Muscoloskeletal manifestations in inflammatory bowel disease

This mini-review was prepared from a presentation made at the World Congress of Gastroenterology, Vienna, Austria, September 6 to 11, 1998 1Unit of Gastroenterology, and 2Unit of Rheumatology, Arcispedale S Maria Nuova, Reggio Emilia, Italy; 3Department of Gastroenterology University Hospital Maastricht, The Netherlands Correspondence and reprints: Dr Giovanni Fornaciari, Medicina III e Gastroenterologia, Arcispedale S Maria Nuova, viale Umberto I, 50, 42100, Reggio Emilia, Italy. Telephone +39-0522-296687, fax +39-0522-296604, e-mail fornaciari.giovanni@asmn.re.it Received for publication November 28, 1999. Accepted November 30, 1999 G Fornaciari, C Salvarani, M Beltrami, P Macchioni, RW Stockbrügger, MG Russel. Musculoskeletal manifestations in inflammatory bowel disease. Can J Gastroenterol 2001;15(6):399-403. Muscoloskeletal manifestations are the most common extraintestinal complications of inflammatory bowel disease. Wide ranges in prevalence have been reported, depending on the criteria used to define spondylarthropathy. In 1991, the European Spondylarthropathy Study Group developed classification criteria that included previously neglected cases of undifferentiated spondylarthropathies, which had been ignored in most of the oldest epidemiological studies on inflammatory bowel disease. The spectrum of muscoloskeletal manifestations in inflammatory bowel disease patients includes all of the clinical features of spondylarthropathies: peripheral arthritis, inflammatory spinal pain, dactylitis, enthesitis (Achilles tendinitis and plantar fasciitis), buttock pain and anterior chest wall pain. Radiological evidence of sacroiliitis is common but not obligatory. The articular manifestations begin either concomitantly or subsequent to the bowel disease; however, the onset of spinal disease often precedes the diagnosis of inflammatory bowel disease. The prevalence of the different muscoloskeletal manifestations is similar in ulcerative colitis and Crohns disease. Symptoms usually disappear after proctocolectomy. The pathogenetic mechanisms that produce the muscoloskeletal manifestations in inflammatory bowel disease are unclear. Several arguments favour an important role of the intestinal mucosa in the development of spondylarthropathy. The natural history is characterized by periods of flares and remission; therefore, the efficacy of treatment is difficult to establish. Most patients respond to rest, physical therapy and nonsteroidal anti-inflammatory drugs, but these drugs may activate bowel disease. Sulphasalazine may be recommended in some patients. There is no indication for the systemic use of steroids.

T he occurrence of extraintestinal manifestations in patients with inflammatory bowel disease (IBD) has been well recognized for many years; these manifestations are listed in Table 1.Muscoloskeletal disorders are the most common extraintestinal findings in both ulcerative colitis (UC) and Crohn's disease (CD).In 1930, Bargen (1) described, for the first time, arthritis complicating UC; in the following years, it was commonly believed that arthritis in patients with IBD was rheumatoid arthritis.After the introduction of the Rose-Waaler agglutination test, which helped to distinguish coincidental cases of rheumatoid arthritis, the term 'colitic arthritis' was proposed, and the first attempt was made to categorize the rheumatic complaints (2).Colitic arthritis was defined as recurrent, brief attacks of synovitis, usually asymmetrical and associated with exacerbation of intestinal symptoms, without progression to deformity.In 1976, Wright and Moll (3) proposed the inclusion of enteropathic arthropathy among the seronegative spondylarthropathies. UC and CD are not the only gastrointestinal disorders associated with rheumatological complications.As reported in Table 2, 'enteropathic arthropathy' is described in several other conditions as well.

DEFINITIONS
Arthritis associated with IBD belongs to the category of spondylarthropathies, which consists of several disorders (reactive arthritis, psoriatic arthritis, and ankylosing spondylitis in its juvenile and adult form).Two clinical patterns can occur: peripheral arthritis or axial disease.However, the clinical spectrum of spondylarthropathies is wider and includes other manifestations (Table 3).In 1991, the European Spondylarthropathy Study Group (ESSG) proposed new classification criteria (Table 4) that were easy to apply in clinical practice, with the aim of including previously neglected cases of undifferentiated disease (4).These criteria resulted in a sensitivity of 86% and a specificity of 87% in the diagnosis of spondylarthopathies (4).These criteria are superior to the New York modified criteria (Table 5) (5) for the diagnosis of ankylosing spondylitis; the New York modified criteria have a low sensitivity and are inadequate in describing the full clinical spectrum of spondylarthropathies (in particular, the undifferentiated forms).
In daily practice, a presumptive diagnosis of spondylarthropathies is usually supported by radiological evidence of sacroiliitis.However, the presence of sacroiliitis is a very frequent, but not necessarily early and obligate, manifestation of these conditions.Some clinical characteristics are common to all forms of spondylarthropathies: • Peripheral arthritis predominantly located in the lower limb (asymmetric) • Tendency to sacroiliitis on x-ray   reported to be 11% to 20% (6,7).Ankylosing spondylitis has been diagnosed in 3% to 6% of patients with IBD; however, radiological evidence of sacroiliitis has been reported much more frequently (14% to 20%).In UC, a higher frequency of axial involvement (43%) was reported by Scarpa et al (8).Of the patients studied by these authors, 25% satisfied the modified New York criteria for ankylosing spondylitis (5).In 14 (18%) additional patients, inflammatory spinal pain was the only rheumatological manifestation.In an inception cohort of newly diagnosed IBD patients (9), 30.7% had at least one muscoloskeletal manifestation, 18.5% satisfied the ESSG criteria for spondylarthropathy (4), and 2.6% satisfied only the criteria for ankylosing spondylitis (5; unpublished data).The results of these two studies show that the clinical spectrum of rheumatological manifestations is broader than that defined by spondylarthropathy criteria and that the prevalence of rheumatological findings in IBD may be higher than reported in the oldest studies.
There are no major differences between UC and CD in the occurrence of spondylarthropathy; it seems to be more prevalent in UC patients with chronic intermittent or continuous symptoms (10), and in ulcerative pancolitis (7).The presence of peripheral arthritis is frequently associated with other extraintestinal manifestations, such as erythema nodosum and anterior uveitis (11,12).There is a strong association between peripheral arthritis and colonic localization of CD (12,13).A recent prospective study reported that peripheral arthritis occurred more frequently in patients with CD than in patients with UC (20.2% compared with 11.0%, respectively) (12).

CLINICAL COURSE
Although in most cases intestinal symptoms coincide with or precede the articular manifestations, spinal involvement can precede the diagnosis of IBD.The onset of peripheral arthritis is often abrupt, with spontaneous pain, erythema, hyperemia and effusion.The joints of the lower limb are most commonly affected, but elbows, metacarpophalangeal joints and shoulders can be involved as well (14).The peripheral arthritis is frequently self-limiting and nondeforming, but may become erosive and chronic in a limited number of patients (15).A new classification of peripheral arthritis has been proposed according to presentation, joint involvement and course of the disease (Table 6) (16).Clinically, type 1 arthropathy was similar to reactive (infectious) arthritis, with self-limiting attacks of oligoarthritis, while type 2 arthropathy was reported to run a more severe course independent of IBD activity.This classification is helpful to divide these syndromes into subgroups, but its usefulness has to be confirmed in clinical practice.
Axial involvement in IBD patients includes radiological evidence of sacroiliitis, ankylosing spondylitis and undifferentiated spondylarthropathies. Usually, there is no association between the severity of bowel disease and the course of spinal involvement.The association with other extraintestinal manifestations is less evident than in peripheral arthritis.Symptoms at onset are similar to idiopathic ankylosing spondylitis: the patient complains of low back pain with morning stiffness, and alternating buttock or chest pain.The back pain is usually exacerbated by prolonged sitting or standing, or after night rest.
Usually, arthritic symptoms disappear after proctocolectomy (13); however, joint symptoms may reappear after restorative proctocolectomy (17,18).The relationship between the inflammation of reconstructed ileal pouch (pouchitis) and the occurrence of arthropathy is unclear.A recent well planned prospective case-control study showed no correlation between occurrence of pouchitis and occurrence of arthropathy in UC patients (18).

DIAGNOSIS
The diagnosis of arthropathy in IBD patients is mainly based on history and clinical evaluation; the importance of clinical evaluation performed by a rheumatologist has been stressed previously (8).For the detection of sacroiliitis, conventional radiography, bone scanning, computed tomography and magnetic resonance imaging are used (14,19).In clinical practice, the diagnosis of sacroiliitis is accurately assessed by a simple pelvic x-ray (20).Sacroiliac joint involvement is graded according to the New York criteria (21).
The diagnosis of peripheral arthritis is clinical.The evidence of joint swelling or effusion is diagnostic.Radiographs of the involved joints usually show no abnormalities.Erosive disease of the hip, as well as metacarpophalangeal and metatarsophalangeal joints, has been reported (22,23).Synovial fluid analysis and histology of synovial tissue usually show a nonspecific inflammation (11).

PATHOGENESIS
The pathogenesis of peripheral arthritis is unclear; the role of bacterial antigens, such as those in reactive arthritis and arthritis following intestinal bypass surgery, seems to be important (26).Several studies have focused on an important 'gut-synovium axis' (11,(26)(27)(28).Furthermore, a crossreactivity between gut bacteria and cartilage in patients with CD has been demonstrated (29).
Genetic predisposition may not be as important in patients with IBD who have spondylitis as in patients without IBD who have spondylitis, because these latter patients have much stronger association with HLA-B27 (8,24,25).The altered gut permeability could be a key factor in the development of spondylarthropathy.
The relationship between seronegative spondylarthropathy and IBD is very interesting.A non-negligible number of patients may be affected by rheumatological symptoms many years before the diagnosis of IBD (16).Recent studies have suggested that 6% of patients with spondylarthropathy will develop IBD.However, patients with negative gut histology at the time of arthritis will never develop IBD (30,31).In one study, colonoscopy was performed in 118 patients with various inflammatory and noninflammatory joint conditions.Endoscopic lesions were reported in 44% of patients with spondylarthropathy (32), and 26% of patients had histology consistent with CD.According to these data, it can be hypothesized that gut and joint inflammation are coincidental, and that they can be triggered by the same agent.The sharing of certain peptides by colonic epithelium, ciliary processes of the eye and chondrocytes of the joints is a possible pathogenic mechanism (33) that could also explain the association of arthritis with other extraintestinal manifestations.
The inflammatory lesions in pouchitis are different from those present in UC, because pouchitis usually responds to antibiotic treatment (34).Studies exploring the relationship between arthropathy and pouchitis may be very useful in clarifying the pathogenic mechanisms of joint involvement in pouchitis.

TREATMENT
The natural history of muscoloskeletal manifestations in IBD is characterized by alternating periods of flares and spontaneous remission; therefore, the usefulness of treatment is difficult to assess.The aims of therapy are to reduce inflammation, and to prevent disability or deformity.
In general, patients are managed by simple means: rest, physical therapy and intra-articular steroid injection.In patients with axial involvement, intensive physiotherapy is useful to prevent spinal joint fusion and to maintain optimal motility (14,35).Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to control peripheral arthritis, back pain and stiffness.Caution is necessary because these drugs may activate quiescent IBD (36,37).In patients with joint symptoms preceding IBD onset, it has been claimed that there is a causal relationship of IBD onset with NSAID therapy (11,38).
In axial involvement, sulphasalazine (SASP) has been recommended as the drug of choice, and a shift from mesalazine to SASP has been suggested if the colon is intact (34).Several placebo controlled trials have reported a beneficial effect of SASP (39,40).The efficacy of SASP appears to be related to sulphapyridine, although this question has not been completely answered (41).Data about the long term results of SASP treatment are more scarce; the drug seems to achieve better results on peripheral arthritis than on axial involvement (40).
Other slow acting agents, such as azathioprine and 6-mercaptopurine, have not been studied as closely (42).The occurrence of arthritis is not an indication for steroid therapy; however, if the previously reported treatments are scarcely effective, a short course of steroids is mandatory.The spontaneous remission of joint symptoms, particularly in peripheral arthritis, must always be considered for the management of patients with rheumatic symptoms secondary to IBD.

CONCLUSIONS
Inflammatory bowel disease is a heterogeneous disorder in which patients manifest a spectrum of symptoms related to intestinal and extraintestinal manifestations.Muscoloskeletal manifestations are the most common IBD extraintestinal manifestations and may be present in 30% of patients.Their spectrum is wider than that defined by the spondylarthropathy criteria.In most cases, intestinal symptoms coincide with or precede articular manifestations.The gut-joint axis appears to be an important pathogenic factor.Rest, physical therapy, intra-articular steroid injection and NSAIDs are usually prescribed to control peripheral arthritis, back pain and stiffness.SASP seems to be more effective for peripheral arthritis than for axial disease.

TABLE 1 Extraintestinal manifestations of inflammatory bowel disease Area Manifestation
• Absence of rheumatoid factor • Absence of subcutaneous nodules and other extra-articular features of rheumatoid arthritis • Association with anterior uveitis • Familial aggregation • Association with human leukocyte antigen (HLA)-B27 EPIDEMIOLOGY Differences in patient selection and in the definition of spondylarthropathy can explain, in part, the wide range in the prevalence of musculoskeletal disorders reported previously in IBD.Prevalence of peripheral arthritis has been Fornaciari et al Can J Gastroenterol Vol 15 No 6 June 2001 400

TABLE 3 Muscoloskeletal manifestations of spondylarthropathies
Peripheral arthritis -One or more swollen and tender joint(s); the synovitis is asymmetric and predominantly in lower limbs Inflammatory spinal pain* -Symptoms of back pain in lumbar, dorsal or cervical regions associated with at least four of the following:*Criteria ofCalin et al (reference 43)