Enteropathic Arthritis Enteropathic Arthropathies
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What is enteropathic arthritis?
Synonyms: enteropathic arthropathy, arthritis associated with inflammatory bowel disease, reactive arthritis
Enteropathic arthropathy, or enteropathic arthritis, is an umbrella term used to describe various patterns of inflammatory arthritis which may be associated with a range of gastrointestinal (GI) pathologies. Its constituent conditions are classified as part of the seronegative spondyloarthropathies. Its various associated diseases are outlined below.
- Spondyloarthritis and peripheral arthritis due to inflammatory bowel disease (IBD), ie Crohn's disease and ulcerative colitis.
- Types of arthritis associated with other GI pathologies include coeliac disease, Whipple's disease, and collagenous colitis, and following intestinal bypass surgery.
- Reactive arthritis.
Spondyloarthritis (SpA) is a variety of inflammatory disorders that primarily affect entheses (the connective tissue between tendon/ligament and bone), small and large joints, and the axial skeleton joints. SpA includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, SpA associated with inflammatory bowel disease (IBD), and non-radiographic axial SpA.
This is poorly understood in enteropathic arthritis. Abnormal permeability of the bowel to bacterial antigens, which then locate in articular tissues and lead to an inflammatory response, is one possible mechanism. Genetic susceptibility (particularly HLA-B27 positivity) and immunological dysmodulation may also play a role. Cross-reactivity between articular tissue self-antigens and bacterial antigens may be the underlying immunological mechanism. HLA-B27 positivity may play its role by allowing bacterial peptide antigens to be presented to CD8+ cells, inducing a cellular immune cascade. Intestinal bacterial overgrowth is thought to be important where the condition develops after intestinal bypass surgery.
Enteropathic arthritis epidemiology[3, 4, 5]
Rheumatic manifestations are the most frequent extra-intestinal findings of IBD with a prevalence between 17% and 39%. IBD is also associated, less frequently, with other rheumatic disease such as rheumatoid arthritis, Sjögren's syndrome, Takayasu's arteritis and fibromyalgia.
The joint involvement observed in IBD is usually classified into axial (including sacroiliitis with or without spondylitis) and peripheral. Axial involvement is found to be present in 2-16% of patients with IBD. Peripheral joint involvement has been reported in a wide range (0.4-34.6%) of patients with IBD. It predominantly affects the joints of the lower limbs. Women show more frequently a peripheral joint involvement, whereas men tend to have an axial involvement.
Joint involvement is the most common extra-intestinal manifestation in children with IBD and may involve 16-33% of patients at diagnosis or during follow-up.
Reactive arthritis typically affects around 2-3% of all patients with Salmonella spp., Shigella spp. and Campylobacter spp. infections. Arthritis in patients who have undergone intestinal bypass surgery is relatively common.
Risk factors for enteropathic arthritis
HLA-B27 positivity is strongly associated with axial (spondylitic) forms of the disease in IBD, but not the peripheral form; reactive arthritis is also strongly associated with HLA-B27 positivity.
Potential risk factors for arthritis in patients with IBD include active bowel disease, family history of IBD, appendectomy, cigarette smoking and the presence of other extra-intestinal manifestations, such as erythema nodosum or pyoderma gangrenosum.
Enteropathic arthritis symptoms[3, 7]
Joint symptoms may present before, simultaneously or after the diagnosis of IBD. Symptoms include:
- Axial arthritis (spondylitis and sacroiliitis) associated with IBD:
- The condition may precede any GI symptoms and be active despite good control of bowel disease.
- There is a gradual onset of low back pain radiating down the back of the legs.
- Symptoms tend to be worse in the morning.
- Prolonged sitting or standing can bring the symptoms on.
- Moderate movement tends to improve the symptoms.
- The arthritis tends to be chronic and long-standing.
- Peripheral arthritis of IBD:
- The condition is usually associated with GI symptoms, but may take some time to emerge after the onset of bowel problems.
- It is more likely to affect sufferers of Crohn's disease rather than ulcerative colitis.
- There is an asymmetric, oligoarticular arthritis that predominantly affects the lower limbs.
- The arthritis is usually transient and migratory but may affect progressively more joints in some cases.
- Enthesopathy of IBD:
- This tends to cause severe localised pain in the heel where the insertion of the Achilles tendon is affected; disease of the patellar tendon causes pain on the tibial tuberosity or on the patella itself; the insertion of other tendons or other fascial areas can be inflamed causing, for example, buttock pain or pain in the sole of the foot (plantar fasciitis).
- Extra-articular manifestations of IBD:
- Intestinal symptoms can include abdominal pain, diarrhoea, cramping, weight loss and the passage of blood or mucus per rectum.
- There are dermatological associations with pyoderma gangrenosum affecting ulcerative colitis cases, and erythema nodosum being seen with Crohn's disease.
- The mouth may be affected by frequent, recurrent, painful aphthous ulcers.
- The eye may be painful and red with blurred vision due to anterior uveitis.
- Fever may be associated with IBD; a chronic low-grade fever may be a manifestation of secondary amyloidosis in Crohn's disease.
- Reactive arthritis following intestinal infection:
- This typically manifests as an acute asymmetrical oligoarthritis with a predilection for the knees and ankles.
- It may occur several weeks or months after the initial bout of enteritis.
- Arthritis due to intestinal bypass surgery performed to correct morbid obesity:
- Polyarthritis and an associated dermatitis may occur and are thought to be due to bacterial overgrowth occurring in the bypassed section of bowel, leading to the formation of pathological immune complexes; if the procedure is reversed then the symptoms resolve.
- Whipple's disease arthritis:
- This occurs most commonly in middle-aged men.
- As well as the typical GI symptoms, there is a migratory polyarthritis that can precede GI symptoms by months to years.
- Coeliac disease arthritis:
- This is a relatively rare feature of the condition.
- It tends to present as a symmetrical arthritis of the lumbar spine, hips, knees and shoulders and may be the presenting feature of the illness before typical coeliac symptoms become apparent.
- The arthritis usually resolves when the gut symptoms respond to a gluten-free diet.
- Collagenous colitis:
- This is a rare condition of unknown cause where there is linear deposition of collagen beneath the epithelium of the colon.
- It causes chronic watery diarrhoea and abdominal pain.
- About 10% of those with the condition have peripheral arthritis of the hands and wrists that is responsive to non-steroidal anti-inflammatory drugs (NSAIDs).
- The condition appears to be benign and self-limiting in the majority of cases but may cause long-term chronic disease in a minority.
- Check the temperature to look for evidence of fever.
- Look at the eyes for evidence of anterior uveitis.
- Look in the mouth to detect any ulceration or other oral manifestations of IBD.
- Check the skin for rashes, particularly pyoderma gangrenosum and erythema nodosum.
- The joints should be carefully examined to establish the presence of inflammation and to determine the symmetry and severity of the arthritis.
- The spine needs careful assessment of its range of motion; palpate for tenderness over the sacroiliac joints.
- Periarticular structures should be palpated to look for evidence of enthesopathy.
- Palpate the heel and soles of the feet to detect tenderness and swelling due to Achilles tendonitis or plantar fasciitis.
- Abdominal examination is necessary to detect any tenderness or suggest an alternative cause for intestinal symptoms.
Differential diagnosis of enteropathic arthritis
- Any cause of peripheral polyarthritis.
- Any cause of spondyloarthritis.
- Rheumatoid arthritis.
- Gonococcal arthritis.
- Behçet's disease.
- Lyme disease.
- Septic arthritis.
- Stool microscopy and culture where the aetiology of any bowel disease is undetermined.
- Sigmoidoscopy/colonoscopy/upper GI endoscopy may be needed.
- FBC to detect iron-deficiency anaemia, leukocytosis or thrombocythaemia associated with IBD or other GI conditions.
- ESR/CRP are usually elevated.
- X-ray of affected joints (particularly the spine/sacroiliac joints/calcaneum).
- Synovial fluid aspiration and analysis (shows mononuclear inflammatory cells and is culture-negative without crystals).
- Consider autoimmune screen and anti-endomysial antibodies if there is suspicion of any other inflammatory condition/coeliac disease.
See list in description section at head of article.
The National Institute for Health and Care Excellence (NICE) recommends:
- Urgently refer people with suspected new-onset inflammatory arthritis to a rheumatologist for a spondyloarthritis assessment, unless rheumatoid arthritis, gout or acute calcium pyrophosphate arthritis ('pseudogout') is suspected.
- Refer people with dactylitis to a rheumatologist for a spondyloarthritis assessment.
- Refer people with enthesitis without apparent mechanical cause to a rheumatologist for a spondyloarthritis assessment if:
- It is persistent; or
- It is in multiple sites; or
- Any of the following are also present:
- Back pain without apparent mechanical cause.
- Current or past uveitis.
- Current or past psoriasis.
- Gastrointestinal or genitourinary infection.
- Inflammatory bowel disease (Crohn's disease or ulcerative colitis).
- A first-degree relative with spondyloarthritis or psoriasis.
Enteropathic arthritis treatment and management
The BNF recommends the following for peripheral spondyloarthritis:
- Monotherapy with local corticosteroid injections should be considered for non-progressive monoarthritis.
- Standard disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide or sulfasalazine, can be used for patients with peripheral polyarthritis, oligoarthritis, or persistent or progressive monoarthritis associated with peripheral spondyloarthritis.
- If a standard DMARD taken at the maximum tolerated dose for at least three months does not provide adequate relief from symptoms, a switch to, or the addition of, another standard DMARD can be considered.
- An NSAID can be used as an adjunct to standard DMARDs or biological DMARDs to manage symptoms. If NSAIDs do not provide adequate relief from symptoms, consider corticosteroid injections or short-term oral corticosteroid therapy as an adjunct to standard DMARDs or biological DMARDs to manage symptoms.
- If extra-articular disease is adequately controlled by an existing standard DMARD but peripheral spondyloarthritis is not, consider adding another standard DMARD.
- Maintenance of moderate activity and spinal mobility with physiotherapy and exercises is important, particularly for axial forms of the disease.
- Modification of the diet, based on the underlying GI condition, may help to alleviate gut-related symptoms.
- Extra-articular disease, particularly that affecting the eyes, requires early recognition and referral to specialist services for management and monitoring.
- When ulcerative colitis requires a colectomy; it has been shown to subsequently resolve peripheral joint disease but not axial arthritis.
- NSAIDs may be used to treat acute joint inflammation but must be given with care as they may worsen gastrointestinal symptoms.
- Consider NSAIDs as an adjunct to standard DMARDs or biological DMARDs to manage symptoms. If NSAIDs do not provide adequate relief from symptoms, consider steroid injections (local or intramuscular) or short-term oral steroid therapy as an adjunct to standard DMARDs or biological DMARDs to manage symptoms.
- Control of the underlying GI condition may improve the arthritis but this is often not the case for axial arthritis associated with IBD.
- Intra-articular and systemic corticosteroids are useful for the peripheral arthritis of IBD but have little effect on axial involvement.
- Sulfasalazine is widely used and is effective in treating both GI and rheumatological symptoms in IBD; it should be given under specialist supervision.
- Methotrexate, azathioprine, pamidronate and ciclosporin have all been used as disease-modifying drugs with variable success, under specialist supervision.
- Tumour necrosis factor (TNF) antagonists are increasingly being shown to be effective agents in the management of inflammatory arthritis and bowel disease in IBD. They appear to be very effective against enthesopathy and axial disease, which have traditionally been very hard to treat. They are expensive and can have significant side-effects; their use should be supervised in specialist clinics, preferably as part of a clinical audit and ongoing guideline development programme. NICE guidance on their use in IBD and arthropathies is now available[13, 14].
- Treatment or prophylaxis of osteoporosis using bisphosphonates, calcium and vitamin D may be necessary.
- Side-effects and toxicity caused by drug therapy.
- Complications of IBD.
- Ocular complications due to uveitis.
- Secondary amyloidosis of Crohn's disease.
- Loss of mobility and increasing disablement in severe cases of axial arthritis (rare).
Enteropathic arthritis prevention
This is dependent very much on the specific underlying cause. IBD-related arthritis tends to carry the worse long-term prognosis, particularly where there is severe axial involvement. The use of TNF-alpha antagonists is offering new hope in treating severe cases. The majority of cases are amenable to useful therapy and maintain an active and independent lifestyle.
Disability can be circumvented in those with axial arthritis, by the maintenance of an exercise programme to preserve spinal mobility. There are no known strategies to prevent IBD or enteropathic arthropathy.
Further reading and references
Consensus guidelines on the management of inflammatory bowel disease in adults; British Society of Gastroenterology (2019)
Leukapheresis for inflammatory bowel disease; NICE Interventional Procedure Guidance, June 2005
Conigliaro P, Chimenti MS, Ascolani M, et al; Impact of a multidisciplinary approach in enteropathic spondyloarthritis patients. Autoimmun Rev. 2016 Feb15(2):184-90. doi: 10.1016/j.autrev.2015.11.002. Epub 2015 Nov 7.
Kim TH, Uhm WS, Inman RD; Pathogenesis of ankylosing spondylitis and reactive arthritis. Curr Opin Rheumatol. 2005 Jul17(4):400-5.
Peluso R, Di Minno MN, Iervolino S, et al; Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 20132013:631408. doi: 10.1155/2013/631408. Epub 2013 Apr 15.
Colombo E, Latiano A, Palmieri O, et al; Enteropathic spondyloarthropathy: a common genetic background with inflammatory bowel disease? World J Gastroenterol. 2009 May 2815(20):2456-62.
Resende GG, Lanna CC, Bortoluzzo AB, et al; Enteropathic arthritis in Brazil: data from the Brazilian Registry of Spondyloarthritis. Rev Bras Reumatol. 2013 Nov-Dec53(6):452-9. doi: 10.1016/j.rbr.2013.04.001.
Cardile S, Romano C; Current issues in pediatric inflammatory bowel disease-associated arthropathies. World J Gastroenterol. 2014 Jan 720(1):45-52. doi: 10.3748/wjg.v20.i1.45.
Brakenhoff LK, van der Heijde DM, Hommes DW, et al; The joint-gut axis in inflammatory bowel diseases. J Crohns Colitis. 2010 Sep4(3):257-68. doi: 10.1016/j.crohns.2009.11.005. Epub 2009 Nov 30.
Madisch A, Miehlke S, Lindner M, et al; Clinical course of collagenous colitis over a period of 10 years. Z Gastroenterol. 2006 Sep44(9):971-4.
Spondyloarthritis in over 16s: diagnosis and management; NICE Guidance (Feb 2017)
British National Formulary (BNF); NICE Evidence Services (UK access only)
Reveille JD, Arnett FC; Spondyloarthritis: update on pathogenesis and management. Am J Med. 2005 Jun118(6):592-603.
Varkas G, Van Praet L, Cypers H, et al; Spondyloarthritis and inflammatory bowel disease. Comorbidity and treatment implications. Z Rheumatol. 2013 Aug72(6):524-9. doi: 10.1007/s00393-012-1114-5.
Infliximab (review) and adalimumab for the treatment of Crohn's disease; NICE Technology Appraisal Guidance, May 2010
Infliximab for the treatment of acute exacerbations of ulcerative colitis; NICE Technology Appraisal Guidance, December 2008