as celiac disease, Whipple disease, and collagenous colitis may also experience arthritis.[1]

Axial joint involvement in enteropathic arthropathy varies from subclinical inflammation observed on imaging to severe symptoms with functional limitations, which may progress independently of the underlying IBD activity.[1][4] Peripheral joint disease exhibits an oligoarticular or polyarticular pattern, with symptoms more often correlating with bowel inflammation. The symptoms and findings associated with peripheral spondyloarthritis are predominantly or entirely peripheral rather than axial. Arthritis, which is asymmetric or predominantly of the lower limbs, enthesitis, and dactylitis are all common features of peripheral spondyloarthritis.

The Oxford criteria classifies enteropathic spondyloarthritis into 3 types.[5] Type 1 describes oligoarticular disease correlating with bowel inflammation, type 2 describes chronic symmetric polyarticular disease independent of IBD activity, and type 3 presents as axial and sometimes peripheral involvement whose progression does not correlate with IBD activity. Healthcare professionals seldom utilize this classification and designate all subtypes as peripheral spondyloarthritis. 

The emergence of biological therapies has significantly improved outcomes for both IBD and associated arthropathies. The interconnection between arthritis and bowel inflammation is continually unfolding, with emerging evidence of dysbiosis and decreased microbiota diversity impacting disease onset and progression. Healthcare professionals can further classify axial disease using the Assessment of Spondyloarthritis International Society classification criteria.[6] Assessing joint disease is crucial for selecting treatments that cover all aspects of the condition. When choosing therapies, clinicians should also consider related manifestations such as uveitis, psoriasis, and pyoderma gangrenosum. This method guarantees comprehensive coverage, effectively addressing all relevant disease domains.[7][8]

Etiology

Axial involvement is associated with the human leukocyte antigen B27 (HLA-B27), a class I molecule, and follows a course independent of IBD activity.[1] Reactive arthritis and spondylitis are also strongly associated with the presence of HLA-B27. Polymorphisms in the genes for tumor necrosis factor and interleukin-23 (IL-23), also shared with IBD and psoriasis, and endoplasmic reticulum aminopeptidase-1 (ERAP-1) and endoplasmic reticulum aminopeptidase-2 (ERAP-2) are also associated with enteropathic arthritis. ERAP-1 is key in antigen processing and presentation to HLA class I molecules.[9] Type 1 peripheral arthritis is associated with HLA-DRB1*0103, HLA-B27, and HLA-B35. In contrast, HLA-B44 predominates in association with type 2 peripheral arthritis.[4] 

IL-23 receptor polymorphisms and caspase recruitment domain-containing protein 9 (CARD9) mutations are also associated with inflammatory bowel disease and enteropathic arthritis. CARD9 mutations can activate inflammasomes in response to bacterial and fungal proteins.[10] IL-23 plays a significant role in activating macrophages. The T helper 17 (Th17) pathway activates innate lymphoid cells, including intestinal luminal cells. These intestinal luminal cells can produce interleukin-17 (IL-17) and interleukin-22 (IL-22). IL-22 protects mucosal cells; however, IL-17 and IL-22 can trigger tissue inflammation. See Table 1. Genes Associated with Chron Disease and Ankylosing Spondlytis for a comprehensive list of genes associated with these conditions.

Table 1. Genes Associated with Crohn Disease and Ankylosing Spondylitis

Epidemiology

The global estimated incidence of IBD is 6.7 million. The estimated incidence of arthralgia in patients with IBD is 6% to 46%.[12] Approximately 5% to 20% of individuals with IBD develop peripheral arthritis or spondylitis. Study results reveal that peripheral arthritis occurs in approximately 20% of patients with Crohn's disease and 12% of patients with ulcerative colitis.[13] In addition, results from another study shows that peripheral arthritis, sacroiliitis, and ankylosing spondylitis are present in 13%, 10%, and 3% of patients with IBD, respectively.[14] 

The prevalence of IBD in patients with ankylosing spondylitis is 5% to 10%, with colonoscopy findings indicating subclinical inflammation in one-third to two-thirds of patients with ankylosing spondylitis. Up to 20% of patients with IBD have asymptomatic sacroiliitis.[1][14] 

Results from a cohort study following 599 patients with IBD for 20 years reveal the development of ankylosing spondylitis in 4.5%, axial spondyloarthritis in 7.7%, inflammatory back pain in 11.5%, and chronic back pain in 46.8%.[15] Within this cohort, the incidence of HLA-B27 in patients with IBD and ankylosing spondylitis is 57.1%, axial spondyloarthritis 69.4%, and inflammatory back pain 25.9%. No association between IBD, chronic back pain, and HLA-B27 is evident. 

Spondyloarthritis has no sex predilection, but axial involvement is more common in men. In contrast to idiopathic ankylosing spondylitis, the incidence of ankylosing spondylitis associated with IBD is equal in both men and women. Axial involvement can begin at any age.[16] Notably, Black patients with IBD show elevated rates of arthralgias, ankylosing spondylitis, and sacroiliitis compared to White counterparts.

Pathophysiology

Two prevailing hypotheses regarding the link between joint and intestinal inflammation exist. One theory suggests that independent inflammatory processes coexist in these 2 organ systems due to shared genetic risk factors and environmental triggers.[17] However, recent study results support an alternative mechanism where intestinal inflammation leads to increased gut permeability, allowing antigenic material absorption, including microbial antigens. Changes in the gut bacterial flora, such as increased levels of Klebsiella pneumoniae in the gastrointestinal tract, indicate a link between bacteria and the activity of these diseases.[18][19] Dysbiosis in the gut microbiota activates resident dendritic cells and macrophages to produce IL-23.[20][21][22][23][24] The absorbed antigens localize to musculoskeletal tissue and cause an inflammatory cascade leading to systemic translocation of immune complexes and innate lymphoid cells to synovium and entheses. This hypothesis is supported by studies demonstrating shared macrophages in the gut and synovium of patients with spondyloarthritis and increased affinity of innate lymphoid cells for specific synovial proteins, including mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1).[25] IL-23 levels are higher in patients with IBD, particularly in those with Crohn disease, especially when arthritis is present.[26] 

Dysregulated sensing of local microbial products, possibly by HLA-B27 on antigen-presenting cells, triggers inflammatory signaling pathways, mainly through IL-23 and Th17 cells.[10][11][27] Data suggest that misfolding of HLA-B27 molecules in the endoplasmic reticulum of intestinal cells activates autophagy, a process where the cell breaks down and recycles its cellular components, including cellular debris. The activation of autophagy results in increased production of IL-23.[28] IL-23 plays a crucial role in differentiating naive CD4+ T cells into Th17 cells and activating natural killer T cells, γδ T cells, and mucosal-associated invariant T cells. These cells produce IL-17, IL-22, and TNF-α.[21][22][23][24][29][30] IL-23 also activates ILC3, which produces IL-17 and IL-22.

IL-17 stimulates the production of chemokines and cytokines, including TNF-α, resulting in a robust inflammatory response, including neutrophils and, to a lesser extent, monocytes in the target tissue.[23] IL-17 secretion by Th17 cells, ILC3, and other cells results in immune-mediated inflammation. These inflammatory responses are associated with chronic inflammatory diseases such as Crohn disease, spondyloarthritis, and psoriasis.[23] 

IL-22 exhibits proinflammatory properties and promotes new bone formation in entheses and periosteum.[23][31] The presence of cells residing in entheses expressing the IL-23 receptor suggests a potential mechanism by which IL-23 production in the gut can result in arthritis and enthesis.[31][32] The presence of immune cells with IL-23 receptors in entheses in animal models suggests a potential association between gut inflammation and arthritis.[31][32]

Researchers have investigated changes in the gut microbiome in Crohn disease and ankylosing spondylitis. Patients with spondyloarthritis, including ankylosing spondylitis, without any gastrointestinal symptoms, often have subclinical gut inflammation, as observed on intestinal biopsies.[33][34][35][36] ILC3s appear to be important in maintaining immunologic tolerance and intestinal homeostasis.[37] IL-23 levels in patients with IBD are elevated, with levels being higher in Crohn disease compared to ulcerative colitis, and in patients with Crohn disease, the IL-23 levels were higher in patients with arthritis compared to those without.[26]

History and Physical

Important historical information includes a detailed history of the patient's joint pain, focusing on factors such as morning stiffness, swelling, and changes in pain with activity. Clinicians should also inquire about changes in bowel habits, appetite, weight loss, blood and mucous in the stools, tenesmus, nocturnal passage of stool, recurrent oral ulcerations, and perianal pain or discharge. Although some patients may report a correlation between the severity of joint pain and bowel symptoms, these symptoms may not always align. Inquiring about a family history of IBD, spondyloarthritis, psoriasis, or uveitis, and reviewing the patient's medication history are important. Clinicians should pay particular attention to the use of nonsteroidal anti-inflammatory drugs, which patients may use for joint pain with potential adverse impacts on gastroenterological symptoms.[17] 

Inflammatory Bowel Disease-Associated Arthropathy

IBD-associated arthropathy presents with axial or peripheral symptoms, and in some cases, patients may present with a combination of both. Axial symptoms involve the spine and sacroiliac joints, characterized by spondylitis and sacroiliitis. Patients with axial involvement typically present with an insidious onset of back pain associated with morning stiffness that worsens with rest, prolonged sitting, or standing. Their symptoms tend to improve with activity. Physical examination may reveal limited spinal flexion and reduced chest expansion in patients with longstanding spondyloarthritis. Axial involvement is typically independent of gastrointestinal symptoms and more common in Crohn disease compared to ulcerative colitis.[12][13][14][38]

Peripheral arthritis associated with IBD is non-erosive and nondeforming and most common in patients with Crohn disease affecting the colon.[1] Peripheral arthritis may precede gastrointestinal symptoms, but most often presents concurrently or as late as 10 years following the development of bowel disease. Enthesitis, inflammation of the tendon insertion to the bone, and dactylitis, inflammation of the digit, may occur in patients with IBD-associated arthritis. The most common physical examination finding associated with enthesitis is severe pain and tenderness, along with swelling at the heels, either at the insertion of the Achilles tendon or the plantar fascia ligament into the calcaneus. Patients may experience difficulty walking on their heels when barefoot. Dactylitis can affect the toes or fingers and involves swelling of the entire digit, lending to the name sausage digit.

Historically, peripheral arthritis has been categorized into 2 types.

• Type 1: The oligoarticular form affects <5 joints. Attacks are self-limited and last approximately 10 weeks or less. Joint involvement is usually asymmetrical, affecting large joints such as the knees, hips, and shoulders. Oligoarticular peripheral joint arthropathy has a strong correlation to IBD activity. This arthropathy often appears with extensive ulcerative colitis or colonic involvement in Crohn's disease. Affected patients often have additional extraintestinal manifestations of IBD, including pyoderma gangrenosum, erythema nodosum, aphthous ulcers, uveitis, and secondary amyloidosis.[5][13] Uveitis is typically unilateral, characterized by redness, pain, and photophobia.
• Type 2: The polyarticular form affects >5 joints. The attacks are chronic and can last months to years. Joint involvement is more likely to be symmetrical and involve the small joints of the hands. Joint symptoms of this type are typically independent of IBD activity.[1][13]

Evaluation

Healthcare professionals should consider the possibility of enteropathic arthritis when a patient with IBD experiences joint pain and swelling or inflammatory back pain. Clinicians should examine the joints for evidence of inflammation, noting the pattern and symmetry. In addition, they should examine the digits and periarticular soft tissues for edema and tenderness, focusing on the Achilles tendon insertion. The clinical assessment should include an examination of the spine and sacroiliac joints, flexibility, range of motion, and tenderness of the sacroiliac joints.

Additional maneuvers are the modified Schober test and occiput-wall distance. To perform the modified Schober test, the patient stands, and the clinician marks both posterior superior iliac spines and then draws a horizontal line at the center of both marks. The clinician then marks a second line 5 cm below the first line and a third line 10 cm above the first line. Then, the patient bends forward, and the clinician measures the distance between the top and bottom lines. Patients who show a <5 cm increase in length with forward flexion have a decreased lumbar spine range of motion.

The occiput-wall distance is used to assess the severity of the axial disease. To perform this assessment, the patient stands with their back against the wall and posture as straight as possible, ensuring the heels, calf, buttocks, and shoulders touch the wall. Then, they attempt to have their occiput touch the wall, ensuring that the orbit's lower margin and the acoustic meatus's upper margin are aligned horizontally. The occiput touches the wall in most normal patients, and the measurement is 0. If the occiput does not touch the wall, the distance is measured. A distance >2 cm is considered abnormal.

A focused abdominal examination is crucial for identifying tenderness, and a perianal examination is essential for detecting the perirectal disease. Clinicians should assess the skin for pyoderma gangrenosum, most often noted with ulcerative colitis, and erythema nodosum, frequently associated with Crohn disease. An ophthalmologic examination is necessary to evaluate for evidence of uveitis or conjunctivitis. 

Diagnostic Studies

Laboratory studies: Laboratory tests are nonspecific. Indicated labs are a complete blood count, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-endomysial and anti-transglutaminase antibodies. A complete blood count may reveal various abnormalities, including anemia, thrombocytosis, and leukocytosis. Both the CRP and ESR are likely to be elevated. The RF should be negative. CRP levels are higher in patients with enteropathic arthritis with axial involvement.[39] In patients with one or only a few involved joints, arthrocentesis and synovial fluid analysis should be performed to exclude septic arthritis. Septic arthritis can present in an atypical manner in patients with IBD who are receiving immunosuppressant medications. Synovial fluid should reveal mild to moderate inflammatory fluids with predominately mononuclear cells. The cultures should be negative, and no crystals should be present. 

Fecal calprotectin elevations occur in inflammatory colorectal disease, but this test lacks the necessary sensitivity and specificity for diagnosing IBD in patients with enteropathic arthritis. Endoscopy with biopsy is the preferred diagnostic modality for patients presenting with symptoms suggestive of IBD.[17]

Imaging studies: When the clinical signs of inflammatory arthritis are present, there is no need for imaging studies of joints to establish the diagnosis. However, they are crucial in evaluating joint damage and disease progression. 

The preferred initial imaging modality for patients presenting with inflammatory back pain is plain radiographs of the spine and sacroiliac joints.[40][41] Lumbar spine and sacroiliac joint radiography can reveal signs of enthesitis at the annulus fibrosis, appearing as squaring of vertebral bodies, erosions and sclerosis of superior and inferior margins, and formation of marginal ossification of the annulus fibrosis called syndesmophytes. Sacroiliac joint radiographs may reveal erosions, sclerosis, and ankylosis with symmetric involvement. 

Musculoskeletal ultrasound can assist in evaluating peripheral joint involvement. Pertinent findings are joint effusions, and color-power Doppler signals consistent with active inflammation. Ultrasound is also a sensitive method to detect tendinopathy, bursal involvement, and inflammatory abnormalities at the entheses during the early phase of the disease. A study reveals that 87.8% of patients with IBD exhibit signs of enthesitis when assessed using ultrasound.[42] 

Sacroiliac and lumbar magnetic resonance imaging (MRI) with short tau inversion recovery is considered the gold standard for assessing axial spondyloarthritis and sacroiliitis. This method identifies active inflammation when plain radiography appears normal. MRI findings of active sacroiliitis include osteitis, bone marrow edema, and enthesitis. Bone marrow edema located in the subchondral bone adjacent to the articular surface of the sacroiliac joint is the most crucial criterion for the diagnosis of active sacroiliitis.

Signs of structural damage from prior inflammation, such as subchondral sclerosis, subchondral or periarticular erosions, periarticular fat deposition, or ankylosis, can also be helpful in disease monitoring. MRI may reveal evidence of sacroiliitis in 15% to 20% of patients with IBD but no axial symptoms.[43][44] The 2015 European Alliance of Associations for Rheumatology guidelines recommend sacroiliac MRI imaging if a clinician is unable to establish the diagnosis of spondyloarthritis based on clinical history and conventional radiography.[40] Magnetic resonance enterography, a diagnostic imaging technique used to assess bowel inflammation, may detect inflammatory lesions at the sacroiliac joints in asymptomatic patients who are asymptomatic.[45]

Computed tomography (CT) scans of the abdomen and pelvis are often used to assess the activity of bowel disease in patients with IBD. [46] Visualizing the sacroiliac joints and spine allows for noting sacroiliitis and spondylitis. While MRI is useful for showing inflammation related to active disease, CT scanning is highly sensitive to bone changes, including erosions, syndesmophytes, and fusion.

Additional testing: Enteropathic arthritis and other inflammatory diseases substantially impact functional status and quality of life. Depression is a frequent comorbidity of enteropathic arthritis; screening using tools such as the Patient Health Questionnaire-2 (PHQ-2) and PHQ-9 is helpful. 

Clinicians can extrapolate arthritic disease activity from existing disease activity scores for axial spondyloarthritis, including the Bath Ankylosing Spondylitis Disease Activity Index and the Ankylosing Spondylitis Disease Activity Score.[47][48] Bowel assessment measurements to assess severity include the Crohn's Disease Activity Index.[49]

Treatment / Management

Separate guidelines exist for treating IBD, axial spondyloarthritis, and peripheral spondyloarthritis. The therapeutic strategy must be individualized to encompass the combination of IBD and spondyloarthritis clinical manifestations, while also considering skin and eye manifestations. The main objective is to enhance the long-term quality of life and prevent damage by managing inflammation in all affected organ systems.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line agents for both axial and peripheral enteropathic arthritis is controversial. Research investigating the connection between NSAIDs and the recurrence or exacerbation of IBD yields contradictory findings. Evidence supports the safety of brief NSAID courses, particularly during periods of inactive IBD. Several studies suggest that COX-2 inhibitors are safe for short-term usage, typically up to 3 months.[50][51] Given the limitations in evidence, the American College of Rheumatology (ACR) 2019 spondyloarthritis management guidelines do not recommend selective COX-2 inhibitors over other NSAIDs in patients with IBD.[52] 

Management of Peripheral Arthritis

Nonsteroidal anti-inflammatory drugs: Patients with peripheral disease begin treatment with NSAIDs and local glucocorticoid injections or low-dose oral glucocorticoids. Experts recommended the use of nonselective NSAIDs such as naproxen at doses of 375 to 500 mg twice daily or the COX-2-selective NSAID celecoxib at a dose of 100 mg twice daily. A proton pump inhibitor should accompany the administration of nonselective NSAIDs.

Disease-modifying antirheumatic drugs: If NSAIDs and local glucocorticoid injections prove insufficient, clinicians may add conventional disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine. If one NSAID proves ineffective, conduct a second NSAID trial unless the first NSAID exacerbated IBD symptoms. Sulfasalazine is the preferred choice, with an initial dose of 500 mg twice daily, followed by an increase in the daily dose to 1000 mg every 2 weeks until arthritis symptoms improve or until the patient reaches a maximum dose of 1000 mg 3 times daily. Patients should undergo a trial of at least 12 weeks before determining efficacy. The dosing for methotrexate is 10 mg once weekly, with gradual dose increments of 2.5 to 5 mg weekly until the patient achieves control of their joint inflammation or reaches a dose of 25 mg per week. No robust data support the use of azathioprine, an immunosuppressant used to treat IBD, for enteropathic arthritis.

Tumor necrosis factor inhibitors: Clinicians should aim to achieve concurrent control of underlying IBD symptoms as well. Patients with new-onset enteropathic arthritis and quiescent IBD should undergo evaluation by their gastroenterologist for possible asymptomatic gastrointestinal inflammation. For those who continue to have inadequate control of their symptoms, clinicians should try TNF inhibitors. TNF inhibitors effectively treat enteropathic-related peripheral and axial arthritis, dactylitis, enthesitis, and uveitis.[53] The monoclonal antibody TNF inhibitors, including infliximab, adalimumab, golimumab, and certolizumab pegol, are all effective for joint and bowel disease.[54][55] 

Etanercept, a receptor fusion protein, should be avoided in enteropathic arthritis as it provides beneficial results on joints but not on bowel disease.[56][57][58][59] Etanercept is associated with worsening inflammatory bowel disease.[60] TNF inhibitors are also a good choice for patients with axial disease unresponsive to NSAIDs or severe or resistant gastrointestinal disease activity. Before initiating TNF inhibitor therapy, healthcare professionals must screen patients for latent tuberculosis and perform baseline chest radiography to assess the risk of reactivating latent tuberculosis. Patients with evidence of latent, previously untreated tuberculosis should begin antituberculous therapy before beginning TNF inhibitor therapy. Clinicians should assess the efficacy of the TNF inhibitor after 3 months, and if it is found to be ineffective, a second TNF inhibitor should be attempted.

Interleukin inhibitors: Failure of a TNF inhibitor to control symptoms prompts a therapeutic trial of ustekinumab, which inhibits IL-12 and IL-23 and has demonstrated effectiveness in treating Crohn's disease and psoriatic arthritis. While its efficacy for IBD-related peripheral arthritis is unclear, evidence suggests that it may be effective for axial symptoms. Although IL-17 inhibitors such as secukinumab and ixekizumab are commonly used to treat spondyloarthritis, they are not used in enteropathic arthritis because IL-17 inhibition is ineffective in treating and may induce flares of IBD.[61][62]

Janus kinase inhibitors: Janus kinase (JAK) inhibitors, including tofacitinib and upadacitinib, have a role in managing both peripheral and axial symptoms related to enteropathic arthritis.[63][64] This drug class also effectively controls aspects of IBD at higher doses. However, in 2021, the United States Food and Drug Administration issued a black box warning regarding the increased risk of heart disease, thromboembolism, cancer, and death with JAK inhibitors, potentially limiting their use.

Integrin inhibitors: Monoclonal antibodies against integrin α4β7 specifically target gastrointestinal tract disease. A post-hoc analysis of the GEMINI trial demonstrates a significant reduction of arthralgia and arthritis in patients with IBD treated with vedolizumab compared to placebo.[65][66] Potential adverse effects associated with vedolizumab are new and worsening arthralgia, de novo severe spondyloarthritis, and enthesopathy.[67] Healthcare professionals do not commonly use vedolizumab monotherapy in the treatment of enteropathic arthritis. Combination therapy with TNF inhibitors is a potential option for patients with TNF inhibitor-responsive spondyloarthritis who have poorly controlled IBD. Several case reports and series have reported successful combination therapy of TNF and integrin inhibitors without increasing adverse events.[68][69] 

Systemic glucocorticoids: Systemic glucocorticoids can be appropriate for acute flares of peripheral joint involvement and IBD. Glucocorticoids should be used at the lowest effective dose for the shortest duration possible due to adverse events. Recommended dosing regimens include methylprednisolone 80 to 120 mg administered through an intramuscular injection or a short course of oral glucocorticoids such as prednisone, initially starting at 20 mg per day and then tapered over 2 weeks. Intraarticular joint injections, including sacroiliac injections, are also utilized for more limited joint involvement.

Management of Axial Arthritis

NSAIDs and an exercise program are first-line agents for axial arthritis. Back strengthening and stretching are imperative for long-term management, and patients with axial involvement should seek assistance from a physical therapist for assessment and proper instruction. Failure of NSAIDs to treat the patient adequately prompts the addition of a TNF inhibitor. There is no evidence to support the use of sulfasalazine or methotrexate. Conventional disease-modifying antirheumatic drugs are ineffective in controlling axial inflammation. The treatment approach for patients who have not received adequate results with 2 TNF inhibitors follows the same algorithm as that for peripheral arthritis.

Differential Diagnosis

Fibromyalgia

Patients with fibromyalgia experience disturbed pain processing and amplified pain. Classic symptoms include widespread arthralgias and myalgias in combination with extra-articular symptoms such as diarrhea, constipation, abdominal pain, bloating, headaches, poor sleep, and cognitive dysfunction. Fibromyalgia frequently coexists with other autoimmune disorders, including inflammatory bowel disease. Utilization of the widespread pain index and symptom severity score assists in diagnosing fibromyalgia.[70] 

Irritable Bowel Syndrome 

Irritable bowel syndrome is a functional disorder of the gastrointestinal system marked by abdominal bloating, diarrhea, constipation, alternating diarrhea and constipation, and abdominal pain that resolves with defecation. Some patients may present with mucus in the stool. Patients can also experience arthralgia with IBS. Large-volume diarrhea, bloody stools, nocturnal diarrhea, and greasy stools are not associated with irritable bowel syndrome.

Whipple Disease

Whipple disease, caused by infection with Tropheryma whippleii, typically presents with primary symptoms such as diarrhea, weight loss, and malabsorption. Whipple disease is most common in men who are 50 or older, with 90% of patients presenting with migratory polyarthritis that can precede gastrointestinal symptoms by years. Occasionally, affected patients may develop sacroiliitis. 

Collagenous and Lymphocytic Colitis 

The cause of collagenous and lymphocytic colitis is unknown. Affected patients have linear collagen deposits in the subepithelia layer of the colon. The primary symptoms include watery diarrhea and abdominal pain associated with arthritis of the hands and wrists. Around 10% of patients may develop joint symptoms years before the onset of gastrointestinal symptoms.

Intestinal Bypass Arthritis

Tenosynovitis is common in patients who undergo intestinal bypass. Episodes may last for days or months and affect the knee, wrist, ankle, shoulder, and finger joints. Patients often experience urticarial, vesicular, pustular, macular, or nodular skin eruptions, and the Raynaud phenomenon. 

Celiac Disease

Celiac disease, an immune-mediated inflammatory condition of the small intestine triggered by sensitivity to dietary gluten and related proteins, is a prevalent disorder in genetically susceptible individuals. Most of those affected are HLA DR3-DQ2 or HLA DR4-DQ8 positive. The most common presentation includes diarrhea, steatorrhea, and malabsorption. Approximately 26% of patients with celiac disease present with peripheral or axial arthritis.[71] Patients with an atypical presentation of celiac disease may have mild gastrointestinal complaints, with the predominant symptoms including anemia, dental enamel defects, osteoporosis, arthritis, increased aminotransferases, neurological symptoms, infertility, and several associated autoimmune diseases. 

Brucellosis

Brucellosis, resulting from Brucella melitensis, is a zoonotic ailment manifesting as a systemic febrile illness or a localized infection in approximately 30% of individuals. Articular manifestations of the disease can encompass peripheral arthritis, sacroiliitis, or spondylitis.[72]

Poncet Disease

Poncet disease is a reactive polyarthritis associated with active tuberculosis. The clinical presentation may include symmetric polyarthritis, sacroiliitis, and enthesitis.[73]

Reactive Arthritis

Reactive arthritis is an inflammatory arthropathy following an infection caused by Chlamydia trachomatis, Yersinia, Salmonella, Shigella, Campylobacter, Escherichia coli, Clostridioides difficile, or Chlamydia pneumoniae. Reactive arthritis typically manifests as acute, asymmetrical oligoarthritis within weeks of the infection. The knees and ankles are predominantly affected, accompanied by urethritis, cervicitis, conjunctivitis, and uveitis.

Microscopic Colitis

Microscopic colitis presents with chronic, non-bloody, watery diarrhea with a median age at diagnosis of 65. This disease can be associated with uveitis and axial or peripheral arthritis.[74]

Bowel-Associated Dermatosis-Arthritis Syndrome

Bowel-associated dermatosis-arthritis syndrome is a neutrophilic dermatosis presenting with fever, arthralgia, myalgia, and skin eruptions noted in patients after abdominal surgery, jejunoileal bypass, and those with IBD. The articular manifestations present as oligoarticular, asymmetric, non-erosive arthritis involving large and small joints, tenosynovitis, and enthesitis.[75]

Behçet Disease

This systemic vasculitis shares many features with enteropathic arthritis. Affected patients present with recurrent oral aphthae and a combination of other systemic manifestations, including genital aphthae, ocular disease, skin lesions, gastrointestinal disease, neurologic disease, vascular disease, and arthritis.[76]

Hypertrophic Osteoarthropathy

Hypertrophic osteoarthropathy is associated with lung cancer and other pulmonary disorders and involves abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities. Clinical features include digital clubbing, periostosis of tubular bones, and synovial effusions, which are most prominent in the large joints. Painful arthropathy may precede clubbing in some patients, giving the appearance of inflammatory arthritis. The synovial fluid tends to be thick and clot on joint aspiration. Digital clubbing, dermal hypertrophy, and the presence of the characteristic synovial fluid help differentiate the 2 diseases. Patients with IBD can develop hypertrophic osteoarthropathy.

Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis Syndrome

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, believed to be a part of the spondyloarthritis spectrum, is an inflammatory disorder involving the skin, bone, and joints. Manifestations include synovitis, acne, pustulosis, hyperostosis, and osteitis. Some studies show an association with HLA-B27. SAPHO syndrome affects 0.2% of patients with IBD.[77]

Osteonecrosis

Osteonecrosis or avascular necrosis of the bone is due to decreased perfusion, causing ischemia and death of bone and marrow cells. Patients with IBD often receive glucocorticoid therapy, a known risk factor for the development of avascular necrosis. The hip, knee, and shoulder are frequently affected joints. The physical examination may be nonspecific, and patients often experience pain levels higher than expected based on the findings.

Infectious Arthritis

Infectious arthritis in patients with IBD can present as monoarthritis or oligoarthritis. Clinicians must exclude infectious arthritis in any patient with IBD and new-onset monoarthritis. 

Erythema Nodosum

Although erythema nodosum may occur in patients with IBD, distinguishing erythema nodosum from arthritis may pose a challenge if the primary lesions are periarticular in location. The inability to aspirate synovial fluid from an affected joint is a clue to the diagnosis. 

Parasitic Arthritis 

Gastrointestinal infections caused by Strongyloides stercoralis, Taenia saginata, Endolimax nana, Dracunculus medinensis, Giardia lamblia, and Necator americanus can lead to the development of arthritis. Parasitic arthritis may be classified as infectious arthritis or reactive arthritis, as parasites may be isolated from the joints in some cases.

Prognosis

The outlook for both peripheral and axial arthritis linked to IBD closely resembles that of individuals without IBD. Those with axial disease confined to a limited region generally maintain full functionality. However, some may encounter progressive spondylitis, leading to persistent spinal pain, hip damage, and spinal fusion. Peripheral arthritis typically lacks erosiveness and does not induce joint deformities. Except for patients with progressive spondylitis, the long-term prognosis is more defined by the trajectory of IBD than the arthritis.[78]

Complications

Enteropathic arthritis significantly impacts health-related quality of life, and inflammatory bowel diseases can lead to multiple intestinal, articular, and extra-articular complications.

Gastrointestinal Complications 

Gastrointestinal complications include Obstruction, strictures, fistulas, abscesses, primary sclerosing cholangitis, colorectal cancer, small bowel malignancies, osteoporosis, and fragility fractures.[78] Patients with ileal Crohn disease are at the highest risk of developing intestinal strictures and fistulas. In contrast, ulcerative colitis is commonly associated with colorectal cancer and primary sclerosing cholangitis.

Articular Complications

Articular complications include chronic pain and disability, loss of lumbar lordosis and spinal mobility, spinal deformities, vertebral fractures and subluxation, and spinal cord injury due to vertebral fractures.

Extra-Articular Complications

Extra-articular complications include uveitis, aortic insufficiency, cardiac conduction abnormalities, and pyoderma gangrenosum.[78] Uveitis, aortic insufficiency, and cardiac conduction abnormalities are most common in patients who are HLA-B27 positive, with axial involvement and increased disease duration. Patients with inflammatory bowel disease associated with peripheral polyarticular joint involvement show an increased prevalence of autoimmune thyroiditis.[2] Several studies reveal an increased arterial and venous thrombosis and cardiovascular risk in patients with IBD and spondyloarthritis. However, data regarding thrombotic and cardiovascular risk in enteropathic arthritis are lacking.[79][80]

Deterrence and Patient Education

Early recognition of enteropathic arthritis is crucial; therefore, clinicians should maintain a heightened awareness, especially when patients with IBD present with musculoskeletal symptoms. Regular musculoskeletal examinations during IBD management appointments are essential to detect joint involvement promptly. Collaborative efforts between gastroenterology and rheumatology clinicians are essential for a comprehensive approach. Clinicians should emphasize the risks associated with the various treatments, ensuring patients are well-informed about the benefits and potential adverse effects. Making lifestyle changes, such as quitting smoking and adopting a healthy lifestyle, can lead to better outcomes. Clinicians should integrate mental health screening, recognizing the impact of enteropathic arthritis on psychological well-being.

Patients should understand the need for regular monitoring and follow-up appointments to track disease progression. In addition, clinicians should provide information about patient support groups and online communities to foster mutual support. Comprehensive discussions about the risks and benefits of surgical and medical interventions facilitate shared decision-making, empowering patients to participate in their care actively. By implementing these strategies, clinicians can enhance early detection, proactive management, and the overall well-being of patients with enteropathic arthritis.

Enhancing Healthcare Team Outcomes

Enteropathic arthritis encompasses a spectrum of immune-driven rheumatologic disorders linked to gastrointestinal pathology, including inflammatory spondyloarthritis associated with IBD and reactive arthritis triggered by infections. Joint involvement, a common extraintestinal manifestation of IBD, varies from axial to peripheral, often preceding intestinal symptoms. Emerging evidence suggests that increased gut permeability, which allows for the absorption of the antigenic material, may impact the disease onset. Given the disorder's complexity, understanding diagnostic criteria and implementing evidence-based approaches are crucial across healthcare specialties. Treatment involves NSAIDs, disease-modifying antirheumatic drugs, and biological therapies. Introducing biological therapies has significantly improved outcomes, highlighting the interconnection between arthritis and bowel inflammation.

Effective treatment requires a multidisciplinary approach involving primary care, rheumatology, gastroenterology, dermatology, and ophthalmology.[8][81][82] Clinicians must tailor medical therapy to each patient's specific disease manifestations. Successful treatment also relies on open communication among team members to facilitate collaborative decision-making. Physical and occupational therapists play a crucial role in preventing long-term disability and maximizing patient function, and close collaboration with clinical pharmacists is required to manage complex biological therapies. Patients receiving combined gastroenterology and rheumatology team-based care experience fewer diagnostic delays, improving overall patient care.[39]