The enteropathic arthropathies are a group of rheumatologic conditions that share a link to gastrointestinal (GI) pathology. However, the term typically refers to the inflammatory spondyloarthropathies associated with inflammatory bowel disease (IBD) and to reactive arthritis caused by bacterial (eg, Shigella, Salmonella, Campylobacter, Yersinia, Clostridium difficile) and parasitic (eg, Strongyloides stercoralis, Giardia lamblia, Ascaris lumbricoides, Cryptosporidium species) infections. (See Etiology.)
Psoriatic arthritis, ankylosing spondylitis (AS), and undifferentiated spondyloarthropathy are the other conditions included in the inflammatory spondyloarthropathies that share common clinical and possible etiologic features. (See Etiology and Presentation.)
Other GI conditions with musculoskeletal manifestations include the following:
Patients with IBD-associated arthropathies present with axial arthritis (sacroiliitis and spondylitis), peripheral arthritis, and enthesitis. Extra-articular IBD manifestations include the following::
See Presentation for more detail.
Laboratory study results in patients with IBD include the following:
In select patients, additional lab studies, procedures, and imaging studies may be indicated. See Workup for more detail.
Treatment of IBD, including surgery, should always be the initial strategy to induce remission of peripheral arthritis. Medical therapy varies, depending in part on the Gi pathology. See Treatment, and Medication for more detail.
Complications of enteropathic arthropathy are primarily related to IBD and include the following:
Prognosis depends mainly on the prognosis of the underlying GI disease. Severe spinal inflammatory disease may occur, but this is rare.
The precise causes of the enteropathic arthropathies are unknown.[1] 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 membranes 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; other polymorphisms in non-HLA genes, involved in innate immune recognition and cytokine signaling pathways, are linked with spondyloarthropathy.[2] Such genes include tumor necrosis factor (TNF) and IL-23, which are also involved in IBD and psoriasis.[3, 4]
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; peripheral arthritis and/or spondylitis develop in approximately 5-20% of individuals with IBD.
The prevalence of IBD in ankylosing spondylitis (AS) is 5-10%, although subclinical GI inflammation has been found on colonoscopy in up to one third to two thirds of patients with AS. Axial involvement occurs more commonly in CD than in UC.
The incidence rates of spondyloarthropathy vary between 0.48 and 63 per 100,000 population, whereas the prevalence ranges from 0.01 to 2.5%.[3] 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[5] :
In an Italian study of 269 patients with IBD and joint pain, the prevalence of enteropathic-related spondyloarthritis was 50.5%. The spondyloarthritis was peripheral in 53% of cases, axial in 20.6%, and peripheral and axial in 26.4%.[6]
The incidence of IBD is higher in Whites, especially those of Ashkenazi Jewish descent, than in other racial groups. Spondyloarthropathy affects both sexes with equal frequency, but axial involvement is more frequent in men.[3]
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.[7] Whipple disease is far 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 can occur 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 White 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 White patients. African-American UC patients were older at diagnosis than White UC patients and had higher rates of arthralgias and ankylosing spondylitis/sacroiliitis.[8]
Axial arthritis (sacroiliitis and spondylitis) associated with inflammatory bowel disease (IBD) has the following characteristics:
Peripheral arthritis in IBD demonstrates the following characteristics:
Enthesitis affects the following parts of the body:
Extra-articular IBD demonstrates the following characteristics:
Reactive arthritis shows the following characteristics[10] :
Intestinal bypass arthritis is a complication of procedures for morbid obesity (jejunocolostomy or jejunoileostomy). The proposed mechanism is bacterial overgrowth in the bypassed bowel, which causes inflammation and synthesis of immune complexes. Intestinal bypass arthritis has the following traits:
Enteropathy associated with celiac sprue has the following characteristics:
Collagenous and lymphocytic colitis can be characterized as follows:
Whipple disease demonstrates the following characteristics:
The physical examination should include the following:
Laboratory study results in patients with inflammatory bowel disease (IBD) include the following:
Although more than 90% of patients with ankylosing spondylitis (AS) alone carry the HLA-B27 gene, only 30-70% of those with IBD-associated AS do so. However, nearly all IBD patients with a positive HLA-B27 antigen develop AS.
Anti–Saccharomyces cerevisiae antibodies (ASCA) have shown meaningful accuracy in the diagnosis of Crohn disease. However, studies of ASCA as a biomarker for IBD-related enteropathies have yielded conflicting results.[11]
The following procedures may be performed in selected cases:
Imaging study findings include the following:
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.[14] Use of more cyclooxygenase-2 (COX-2)–selective NSAIDs may reduce the risk of bowel flares.[15, 16] Corticosteroids may be administered 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.
Sulfasalazine (2-3g/day) has been shown to be effective for treatment of the peripheral arthropathy associated with IBD, but not axial disease.[17] While methotrexate can be useful to treat bowel activity in Crohn disease, its effect on joint disease with IBD is less certain.
Although not specifically indicated for 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).[18, 19, 20, 21, 22]
In a cohort of 30 patients with enteropathic arthropathy who had active articular and GI disease, or active axial articular inflammation, adalimumab led to sustained improvement in both articular and GI disease. Significant improvement was demonstrated at the earliest (6-month) assessment and maintained at the 12-month follow-up.[23]
Etanercept and golimumab are indicated to treat AS.[24] However, neither agent has been shown to be helpful with bowel disease, and cases of new-onset IBD have been reported with those agents.[25, 26]
The Janus kinase (JAK) inhibitors tofacitnib and upadacitinib may have a role in the treatment of enteropathic arthritis.[27] A review of tofacitinib theapy in seven patients with IBD and enteropathic arthritis reported that three of the patients achieved complete clinical remission.[28] Upadacitinib has shown efficacy in treating nonradiographic axial spondyloarthritis in two phase 3 trials.[27, 29]
Ustekinumab is a human monoclonal antibody directed against interleukin-12 (IL-12) and IL-23, thereby interfering with T-cell differentiation and activation and subsequent cytokine cascades. It is approved for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn disease, and moderate to severe ulcerative colitis. A literature search that identified 11 patients treated for IBD with enteropathic arthritis found that all patients achieved remission of IBD and nine of them achieved remission of enteropathic arthritis.[30]
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 no strong evidence of efficacy for treating existing arthritis.[31]
Total colectomy or removal of affected colon induces remission of the peripheral arthritis in ulcerative colitis, but not in Crohn disease. Surgery provides no benefit for axial involvement in IBD.
Consultations with the following specialists can be beneficial:
A gluten-free diet is used to treat celiac disease.
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.
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, and corticosteroids; however, NSAIDs may exacerbate gastrointestinal symptoms.
Second-line agents include 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 administered 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.
Clinical Context: 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.
Clinical Context: Meloxicam decreases the activity of COX, which, in turn, inhibits prostaglandin synthesis. These effects decrease the formation of inflammatory mediators.
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.[15, 16]
Clinical Context: 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).
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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
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.[22] 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.[25, 26]