BOWEL INFLAMMATION AND THE SPONDYLOARTHROPATHIES

SPONDYLOARTHROPATHIES

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BOWEL INFLAMMATION AND THE SPONDYLOARTHROPATHIES Filip De Keyser, MD, PhD, Dirk Elewaut, MD, PhD, Martine De Vos, MD, PhD, Kurt De Vlam, MD, Claude Cuvelier, MD, PhD, Herman Mielan&, MD, PhD, and Eric M. Veys, MD, PhD

The concept of spondyloarthropathies (SpA) gathers together a group of chronic diseases with common clinical, biological, genetic and therapeutic characteristics. The concept forms a distinct entity, different from other rheumatic diseases. The target organs are not only the joint, but also the axial skeleton, the enthesis, the eye, the gut, the urogenital tract, the skin and sometimes the heart. The prevalence of this entity in the general population is estimated 1%, equal to the prevalence of rheumatoid arthritis. Diseases included within this concept are ankylosing spondylitis (AS), reactive arthritis (ReA) and Reiter’s disease, undifferentiated spondyloarthropathies (Undiff SPA), some forms of psoriatic arthritis (PsA), of juvenile chronic arthritis (JCA), of acute anterior uveitis (AAU), and the idiopathic inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). Clinical characteristics of these diseases are the absence of rheumatoid factor and rheumatoid nodules, the presence of a typical pattern of inflammatory arthritis (pauci-articular, asymmetrical, involving large and small joints mostly of the lower limbs), the presence of inflammatory enthesiopathies (mostly of the feet), the presence of sacroiliitis and sometimes spondyliSupported by NFWO grant 3.0028.95 and 3.0022.96 and by a concerted action grant GOA96001 of the University of Belgium. Dr. Elewaut is a NFWO Research Assistant.

From the Departments of Rheumatology (FD, DE, KD, HM, EMV), Gastroenterology (MD) and Pathology (CC), University Hospital, Ghent, Belgium

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tis, the clinical overlap between different diseases of the concept, the familial aggregation of these diseases, and the strong genetic relationship to human leukocyte antigen (HLA) B27. The axis between the gut and the joints is suggested by several clinical situations as the arthritis occurring in Whipple’s disease70and in celiac disea~e.~, 74 Inflammatory polyarthritis has been reported after intestinal bypass surgery for morbid obesity.20,144 Enterogenic ReA induced by Salmonella typhimurium, Shigella enteritidis, Yersinia enterocolitica, and Campylobacter enteritidis and the peripheral arthritides occurring in UC and CD are other evidence of the relation between the locomotor system and the gastrointestinal tract. In animal models, peripheral arthritis was described .in pigs by feeding them a protein-rich diet, and an intestinal overgrowth of Clostridium perfringens was observed.81A mouse model of peripheral arthritis was reported by oral challenge with bovine serum albumin.68More recently, in transgenic HLA-B27 rats and mice, inflammatory bowel lesions, especially located in the colon, were found in all diseased animals.51,59 The gut lesions and the joint abnormalities did not occur in animals developed in germ-free conditions, and these phenomena appear once the animals are put in normal ~0nditions.l~~ All these findings suggest that the gut can play an important role in the pathogenesis of many rheumatic conditions even if the clinical gut manifestations are minimal or absent or when they follow inflammatory joint features. GUT INVOLVEMENT IN SPONDYLOARTHROPATHIES Prevalence of Gut Abnormalities in Spondyloarthropathies

Since the first report on subclinical gut inflammation in SPA patients,88revealed by ileocolonoscopy, exploring the whole colon, cecum, and terminal ileum, several authors have confirmed these findings in different forms of spondyloarthropathy SPA).^, 29, 32, 49, 66, 67, 95, 137 The prevalence of macroscopic and microscopic signs of gut inflammation reported by the respective authors is listed in Table 1. In enterogenic ReA, macroscopic lesions were found in approximately 50% of patients, whereas the prevalence of histologic signs of inflammation ranged from 25% to 100%. The variation of the prevalence of histologic abnormalities in this group of patients and also in others may be caused by the fact that some investigators are sampling the biopsies especially at the places where macroscopic abnormalities are seen, whereas others specifically took the samples in normal-appearing gut mucosa. In urogenital ReA, macroscopic lesions are uncommon, but practically all authors found some patients presenting with histologic signs of gut inflammation. In undifferentiated SPA, gut inflammation was more frequent (macroscopically, 2638%; microscopically, 2672%). In AS, macroscopic signs of gut

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Table 1. PREVALENCE (%) OF INFLAMMATORY GUT LESIONS OBSERVED BY ILEOCOLONOSCOPY IN SPA PATIENTS Lesion Enterog ReA Macro Histol Urog ReA Macro Histol Undiff SPA Macro Histol AS Macro Histol Controls Arthritis Macro Histol Spastic colon Macro Histol

Mielants et alaO n = 12 50 100 n = 21

0 14 n = 120 35 72 n = 79 29 57 n = 37 0 3 n = 28 0 0

Grillet49 S i r n e r ~ o n ~Leirisalo-RepoS7 ~~ (1987) (1990) (1994) n = 6 33 33 n = 2 0 0 n = 17 24 24 n=28 29 25 n=24 4 4

n=96 37.5 66.7 n=17 5.6 12.5 n = 19 0 15.8

n = 18 50 28 n = 24 29 36 n = 16 38 31n = 37 49 41 n = 33 6 36

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Lee66 (1997)

n = 24 29 58

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inflammation are found in 29% to 49% of cases, whereas histologic inflammatory lesions are found in 25% to 62% of cases. Prevalence of gut inflammation in AS was higher in patients with associated peripheral 66, 67, y5 In arthritis than in those only presenting axial invol~ement.~~, control groups, consisting of patients with spastic colon or of patients with other inflammatory joint diseases, the prevalence of gut inflammation was significantly lower. Gut inflammation was also found in other diseases included in the concept of SPA. In JCA, ileocolonoscopy was performed in the subgroup presenting a pauciarticular late onset. In the first study, of 32 adult patients with SpA in whom the disease started before the age of 16, histologic evidence of gut inflammation was found in 80% of the patients.lo2In a second study, the ileocolonoscopy was performed earlier in the disease history, at a juvenile age, on 12 children with pauciarticular late-onset JCA; gut inflammation was found in nine of them (75'/0).~~ In PsA, gut inflammation was found only in those groups related to the SPA concept, that is, in the axial and the pauciarticular group and not in the polyarticular group130; however, the prevalence of gut lesions was lower than in the other SPA (26%). In patients with AAU, presenting no locomotoric or gastrointestinal symptoms, gut inflammation was suggested by case reports.'05 A systematic study analyzing a group of 27 patients with AAU with or without axial joint inflammation revealed gut inflammation in 66% of cases.5

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Histologic Pictures and Corresponding Rheumatic Manifestations

The lesions were histologically different and two types of inflammation, acute and chronic, could be disting~ished.~~ The classification of the inflammatory lesions is a morphologic interpretation and is not related to the duration of the disease. The acute type (Fig. 1) resembles acute bacterial enterocolitis. The mucosal architecture is well preserved. The ileal villi and crypt epithelial cells are infiltrated by polymorphonuclear cells. In the lamina propria, there is an increased number of inflammatory cells, consisting of a mixture of granulocytes, lymphocytes, and plasma cells. Further ileocolonoscopic studies demonstrated that the acute type of intestinal inflammation was mainly found in patients with enterogenic ReA.29,96 The chronic type (Fig. 2) resembled chronic ileocolitis, mostly indistinguishable from CD. Here, the mucosal architecture is clearly disturbed. The villi are irregular, blunted, and fused. The crypts are distorted and the lamina propria is edematous and infiltrated by mononuclear cells. Basal lymphoid follicles occur. This chronic type 96 of inflammation was preferentially present in ankylosing ~pondylitis.~~, Electron microscopic examination of ileal biopsies from SpA patients revealed an increase in the number of membranous (M) epithelial cells, specialized in uptake and handling of antigen from the intestinal lumen to the underlying lymphoid

Figure 1. Acute ileitis. Ileal villi are infiltrated by polymorphonuclear cells. The lamina propria contains an increased number of inflammatory cells. The ileal mucosal architecture is preserved (hematoxylin-eosin,original magnification x 160).

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Figure 2. Chronic ileitis. The mucosal architecture is changed; villi are blunted and crypts are irregular and grouped. The lamina propria contains an increased amount of mononuclear cells (hematoxylin-eosin,original magnification x 160).

Moreover, in the chronic type of inflammation, necrotic M-cells were present (Fig. 3). Their cytoplasm was either ruptured by lymphocytes or featured blebbing. The occurrence of M-cell ruptures or bursts induces interruption of the intestinal epithelial integrity and allows the luminal content to contact the gut lymphoid tissue. Acute lesions are mainly seen in patients with ReA. In enterogenic ReA, 70% of patients presented with acute lesions, whereas only 26% showed chronic lesions?* In urogenital ReA, chronic lesions were observed in 1 of 30 patients; all the other patients presenting with histologic gut inflammation had features of acute inflammation. In undifferentiated SPA chronic lesions ( 3 2 4 % ) were slightly more prevalent than acute lesions (29%)?' In AS, chronic lesions (39-52%) are significantly more frequent than acute lesions (10-15%), especially when peripheral arthritis is associated (46% versus 11%). Recently, this was confirmed in a Korean AS population (50% chronic lesions versus 16% acute lesions).66In an

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Figure 3. Electron micrograph of a ruptured M-cell in chronic ileitis. The M-cell cytoplasm is damaged by a perforating lymphocyte. Bar = 1 bm.

ileocolonoscopic study on 354 patients with SPA in whom psoriasis and inflammatory bowel disease (IBD) were excluded at the start, microscopic gut mucosa morphology correlated with different clinical, biologic, and radiologic manifestations of the disease.97Chronic lesions were significantly more frequent in patients with a family history of SPA, AS, or CD. Chronic lesions were more prevalent in patients with reduced axial mobility, in patients with increased stool frequency, and in patients reporting several periods of diarrhea. Inflammatory serum variables (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) were significantly higher in SPA patients with chronic inflammatory gut lesions than in patients who presented with normal gut histology and those with acute lesions. Patients with chronic gut lesions presented with significantly more advanced stages of sacroiliitis (stage 2 or more) and more syndesmophytes, and a bamboo spine evolution was also more frequent. Destructive and erosive articular abnormalities of the small joints were more prevalent in patients with SPA presenting with chronic gut lesions.1ooConcerning the hip joints, the concentric form of hip abnormality was not related to any form of gut involvement (Fig. 4), whereas the destructive type of hip lesions was related to chronic gut inflammation (Fig. 5)?, Chronic gut lesions were related to the presence of HLA-BW62, which is also reported to be increased in proven CD.92

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In patients in whom a second ileocolonoscopy was performed, remission of the joint inflammation was always associated with a disappearance of the gut inflammation, whereas persistence of locomotor inflammation was mostly associated with the persistence of gut inflammation?l, Io3 confirming the strong relationship between gut and joint inflammation. Evolution of Gut Inflammation in the Long Term In an extensive prospective study of the clinical evolution of spondyloarthropathy, 123 patients who previously underwent an ileocolonoscopy were reviewed clinically after 2 to 9 years?l At the time of clinical review, 43% of the patients were in clinical remission, presenting no synovitis, tendinitis, axial inflammation, or morning stiffness. The remission rate was higher in patients with SPA, not fitting the criteria for AS (non-AS SPA) (60%) than in patients with AS (19”/.), pointing out the good long-term prognosis in these patients. Nevertheless, 20% of pa-

Figure 4. Concentric hip involvement in spondyloarthropathy. The cartilage is equally narrowed on the whole articular surface. New bone formation is present on the femoral head and on the acetabular part of the joint.

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Figure 5. Destructive hip involvement in spondyloarthropathy.The superior area of the joint space is eroded and repair phenomena are absent.

tients with non-AS SPA developed AS, all except one of whom initially presented with gut inflammation, mostly of the chronic type. Five percent of these patients developed IBD, all of these patients initially presented gut inflammation, and all of them had also developed AS. In patients with AS, the remission rate was lower; 7.7% of the patients developed IBD, all of whom initially presented chronic gut inflammation. In total, 6.5% of the SPA patients who did not present with any clinical sign of gut abnormality developed IBD during the disease course. All of these patients initially presented subclinical inflammatory gut lesions, and all but one had the features of chronic inflamrnati~n.~~ These findings were responsible for the consideration that at the start these patients may have suffered from ”subclinical CD.”s7 A number of ”chronic” lesions, such as aphthoid ulceration, histiocytic microgranulomas, pseudopyloric metaplasia, and sarcoidlike granulomas, bear close resemblance to those found in proven CD and have been regarded as the earliest manifestations of the disease.122Epidemiologic studies demonstrated that the true prevalence of IBD, and especially the prevalence of CD, may have been underestimated by 27% to 38’/0.~~

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The following arguments substantiate the hypothesis of the existence of subclinical IBD in some patients with SPA: CD-like lesions are found in patients with SpA and a negative 97 history for gut In family studies, CD-like lesions were found in patients with AS of whom the next-of-kin suffered from proven CD.'O' Immunohistologic studies" demonstrated that the pattern of immunoglobulin containing cells in the lamina propria of patients with "chronic" lesions was similar to that of patients with proven CD and was significantly different from the pattern observed in patients with acute lesions, which was similar to the pattern found in patients with infectious colitis. A genetic association with HLA-BW62 was found in 30% of the patients with chronic lesions; the same prevalence of this antigen was found in patients with proven CD.9Z The finding that 6% of the SpA patients who initially did not show any clinical symptoms of IBD but presented chronic inflammatory gut lesions at ileocolonoscopy developed CD 2 to 9 years later.91,93 _I

Prognostic Factors in Relation to Gut Involvement

By comparing SpA patients with an evolution to IBD with those who did not evolve to IBD, risk factors could be evaluated. The experience of regular episodes of diarrhea early in the disease history, the persistence of raised inflammatory serum parameters, and the presence of chronic inflammatory gut lesions were found to be risk factors for the development of IBD. HLA-827 negativity in the presence of sacroiliitis is another important risk factor, confirming the hypothesis that 827negative patients with AS are at a greater risk for IBD.73,98 SpA may develop in B27-negative patients who carry genes associated with IBD, without showing clinical signs of IBD.63 The evolution of disease was also evaluated in relation to the presence of HLA-B27 and HLA-BW62.92As in previous studies, HLA-B27 was equally present in patients presenting a normal gut histology at ileocolonoscopy as in those with the two different types of gut inflammation, whereas HLA-BW62 was significantly elevated in patients with chronic inflammatory gut lesions. At review, HLA-B27 was statistically significantly more prevalent in patients with persistent locomotor inflammation than in patients in articular remission, whereas the reverse applied to HLA-BW62. HLA-B27 positivity could predispose to the evolution of SpA to full-blown AS, whereas HLA-BW62 could have a protective role in the evolution of locomotor inflammation; at the contrary, it seems to be associated with subclinical CD. By performing a second ileocolonoscopy, all of the patients who were in clinical remission seemed to have a normal gut histology.93About half of them with active

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locomotor inflammation still presented with inflammatory gut lesions, predominantly of the chronic type; in 6 of these 14 patients, IBD developed. None of the patients with an initially normal gut histology had gut inflammation at second examination. From this, the finding of a normal gut histology on ileocolonoscopy seems to be predictive of a good prognosis in patients with SPA. Evolution of non-AS SpA to full-blown AS and evolution of uncomplicated SPA to IBD was always associated with the presence of gut inflammation at disease onset, and one of five patients with SpA and chronic gut inflammation will develop IBD within the next 5 to 9 years.

Therapeutic Consequences Sulfasalazine is an effective drug in the treatment of UC, as has been demonstrated in the treatment of active disease and in the prevention of 31 The efficacy of sulfasalazine in the treatment and in the 141 prevention of recurrences of CD is more contr~versial.~~, Sulfasalazine is split in the colon into two components: (1) a sulfamide component that has been shown to be the active component in the treatment of the arthritis in and a 5-ASA component that is the active moiety in the treatment of colonic inflammation in patients with IBD.4Because arthritis is a major manifestation in SPA and because the gut seems to play a role in the disease, it was assumed that sulfasalazine could provide some benefit in treating patients with the various SpAs. Sulfasalazine has been found to be effective in placebo-controlled, double-blind studies in patients with AS, mainly for peripheral arthritis but in some studies also for axial disease.33, 64,lO9 Efficacy has also been ~ reported in other forms of SPA, including ReA,’04,140 P s A , ~late-onset pauciarticular JCAPl,6o and AAU.34 Recently two large, double-blind, multicenter studies performed in and in the United Statesl7-l9in AS, ReA, and PsA confirmed the overall beneficial effect of the drug with improvement in both clinical and laboratory markers. The most pronounced effects were seen in patients with PsA. The prevalence of side effects was relatively low. Although initial trials33,lO9 showed some benefit for both axial and peripheral arthritis in AS, the recent large, multicenter trialsI8,35 confirmed that the efficacy of sulfasalazine in SPA is only demonstrable on peripheral arthritis and tendinitis. 383

Why Perform an Ileocolonoscopy? Although the main reason to perform ileocolonoscopy was initially to detect patients with SPA who could have presented an occult, subclinical form of IBD, it turned out that abnormalities in the gut could have major consequences in the development of joint symptoms in many patients with SPA.

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Ileocolonoscopic findings have some clinical and prognostic importance. As described earlier, that presence of gut inflammation is clearly related to a more severe clinical and radiologic expression of disease in most of the SPA entities and especially in AS?7 Presence of chronic gut inflammation can be the first sign of CD, and in the future, early treatment of the gut inflammation could prevent this evolution when the appropriate drug becomes available. Actually, we still do not have the management plan that prevents further evolution of inflammatory lesions in the gut, but we can speculate that some new developments will happen in this field by which the immune mechanisms in the gut will be elucidated. _I

RHEUMATIC MANIFESTATIONS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE Rheumatic symptoms are the most common extraintestinal manifestations in patients with IBD. In some cases, the occurrence of arthritis is related to the presence of other extraintestinal manifestations, such as uveitis and erythema nodosum. The peripheral arthritis and the spondylitis occurring in patients with IBD are considered as enteropathic arthritides. Other locomotor extraintestinal manifestations include granulomatous joint and bone involvement, periostitis, clubbing, and osteoporosis. For several years, the enteropathic arthritis in patients with IBD, unlike the arthritis in Whipple's disease and celiac disease, has been included in the SpA concept. According to the European Spondyloarthropathy Study Group (ESSG) criteria for SPA,^^ patients with IBD presenting with inflammatory low back pain or peripheral synovitis are classified as having SPA. Patients with IBD who present with an asymptomatic sacroiliitis do not fulfill the ESSG criteria; however, the enteropathic arthritides in patients with IBD differ in genetic and clinical ways from the entire group of spondyloarthropathies. The presence of HLA-B27 antigen is not related to peripheral arthritis in patients with CD, whereas it is strongly related to peripheral arthritis in patients with ReA. The prevalence of HLA-B27 is lower in patients with an axial involvement compared with idiopathic AS, although they are indistinguishable on roentgenogram. Erosive joint disease is seen in less than 10% of patients with IBD, but in patients with SPA, erosive joint disease of the hands and feet joints is seen in 25%.'O0 The prevalence of peripheral enthesiopathy is even lower in patients with IBD than in patients with the other spondyloarthropathies. Long-term prospective studies in patients with IBD are needed to evaluate the utility of actual sets of classification criteria and to distinguish specific IBD-related rheumatic entities.

Clinical Manifestations and Clinical Patterns and Differences with Rheumatoid Arthritis The rheumatic manifestations associated with IBD may be subdivided into four groups: peripheral arthritis, spondyloarthritis, peripheral

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enthesiopathy and a fourth group of less common rheumatologic entities including clubbing, periostitis, amyloidosis, and granulomatous disease of bone and joint. Osteoporosis and osteomalacia are not considered in this review. In respective studies, the prevalence rates of articular involvement in IBD vary from 2% to 26%.48,lg5The prevalence of arthritis in children with IBD is about the same as in adults.lll The Peripheral Arthritis in Inflammatory Bowel Disease is a Nondeforming Arthropathy

The overall incidence of peripheral arthritis in patients with IBD ranges from 2% to 20%.48,52 Disease duration has no influgnce on the prevalence of arthritis. There is an equal incidence among sexes. Peak age of onset is 25 to 44 years. Data on the incidence of peripheral arthritis in CD distinct from UC are conflicting, but recent studies suggest an incidence of peripheral arthritis of 20% in CD and of 12% in UC.48,52 The clinical characteristics of the arthritis are similar in CD and UC. The arthritis is generally pauciarticular and asymmetric, involving preferentially the lower limbs, although polyarticular disease is also described."O Usually the arthritis is transient and migratory. In general, it subsides over 6 to 8 weeks but evolves to a chronic arthritis in 10% of cases.83Recurrences are common. Synovial fluid analysis reveals lowgrade to severe inflammation, with leukocyte counts ranging from 1000 to 50,000 cells/ kL, predominantly n e ~ t r o p h i l sRoentgenograms .~~ of peripheral joints show generally no erosions, although erosive disease of the hip, metacarpophalangeal, and metatarsophalangeal joints has been described.=, In the latter two, they differ from rheumatoid arthritis in their asymmetric and pauciarticular involvement and in the presence of repair phenomena (Fig. 6). Histopathology of the synovium shows a mild chronic inflammation indistinguishable from rheumatoid arthritis. Peripheral arthritis can occur with axial arthropathy and other extraintestinal manifestations like uveitis and erythema nodosum. According to the ESSG criteria for SpA all IBD patients with peripheral arthritis are classified as SPA.^^ Recently the prevalence of SPA in CD was estimated at 11%in CD and at 14% in UC.l18 In this study 28% of the SPA patients presented with an isolated peripheral arthritis. Distinct from the above-mentioned peripheral arthritis, a destructive arthritis involving the large joints, especially the hip, is reported. This is seen in patients with spondylitis and resembles the hip involvement in AS patients. A destructive coxopathy is described in 2% of the patients with CD.'j Before classification of peripheral arthritis as an SPA, other diagnoses of rheumatic diseases, like rheumatoid arthritis, scleroderma and systemic lupus erythematosus in patients with IBD have to be ruled out. Sometimes the latter diseases can also present as a asymmetric synovitis. Differences between peripheral arthritis in IBD and rheumatoid arthritis are listed in Table 2. There is no increased incidence of the HLA-B27 antigen in patients with IBD and peripheral arthritis in contrast to other

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Figure 6. Erosive arthritis of metatarsophalangeal joints in a spondyloarthropathy patient. New bone formation at the margins of the joints is present.

enterogenic SPA such as ReA in which a frequency of 60% of HLA-B27 is observed. Ankylosing Spondylitis and Asymptomatic Sacroiliitis

Two forms of axial arthropathy can be associated with IBD: (1) ankylosing spondylitis, radiologically and clinically indistinguishable

Table 2. DIFFERENCES BETWEEN RHEUMATOID ARTHRITIS AND PERIPHERAL ARTHRITIS IN INFLAMMATORY BOWEL DISEASE Characteristic Age Sex predominance Onset Behavior Affected joints Course Rheumatoid factor Shared epitope Radiology

Peripheral Arthritis in IBD

Rheumatoid Arthritis

Younger (av., 30 y) No Abrupt Migratory Pauciarticular (<5) Asymmetric Lower limbs Nondeforming Absent Not evaluated No erosions (generally)

Older (av., 50 y) Female Gradual Nonmigratory Polyarticular Symmetric Hands and feet Deforming Present Present Erosions

IBD, inflammatory bowel disease; av., average

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from idiopathic AS; and (2) asymptomatic sacroiliitis. Symptomatic spondylitis is reported to occur in 1% to 20% of patients with IBD, although actual prevalence is probably higher.27,131, 145 Spondylitis in IBD may occur at any age, whereas in AS the peak age of onset is 18 to 40 years. The sex ratio is 1:1, obviously distinct from the ratio in AS. In women with IBD, AS is more prone to develop, they are younger at disease onset, and the prognosis is worse. Asymptomatic bilateral sacro145 and iliitis is seen in approximately 4% to 25% of patients with IBD,Z6* progress to spondylitis is not The reported incidence of HLA-B27 in patients with IBD and spondylitis is in the range of 50% and 75% and is significantly lower than The addition of HLA-B6O increases the risk for those in AS (90%).57,80,129 AS in IBD.125Incidence of AS seems highest in patients with HLA-B27, B44 phenotype.*20Isolated sacroiliitis in patients with IBD is not associated with an increased incidence of HLA-B27 ~ h e n 0 t y p e . l ~ ~ Enthesiopathy Peripheral enthesiopathy, especially inflammation of the Achilles tendon and the insertion of the fascia plantaris, is a common manifestation in patients with SPA but is apparently less common in patients with IBD. Peripheral enthesiopathy occurs in 6% of the patients with IBD.lz9Peripheral enthesiopathies are hardly looked for in patients with IBD. More attention should be drawn to the presence of peripheral enthesiopathy in clinical studies because it is the most specific feature of the SpA and it can be the first symptom of it, especially in younger patients. Miscellaneous Clubbing occurs in 8% to 11%of patients with IBD, either with CD or UC, mostly at the fingers, and it may be associated with the presence is more common in patients with CD of erythema n o d o s ~ mClubbing .~~ and ileal involvement than in patients in whom the disease is restricted to the colon. Rarely, clubbing is accompanied by periostitis and consequently it is not considered a hypertrophic osteoarthropathy. Periostitis is infrequently seen in patients with IBD and can be painful.47 Granulomatous synovitis is described in numerous cases of patients 55* 72 The hip, knee, ankle, and with IBD and persisting monoarthriti~.~~, wrist may be involved. Pathologic examination reveals a chronic synovitis with noncaseating epithelioid granulomata. Sequence of Events Between Joint and Gut Manifestations

In general in IBD patients, peripheral arthritis occurs simultaneously or after the onset of IBD, but cases of antedating peripheral arthritis

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have been In young children, arthritis has also been reported as the initial manifestation of IBD.145The incidence of peripheral arthritis is not influenced by the presence of gastrointestinal complications, such as fistula, strictures, or abscesses.48In contrast to peripheral arthritis, the onset of axial involvement is independent of the bowel disease and may 118 Its subsequent clinical precede the intestinal symptoms by 20 years.11o, course is independent of the severity, extent, location, and duration of IBD. An increased frequency of SPA, antedating intestinal disease, as high as 27%, has been reported.'ls This was also seen in patients with isolated peripheral disease or axial disease and in patients with peripheral and axial involvement. Furthermore, the presence of subclinical IBD has been reported in patients with SPA undergoing ileocolonoscopy and histology study of biopsy specimens. Subclinical gut inflammation has been found in 60% of patients with SPA.^^ An evolution to clinical IBD has been observed in 20% of patients with an initial subclinical chronic gut inflammation, indicating that joint and tendon inflammation may be the first clinical manifestation of IBD.9l Noteworthy was the evolution of articular disease to AS in all patients evolving from subclinical gut inflammation to overt IBD.91 The presence of peripheral arthritis is frequently associated with other extraintestinal manifestations such as skin and eye involvement. Erythema nodosum occurs in 4% of patients with IBD, with a higher frequency in patients with CD,4s and it correlates with the disease activity but not with the extent of the lesions. Erythema nodosum is frequently seen in association with arthritis and uveitis. Arthritis is seen simultaneously in 70% of patients with IBD and erythema nodosum. Flare-ups of erythema nodosum and arthritis seem to parallel each other. Pyoderma gangrenosum occurs in 2% of patients with IBD and is more common in patients with UC than in those with CD? Arthritis is seen in 38% of the patients with IBD and Pyoderrna gangrenosurn infection.26 AAU and panuveitis are common manifestations in patients with IBD and are associated with arthritis in 25% to 33% of patients.83,145 AAU is reported as the unique clinical manifestation in 2% of patients with subclinical CD.lo5 Effects of Flares or Remission in the Gut on Rheumatic Manifestations

Exacerbations of IBD and flares of peripheral arthritis tend to coincide, and arthritis is more common in patients with chronic disease than in patients with an acute fulminant colitis.1o6The frequency and severity of the peripheral arthritis complicating IBD is correlated to the severity of the IBD and to the extent of colonic i n v o l ~ e m e n tArthritis .~~ is more common in patients with CD and colonic involvement than in those with isolated small bowel lesions, although involvement of the ileum alone can be associated with peripheral arthritis.48In patients with UC, total colectomy may prevent further articular attacks. Bowel surgery

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does not influence the articular manifestations in patients with CD. Attacks in children generally occur during or within 1 month of bowel flare, but joint involvement occurs only in a small percentage of the flares and does not reflect the extent or severity of bowel disease."l Persisting arthritis in patients with no bowel symptoms may signal the silent progression of the bowel disease. In contrast, symptoms of spondylitis tend to be unrelated to exacerbations and remissions of bowel disease. Bowel surgery does not alter the course of associated spondylitis or sacroiliitis. Treatment of Spondyloarthropathy in Patients with Inflammatory Bowel Disease

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The natural history of SpA 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 SPA rapidly respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Because these drugs may reactivate quiescent IBD,27caution is in order. For peripheral arthritis, an optimal treatment of the bowel disease is the first goal of therapy, considering the known relationship between intestinal and articular disease. For axial disease, sulfasalazine (SASP) was proposed as a drug of choice because its beneficial effect has been demonstrated in several placebo-controlled trials.*l Efficacy seems related to SASP and not to 5ASA.138Data on the long-term efficacy of SASP are more scarce and disparate: A large, placebo-controlled study including 264 patients with AS failed to show a significant effect of SASP after 9 months of treatment of patients with chronic longstanding AS but demonstrated an improvement of associated peripheral arthritis.17In contrast, another large trial including 351 patients with AS showed a significant improvement in the but overall assessment in 60% of patients after 6 months of once again the activity of the drug was more obvious on peripheral joints than on the axial involvement. Data about azathioprine and 6-mercaptopurine and methotrexate in severe cases of SPA are anecdotal but promising.21Because azathioprine and 6-mercaptopurine is an increasingly used form of chronic treatment of patients with IBD, efficacy can be expected in IBD with longstanding SPA. Finally, arthritis is not an indication for systemic use of corticosteroids, although associated exacerbation of bowel disease may require its use. Effects of Nonsteroidal Anti-Inflammatory Drugs on the Gut

Morphologic Lesions Intestinal lesions caused by the intake of NSAIDs are rare and mostly restricted to case reports. Several cases have been described

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associating the presence of diaphragm-like webs in small or large bowel with the intake of NSAIDS.~, 27, lZ4 Characteristically, these webs consist of small, circular rings of submucosal fibrosis frequently associated with small ulcers at the crest. Inflammation is mild and atypical at histology. These lesions can be the result of scarring of local ulcerations caused by direct contact of NSAIDs. Although these webs are mostly asymptomatic, obstruction, bleeding, and perforation have been rep0~ted.I~~ Small intestinal and colonic ulcers have been described in patients taking NSAIDs, and they are associated mostly with bleeding or perforations>* Moreover, retrospective epidemiologic studies reported a higher rate of intestinal hemorrhages and perforations in patients taking NSAIDs than in control populationsF, NSAID-induced colitis is rare and is described after the intake of fenemates, ibuprofen, naproxen, piroxicam, and di~lofenac.~~ This colitis is nonspecific and disappears after discontinuation of the drug. A possible association between NSAIDs and collagenous colitis was also reported in a case control Effect on Preexisting Disease

NSAIDs may be responsible for complications in diverticular disease, as was suggested by a case control studyI6 and supported by a prospective Several cases of reactivation of IBD attributable to NSAIDs have been d e s ~ r i b e d ? ~The , ~ ~intake , ~ ~ ~of NSAIDs may be associated with an increased risk for emergency admission to the hospital for colitis caused by IBD, particularly among patients with no previous hist0ry.3~The intake of NSAIDs makes suspect the concomitant joint disease in these patients, but this issue was not approached by the authors. Subclinicat Lesions An increase of paracellular permeability for chrome ethylenediaminetetraacetate (Cr EDTA) and low molecular weight polyethylene glycol (PEG 400) has been demonstrated.8,89This increase seems to result from primary biochemical damage inducing an uncoupled mitochondrial oxidative phosphorylation with disruption of the tight junctions.8 The increase of the permeability can be the cause of inflammatory infiltrations in the gut mucosa by enhanced challenge of toxins, bacteria, and luminal This inflammation was objectivated by indiumlabeled leukocyte scan? Scintigraphic studies in patients with RA and osteoarthritis have shown an accumulation of indium in the mid-small intestine in about half of patients; however, because the interpretation of these scans is subjective, the significance of these data remains controversial. Moreover, the relationship between inflammation and NSAIDs reported by Bjarnasson7was not confirmed by Segal and colleagues.132 A small bowel examination with a sonde enteroscope added some morphologic support to the functional studies and demonstrated sub-

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clinical mucosal lesions in 27% of patients.lo7Finally, a large prospective postmortem study described nonspecific small intestinal ulcers in 8% of patients on NSAIDS.~ No definite conclusion can be drawn from the existing data. A longterm prospective study on a large number of patients, including a placebo group and in whom ileocolonoscopy is performed, can bring a definite answer to the key question.

FROM THE GUT TO EXTRAINTESTINAL TARGET ORGANS The Gut in Animal Models of Spondyloarthropathy The challenging link between gut inflammation and arthropathies in humans has also been documented in some animal models of SPA. HLA-B27 transgenic rats provide the first and most convincing model in which a relationship between gut and synovial inflammation was observed. Several lines of rats transgenic for various class 1 HLA heavy chains and human Pnm-microglobulin (hP2m) genes have been establ i ~ h e d Half . ~ ~ of the lines expressing HLA-B27 and hP2m develop a spontaneous, multisystem, inflammatory disorder resembling the human SPA in many ways. The disease is characterized by the presence of prominent gut inflammation, peripheral sterile arthritis, and inflammatory lesions of intervertebral discs reminiscent of AS. Other features are skin and nail changes reminiscent of human psoriasis. Apparently less relevant to the human disease are the male orchitis and demyelinating lesions of the brain. None of the A2 or B7 control transgenic rat lines developed inflammatory changes comparable with the B27 lines. The role of bacterial flora in these rats became apparent when these B27 rats were bred in a specific pathogen-free environment. In the absence of bacterial flora, the gut and joint inflammation were totally suppressed, whereas skin lesions and male orchitis persisted unchanged. In addition, exposure of germ-free 827 transgenic rats to conventional flora induced gut inflammation similar to the spontaneous disease.139This indicates not only that bacteria play a triggering role in the disease but also that the gut and joint symptoms in this model are linked. The second model in which gut inflammation has been described is observed in the HLAB27 transgenic mice. Introduction of a hp,m transgene in these mice was found necessary to achieve a stable expression of the HLA molecule at the cell surface. Although these mice have a functional HLA-B27 product, B27 transgenic mice usually remain healthy. One group found diminished clearance of Yersiniu enterocoliticu after intestinal infection in B27 transgenic mice compared with mice transgenic for another human ~ of gut inflammation class 1 locus (A2) or to nontransgenic m i ~ e . 5Foci

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and minimal sterile joint synovitis were described only in these B27 transgenic mice.

Enteropathogens in the Joints In ReA, the triggering infection is known in many cases, and the hypothesis has been that this complication is caused by persistent infection or by persistence of bacterial components in the body.12,43, 76 In patients with Yersinia-triggered reactive arthritis, Yersinia bacteria persist for years in intestinal mucosa, where they have been demonstrated with immunochemical techniques.28Consequently, comgonents of the causative microbes have been detected also in inflamed joints. In reactive arthritides following enteric infections, such as Yersinia, Salmonella, and Shigella infections, components of lipopolysaccharide have been specifically detected in synovial fluid cells, in mononuclear and polymorphonuclear phagocytes.44-46The same antigens have been found also in synovial membrane.%In all of these cases, in immunofluorescence, and in immunoblotting, the detected lipopolysaccharide was highly processed, and no intact-looking bacteria were seen; however, the same samples were carefully cultured to isolate possible living organisms, but the results have always been negative. PCR analysis to demonstrate Yersinia DNA in synovial fluid cells or in synovial membrane have been negative as well.los,142 In the synovial membrane of patients with Yersiniatriggered ReA, another component of the Yersinia outer membrane, YadA, has been detected.5O Whether these lipopolysaccharide components detected in the joints could be target antigens for cellular immune responses is not known. Interestingly, they obviously induce local antibody production in the joint in ReA after SaZmonelZa and Yersinia infections.n,78 An effective immune response to intracellular microorganisms depends on T cells, and, consequently, bacteria-specific T cells in the synovial fluid are thought to play an important role in the pathogenesis of ReA. Several groups have found that T-cell proliferative responses to bacteria triggering ReA are clearly higher in synovial fluid than in peripheral blood.4°,135 This might be caused by two factors: (1)presentation of bacterial antigens has been shown to be more effective by synovial antigen-presenting cells than by antigen-presenting cells from peripheral and (2) the frequency of antigen-specific T cells in synovial fluid is clearly higher than in peripheral bl00d.l~~ These findings support the theory that synovial inflammation in ReA is caused by a synovial immune response against local microbial structure^.^^ In some cases, the triggering bacterium can be identified by means of antigenspecific proliferative response of synovial fluid T cells.136More specific information about antigenic specificity has been obtained by investigating T-cell clones. Immunodominant 60-kd heat-shock protein of ReA triggering bacteria has been first found to be a target antigen for the cellular immune responses.116,117, 143 Interestingly, this same structure of

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Yersinia has recently been detected with a specific antibody in synovial fluid cells from patients with Yersinia-triggered reactive arthritis (Granfors and colleagues, unpublished observations, 1997). From the synovial fluid of a patient with Yersinia-triggered ReA, a clone that recognizes both enterobacterial and human heat shock protein has been isolated, suggesting that autoimmune mechanisms also play a Other immunodominant proteins of Yersinia are the highly conserved ribosomal proteins L2 and L23 and the 19-kD subunit of the urease of Yer~inia.~~ The capability of the causative agents to live intracellularly has raised the question of whether peptides of these bacteria are presented by MHC class 1 antigens to CD8+ T cells. Information obtained so far has indicated that T-cell responses to bacterial antigens in the jdnts are 134 but CD8 + responses have been found mostly driven by CD4 cells,40* in 30% of synovial fluid mononuclear cells from patients with ReAll and in 20% of cellular infiltrates in the synovial membrane of the sacroiliac joints of patients with AS.l0 HLA-B27-restricted cytotoxic CD8 T cells with specificity for arthritogenic bacteria are also found among synovial fluid cells from patients with Yersinia- or Salmonella-triggered reactive arthritis.54They obviously are important for elimination of bacteria and their antigens. Disturbances in presentation of bacterial peptides by HLA-B27 in Salmonella and Yersinia infections might lead to impaired elimination and persistence of these bacteria. So far, no epitope recognized by these CD8+ cells has been identified.

+

+

Gut lteropathy Concept

An intriguing relationship exists between gut and synovium in patients with SPA. A high frequency of inflammatory gut lesions has been described previously in these patients.90,95, 96 Also, prospective follow-up studies in a large cohort of patients with SPA demonstrated that all the patients who went into clinical remission after treatment had normal gut histology at review, whereas active locomotor inflammation lo3 As was usually associated with the presence of gut inflammati~n.~~. mentioned earlier, a similar linkage between gut and articular symptoms has been described in HLA-B27 transgenic rats. The mechanisms that link gut and synovium in SpA are still unknown. Some hypotheses are: Spreading of infectious microorganisms Transportation of antigenic determinants Antigenic cross-reactivity Gut-iteropathy (homing receptors) Hemodynamic circulatory aspects Recirculation of antigen-specific memory T cells from gut to synovium is at the basis of the relation between gut and synovial inflammation. Previously, such a migratory pathway has been termed g~t-iferopathy.'~~ The immune system can be divided into three compartments: (1) the primary, (2) secondary, and (3) tertiary lymphoid organs.113The

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maturation of nonfunctional precursor cells to mature, albeit naive lymphocytes, occurs in primary lymphoid organs and is represented by the bone marrow and the thymus. The secondary lymphoid differentiation occurs in specially organized microenvironments that support the antigen-specific differentiation and proliferation of lymphocytes. In particular, these are the sites where naive lymphocytes respond for the first time to specific antigens and undergo an antigen-initiated differentiative process, that is, the virgin to memory-effector transition. These tissue compartments (e.g., lymph nodes, spleen, and Peyer's patches) are referred to as secondary lymphoid organs. Tertiary lymphoid tissues include all other body tissues, such as synovial tissue. Under normal conditions, these contain only a limited number of lymphoid eel&: however, upon the presence of inflammatory stimuli, they may become populated with immune competent cells, including memory lymphocytes and effector cells that can be restimulated by antigen. One of the interesting aspects of the gut, from an immunologic point of view, is that it combines secondary lymphoid tissue (Peyer's patches) and tertiary lymphoid organs (lamina propria and gut epithelium). The recirculation of lymphocytes throughout the body is an essential phenomenon in the whole cascade of immune sur~eillance.'~~ This process of lymphocyte trafficking is mainly regulated by receptors belonging to a group of molecules referred to as adhesion moZecuZes, which constitute the molecular basis for cell-cell and cell-matrix interactions.', 112, These receptors not only regulate cell migration but also mediate important functional activities of the cell. Adhesion molecules can be divided, according to their molecular structure, into three broad families: (1) the integrins, (2) the selectins, and (3) the immunoglobulin superfamily members.', 22, '12 Naive lymphocytes probably traffic continuously between the various lymphoid organs until they die or respond to their cognate antigen.l14On the contrary, memory and effector lymphocytes, generated in secondary lymphoid tissues in response to antigen and exported back into the circulation, display different migratory properties compared with naive cells. These cells can traffic effectively to tertiary lymphoid tissues, particularly when these tissues are inflamed.75,'15 In addition, differentiation into the memory subset is accompanied by the development of tissue-restricted homing ~apabi1ity.l'~ The tissue-selective homing properties of memory and effector cellular subsets may enhance the efficiency of the immune system by targeting immune surveillance to tissues that are most similar to those in which the antigen initially entered the body.113In other words, after engagement of their cognate antigen, lymphocytes selectively accumulate at the sites similar to their original activation to destroy the invading stimulus. Thus, according to the current paradigm, small lymphocytes that mature into immunoblasts in mesenteric lymph nodes return to the systemic circulation via efferent lymphatics and then enter into the gut lamina propria to exert their effector functions. In addition to the physiologic role of lymphocyte recirculation in

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the immune surveillance, recirculation of pathogenic T cells may also be one of the clues to the presence of the gut-synovium axis in patients with SPA. In this view, antigen-induced activation, proliferation, and partial differentiation of T cells in the gut would be followed by migration of primed T cells to regional lymph nodes, from which (probably after further differentiation) they go via lymph into the peripheral blood circulation and extravasate at synovial high endothelial venules, causing lymphocytic infiltration of the synovial membrane. This hypothesis is supported by in vitro homing studies (Stamper-Woodruff assay) illustrating that T-cell lines expanded from lamina propria from patients with IBD and from peripheral blood bind significantly more to mucosal and synovial endothelium compared with endothelium from peripheral lymph nodes; moreover, T-cell lines from synovial membranes Sdhere to mucosal end0the1ium.l'~Previous studies in animals, using a similar assay, demonstrated that the in vitro binding results highly correlated with in vivo homing behavior.'" l4 Additional studies on the gut-synovium axis demonstrated that mucosal immunoblasts adhered significantly better than small mucosal lymphocytes to mucosal high endothelial venules (HEV) and that the immunoblasts also bound to synovial HEV almost as efficiently as to mucosal HEV.143In contrast, they did not adhere to peripheral lymph node HEV. In addition, the molecular basis of the interaction between mucosal effector cells and synovial endothelial cells has been further investigated by blocking inhibition studies and One major seemed to rely mainly on vascular endothelial protein l.143 drawback of these studies, however, is that synovial specimens used were selected only on the basis of chronic inflammation and that no subdivision was made on the basis of the clinical diagnosis. Moreover, since these studies were conducted in chronically inflamed synovial tissue at the occasion of joint replacement surgery, one could question whether the information provided from these studies can univocally be extended to the initial phases of the disease. In other words, whether recirculation of lymphocytes is involved in the induction or in the perpetuation of synovial inflammation related to enteropathies is unclear. Thus, other factors may be involved. In particular, the presence of bacterial antigens in the joints of patients with enterogenic ReA has raised the idea that migration of antigen presenting cells may also link gut and joints. In particular, the mucosal macrophages have been indicated as prime candidates to transport antigens introduced via mucosal surfaces to joints. Recently, the results of in vitro binding studies of mucosal macrophages to inflamed synovial HEV have been reported.128 Interestingly, this interaction is completely differently mediated compared with lymphocytes because this binding was P-selectin dependent. Mucosal macrophages do not differ in this respect from the peripheral blood monocytes because their synovial binding is also mediated by P-selectin. The relative importance of macrophage versus lymphocyte migration for the gut synovium axis is not known. A sequential model has been proposed in which the mucosal macrophages carry the trig-

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gering antigens from gut to joints, followed by mucosal effector cells (immunoblasts) that aggravate the inflammatory reaction. The crucial role of T cells in the pathogenesis of arthritis can be deducted from studies conducted in the proteoglycan (PG)-induced arthritis model. These animals (Balb/c-mice) develop AS and peripheral arthritis leading to joint ankylosis with characteristic clinical and histopathologic lesions and features of human SPA.^*, 86 Interestingly, the disease can be transferred by T cells to previously healthy mice (adoptive transfer experiments). Using labeled lymphocytes in adoptive transfer studies, it has been shown that only labeled cells from arthritic animals migrated to the synovial tissue of the recipient mice, and their appearance was associated with the onset of arthritis.86Furthermore, the results of additional studies using T-cell hybridomas are even m r e interesting. Sixteen PG-specific T-cell hybridomas were generated from arthritic mice. Subsequently, the hybridomas were tested for their in vivo arthritogenic potential when injected intravenously into naive irradiated BALB/c mice. Only one hybridoma was capable of inducing arthritis, similar to the PG-induced arthritis.15 A clear joint-specific migration of these cells was evident in mice with arthritic manifestations, as hybridoma cells were abundant in limb sections but hardly detectable in sections of lung, liver, and spleen from arthritic animals. On the contrary, massive tumor cell infiltration in the lung and destruction of the normal spleen structure were noted in mice that were injected with nonarthritogenic hybridomas. Thus, only those antigen-specific T cells or T-cell hybridomas that are capable of entering the joints were able to cause arthritis.

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