Enteropathic Arthropathies

The precise causes of the 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 synovial membrane), 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 synovial membrane and other target organs.

Of particular interest is the strong association (80%) between reactive arthritis and human leukocyte antigen (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.

Sacroiliitis and spondylitis are associated with HLA-B27 (40% and 60%, respectively). HLA-B27 is not associated with peripheral arthritis, with the exception of reactive arthritis.

HLA accounts only for 40% of the genetic risk for spondyloarthropathy (SpA); other polymorphisms in non-HLA genes, involved in innate immune recognition and cytokine signaling pathways, are linked with SpA.[1] Such genes include tumor necrosis factor (TNF) and IL-23, which are shared with IBD and psoriasis.[2]

Occurrence in the United States

The prevalence of ulcerative colitis (UC) and Crohn disease (CD) is estimated to be 0.05-0.1%, with an increasing incidence for each in the last few decades. While extraintestinal manifestations affecting the skin, eyes, and joints, among other systems, develop in about one quarter of patients with IBD, musculoskeletal manifestations are the most common, with approximately 5-20% of individuals with IBD developing peripheral arthritis and/or spondylitis.

The prevalence of IBD in ankylosing spondylitis (AS) is 5-10%, although up to one third to two thirds of patients with AS have been found through colonoscopy to have subclinical inflammation. Axial involvement occurs more commonly in CD than in UC.

International occurrence

The incidence rates of spondyloarthropathy (SpA) vary between 0.48 and 63 per 100,000 population, whereas the prevalence ranges from 0.01 to 2.5%.[2]  The incidence and prevalence rates for UC and CD in northern and western Europe are similar to those in the United States, but rates are lower in other regions of the world.

In a systematic review, Ajene and colleagues estimated that the weighted mean global incidence of reactive arthritis with cases of each of the following infections was as follows[3] :

• Campylobacter - Nine per 1000

• Salmonella - 12 per 1000

• Shigella - 12 per 1000

In an Italian study of 269 patients with IBD and joint pain, the prevalence of enteropathic-related spondyloarthritis (ESpA) was 50.5%. ESpA patients showed a peripheral involvement in 53% of cases, axial in 20.6% and peripheral and axial in 26.4% of cases.[4]

Race-, sex-, and age-related demographics

The incidence of IBD is higher in whites, especially those of Ashkenazi Jewish descent, than in other racial groups. SpA affects both sexes with equal frequency, but axial involvement is more frequent in men.[2]

The peripheral arthritis of UC or CD does not have a sex predilection. IBD-associated AS occurs equally in men and women, while idiopathic AS is 2.5 times more common in men.[5] Whipple disease is more common in men, with a male-to-female ratio of 9:1.

IBD is most common in persons aged 15-35 years. Axial involvement in IBD occurs at any age, in contrast to idiopathic AS, which affects men younger than 40 years.

Sofia and colleagues found significant differences in extraintestinal manifestations and disease characteristics between African-American and Caucasian IBD patients in a cross-sectional study of 1235 CD patients and 541 UC patients. African-American CD patients had higher rates of IBD-related arthralgias and surgery and less ileal involvement than Caucasian patients. African-American UC patients were older at diagnosis than Caucasian UC patients and had higher rates of arthralgias and ankylosing spondylitis/sacroiliitis.[6]

IBD-associated arthropathies

Axial arthritis (sacroiliitis and spondylitis) in inflammatory bowel disease (IBD) has the following characteristics:

• Insidious onset of low back pain, especially in younger persons
• Morning stiffness
• Exacerbated by prolonged sitting or standing
• Improved by moderate activity
• More common in Crohn disease (CD) than in ulcerative colitis (UC) ^[5]
• Independent of GI symptoms

Peripheral arthritis in IBD demonstrates the following characteristics:

• Nondeforming and nonerosive
• More common in CD with colonic involvement than in UC
• May precede intestinal involvement, but usually concomitant or subsequent to bowel disease, as late as 10 years following the diagnosis
• Type 1 (pauciarticular [< 5 joints]) ^[7] - Acute, self-limiting attacks, lasting less than 10 weeks; asymmetrical and affecting large joints, such as the knees, hips and shoulders; strong correlation to IBD activity, most frequently with extensive UC or colonic involvement in CD; associated with other extraintestinal manifestations of IBD
• Type 2 (polyarticular [>5 joints]) ^[7] - Chronic, lasting months to years; more likely symmetrical, affecting small joints of the hands; independent of bowel activity

Enthesitis affects the following parts of the body:

• Heel - Insertion of the Achilles tendon and plantar fascia
• Knee - Tibial tuberosity, patella
• Others - Buttocks, foot

Extra-articular IBD demonstrates the following characteristics:

• Intestinal - Abdominal pain, weight loss, diarrhea, and hematochezia
• Skin - Pyoderma gangrenosum (in UC), erythema nodosum (in CD)
• Oral - Aphthous ulcers (in UC, CD)
• Ocular - Uveitis, anterior, nongranulomatous
• Systemic low-grade fever, secondary amyloidosis (in CD)

Reactive arthritis shows the following characteristics[8] :

• Typically an acute, asymmetrical oligoarthritis
• Knees and/or ankles
• Appears up to several weeks after the initial enteric infection (certain species of Yersinia, Salmonella, Shigella, Campylobacter, among others)
• Urethritis in men
• Cervicitis in women
• Eye inflammation (usually conjunctivitis or uveitis)

Intestinal bypass arthritis demonstrates the following traits:

• Triggered following a procedure for morbid obesity (jejunocolostomy or jejunoileostomy) - The proposed mechanism is bacterial overgrowth in the bypassed bowel, which causes inflammation and synthesis of immune complexes
• Arthritis - Develops in 20-80% of patients 2-30 months after surgery and is chronic in 25% of cases
• Polyarthritis - May occur
• Dermatitis - Associated in 66-80% of cases
• Reversal of procedure produces permanent remission of symptoms

Celiac sprue demonstrates the following characteristics:

• Gluten-sensitive enteropathy
• Arthritis uncommon
• May precede diagnosis of celiac disease
• Lumbar spine, hips, knees, shoulders
• Usually symmetrical
• Improves with gluten-free diet

Collagenous and lymphocytic colitis can be characterized as follows:

• 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 - May precede GI symptoms by years (10% of cases)
• Arthritis improved by nonsteroidal anti-inflammatory drugs (NSAIDs)

Whipple disease demonstrates the following characteristics:

• Rare, multisystemic
• Caused by infection with Tropheryma 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 via small-bowel biopsy
• Symptoms improved by prolonged courses of antibiotics - Eg, penicillin, tetracycline, erythromycin

The physical examination should include the following:

• Articular – (1) Examine the joints for signs of inflammation and note the pattern and symmetry of involvement; (2) test the spine for range of motion, flexibility, and sacroiliac tenderness; (3) look for periarticular soft-tissue swelling and/or tenderness, especially at the heel (eg, enthesitis)
• Skin - Look for pyoderma gangrenosum (ulcerative colitis [UC]) and erythema nodosum (Crohn disease [CD])
• Eyes - Look for acute anterior uveitis or conjunctivitis

Lab studies reveal the following:

• Complete blood count (CBC) - May reveal iron deficiency anemia, leukocytosis, and thrombocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration - Usually elevated
• Rheumatoid factor (RF) - Absent
• Synovial fluid analysis - Shows mild to moderate inflammatory fluid, mononuclear cell predominance (often), negative cultures, and no crystals
• Antiendomysial and antitransglutaminase antibodies - Usually elevated in celiac disease

Although more than 90% of patients with ankylosing spondylitis (AS) alone carry the HLA-B27 gene, it is found in only 30-70% of those with IBD-associated AS. However, nearly all IBD patients with a positive HLA-B27 antigen develop AS.

Anti–Saccharomyces cerevisiae antibodies (ASCA) may be helpful in the diagnosis of inflammatory bowel disease (IBD).[9]

Procedures

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

Consider small-bowel biopsy upon clinical suspicion for Whipple disease or for celiac disease when serology findings are equivocal.

Endoscopy and biopsy may reveal subclinical bowel inflammation in patients with spondyloarthropathy.[10]

Radiography

The anteroposterior pelvis or the sacroiliac joints show bilateral sacroiliitis, usually symmetrical 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.[11]

MRI

Magnetic resonance imaging (MRI) is useful for early detection of spinal and sacroiliac lesions characteristic of the spondyloarthropathies.

Bone scintigraphy

This study may show increased uptake in a typical pauciarticular, asymmetrical joint pattern.

Ultrasonography

Ultrasonography may be useful in identifying early soft-tissue pathology, such as tenosynovitis.

Treatment of inflammatory bowel disease (IBD), including surgery, should always be the initial strategy to induce remission of peripheral arthritis.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are usually recommended as first-line therapy for spondyloarthropathies, in patients with IBD, these agents may exacerbate gastrointestinal (GI) symptoms.[12] Selection of more cyclooxygenase-2 (COX-2)–selective NSAIDs may reduce the risk of bowel flares.[13, 14] Corticosteroids may be used systemically or by local injection.

Whipple disease is treated with long-term tetracycline antibiotics. Celiac disease is treated with a gluten-free diet, although response is not always complete.

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) 

Sulfasalazine (2-3g/day) has been shown to be effective for treatment of the peripheral arthropathy associated with IBD, but not axial disease.[15] While methotrexate can be useful to treat bowel activity in Crohn disease (CD), its effect on joint disease with IBD is less certain.

Biologic disease-modifying antirheumatic drugs (bDMARDs)

Although not specifically indicated for an enteropathic arthropathy, the tumor necrosis factor (TNF) antagonists infliximab and adalimumab are indicated to treat ankylosing spondylitis (AS) and IBD, and may be effective for IBD spondyloarthropathy (including axial involvement).[16, 17, 18, 19, 20]

In a cohort of 30 patients with enteropathic arthropathy affected by active articular and GI disease, or axial active articular inflammation, adalimumab led to sustained improvement of both articular and GI disease activities. Significant improvement was achieved at the earliest (6-mo) assessment and maintained at the 12-mo follow-up.[21]  

Etanercept and golimumab are indicated to treat AS,[22] but neither has been shown to be helpful with bowel disease, and there have been reports of new-onset IBD with these 2 agents.[23]  

Vedolizumab is approved for treatment of moderate to severe Crohn disease. A systematic review found evidence that it may be effective in preventing the onset of enteropathic anthropathy but there was no strong evidence for the efficacy of vedolizumab for treating existing arthritis.[24]

Surgical care

Total colectomy or removal of affected colon induces remission of the peripheral arthritis in ulcerative colitis (UC), but not in Crohn disease. Surgery provides no benefit for axial involvement in IBD.

Consultations

Consultations with the following specialists can be beneficial:

• Gastroenterologist
• Rheumatologist
• Ophthalmologist

Diet

A gluten-free diet is used to treat celiac disease.

Activity

Order physical therapy to maintain flexibility, range of motion, and upright posture, especially with axial involvement. Patients must be counseled to continue exercises at home.

Follow-up

Arrange follow-up care with a rheumatologist and gastroenterologist.

If both bowel and joint disease are active, then agents that target both should be preferred choices. Medications used to manage the enteropathic arthropathies include nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, corticosteroids, second-line agents such as sulfasalazine, and tumor necrosis factor (TNF) antagonists.

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

Corticosteroids may be given orally, intravenously, intramuscularly, or intra-articularly to patients for whom NSAIDs alone are not adequate. Consult with a specialist who is familiar with corticosteroids before prescribing them for specific uses.

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) 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. Cyclooxygenase-2 (COX-2) inhibitors may be less toxic to the GI tract.[13, 14]

Celecoxib (Celebrex)

Celecoxib primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, being 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 the lowest dose for each patient. Celecoxib has a sulfonamide chain and depends primarily on cytochrome P450 enzymes (which are hepatic enzymes) for metabolism.

Meloxicam (Mobic)

Meloxicam decreases the activity of COX, which, in turn, inhibits prostaglandin synthesis. These effects decrease the formation of inflammatory mediators.

Class Summary

A second-line agent may be considered for articular disease inadequately controlled by nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids or it may be considered as a steroid-sparing agent. Because of their complex toxicities, second-line agents require administration and monitoring by an experienced medical specialist.

Sulfasalazine (Azulfidine)

Sulfasalazine has been shown to reduce inflammatory symptoms of ankylosing spondylitis (AS) in controlled studies. The most common toxicities include nausea, dyspepsia, vomiting, diarrhea, and hypersensitivity reactions (rash).

Class Summary

After nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy, tumor necrosis factor (TNF) inhibitors are uniquely recommended as the next line of treatment for inflammatory spinal disease and enthesopathy, although they can be effective for all aspects of articular disease.[20] Specific agents may vary in their effectiveness against bowel disease activity; furthermore, new-onset inflammatory bowel disease (IBD) has been described in patients with ankylosing spondylitis (AS) who were treated with TNF antagonists.[23, 25]

Infliximab (Remicade)

Infliximab is a chimeric monoclonal antibody. It neutralizes the cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. Infliximab has GI indications for fistulous Crohn disease (CD) and ulcerative colitis (UC) and rheumatologic indications for rheumatoid arthritis, psoriatic arthritis (and psoriasis), and AS. It has been shown to be effective for extra-articular manifestations, such as refractory uveitis and pyoderma gangrenosum.

Etanercept (Enbrel)

Etanercept is a fusion receptor protein that blocks TNF activity. It inhibits the binding of TNF to cell surface receptors, decreasing inflammatory and immune responses. Etanercept is indicated for AS, psoriatic arthritis, psoriasis, rheumatoid arthritis, and juvenile rheumatoid arthritis.

Adalimumab (Humira)

Adalimumab is a recombinant human immunoglobulin-G1 (IgG1) monoclonal antibody specific for human TNF. It is indicated for moderate to severe rheumatoid arthritis, psoriatic arthritis, AS, and CD.

Golimumab (Simponi)

Golimumab is a TNF-alpha inhibitor. It decreases inflammation caused by the overproduction of TNF associated with chronic inflammatory diseases. Golimumab is indicated for moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active AS. It is available as the 50 mg/0.5 mL, single-dose Simponi SmartJect (Autoinjector) or as a prefilled syringe.