SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE
  4. BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE
  5. CONCLUSIONS
  6. References

The intestinal and articular systems are closely linked in inflammatory bowel disease. Clinical and immunological studies support an important aetio-pathogenetic link between intestinal and articular inflammation. There is increasing evidence for a negative link between bone mass density and intestinal inflammation. This paper will focus on the prevalence, aetio-pathogenesis and treatment of arthritis (peripheral, sacroiliitis and spondylitis) and osteoporosis in inflammatory bowel disease.


INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE

  1. Top of page
  2. Abstract
  3. INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE
  4. BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE
  5. CONCLUSIONS
  6. References

Spondyloarthropathy in inflammatory bowel disease

This type of articular involvement is the most common extraintestinal manifestation of inflammatory bowel disease and occurs in 15–20% of the patients.1[2][3]–4 Two patterns can occur: a peripheral arthritis and a spondylitis. For several years, the enteropathic arthritis in inflammatory bowel disease, unlike the arthritis in Whipple’s disease and coeliac disease, is included in the spondyloarthropathy concept. According to the European Spondyloarthropathy Study Group criteria for spondyloarthropathy, patients with inflammatory bowel disease presenting inflammatory low back pain and/or peripheral arthritis are classified as spondyloarthro- pathy.5

The peripheral arthritis is pauci-articular and asymmetrical, and involves predominantly the large and small joints of the lower limbs. The arthritis is frequently transient, migratory and non-deforming but may become chronic and erosive in 10% of patients.6 Peripheral enthesiopathies (inflammation of the insertion of the tendon to the bone) may occur especially at the Achilles tendon and the insertion of the fascia plantaris.

Generally, radiographs of the involved joints show no abnormalities, although erosive disease of the hip, metacarpophalangeal and metatarsophalangeal joints have been described.4 Synovial fluid analysis and histopathology of the synovium show a low grade of inflammation.

Peripheral arthritis is most frequently seen in patients with extensive ulcerative colitis and in patients with Crohn’s colitis. Especially in ulcerative colitis, a distinct temporal relationship between attacks of arthritis and flares of bowel disease is observed. Although in most cases the intestinal manifestations coincide with the articular manifestations, joint involvement can precede the intestinal symptoms by years. In contrast to other enterogenic arthritides, there is no increased incidence of the HLA B27 antigen. The presence of peripheral arthritis is frequently associated with other extraintestinal manifestations like erythema nodosum and anterior uveitis.

The axial involvement includes sacroiliitis and spondylitis. The true prevalence of ‘sacroiliitis’ is difficult to estimate as the onset is frequently insidious. In a prospective study, we observed radiological signs of sacroiliitis in 25% of our patients with inflammatory bowel disease, mostly asymptomatic and not associated with an increased incidence of HLA B27 phenotype.7

Symptomatic spondylitis has a clinical picture identical to idiopathic ‘ankylosing spondylitis’. The patient complains of low back pain, especially at night with morning stiffness, thoracic or cervical pain, and alternating buttock pain or chest pain. Decreased mobility of the spine and impaired chest expansion are the characteristic clinical signs. Radiographic lesions compatible with spondylitis can be present.

The onset of the axial involvement and the evolution of the disease are independent of the course of the bowel disease. In contrast to the very high incidence of HLA B27 in ankylosing spondylitis (90%), the reported incidence in patients with inflammatory bowel disease and spondylitis ranges between 50 and 75%.7[8]–9 Simultaneous association with HLA B60 and HLA B44 seems to increase the susceptibility.10, 11

Gut inflammation in spondyloarthropathy

The term spondyloarthropathy describes and defines a group of related inflammatory joint diseases that share similar clinical features and a strong association with HLA B27.5 Entities belonging to the concept include not only inflammatory bowel disease but also ankylosing spondylitis, reactive arthritis triggered by an urogenital or enterogenic infection, some form of psoriatic arthritis and a group of undifferentiated spondyloarthropathies. The prevalence of spondyloarthropathy in the general population is estimated to be 1%. Inflammatory gut lesions are found on histology in about 60% of these patients, even in the absence of any abdominal symptoms.12[13][14][15][16][17][18]–19 Endoscopic lesions are more scarce and only present in about 30% of the patients, mostly as small erosions.13

Two types of inflammation can be recognized: an acute type resembling an infectious colitis and a more chronic inflammation resembling Crohn’s disease.20 Acute inflammation is characterized by a well-preserved mucosal architecture and an infiltration of the epithelium by neutrophils and eosinophils. The lamina propria is oedematous and infiltrated by polymorphonuclear neutrophils. In chronic inflammation, the crypts are distorted, and the villous surface blunted and atrophic. The lamina propria is infiltrated by a mixed cellular population. In some patients, aphtoid ulcers, branching and pyloric metaplasia of the crypts, and sarcoid granulomas were found resembling Crohn’s disease.

The relationship between gut and arthritis is further strongly supported by the evolution of the gut inflammation.21 In a large prospective study including 123 patients with spondyloarthropathy and an initial ileocolonoscopy, an evolution to overt inflammatory bowel disease was observed in 6.5% of the patients. Initially, all these patients presented with subclinical gut lesions, mostly as chronic inflammation. In the same study a follow-up endoscopic examination was performed in 49 patients. Disappearance of the gut inflammation was observed in all patients who went into articular remission. By contrast, inflammation persisted in most patients with persistent locomotoric inflammation. Moreover, an evolution to overt inflammatory bowel disease was observed in 20% of patients with an initial chronic inflammation and was always associated with an articular evolution to ankylosing spondylitis.

This human model of subclinical inflammatory bowel disease in patients with spondyloarthropathy, and the studies with HLA B27 transgenic rats developing spontaneous inflammatory disorder with gut inflammation and arthritis, identify an important gut–synovium axis.22 In spondyloarthropathy, an enhanced antigen presentation to lymphoid tissue is supported by an increased expression of HLA-DR by epithelial cells23 and by an increased number of M cells.24 Overstimulation induces a local and a systemic immune response. A recirculation of antigen-specific memory T lymphocytes between the gut and the synovium can be considered as a clue mechanism in the gut–synovium axis. Efficacious adherence of lamina propria lymphocytes to synovial high endothelial venules has been demonstrated.25 This process of lymphocyte trafficking is regulated by receptors belonging to a group of molecules referred to as adhesion molecules, which constitute the molecular basis for cell–cell and cell–matrix interactions.26, 27 These receptors also mediate important functional activities of the cell. Further characterization of the trafficking lymphocytes in gut and synovium, especially for the expression of adhesion molecules, provides some insight into the mechanisms explaining the physical relationship between gut and joint inflammation. Of particular interest is the α4β7 integrin as this adhesion molecule is crucial for the homing of memory lymphocytes to the gut. Alterations in β7 integrins have been observed on intestinal mucosal T-cell lines of inflammatory bowel disease patients, with a decreased α4β7 integrin expression in Crohn’s disease and an increased αEβ7 integrin expression in ulcerative colitis and Crohn’s disease.28 Moreover, an increased expression of β7 integrin on spondyloarthropathy synovial cells as compared to rheumatoid arthritis synovium has been observed, with discriminative correlations between α4β7 and αEβ7. This suggests a different origin of synovial T cells in both diseases, namely an intestinal origin in spondyloarthropathy and a peripheral blood origin in rheumatoid arthritis.29 Studies are in progress in our laboratory to see whether the T-cell subsets, that are characteristic for Crohn’s disease, are also observed in the intestinal mucosa of patients with spondyloarthropathy with or without histological signs of gut inflammation.

Other candidates for the gut–synovium axis are mucosal macrophages transporting antigens from mucosal surfaces to the joints.30 The relative importance of macrophage vs. lymphocyte migration is not known. A sequential model has been proposed.

Therapy

The natural history of spondyloarthropathy is characterized by periods of flares and remission, whatever the treatment. Therefore, efficacy of treatment is difficult to establish and long-term studies are mandatory.

Most patients with spondyloarthropathy respond to a short treatment with non-steroidal anti-inflammatory drugs (NSAIDs). Caution is necessary because these drugs may activate quiescent inflammatory bowel disease.31 For peripheral arthritis, an optimal treatment of the bowel disease is the first goal of therapy because of the known relationship between intestinal and articular disease. As sulphasalazine has been proved to be efficacious in the treatment of reactive arthritis, its use can be recommended as maintenance treatment in patients with inflammatory bowel disease and peripheral arthritis.32

For axial disease, sulphasalazine can also be recommended as the drug of choice, as its beneficial effect has been demonstrated in several placebo-controlled trails.33 Efficacy seems related to the molecule sulphasalazine and not to 5-aminosalicylic acid (5-ASA).34

Data about the long-term efficacy of sulphasalazine in ankylosing spondylitis are more scarce and disparate: a large placebo-controlled study, including 264 patients with ankylosing spondylitis, failed to show a significant effect of sulphasalazine after 9 months of treatment in chronic long-standing ankylosing spondylitis.35 Only the subgroup of patients with peripheral arthritis had some beneficial effect of the treatment. In contrast, another large trial including 351 spondyloarthropathy patients showed an improvement in patients’ overall assessment of disease activity in 60% of patients after 6 months of treatment, but once again the activity of the drug was more obvious on peripheral joints than on axial involvement.36

Data about azathioprine–6-mercaptopurine and methotrexate in severe cases of spondyloarthropathy are anecdotal but promising.33 Because azathioprine–6-mercaptopurine is an efficacious chronic treatment of inflammatory bowel disease, and as peripheral arthritis follows activity of bowel disease, efficacy can be expected in inflammatory bowel disease with spondyloarthropathy. Similar conclusions can be drawn from corticosteroids, although the occurrence of arthritis is not an indication for systemic use of corticosteroids.

BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE

  1. Top of page
  2. Abstract
  3. INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE
  4. BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE
  5. CONCLUSIONS
  6. References

Definitions

Osteoporosis is a systemic skeletal disease characterized by a low bone mass and a micro-architectural deterioration leading to an increased bone fragility and susceptibility to fracture.37

Osteoporosis depends on the peak bone mass and the rate of bone loss. Peak bone mass is determined by nutritional, hormonal, environmental and genetic factors. The rate of bone loss is predominantly determined by calcium and vitamin D absorption, and the resulting parathormone levels.

A low bone mass can result from a decreased bone formation/resorption ratio and/or an increased remodelling process. The diagnosis is preferentially based on bone mass density measurements and their related risk for fracture in post-menopausal women. Although it seems reasonable to suppose that, for the same bone mass density, the risk for fractures differs in different age categories, and perhaps between men and women, no other reference populations are available.

Bone mass densitometry

Bone mass density can be measured by several techniques. The preferred method is the dual energy X-ray absorptiometry (DEXA) measuring the attenuation of X-ray during its passage in bone. This method is highly sensitive and precise and can assess the bone mass simultaneously in cortical (radius or femur) and trabecular (lumbar spine) bone.

Densiometric criteria of bone loss are based on T and Z scores which are standard deviation scores expressed in relation to reference values in young healthy subjects (T score) or sex- and age-matched healthy controls (Z score).

Osteopenia is defined as a score of between −1 and −2.5. Osteoporosis is defined as a score lower than −2.5.37

Biochemical markers

Bone turnover can also be estimated by biochemical markers. Bone-specific alkaline phosphatase, osteocalcin (non-collagenous protein synthesized by osteoblasts) and procollagen I carboxy terminal peptide reflect bone formation and can be used as osteoblast markers. The osteoblast markers reflecting the rate of bone resorption are degradation products of type I collagen fibril cross-links including urinary pyridinoline, deoxypyridinoline and serum type I collagen carboxy terminal teleopeptide. No correlation is observed between bone mass density and biochemical markers. A possible explanation is the fact that bone mass density is a result of a cumulative effect over several years, whereas the indices of bone turnover are subject to short-term effects.

Prevalence of low bone mass density in inflammatory bowel disease population

As defined previously, osteopenia is found in about 50% of inflammatory bowel disease patients and osteoporosis in about 30% ( Table 1).38[39][40][41][42][43][44]–45 Particularly, Crohn’s disease seems to be associated with a decreased bone mass, not only in long-standing disease but also at the moment of diagnosis.46 In contrast to earlier studies, recent studies have found no correlation between bone mass density and the location or extension of the disease or ileal resection.39, 41, 47

Table 1.  . Prevalances of osteopenia and osteoporosis in inflammatory bowel disease Thumbnail image of

Several longitudinal studies confirmed an increased rate of bone loss in inflammatory bowel disease patients.39, 40, 42, 43, 46 However, a marked heterogeneity in these rates has been observed between the studies and among the patients within the individual studies. Whereas Clementset al. reported a mean annual change in radial bone mass of −0.74% in women but not in men,43 Motley et al. found no differences between sexes.42 Changes in trabecular and cortical bone are also variable: Motley et al. reported a mean annual change of −2.8% in the spine and only −0.7% in the radius,42 but Staun et al. found only a mean annual change of −1.2% in the femoral bone and no change in the spine.48 Finally, rates of annual bone loss are also very disparate: Roux et al. described a mean change of −3.1% in Crohn’s disease and −6.4% in ulcerative colitis, Vogelsang et al. a decrease of −7.3% in Crohn’s disease, but Ghosh et al. reported no changes.39, 46, 49

Studies with biochemical markers are divergent. It seems unclear whether a decreased bone formation 38, 50 or increased bone resorption41 is the dominant cause of the disease. Very few studies have investigated the changes in bone remodelling associated with bone loss in patients with inflammatory bone disease, but suggest, at least in the later stages of the disease, a remodelling imbalance.50, 51

Pathogenesis

The pathogenesis of osteoporosis in inflammatory bowel disease is likely to be multifactorial.

‘Corticosteroids’ are frequently considered as the major cause of the changes in bone mass. They stimulate bone resorption and inhibit bone formation. The former is mainly mediated by a hyperparathyroidism secondary to calcium malabsorption and renal loss of calcium; the latter is mediated by a direct inhibitory effect on the proliferation and differentiation of osteoblast precursors and on the function of mature osteoblasts. Trabecular bone is preferentially affected.

Most cross-sectional studies support the contributive role of corticosteroids in the decrease in bone mass density observed in inflammatory bowel disease patients.38,47, 52[53]–54 However, other studies were unable to demonstrate a relationship between the past or current use of steroids,39, 41 although very low T scores are most often observed in patients receiving large doses.41 Moreover, osteopenia has been reported in 28–30% of patients who never received such treatment.38, 46 Because the use of corticosteroids and life-time dosage reflect the severity of the disease, both effects interfere and so are difficult to evaluate separately.

Results of longitudinal studies are also variable. Ghosh et al. found no additional bone loss at 1 year.46 Similarly, Staun et al. found no relationship between the changes in bone mass density, over a mean period of 5.5 years, and the duration of the use of prednisolone.48 In contrast, Roux et al. found significantly higher bone loss in patients with steroids than without, although 26% of patients on steroid therapy did not lose bone, whereas 34% with significant bone loss did not receive steroid therapy during a follow-up period of 19 ± 8 months.39 Finally, Motley et al. only found a significant correlation between the total dose of steroids and spiral trabecular bone loss in males.42

Calcium and vitamin D malabsorption, secondary to extensive ileal disease, may result in secondary hyperparathyroidism leading to increased bone resorption. However, in most studies no correlation between the changes in bone mass density and disease location could be observed.41, 46, 54 Normal calcium homeostasis is mostly reported.41, 46 The importance of vitamin D deficiency is also controversial: low serum levels of vitamin D metabolites40, 53, 55 and a correlation with subsequent risk for significant bone loss39 suggest an aetio-pathogenetic role. Long-term oral vitamin D supplement seems to prevent bone mineral loss in patients with Crohn’s disease.49 However, in other studies, serum levels of vitamin D metabolites are normal even in patients with osteopenia.38, 44, 46

Inflammation on its own may be one of the principle aetio-pathogenetic mechanisms of osteopenia in inflammatory bowel disease. This statement is supported by a recent study in rats reporting a rapid and reversible bone loss in TNBS-induced colitis.56 In man, osteopenia has been observed in about 50% of Crohn’s disease patients at the moment of diagnosis, before any treatment.46 Finally, a correlation has been described between the control of disease activity and the increase in Z score.46 Cytokines like IL1, IL6 and TNFα are candidates because of their effect on osteoclasts: IL1 and TNFα have an inhibitory effect on bone formation and increase osteoclasts activity, whereas IL6 increases the number of osteoclast progenitor cells.57

Secondary amenorrhoea may be an important factor in the development of the disease in women. Hormone replacement therapy has been shown to prevent bone loss in the spine and radius in post-menopausal women with inflammatory bowel diseases.58 Mild hypogonadism may play a role in men.59

Finally, female ex- or current smokers with inflammatory bowel disease have lower Z scores than non-smoking counterparts suggesting a role of nicotine.60 This association was not related to the body mass index, the medical treatment, current or previous symptoms, or use of oestrogen preparations. The exact mechanism remains unknown: lower urinary oestrogen excretion, accelerated hepatic metabolism of oestrogen and an anti-oestrogen effect of nicotine have been suggested.

The aetio-pathogenesis of osteoporosis in inflammatory bowel disease is multifactorial. The failure to demonstrate clear relationships between one of these several factors and the presence of bone disease reflects the heterogeneity of the studied patients and the variable course of the disease.

Treatment

Body mass density measurements can be recommended at diagnosis and repeatedly at 2–3 yearly intervals. If osteopenia is present, or if corticosteroids have to be started, preventive measures with oral calcium (1–1.5 g/day) should be considered, although a recent prospective study failed to show a significant benefit at 1 year.61 Long-term oral vitamin D supplementation (1000 IU/day) can be recommended, especially for patients at high risk of osteoporosis.55

In post-menopausal or amenorrhoeic pre-menopausal women, hormonal treatment should always be considered. It is important to detect and treat hypogonadism in men. There is also some evidence of the effectiveness of calcitonin and fluoride in this context.

Studies are in progress to confirm the beneficial effect biphosphanates (cyclic oral etidronic acid) on the prevention and treatment of corticosteroid-induced osteoporosis. The biphosphanates are analogues of pyrophosphate that binds avidly to bone mineral and inhibits osteoclastic bone resorption. Recently, prevention of bone loss was demonstrated with an intermittent therapy with etidronate in a large trial, including more than 100 patients who had recently begun high-dose glucocorticoid therapy.62 However, in this study the number of inflammatory bowel disease patients was extremely small.

Because the aetiology of osteoporosis in inflammatory bowel disease is multifactorial, and probably related not only to the use of corticosteroids but also to intestinal inflammation, trials are mandatory to evaluate the possible additional beneficial effect of immunomodulatory drugs by controlling the inflammation.

Complications

The clinical importance of osteoporosis is mainly related to the morbidity associated with the occurrence of vertebral compression fractures and hip fractures. Several investigators reported fractures in patients with Crohn’s disease, most often after significant exposure to corticosteroid medication (lifetime dose of more than 30 g).38, 44, 45 Recently, vertebral compression fractures were reported in five paediatric patients with Crohn’s disease and high exposure to corticosteroids, emphasizing the gravity of the problem.63

Osteoporosis in spondyloarthropathy

Two studies demonstrated an association between disease activity and increased bone resorption in spondyloarthropathy, supporting the hypothesis that uncontrolled inflammation is associated with bone loss.64, 65

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE
  4. BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE
  5. CONCLUSIONS
  6. References

The gut–joint axis appears to be a very important pathway of circulation of disease-related cells. Further elucidation of these mechanisms of recirculation, adhesion and disease-inducing features, will help to understand to aetio-pathogenesis of extraintestinal manifestations of inflammatory bowel disease.

Elucidation of the early intestinal events initiating spondyloarthropathy may help in understanding the aetio-pathogenesis of inflammatory bowel disease, and provide a therapeutic goal for early treatment of both intestinal and articular disease.

Identification of the inflammatory mechanisms that reduce bone mass density should help to prevent and to treat this important disease-related morbidity.

References

  1. Top of page
  2. Abstract
  3. INFLAMMATORY JOINT DISEASE AND INFLAMMATORY BOWEL DISEASE
  4. BONE MASS DENSITY AND INFLAMMATORY BOWEL DISEASE
  5. CONCLUSIONS
  6. References
  • 1
    Gravallese EM & Kantrowitz FG. Arthritic manifestations of inflammatory bowel disease. Am J Gastroenterol 1988; 83: 703 9.
  • 2
    Greenstein AJ, Jarowitz HD, Scalar BD. The extra-intestinal manifestations of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine 1976; 55: 401 12.
  • 3
    Haslock I & Wright V. The musculoskeletal complications of Crohn’s disease. Medicine 1973; 52: 217 25.
  • 4
    Protzer U, Duchmann R, Höhler T, et al. Enteropathic spondyloarthropathy in chronic inflammatory bowel disease: prevalence, pattern of manifestations and HLA-association. Ed Klin 1996; 91: 330 5.
  • 5
    Dougados M, Van Der Linden J, Juhlin R, et al. The European Spondyloarthropathy Group: The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. Arthritis Rheum 1991; 34: 1218 26.
  • 6
    Mielants H, Veys EM, Goethals K, et al. Destructive lesions of small joints in seronegative spondyloarthropathies: relation to gut inflammation. Clin Exp Rheumatol 1990; 8: 23 7.
  • 7
    Huaux JP, Faissi R, De Bruyere M. HLA B27 in regional enteritis with and without ankylosing spondylitis or sacroilitis. J Rheumatol 1997; 4(Suppl. 3): 60 3.
  • 8
    Mallas EG, Mackintosh R, Asquith P. Histocompatibility antigens in inflammatory bowel disease: their clinical significance and their association with arthropathy with special reference to HLA B27. Gut 1976; 17: 906 10.
  • 9
    Scarpa R, Del Puente A, D’arienzo A, et al. The arthritis of ulcerative colitis: clinical and genetic aspects. J Rheumatol 1992; 19: 373 7.
  • 10
    Purrman J, Zeidler H, Bertrams J, et al. HLA antigens in ankylosing spondylitis associated with Crohn’s disease. Increased frequency of the HLA phenotype B27, B44. J Rheumatol 1988; 15: 1658 61.
  • 11
    Robinson WP, Van Der Linden SM, Khan MA, et al. HLA-Bw60 increases susceptibility by ankylosing spondylitis in HLA-B27 positive individuals. Arthritis Rheum 1989; 32: 1135 41.
  • 12
    Mielants H, Veys EM, Cuvelier C, De Vos M. Ilecolonoscopic findings in seronegative spondyloarthropathies. Br J Rheumatol 1988; 27: 95 105.
  • 13
    De Vos M, Cuvelier C, Mielants H, et al. Ileocolonscopy in seronegative spondyloarthropathy. Gastroenterology 1989; 96: 339 44.
  • 14
    Dougados M, Allemanni M, Tulliez M, et al. Iléocolonoscopie systhématique au cours des spondyloarthropathies séronégatives. Rev Rhum 1987; 54: 279 83.
  • 15
    Simenon G, Van Gossum A, Adler M, et al. Macroscopic and microscopic gut lesions in seronegative spondyloarthropathies. J Rheumatol 1990; 17: 491 4.
  • 16
    Altomente L., Zoli A, Veneziania A, et al. Clinical silent inflammatory gut lesions in undifferentiated spondyloarthropathies. Clin Rheumatol 1994; 13: 565 70.
  • 17
    Leirisalo-Repo M, Turunen U, Stenman S, et al. High frequency of silent inflammatory bowel disease in spondyloarthropathy. Arthritis Rheum 1994; 37: 23 31.
  • 18
    Schatteman L, Mielants H, Veys EM, et al. Gut inflammation in psoriatic arthritis: a prospective ileocolonoscopic study. J Rheumatol 1995; 22: 680 3.
  • 19
    Mielants H, Veys EM, Joos R, et al. Late onset pauciarticular juvenile chronic arthritis: relation to gut inflammation. J Rheumatol 1987; 14: 459 65.
  • 20
    Cuvelier C, Barbatis C, Mielants H, et al. Histopathology of intestinal inflammation related to reactive arthritis. Gut 1987; 28: 394 401.
  • 21
    De Vos M, Mielants H, Cuvelier C, Elewaut A, Veys E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 1996; 110: 1696 703.
  • 22
    Hammer RE, Maika SD, Richardson JA, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: an animal model of HLA-B27-associated human disorders. Cell 1990; 63: 109 12.
  • 23
    Cuvelier C, Mielants H, De Vos M, et al. Major histocompatibility class II antigen (HLA-DR) expression by ileal epithelial cells in patients with seronegative spondyloarthropathies. Gut 1990; 31: 545 9.
  • 24
    Cuvelier CA, Quatacker J, Mielants H, et al. M-cells are damaged and increased in number in inflamed human ileal mucosa. Histopathology 1994; 24: 417 26.
  • 25
    Salmi M, Andrew DP, Butcher EC, et al. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J Exp Med 1995; 181: 137 49.
  • 26
    Adams DH & Shaw S. Leucocyte–endothelial interactions and regulation of leucocyte migration. Lancet 1994; 343: 831 6.
  • 27
    Picker LJ. Control of lymphocyte homing. Curr Opin Immunol 1994; 6: 394 406.
  • 28
    Elewaut D, De Vos M, De Keyser F, et al. Distinctive cell activation markers in colon from patients with Crohn’s disease and ulcerative colitis. Gastroenterology 1997; 112: A718.
  • 29
    Elewaut D, De Keyser F, Lazarovits A, et al. Inflamed synovial tissue from patients with spondyloarthropathy is enriched with activated T-cells carrying β7 integrins. Arthritis Rheum 1996; 39: S162.
  • 30
    Salmi M, Rajala P, Jalkanen S. Homing of mucosal leukocytes to joints: distinct endothelial ligands in synovium mediate leukocyte subtype specific adhesion. J Clin Invest 1997; 99: 2165 72.
  • 31
    Kaufman HL, Fischer AH, Carroll M, Becker JM. Colonic ulceration associated with nonsteroidal antiinflammatory drugs. Dis Colon Rectum 1996; 39: 705 10.
  • 32
    Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). Arthritis Rheum 1996; 39: 2021 7.
  • 33
    Creemers MCW, Van Riel PLCM, Franssen MJAM, et al. Second-line treatment in seronegative spondyloarthropathies. Sem Arthritis Rheum 1994; 24: 71 81.
  • 34
    Taggart AJ, Gardiner P, McEvoy FM, et al. Which is the active moiety of sulphasalazine in ankylosing spondylitis? Arthritis Rheum 1996; 39: 1400 5.
  • 35
    Clegg Do, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. Arthritis Rheum 1996; 39: 2004 12.
  • 36
    Dougados M, Van Der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondyloarthropathy. Arthritis Rheum 1995; 38: 618 27.
  • 37
    Compston JE. Review article: osteoporosis, corticosteroids and inflammatory bowel disease. Aliment Pharmocal Ther 1995; 9: 237 50.
  • 38
    Abitbol V, Roux C, Chaussade S, et al. Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 1995; 108: 417 22.
  • 39
    Roux C, Abithol V, Chaussade S, et al. Bone loss in patients with inflammatory bowel disease: a prospective study. Osteoporos Int 1995; 5: 156 60.
  • 40
    Vogelsang H, Klamert M, Resch H, Ferenci P. Dietary vitamin D intake in patients with Crohn’s disease. Wien Klin Wochenschr 1995; 19: 578 81.
  • 41
    Bjarnason I, MacPherson A, Mackintosh C, et al. Reduced bone density in patients with inflammatory bowel disease. Gut 1997; 40: 228 33.
  • 42
    Motley RJ, Clements D, Evans WD, et al. A four-year longitudinal study of bone loss in patients with inflammatory bowel disease. Bone Miner 1993; 23: 95 104.
  • 43
    Clements D, Motley RJ, Evans WD, et al. Longitudinal study of cortical bone loss in patients with inflammatory bowel disease. Scand J Gastroenterol 1992; 27: 1055 60.
  • 44
    Compston JE, Judd D, Crawley EO, et al. Osteoporosis in patients with inflammatory bowel disease. Gut 1987; 28: 410 15.
  • 45
    Pigot F, Roux C, Chaussade S, et al. Low bone mineral density in patients with inflammatory bowel disease. Dig Dis 1992; 37: 1396 403.
  • 46
    Ghosh S, Cowen S, Hannan WJ, Ferguson A. Low bone mineral density in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology 1994; 107: 1031 9.
  • 47
    Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 1995; 37: 71 6.
  • 48
    Staun M, Tjellesen L, Thale M, Schaadt O, Jarnum S. Bone mineral content in patients with Crohn’s disease. A longitudinal study in patients with bowel resections. Scand J Gastroenterol 1997; 32: 226 32.
  • 49
    Vogelsang H, Ferenci P, Resch H, Kiss A, Gangl A. Prevention of bone mineral loss in patients with Crohn’s disease by long-term oral vitamin D supplementation. Eur J Gastroenterol Hepatol 1995; 7: 609 14.
  • 50
    Croucher PI, Vedi S, Motley RJ, et al. Reduced bone information bone formation in patients with oesteoporosis associated with inflammatory bowel disease. Osteoporos Int 1993; 3: 236 41.
  • 51
    Hessov I, Mosekilde L, Melsen F, et al. Osteopenia with normal vitamin D metabolites after small bowel resection for Crohn’s disease. Scand J Gastroenterol 1984; 19: 691 6.
  • 52
    Lukert BP & Raisz LG. Glucocorticoid induced osteoporosis pathogenesis and management. Ann Intern Med 1990; 112: 352 64.
  • 53
    Bernstein CN, Seeger LL, Sayre JW, et al. Decreased bone density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis. J Bone Miner Res 1995; 10: 250 6.
  • 54
    Jahnsen J, Falch JA, Aadland E, Mowinckel P. Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitis: a population based study. Gut 1997; 40: 313 19.
  • 55
    Driscoll RH, Meredith SC, Sitrin M, Rosenberg IH. Vitamin D deficiency and bone disease in patients with Crohn’s disease. Gastroenterology 1982; 83: 1252 8.
  • 56
    Lin CL, Moniz C, Chambers TJ, Chow JWM. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996; 111: 1263 71.
  • 57
    MacDonald BR & Gowen M. Cytokines and bone (review). Br J Rheumatol 1992; 31: 149 55.
  • 58
    Clements D, Compston JE, Evans WD, Rhodes J. Hormone replacement therapy prevents bone loss in patients with inflammatory bowel disease. Gut 1993; 34: 1543 6.
  • 59
    Francis RM, Peacock M, Aaron JE. Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption and low bone formation. Bone 1986; 7: 261 8.
  • 60
    Silvennoinen JA, Lehtola JK, Niemelä SE. Smoking is a risk factor for osteoporosis in women with inflammatory bowel disease. Scand J Gastroenterol 1996; 31: 364 71.
  • 61
    Bernstein CN, Seeger LL, Anton PA, et al.A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease: a pilot study. Aliment Pharmacol Ther 1996; 10: 777 86.
  • 62
    Adachi JD, Bensen WG, Brown J, et al. Intermittent eridronate therapy to prevent corticosteroid-induced osteoporosis. N. Engl J Med 1997; 337: 382 7.
  • 63
    Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression fractures in pediatric patients with Crohn’s disease. Gastroenterology 1997; 112: 1710 13.
  • 64
    MacDonald AG, Birkinshaw G, Durham B, Bucknall RC, Fraser WD. Biochemical markers of bone turnover in seronegative spondyloarthropathy: relationship to disease activity. Br J Rheumatol 1997; 36: 50 3.
  • 65
    Marhoffer W, Stracke H, Masoud I, et al. Evidence of impaired cartilage/bone turnover in patients with active ankylosing spondylitis. Ann Rheum Dis 1995; 54: 556 9.