Definition and Classification
The arthropathies of inflammatory bowel disease (IBD) may be defined as any noninfectious arthritis occurring before or during the course of Crohn’s disease (CD), indeterminate colitis (IC), or ulcerative colitis (UC). Arthritis is the most common extraintestinal complication of these disorders. There are two patterns of joint inflammation that can accompany IBD: peripheral polyarthritis and, less commonly, involvement of the sacroiliac (SI) joints and axial skeleton. Arthritis associated with IBD is not included in the American College of Rheumatology classification of childhood arthritis but is included in both the European League Against Rheumatism and the International League of Associations for Rheumatology criteria (see Chapter 15 ).
Epidemiology
Incidence and Prevalence
Arthropathy has been reported in 7% to 21% of children with IBD ( Table 21-1 ). Passo and colleagues found arthritis in 9% of 44 children with UC and in 15.5% of 58 children with CD. Arthralgia was much more common than arthritis in children, occurring in 32% of those with UC and 22% of those with CD. Differentiation of UC from CD is not always easy, and differences in the reported frequencies of arthritis in each may reflect the accuracy of diagnosis in these types of IBD. A recent study showed much lower frequencies of 1% in CD and 2% in UC. These lower frequencies may reflect the current biological therapies for IBD. However, a recent study of adults with spondyloarthropathy showed a fourfold cumulative incidence over 30 years. A Swedish study reported a stable and unchanged rate of UC and CD during the past 30 years. Regional differences may also exist, as shown by a recent study of northeastern Slovenia children, which demonstrated an increased incidence.
| AUTHOR AND YEAR | DISEASE | NUMBER OF PATIENTS | NUMBER WITH ARTHRITIS | % WITH ARTHRITIS |
|---|---|---|---|---|
| Farmer & Michener, 1979 | CD | 522 | 39 | 7 |
| Hamilton et al., 1979 | CD | 58 | 11 | 19 |
| Burbige et al., 1975 | CD | 58 | 6 | 10 |
| Lindsley & Schaller, 1974 | CD | 50 | 5 | 10 |
| Passo et al., 1986 | CD | 58 | 9 | 15 |
| Lindsley & Schaller, 1974 | UC | 86 | 18 | 21 |
| Hamilton et al., 1979 | UC | 87 | 8 | 9 |
| Passo et al., 1986 | UC | 44 | 4 | 9 |
Musculoskeletal pain in children with IBD may be related to other causes including bone fractures secondary to osteoporosis (disease and glucocorticoid induced), secondary hypertrophic osteoarthropathy and noninflammatory causes such as hypermobility.
Age at Onset and Sex Ratio
In a study of 136 patients with onset of IBD before the age of 20 years, age at onset did not differ in patients who had arthritis or those who did not. The ratios of boys to girls in those with and without peripheral arthritis were almost identical, although the five children who developed spondylitis were boys.
Etiology and Pathogenesis
The causes of both IBD and its accompanying arthritis are obscure. The possible roles of gastrointestinal (GI) infections or allergic reactions to foods absorbed across an inflamed mucosa remain speculative. The SI arthritis probably shares its etiology with that of ankylosing spondylitis (AS), and studies of associated enteric species and immunity to them may be relevant. Peripheral arthropathy may involve entirely different immunoinflammatory mechanisms (immune complexes), however, and it is clinically more closely related to the activity of the intestinal disease. Picco and colleagues found increased gut permeability in all subtypes of juvenile arthritis using the lactulose/mannitol test, but IBD patients with spondyloarthropathy had the highest levels. Reciprocally, subclinical gut inflammation in the majority of patients with seronegative spondyloarthropathy has been described.
Genetic Background
There is a pronounced tendency for familial, racial, and ethnic clustering of UC and CD. Hamilton and associates reported that approximately 15% of children with UC and 8% of those with CD had first-degree relatives with IBD. Both diseases are more common in children of Jewish descent, who comprised 21% of the IBD population but only 2% of the general population in one study. Published reports support the view that genes of the major histocompatibility complex are important in determining susceptibility to UC in particular, but inherited predispositions are undoubtedly polygenic. In Japanese and Jewish patients, but not in other ethnic groups, the human leukocyte antigen (HLA) DRB1*1502 (DR2) allele is increased in frequency. It is estimated that SI arthritis is at least 30 times more common in patients with IBD than in the general population, a fact that reflects the high frequency of HLA-B27 in such patients. The peripheral polyarthritis accompanying IBD has no known HLA association.
Studies have identified NOD2/Card 15 variants that are associated with CD in both children and adults, particularly in those with ileal disease and lower weight at time of diagnosis. However, no association has been reported with articular involvement or AS. Recently, genome-wide associations between the IL-23R gene and CD have been shown in the pediatric age group. In a separate study, Leshinsky and colleagues showed that haplotypes without the common disease-associated mutations in the NOD2/Card 15 and Toll-like receptor (TLR) genes are associated with age at onset of the IBD. Epigenetic factors may also play a role, adding complexity to understanding IBD.
Clinical Manifestations
Arthritis and Enthesitis
Two distinct patterns of joint disease occur. The more common one in patients with IBD is peripheral arthritis. Lower extremity joints, especially ankles and knees, are most frequently affected, although upper extremity joints, occasionally also including small joints of the hand and the temporomandibular joints, may be involved. Lindsley and Schaller reported that four or fewer joints were affected at onset or during the course of the illness in 11 of 18 children; in five children, five to nine joints were affected; in only two children were more than 10 joints affected, including small joints of the hand. Episodes of acute peripheral arthritis are usually brief, lasting 1 or 2 weeks (occasionally longer), and tend to recur. In some children, arthritis may last for several months, particularly if the GI disease is active. If joint inflammation persists for months, permanent functional loss or joint damage is unusual. However, erosive disease has been described in young adults with juvenile-onset disease. Whereas the SI arthritis bears little relation to the activity of the gut disease, the peripheral arthritis may reflect the activity and course of the GI inflammation. A clinical flare in a child’s arthritis was associated with increased musculoskeletal symptoms in 33% of patients with IBD, and an additional 7% had increased symptoms just prior to an IBD flare.
In adult patients, additional clinical phenotypes have been described in the peripheral arthropathy group (non–HLA-B27 associated): type I, which is similar to the previously described disease and is frequently associated with uveitis and erythema nodosum (EN), and type II, which is a symmetrical polyarthritis that is independent of IBD activity, of longer duration, and rarely associated with EN.
SI arthritis, which may be asymptomatic but often is characterized by pain and stiffness in the lower back, buttocks, or thighs, is a much less common complication of IBD than is polyarthritis. It is sometimes accompanied by enthesitis identical to that occurring in other forms of spondyloarthritis. SI arthritis may also be associated with chronic symmetrical oligoarthritis predominantly affecting the joints of the lower limbs: 5% to 10% of established cases of AS in adults are associated with chronic IBD. Also, an additional category of asymptomatic SI disease (18%) occurs in patients with IBD, most often in those with greater disease duration. This may apply to the pediatric age group as well.
Hypertrophic osteoarthropathy is a relatively rare, very painful musculoskeletal complication of IBD. The pain occurs symmetrically in the limbs (rather than the joints) and may be accompanied by increased sweating and purple discoloration of the affected limbs.
Osteoporosis can be a significant component of articular disease or, rarely, a presenting manifestation when associated with fractures. Patients treated with corticosteroids are especially at high risk. In addition they may develop avascular necrosis, most commonly involving the femoral head. However, patients who were not treated with steroids have about a 12% risk of developing osteoporosis as well. Chronic recurrent multifocal osteomyelitis has been associated with IBD in some patients.
Infantile-onset IBD is a particularly severe form of IBD that appears to be an autoinflammatory disease. It results from mutations in interleukin (IL)-10 or its receptor and has been associated with treatment-resistant colitis, perianal fistula formation, folliculitis, and arthritis. Due to the severe morbidity and mortality, hematopoietic stem-cell transplantation should be considered early in the course of disease and may be curative.
Gastrointestinal Disease and Extraarticular Manifestations
Gastrointestinal Disease
Cramping abdominal pain, often with localized or generalized tenderness, anorexia, and diarrhea, sometimes occurring at night, is characteristic of IBD. Differentiation of UC and CD on the basis of GI symptoms alone is unreliable, although bloody diarrhea is highly suggestive of UC, whereas perianal skin tags and fistulae are typical of CD ( Table 21-2 ). More recent terminology adds the category of IC. Many of these patients will meet criteria for a revised diagnosis, usually UC, within 2 years.
| SYMPTOM OR SIGN | ULCERATIVE COLITIS | CROHN’S DISEASE |
|---|---|---|
| Diarrhea | ++++ | ++ |
| Hematochezia | ++ | + |
| Abdominal pain | ++ | +++ |
| Weight loss | ++ | ++++ |
| Fever | + | +++ |
| Vomiting | + | ++ |
| Perianal disease | + | +++ |
| Finger clubbing | + | ++ |
| Erythema nodosum | + | + |
| Oral lesions | + | + |
| Uveitis | (+) | (+) |
| Pyoderma gangrenosum | (+) | (+) |
GI symptoms usually precede joint disease by months or years. However, occasionally both systems are affected simultaneously, or joint symptoms can precede intestinal disease. In the latter case, the arthritis resembles that of juvenile idiopathic arthritis (JIA), juvenile AS, or the seronegative enthesopathy and arthropathy syndrome, with a course punctuated by intermittent abdominal pain that may be incorrectly ascribed to the effects of antiinflammatory drugs. Low-grade diarrhea, anemia, unexplained fever, weight loss, growth retardation out of proportion to the extent and activity of the joint disease, or a family history of IBD should alert the physician to the possibility of occult IBD. Mucocutaneous lesions (EN, aphthous stomatitis, pyoderma gangrenosum) seem to be more common in children who have arthritis (especially peripheral arthritis) as a complication of IBD, although this association is not supported by some clinical studies.
Although there are no clear-cut correlations between the extent of GI inflammation and arthritis, most reports support the view that there is a higher frequency of arthritis in children with extensive, as opposed to segmental, bowel disease. Patients with arthritis usually have active gut disease, although the onset of arthritis is not necessarily related to obvious flare-ups in GI tract inflammation. The occurrence of first-time joint symptoms after proctocolectomy for UC has been associated with the development of “pouchitis.”
Erythema Nodosum
The lesions of EN (nodular panniculitis) occur most commonly in the subcutaneous fat of the pretibial region ( Fig. 21-1 ) as erythematous, painful, slightly elevated lesions, 1 to 2 cm in diameter, which erupt in groups and reappear sequentially in new areas after several days. The nodules tend to persist for several weeks and recur in crops for several months. As they heal, they frequently leave pigmented areas that persist for many months. Articular pain and synovitis accompany each exacerbation in approximately two thirds of instances. Erythema nodosum is more likely associated with peripheral arthritis that is of short duration and involving few joints.
