AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Enteropathic arthropathies comprise a collection of rheumatologic conditions that share a link to GI pathology. These conditions include reactive (ie, infection-related) arthritis caused by bacteria (eg, Shigella, Salmonella, Campylobacter, Yersinia species, Clostridium difficile), parasites (eg, Strongyloides stercoralis, Taenia saginata, Giardia lamblia, Ascaris lumbricoides, Cryptosporidium species), and spondyloarthropathies associated with inflammatory bowel disease (IBD).

Other conditions and disorders include intestinal bypass (jejunoileal), arthritis, celiac disease, Whipple disease, and collagenous colitis.

Pathophysiology

The precise causes of enteropathic arthropathies are unknown. Inflammation of the GI tract may increase permeability, resulting in absorption of antigenic material, including bacterial antigens. These arthrogenic antigens may then localize in musculoskeletal tissues (including entheses and synovium), thus eliciting an inflammatory response. Alternatively, an autoimmune response may be induced through molecular mimicry, in which the host's immune response to these antigens cross-reacts with self-antigens in synovium.

Of particular interest is the strong association between reactive arthritis and HLA-B27, an HLA class I molecule. A potentially arthrogenic, bacterially derived antigen peptide could fit in the antigen-presenting groove of the B27 molecule, resulting in a CD8+ T-cell response. HLA-B27 transgenic rats develop features of enteropathic arthropathy with arthritis and gut inflammation.

Frequency

United States

In patients with IBD, the prevalence of peripheral arthritis and/or sacroiliitis/spondylitis is 10-20%. The incidence of ulcerative colitis (UC) is 6-8 cases per 100,000 population per year, and prevalence is 70-150 cases per 100,000 population. The incidence of Crohn disease (CD) is 2 cases per 100,000 population per year; prevalence is 20-40 cases per 100,000 population. The incidence of IBD and Crohn disease is increasing, especially that of Crohn disease.

International

The incidence and prevalence rates of ulcerative colitis and Crohn disease are similar in northern and western Europe compared with those in the United States, but rates are lower in other regions of the world.

Race

Incidence of IBD is higher in whites, especially those of Jewish descent, than in other racial groups.

Sex

No sexual predilection exists in peripheral arthritis of ulcerative colitis or Crohn disease. The incidence of spondylitis is higher in males than females.

Age

Peak incidence of IBD occurs in persons aged 15-35 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Axial arthritis (sacroiliitis and spondylitis) in inflammatory bowel disease (IBD)
• • Insidious onset of low back pain, especially in younger persons
  • Morning stiffness
  • Exacerbated by prolonged sitting or standing
  • Improved by moderate activity
  • Independent of GI symptoms
• Peripheral arthritis in IBD (colitic arthritis)
• • Oligoarticular
  • Asymmetric, predominantly involving the lower extremities
  • Associated with GI symptoms
  • Frequently transient and migratory, occasionally additive
  • More common in Crohn disease than ulcerative colitis
  • May precede intestinal involvement, but usually concomitant or subsequent to bowel disease
• Enthesitis
• • Heel - Insertion of Achilles tendon and plantar fascia
  • Knee - Tibial tuberosity, patella
  • Others - Buttocks, foot
• Extra-articular IBD
• • Intestinal - Abdominal pain, weight loss, diarrhea, and hematochezia
  • Skin - Pyoderma gangrenosum (ulcerative colitis), erythema nodosum (Crohn disease)
  • Oral - Aphthous ulcers (ulcerative colitis, Crohn disease)
  • Ocular - Acute anterior uveitis
  • Systemic low-grade fever, secondary amyloidosis (Crohn disease)
• Reactive arthritis
• • Typically an acute asymmetric oligoarthritis
  • Knees and/or ankles
  • Appears up to several weeks after the initial enteric infection (certain species of Yersinia, Salmonella, Shigella, Campylobacter, others)
• Intestinal bypass arthritis
• • This is a procedure introduced for morbid obesity (jejunocolostomy or jejunoileostomy).
  • Arthritis develops in 20-80% of patients 2-30 months after surgery and is chronic in 25% of cases.
  • Polyarthritis may occur.
  • Dermatitis is associated in 66-80% of cases.
  • The proposed mechanism is bacterial overgrowth in the bypassed bowel, which causes inflammation and synthesis of immune complexes.
  • Reversal of procedure produces permanent remission of symptoms.
• Celiac disease
• • Gluten-sensitive enteropathy
  • Arthritis uncommon
  • May precede diagnosis of celiac disease
  • Lumbar spine, hips, knees, shoulders
  • Usually symmetrical
  • Improves with gluten-free diet
• Collagenous colitis
• • Unknown cause
  • Linear deposition of collagen in the subepithelial layer of the colon
  • Watery diarrhea and colicky abdominal pain
  • Peripheral arthritis of hands and wrists, which may precede GI symptoms by years (10% of cases)
  • Arthritis improves with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Whipple disease
• • Rare, multisystemic
  • Caused by infection with Trophermyma whippleii
  • Most common in middle-aged men
  • Diarrhea, weight loss, and malabsorption
  • Migratory polyarthritis in as many as 90% of cases, which may precede GI symptoms by years
  • Sacroiliitis (occasional)
  • Diagnosis by small bowel biopsy
  • Symptoms improve with prolonged courses of antibiotics (eg, penicillin, tetracycline, erythromycin).

Physical

• Articular
• • Examine the joints for signs of inflammation, and note the pattern and symmetry of involvement.
  • Test the spine for range of motion, flexibility, and sacroiliac tenderness.
  • Look for periarticular soft tissue swelling and/or tenderness, especially at the heel (eg, enthesitis).
• Skin - Look for pyoderma gangrenosum (ulcerative colitis) and erythema nodosum (Crohn disease).
• Eyes - Look for acute anterior uveitis or conjunctivitis.

Causes

• Causes are unknown but are probably related to immune-mediated inflammation (see Pathophysiology).
• Sacroiliitis is associated with HLA-B27 (40%).
• Spondylitis associated is with HLA-B27 (60%).
• HLA-B27 is not associated with peripheral arthritis with the exception of reactive arthritis (80%).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Synovitis-acne-pustulosis-hyperostosis osteomyelitis (SAPHO) syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count indicates iron deficiency anemia, leukocytosis, and thrombocytosis.
• Erythrocyte sedimentation rate (ESR) is usually elevated.
• C-reactive protein (CRP) concentration is usually elevated.
• Synovial fluid analysis shows mild-to-moderate inflammatory fluid, mononuclear cell predominance (often), negative cultures, and no crystals.

Imaging Studies

• Radiographs
• • Anteroposterior pelvis or sacroiliac joints shows bilateral sacroiliitis, usually symmetric when associated with inflammatory bowel disease (IBD).
  • The spine shows syndesmophytes and apophyseal joint involvement. Bamboo spine is uncommon.
  • Erosive disease is uncommon in the peripheral joints, but bony spurs at the heel (enthesitis) may be observed.

Procedures

• Consider arthrocentesis if joint swelling or effusion is present, especially if concern about infection or crystal disease exists.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treatment of inflammatory bowel disease (IBD), including surgery, alleviates the pain of peripheral arthritis.
• Exercise caution when administering NSAIDs to patients with IBD because these agents may exacerbate GI symptoms.
• With peripheral symptoms, administer corticosteroids for intra-articular and systemic use. These agents are not effective for axial involvement.
• Sulfasalazine is most widely used.
• Methotrexate and azathioprine are not as well studied. Check HIV status before initiation of either drug.
• Tumor necrosis factor (TNF) antagonists (eg, etanercept, infliximab) may be effective for both IBD (especially Crohn disease) and arthritis (including axial involvement).

Surgical Care

Treatment of IBD, including surgery, alleviates the pain of peripheral arthritis.

Consultations

• Gastroenterologists
• Rheumatologists
• Ophthalmologists

Activity

Order physical therapy to maintain flexibility, range of motion, and upright posture, especially with axial involvement.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications used to manage the enteropathic arthropathies include NSAIDs, corticosteroids, and second-line agents such as sulfasalazine, azathioprine, and methotrexate. TNF antagonists may also be used.

The selection of a second-line agents should be left to an experienced rheumatologist or gastroenterologist who is familiar with these agents and who will monitor the patient.

Corticosteroid agents may be given orally, intravenously, intramuscularly, or intra-articularly for patients who are not adequately treated with NSAIDs alone. Consult with a specialist who is familiar with corticosteroids before prescribing them for specific uses.

Drug Category: Nonsteroidal anti-inflammatory drugs

Are the initial choice of medication to control pain and inflammation related to enteropathic arthropathies. The potential benefits of this class of drugs must be weighed against the possibility that they may exacerbate the underlying GI disease. Several NSAIDs effectively treat this condition, and administration of any one of them is appropriate. Newer cyclooxygenase-2 (COX-2) inhibitors may be less toxic to the GI tract.

Drug Name	Celecoxib (Celebrex)
Description	Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced by pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, incidence of GI toxicity, such as endoscopic peptic ulcers, bleeding ulcers, perforations, and obstructions, may be decreased when compared with nonselective NSAIDs. Seek lowest dose for each patient. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates pro-inflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T cells and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%). Has a sulfonamide chain and depends primarily on cytochrome P450 enzymes (a hepatic enzyme) for metabolism.
Adult Dose	100-200 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration of celecoxib with rifampin may decrease celecoxib plasma concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in third trimester of pregnancy; may cause increased blood pressure in patients with hypertension because of blunting effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; closely monitor renal function in patients with diabetes mellitus

Drug Category: Immunosuppressants

Second-line agents generally used for more aggressive disease inadequately controlled by NSAIDs and corticosteroids or as steroid-sparing agents. Because of their complex toxicities, second-line agents require administration and monitoring by an experienced physician/specialist.

Drug Name	Methotrexate (Rheumatrex, Folex PFS)
Description	Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation with peripheral disease.
Adult Dose	7.5-25 mg PO/SC qwk; gradually adjust dose to attain satisfactory response
Pediatric Dose	5-15 mg/m2/wk PO/SC qwk
Contraindications	Documented hypersensitivity; alcoholism; hepatic disease; documented immunodeficiency syndrome; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; indomethacin and phenylbutazone can increase methotrexate plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of methotrexate; may increase plasma levels of thiopurine
Pregnancy	X - Contraindicated in pregnancy
Precautions	Toxic effects on hematologic, GI, pulmonary, and neurological systems; caution in active infection, bone marrow suppression, underlying parenchymal lung disease; monitor CBC counts and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or with risk of elevated methotrexate levels, eg, dehydration); concomitant aspirin, NSAIDs, or low-dose steroids may be safely administered with methotrexate

Drug Category: Tumor necrosis factor antagonists

After NSAIDs and physical therapy, TNF inhibitors are uniquely recommended as the next line of treatment for inflammatory spinal disease in ankylosing spondylitis and the associated spondyloarthropathies. As do the second-line medications, these agents also reduce inflammatory signs and symptoms of peripheral disease.

Drug Name	Etanercept (Enbrel)
Description	A fusion receptor protein that blocks TNF activity. Inhibits TNF binding to cell surface receptors, decreasing inflammatory and immune responses. Indicated for ankylosing spondylitis, psoriatic arthritis, psoriasis, RA, and JRA.
Adult Dose	50 mg SC qwk or 25 mg twice weekly
Pediatric Dose	<4 years: Not established >4 years with active polyarticular-course JRA: 0.8 mg/kg/wk SC (up to a maximum of 50 mg/wk) Alternatively:<31 kg (68 lb): Single 0.8 mg/kg/wk SC injection 31-62 kg (68-136 lb): 0.8 mg/kg SC 2 times/wk either on same day or 3-4 d apart >63 kg (138 lb): Weekly dose of 50 mg SC
Contraindications	Documented hypersensitivity; sepsis; concurrent live vaccination; active infection; history of demyelinating disease (MS); noncompensated CHF; SLE
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Serious infections may develop and the therapy should be discontinued if they occur; possible adverse effects include injection-site pain, redness and swelling at injection site, and headaches; rare cases of lupuslike symptoms and heart failure have been reported (discontinue treatment if symptoms develop); caution advised in patients with history of malignancy

Drug Name	Adalimumab (Humira)
Description	Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis.
Adult Dose	40 mg SC q2wk; may be increased to qwk if clinical response inadequate
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active infection; history of demyelinating disease (MS); noncompensated CHF; SLE
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	TNF-alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; patients should be screened for previous TB exposure and treated appropriately; caution advised in patients with history of malignancy

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Arrange follow-up care with a rheumatologist and gastroenterologist.

Complications

• Mainly related to inflammatory bowel disease (IBD)
• Chronic arthritis, occasionally extra-articular involvement (uveitis)
• Secondary amyloidosis (mainly with Crohn disease)
• Toxicity of therapy

Prognosis

• Depends mainly on prognosis of underlying GI disease
• Severe spinal inflammatory disease (rare)

Patient Education

• Patients must be counseled to continue exercises at home.
• eMedicine has excellent patient education resources regarding inflammatory bowel disease available at http://www.emedicinehealth.com/articles/40954-1.asp.
• eMedicine has excellent patient education resources regarding Crohn disease available at http://www.emedicinehealth.com/collections/crohn.asp.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The main pitfall is administering medications without proper monitoring for potential toxicities.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Brophy S, Pavy S, Lewis P, et al. Inflammatory eye, skin, and bowel disease in spondyloarthritis: genetic, phenotypic, and environmental factors. J Rheumatol. Dec 2001;28(12):2667-73. [Medline].
• De Keyser F, Elewaut D, De Vos M, et al. Bowel inflammation and the spondyloarthropathies. Rheum Dis Clin North Am. Nov 1998;24(4):785-813, ix-x. [Medline].
• Fomberstein B, Yerra N, Pitchumoni CS. Rheumatological complications of GI disorders. Am J Gastroenterol. Jun 1996;91(6):1090-103. [Medline].
• Grigoryan M, Roemer FW, Mohr A, Genant HK. Imaging in spondyloarthropathies. Curr Rheumatol Rep. Apr 2004;6(2):102-9. [Medline].
• Guignard S, Gossec L, Salliot C, et al. Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis. Dec 2006;65(12):1631-4.
• Holden W, Orchard T, Wordsworth P. Enteropathic arthritis. Rheum Dis Clin North Am. Aug 2003;29(3):513-30, viii. [Medline].
• Katz JP, Lichtenstein GR. Rheumatologic manifestations of gastrointestinal diseases. Gastroenterol Clin North Am. Sep 1998;27(3):533-62, v. [Medline].
• Mielants H, Veys EM. Enteropathic Arthritis. In: Textbook of Rheumatology. 1997:1245-8.
• Reveille JD, Arnett FC. Spondyloarthritis: update on pathogenesis and management. Am J Med. Jun 2005;118(6):592-603. [Medline].
• Szpalski M, Gunzburg R. What are the advances for surgical therapy of inflammatory diseases of the spine?. Best Pract Res Clin Rheumatol. Jan 2002;16(1):141-54. [Medline].
• Wollheim FA. Enteropathic Arthritis. 1997;1006-8.
• Wollheim FA. Enteropathic arthritis: how do the joints talk with the gut?. Curr Opin Rheumatol. Jul 2001;13(4):305-9. [Medline].
• Wright V. Enteropathic arthritis. Cleve Clin J Med. Jan-Feb 1994;61(1):14-6; quiz 80-2. [Medline].

Article Last Updated: Jan 29, 2007