Long-term Evolution of Gut Inflammation in Patients With Spondyloarthropathy

Transcription

1 GASTROENTEROLOGY 1996;110: Long-term Evolution of Gut Inflammation in Patients With Spondyloarthropathy MARTINE DE VOS,* HERMAN MIELANTS, CLAUDE CUVELIER, ANDRÉ ELEWAUT,* and ERIC VEYS Departments of *Gastroenterology, Rheumatology, and Pathology, University Hospital Ghent, Ghent, Belgium Background & Aims: Intestinal inflammation has been The concept is further characterized by a frequent associaobserved in patients with spondyloarthropathy (SpA). tion with the HLA-B27 phenotype and a positive family This prospective study reports the evolution of the in- history of SpA. Several clinical entities belong to this testinal inflammation observed in patients with SpA. concept: ankylosing spondylitis (AS), reactive arthritis in Methods: One hundred twenty-three patients with SpA patients with a recent history of urogenital or intestinal who had undergone initial endoscopy were clinically infection, some forms of psoriatic arthritis or juvenile reassessed. Intestinal evolution was evaluated by ileochronic arthritis, and, finally, the extraintestinal articular colonoscopy and the histological study of biopsy specimanifestations of inflammatory bowel disease (IBD). Pamens in 49 patients. Results: Articular remission rates were independent of initial gut inflammation and assofiable in one of the clinical entities are defined as undiffer- tients fullfilling the criteria of SpA without being classiciated with endoscopic and histological remission. Perentiated SpA. sistent gut inflammation was observed in active joint disease. Gut inflammation rarely disappeared, despite We have described previously the presence of subclini- the persistence of articular complaints. Initial chronic cal gut inflammation in more than half of patients with gut inflammation implied a high risk of evolution to SpA after exclusion of patients with psoriatic arthritis or ankylosing spondylitis. Evolution to inflammatory bowel SpA associated with IBD. 2 5 Recently, these findings disease (IBD) was observed in 7% of patients. Mainly have been confirmed by others. 6,7 Two types of inflampatients with initial chronic inflammation and mild com- mation were distinguished: acute inflammation resemplaints of diarrhea were at risk. Sulfasalazine was more bling infectious enterocolitis and chronic inflammation frequently needed in the treatment of patients with gut more suggestive of early Crohn s disease. 8 inflammation with a beneficial effect on articular and In the present study, the long-term follow-up of these intestinal evolution but did not prevent evolution to IBD. Conclusions: This study supports the etiopathoflammation and its relationship to the articular outcome patients was evaluated and the evolution of the gut ingenetic role of the gut in SpA. Presence of chronic gut inflammation and mild complaints of diarrhea implies and to IBD were studied. The influence of the intake of a high risk of evolution to ankylosing spondylitis and sulfasalazine (SASP) and nonsteroidal anti-inflammatory IBD. Sulfasalazine has a beneficial effect on articular drugs (NSAIDs) on this outcome was also analyzed. activity by controlling gut inflammation, but it cannot prevent evolution to overt IBD. Patients and Methods Three hundred fifty-four patients with SpA underwent ver the last two decades, the concept of spondy- (SpA) has evolved into a distinct clin- an initial ileocolonoscopy with concomitant histological study of the intestinal mucosa. Patients with IBD or psoriasis-associ- Oloarthropathy ated SpA were excluded. ical entity including an axial involvement and/or a pe- All patients with follow-up of longer than 2 years (n Å ripheral inflammatory arthritis. 1 Typical axial symptoms 217) were telephoned: 123 patients (84 men and 39 women; are low-back pain and morning stiffness, alternating but- mean age, 34 years; age range, years) accepted a new tock pain, decreased mobility of the spine, and impaired clinical assessment, whereas 94 patients (65 men and 29 thoracic expansion; characteristic radiographic lesions are women) only accepted an extensive telephone interview. At sacroiliitis and spondylitis. The peripheral arthritis affects the initial endoscopy, gut inflammation, as defined in our predominantly the large and small joints of the Abbreviations used in this paper: AS, ankylosing spondylitis; SASP, lower limbs in an asymmetric pauciarticular pattern and sulfasalazine; SpA, spondyloarthropathy. is frequently associated with an enthesiopathy or in by the American Gastroenterological Association flammation of the insertion of the tendon to the bone /96/$3.00

2 June 1996 GUT INFLAMMATION IN SPONDYLOARTHROPATHY 1697 (erythema in 6 patients and erosions or ulcerations in 14 pa- tients). Microscopic gut inflammation was present in 69% of these patients (acute inflammation in 9 patients and chronic inflammation in 25 patients). Eleven patients underwent a third ileocolonoscopy 1 5 years (mean, 3.5 years) after the second endoscopy. During each ileocolonoscopy, four biopsy specimens were taken from the terminal ileum, three from the ileocecal valve, and six from different sites in the colon. These tissues were fixed in a 10% formalin solution, dehydrated, paraffin embed- ded, and routinely stained with H&E. The endoscopist and histopathologist involved were unaware of the clinical diagno- sis, the abdominal complaints, the disease history, and the previous findings. The diagnoses of acute and chronic inflammation were based on the same criteria as in our previous studies. 2,3,5,8 The most important differences between both types of inflammation con- cerned architectural changes. In acute inflammation, the normal mucosal structure was preserved and changes were limited to an infiltration of the epithelium with neutrophils and eosin- ophils, crypt abscess formation, and an infiltration of the lam- ina propria with polymorphonuclear cells. In contrast, chronic inflammation was characterized by crypt distortion, villous blunting and fusion, increased mixed lamina propria cellu- larity, and presence of basal lymphoid aggregates. In some of these patients, lesions such as sarcoid granulomas, aphthoid ulcers, and pyloric metaplasia were similar to the biopsy find- ings in Crohn s disease. As in our previous studies, macroscopic lesions were defined as grade 1 in the presence of small erythematous spots and grade 2 in the presence of erosions or ulcerations (Figure 1). previous studies, 8 was present in 63% of these 217 patients (acute inflammation in 49 patients and chronic inflammation in 88 patients). The clinically reviewed patients (n Å 123) were separated into two groups: one group with an initial diagnosis of AS (according to Rome classification criteria) 9 (n Å 52) and another group of patients with non-as SpA, including patients with urogenital reactive arthritis (n Å 10) triggered by a proven urogenital infection, patients with intestinal reactive arthritis (n Å 10) triggered by an intestinal infection with an etiologic agent cultured from the stool or with a progressive elevation of germ-specific immunoglobulins, and patients with undifferentiated SpA (n Å 51) (with criteria of SpA but not responding to the Rome classification criteria). At the initial endoscopy, gut inflammation was present in 67% of these 123 patients (acute inflammation in 28 patients and chronic inflammation in 55 patients). After the initial diagnosis of SpA, all patients were treated with NSAIDs. After 3 months, 2 3 g/day SASP (enteric coated) was added to the treatment in patients with still-active articular inflammation. NSAIDs were administered continuously at a low dosage and only stopped 1 year after the induction of clinical remission. If started, SASP was administered continuously and stopped when a sustained clinical remission was obtained for at least 2 years. Treatment was only adapted to clinical activity of the articular disease and not to intestinal complaints or to endoscopic or histological features. At the moment of the clinical reevaluation, the articular disease and intestinal complaints were evaluated by the rheumatologist. All patients were clinically examined with a focus on axial and peripheral joint involvement, chest expansion, Schober index, and the presence of peripheral enthesiopathy and uveitis. Patients were asked about their disease history, abdominal complaints, and drug intake. Radiographs of the sacroiliac joints, axial skeleton, and clinically involved joints were obtained. Clinical remission was defined as the absence of synovitis or tendinitis and the absence of inflammatory axial complaints or morning stiffness for at least 6 months. Diarrhea was defined as a spontaneous report of regular episodes of diarrhea or as daily stool frequencies of more than four stools per day. Diagnosis of IBD included the association of typical endoscopic lesions with histological and clinical features of IBD. This diagnosis was confirmed by the gastroenterologist. To evaluate the long-term evolution of the gut inflammation, 49 of these 123 patients accepted a second ileocolonoscopy. The time interval between two endoscopies was months (mean, 61.9 months; median, 70 months). The initial clinical diagnosis was AS in 30 patients and non-as SpA in 19 patients (including urogenital reactive arthritis in 2 patients, intestinal reactive arthritis in 3 patients, and undifferentiated SpA in 14 patients). Eighteen of these patients had initial complaints of diarrhea as defined in this study. As already mentioned, patients with overt or suspected IBD were excluded from this initial study. During the initial ileocolonoscopy, macroscopic lesions were present in 41% of these patients Figure 1. Endoscopic picture of grade 2 lesion in terminal ileum.

3 1698 DE VOS ET AL. GASTROENTEROLOGY Vol. 110, No. 6 For the statistical analysis, the x 2 test with Yates correction was observed in 13 of 51 patients with initial non-as or Fisher s Exact Test were used. Data were considered signifi- SpA and inflammatory gut lesions (25%) and in only 1 cant with P values of õ0.05. of 20 patients with initial non-as SpA and a normal gut Results histology (5%) (P õ 0.05). Clinical Evolution Table 1. Individual Results of Patients With SpA Who During clinical reevaluation, 53 of 123 patients Underwent Repeat Ileocolonoscopies With (43%) were found to be in articular remission. Remission Biopsies rates in the initial non-as SpA group and in the AS First group were 61% and 19%, respectively (P õ 0.001). ileocolonoscopy Second ileocolonoscopy Three patients were rediagnosed with rheumatoid arthri- Articular NSAID tis. An evolution from non-as SpA to AS was observed Patient Macro Micro Macro Micro Diarrhea disease intake in 19% of patients. Patients without abdominal complaints on first ileocolonoscopy It was impossible to subdivide the telephone group 1 0 N 0 N r N 0 N r / because no clinical or radiological data were available. 3 0 N 0 N r 0 Only some information about the presence or absence of 4 0 N 0 N r N 0 N r / clinical remission was obtained. The articular remission 6 0 C 0 N r 0 rate in the clinically reviewed group (43%) seemed to 7 0 C 0 N r C 0 N r 0 be lower than that in the telephone group (73%). 9 2 C 0 N r 0 The most important intestinal evolution was into full C 0 N r 0 blown IBD in 9 patients of the clinically reviewed group 11 0 C 0 N r A 0 N r 0 (7.3%). In the telephone group, 3 patients (3.2%) re N 0 N a / ported a similar evolution. In all patients with IBD, 14 0 N 0 N a / articular disease evolved into AS N 0 N a / 16 0 N 0 N a / Articular evolution, with respect to initial gut histol N 0 N a 0 ogy in the clinically reviewed group, is shown in Figure 18 0 N 0 N a / 19 0 N 0 N a / 2. No significant differences in remission rates were 20 0 N 0 N a / 21 0 A 0 N a / found between three different histological groups (18 of 22 1 A 0 N P a / 40, 12 of 28, and 23 of 55; P Å 0.9; NS). The remission 23 0 A 0 N a / 24 2 C 0 N a / rates in the non-as SpA subgroup were 13 of 20, 12 of 25 2 C 0 N a / 23, and 18 of 28, respectively (P Å 0.09; NS). In patients 26 2 C 0 N a / 27 0 A 1 A a / with AS, these rates were 5 of 20, 0 of 5, and 5 of 27, 28 2 C 1 A a / respectively (P Å 0.4; NS). However, progression to AS 29 0 A 1 C a / 30 1 A 1 C P a / 31 0 C 2 C a / Patients with abdominal complaints on first ileocolonoscopy 32 0 N 0 N r 33 2 C 0 N r / 34 2 C 0 N r 35 2 C 0 N r / 36 0 N 0 N a / 37 2 C 0 N a / 38 0 C 0 N a / 39 1 A 0 N a / 40 0 C 2 C P a / 41 1 C 2 C P a / 42 2 C 2 C P a / 43 1 N 2 IBD P a / 44 2 C 2 IBD P a / 45 0 C 2 IBD P a / 46 2 C 2 IBD P a 47 2 C 2 IBD P a / 48 2 C 1 IBD P a / 49 0 A 2 IBD P a / a, articular active disease; A, acute gut inflammation; C, chronic gut inflamma- Figure 2. Clinical evolution of patients with SpA according to initial tion; IBD, overt IBD; macro, endoscopic findings on ileocolonoscopy; micro, histology. Acute, acute gut inflammation; chronic, chronic gut inflam- histology of biopsy specimens; N, normal mucosa; P, presence of complaints mation; normal, normal gut histology;, rheumatoid arthritis;, of diarrhea or high stool frequency; r, articular remission; 0, normal; 1, eryarticular remission;, articular active disease. thema; 2, erosions or ulcerations; //0, taking/not taking NSAIDs.

4 June 1996 GUT INFLAMMATION IN SPONDYLOARTHROPATHY 1699 Figure 3. Endoscopic evolution in patients with SpA and who under- went repeat ileocolonoscopies. Grade 1, erythema; grade 2, erosions and ulcerations; normal, normal endoscopic appearance;, normal Relationship Between Intestinal Symptoms and Histology At initial endoscopy, 18 patients (29%) reported complaints of mild diarrhea. Chronic inflammation was present in 13 of these 18 patients (72%) but only found in 11 of 31 patients without intestinal symptoms (35%) (P Å 0.01). Also, at control endoscopy, chronic inflammation was significantly more frequently found in the group of patients with initial abdominal complaints (P Å 0.002). Persistence of diarrhea in 10 patients was associated with an evolution to chronic gut inflammation or overt IBD (Figure 5). The evolution to full-blown IBD was observed in 9 of 123 patients (7.3%). In 7 of these 9 patients, chronic inflammation was already present during the initial en- mucosa;, grade 1 lesions;, grade 2 lesions. doscopy. The 3 patients of the telephone group who mentioned an evolution to IBD also had chronic inflammation at the moment of the first ileocolonoscopy. Evolution of Intestinal Inflammation In clinically reviewed patients, evolution to IBD was observed in 7 of 55 patients with initial chronic inflam- The evolution of endoscopic findings from the mation (13%) but in only 2 of 68 patients with initial first to the second ileocolonoscopy is shown in Table 1 acute inflammation or normal gut histology (3%) (P õ and Figure 3. Ulcerations (grade 2 lesions) appeared in 0.05). 4 of 30 patients with an initial normal endoscopy (13%), evolved from erythema in 2 of 6 patients (33%), and Relationship Between the Articular and persisted in 4 of 14 patients with initial ulcerations Intestinal Evolution (29%) (P Å 0.3; NS). The relationship between the articular and intesti- The evolution of the gut histology from the first to nal evolution is shown in Table 1 and Figure 6. All 16 second ileocolonoscopy is shown in Table 1 and Figure patients in articular remission had a normal endoscopy 4. A normal histology at the onset remained normal and no more abdominal complaints at the moment of in all except one case that evolved to IBD. Acute gut clinical and endoscopic control. In 15 patients, gut ininflammation disappeared in 5 patients, persisted in 1 flammation persisted and was always associated with acpatient, and evolved to chronic inflammation in 3 patients, one of them featuring the histology of Crohn s disease. In 14 of 24 patients with initial chronic lesions, the gut histology normalized. In 1 patient, acute lesions were found, whereas chronic lesions persisted in the remaining 9 patients. From this group of patients, 5 patients developed full-blown IBD. The evolution of the gut histology from the second to third ileocolonoscopy is shown in Table 2. In 2 patients, the inflammation evolved to IBD, and in 1 patient, the inflammation disappeared together with the induction of articular remission. In another patient, chronic inflammation reappeared together with the reactivation of the articular disease. As shown in Table 1, macroscopic lesions were almost always associated with inflammation on histology Figure 4. Evolution of gut inflammation in patients with SpA and who (chronic inflammation in 29 patients, IBD in 5 patients, underwent repeat ileocolonoscopies with biopsies. Acute, acute gut inflammation; chronic, chronic gut inflammation; normal, normal gut and acute inflammation in 5 patients). Only in 1 patient histology;, Normal mucosa;, acute inflammation;, chronic was histology normal, despite the presence of erythema. inflammation.

5 1700 DE VOS ET AL. GASTROENTEROLOGY Vol. 110, No. 6 Table 2. Evolution of Articular Diagnoses and Histological Findings Between Three Consecutive Ileocolonoscopies First ileocolonoscopy Second ileocolonoscopy Third ileocolonoscopy Sex Age Gut Age Gut Age Gut Patient (M/F) (yr) Diagnosis histology (yr) Diagnosis histology (yr) Diagnosis histology 1 M 24 ASC A 27 ASC N 29 ASC N 2 M 31 Undifferentiated SpA C 34 Undifferentiated SpA C 37 ASP C 3 M 31 ASP C 33 Remission N 38 Remission N 4 F 42 Undifferentiated SpA N 46 Undifferentiated SpA N 49 Remission N 5 F 31 Undifferentiated SpA C 33 ASP C / IBD 34 ASP C / IBD 6 F 50 Undifferentiated SpA C 51 Undifferentiated SpA C 54 Remission N 7 M 53 Undifferentiated SpA C 54 ASP C 57 ASP C / IBD 8 M 23 Undifferentiated SpA C 24 Undifferentiated SpA C / IBD 29 ASC C / IBD 9 F 29 Undifferentiated SpA C 30 Remission N 35 Remission N 10 M 12 Undifferentiated SpA C 13 Remission N 16 Undifferentiated SpA C 11 F 24 ASP C 25 ASP C 30 ASP C / IBD A, acute gut inflammation; ASC, ankylosing spondylitis with pure axial involvement; ASP, ankylosing spondylitis with peripheral arthritis; C, chronic gut inflammation; N, normal gut histology. tive articular disease. In 9 patients with normal initial patients was accompanied by chronic inflammation in 6 histology, the gut remained normal, despite the persistent patients and with evidence of IBD in 4 of these 6 pa- articular disease. In 9 patients, gut lesions disap- tients. In 1 patient, clinical evidence of active AS was peared, although the articular complaints persisted. present, despite a normalization of the histology. Similar rates of articular remission were obtained in the group of patients with initial abdominal complaints Analysis of Drug Intake (remission rate, 22%) as in patients without complaints All patients with SpA were treated with NSAIDs. (remission rate, 39%) (NS). However, articular disease At the moment of clinical control, 59 of 67 patients with remained active in 10 of 13 patients with diarrhea and persistent active articular complaints (88%) and only 9 chronic inflammation (79%). of 53 patients in articular remission (17%) were being At the moment of the third endoscopy, 4 of 11 patients treated with NSAIDs independently of the initial histolwere in clinical remission with a normalization of the ogy (P õ 0.001). Three patients rediagnosed with rheugut histology. Persistent articular disease in the other 7 matoid arthritis were excluded from this analysis. At the moment of the second ileocolonoscopy, 21 of 35 patients Figure 5. Relationship between abdominal complaints and histological Figure 6. Relationship between articular and intestinal evolution in evolution of gut inflammation in patients with SpA and who under- patients with SpA and who underwent repeat ileocolonoscopies with went repeat ileocolonoscopies., Normal mucosa;, acute inflammation; biopsies., Normal mucosa;, acute inflammation;, chronic in-, chronic inflammation. flammation.

6 June 1996 GUT INFLAMMATION IN SPONDYLOARTHROPATHY 1701 with a normal histology (60%) and 13 of 14 patients and synovitis was confirmed with a normalization of the with a persistent gut inflammation (93%) were being endoscopic appearance and the gut histology in patients treated with NSAIDs (P õ 0.05). Four patients in clini- evolving to articular remission, a persistence of articular cal remission were being treated with NSAIDs and had complaints in patients with persistent gut inflammation, normal endoscopy and histology. Only 2 patients with and a reappearance of gut inflammation during flare-ups active articular disease were no longer being treated with of the articular disease. However, in 9 patients with NSAIDs: 1 patient with a normal histology and the other SpA, gut lesions disappeared despite the persistence of patient with overt IBD. Eighty-nine of 120 patients with articular complaints, suggesting that the initiating SpA were treated with SASP. Three patients with an events in the gut may act as a trigger for the immune evolution to rheumatoid arthritis were excluded from cascade without a need for their continuous presence. this analysis. Significantly more patients with initial gut The clinical relevance of the gut inflammation became inflammation (68 of 81; 84%) needed SASP than patients evident by the association with mild complaints of diarwith an initial normal gut histology (21 of 39; 54%) rhea. Noteworthy to remember is the exclusion of pa- (P õ 0.001). The remission rate in the SASP-treated tients with overt or suspected IBD at the start of the group (52%) was significantly greater than the rate in study. Complaints of diarrhea were defined as a spontanethe nontreated group (23%) (P õ 0.01). All patients ous report of regular episodes of diarrhea with stool freevolving to IBD were treated with SASP. quencies of more than four stools per day. These symptoms Discussion were recorded by the rheumatologist and were not reported to the gastroenterologist or to the histopathologist, This study confirms the good clinical prognosis excluding a bias in the interpretation of the results. of non-as SpA. In 61% of the patients, articular disease Complaints of diarrhea were mostly reported in patients was temporary and resolved. This evolution correlates with chronic gut inflammation (56%) and rarely in pa- with data in the literature The prognosis of AS is tients with normal mucosa (13%). Although the presence much worse and varies in the literature We observed or absence of diarrhea alone had no predictive value for a remission rate of 19%, significantly lower than the further evolution, simultaneous presence of diarrhea and remission rate in non-as SpA. The rare evolution to chronic inflammation at initial endoscopy were associated rheumatoid arthritis suggests a minor overlap between with a high risk for persistence of active articular disease, both diseases. The documented evolution from undifferevolution. because 79% of these patients had evidence for such entiated SpA to AS confirms its entity and justifies its inclusion in the concept. The association between initial gut inflammation and The much higher remission rate in the telephone IBD was confirmed by the evolution from subclinical group than in the clinical control group suggests that inflammation to overt IBD in 7% of the patients. Al- the noncompliance of these patients was caused by an though it is well recognized that peripheral arthritis and absence of complaints and not by a worsening of the spondylitis are present in about 15% 20% of patients disease. Because these patients were not clinically reas- with IBD, 18 data about articular symptoms preceding sessed, data from this group will not be included further IBD are scarce. 19,20 However, our data confirm the exis- in the analysis. tence of subclinical IBD and imply that chronic gut We found no relationship between the presence or inflammation observed in our initial study can be considabsence of acute or chronic inflammation during the ini- ered as the earliest lesions of IBD reported in literature. tial endoscopy and the articular evolution; remission rates Furthermore, they show that the presence of chronic in- were similar in different groups. However, we observed flammation in patients with SpA implies a high risk of a significantly greater risk of evolution to AS in patients IBD development because 13% of these patients devel- with initial chronic inflammation. oped the disease within the next few years. In contrast, The evolution of gut inflammation was studied in a SpA without gut inflammation implies little risk of later subgroup of patients who underwent a second ileocolonoscopy evolution to IBD. in our department. This subgroup was represen- Finally, although NSAIDs induce small intestinal dis- tative for the total study population because initial gut orders, 21 this study further suggests that the inflamma- inflammation was present in 69% of these patients (vs. tory lesions described in patients with SpA are not caused 67% in the clinically reviewed group) and because articular by NSAID intake. 4 In previous studies, we already de- remission was obtained in 41% of patients (vs. 43%). scribed gut inflammation in 52% of patients not being The important relationship between gut inflammation treated with NSAIDs. We also found a similar prevalence

7 1702 DE VOS ET AL. GASTROENTEROLOGY Vol. 110, No. 6 of the different types of inflammation in patients being We postulate that the increased antigen processing treated with NSAIDs. Meanwhile, this absence of relation observed in patients with SpA 24,25 initiates an immune has been confirmed in other studies. 6,7,22 In the actual cascade responsible for a local inflammation and extrain- long-term study, all patients were treated with NSAIDs. testinal manifestations, such as articular disease. The ex- Duration of intake was only correlated with the persis- act nature of the initiating event remains undetermined tence of articular complaints; at the moment of clinical but may only be temporary. Control of the gut inflam- control, 88% with persistent active articular disease and mation, spontaneously or drug induced, may control the 17% of patients in articular remission were still being articular disease. In some patients, the evolution to fulltreated with NSAIDs (P õ 0.001). Although it remains blown IBD cannot be prevented. difficult to prove, the difference in NSAID intake between normal histology and persistent inflammation was References most probably related to the activity of disease rather 1. Dougados M, Van Der Linden S, Juhlin R, Huitfeldt B, Amor B, than to the intake of drugs. At the time of the second Calin A, Cats A, Jijkmans B, Olivieri I, Pasero G, Veys E, Zeidler H. The European Spondylarthropathy Study Group preliminary criileocolonoscopy, 69% of patients were still being treated teria for the classification of spondylarthropathy. Arthritis Rheum with NSAIDs. All patients in remission had a normal 1991;34: histology, despite previous or actual intake of NSAIDs. 2. De Vos M, Cuvelier C, Mielants H, Veys E, Barbier F, Elewaut A. Ileocolonoscopy in seronegative spondylarthropathy. Gastroen- Moreover, a persistence of a normal histology was noted terology 1989;96: in 8 patients, despite the continuous intake of NSAIDs. 3. Mielants H, Veys EM, Cuvelier C, De Vos M, Botelberghe L. HLA- Disappearance of gut inflammation was observed in 11 B27 related arthritis and bowel inflammation. Part 2: Ileocolonoscopy and bowel histology in patients with HLA-B27 related arthripatients with continuous intake of NSAIDs. tis. J Rheumatol 1985;12: Although the presence of gut inflammation was not a 4. Mielants H, Veys EM, Goemaere S, Goethals K, Cuvelier C, De prerequisite for administering SASP and treatment was Vos M. Gut inflammation in the spondylarthropathies: clinical, radiologic, biologic and genetic features in relation to the type only adapted to articular complaints, significantly more of histology. A prospective study. J Rheumatol 1991;18:1542 patients with histological gut lesions at the moment of the initial endoscopy needed SASP than patients with a 5. Mielants H, Veys EM, Joos R, Cuvelier C, De Vos M, Proot F. Late onset pauciarticular juvenile chronic arthritis: relation to gut normal histology. Because more patients taking SASP inflammation. J Rheumatol 1990;14: went into remission than nontreated patients and because 6. Simenon G, Van Gossum A, Adler M, Rickaert F, Appelboom T. articular remission was associated with the disappearance Macroscopic and microscopic gut lesions in seronegative spondy- of gut inflammation, we may assume that SASP has a larthropathies. J Rheumatol 1990;17: Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppälä beneficial effect on SpA by way of attenuation of this K. High frequency of silent inflammatory bowel disease in spondyinflammation. It remains unsolved whether this benefi- larthropathy. Arthritis Rheum 1994;37: cial effect on joint inflammation was caused by a local 8. Cuvelier C, Barbatis C, Mielants H, De Vos M, Veys E, Roels H. The histopathology of intestinal inflammation in relation to reaceffect of mesalamine on the gut or through a more systive arthritis. Gut 1987;28: temic effect of SASP or sulfapyridine, as in rheumatoid 9. Kellgren JH, Jeffrey MR, Ball J. The epidemiology of chronic rheumatism. arthritis. 23 The effect of SASP on the evolution to fullblown Oxford: Blackwell Scientific, 1963:326. IBD remains unclear. The molecule seems unable 10. Amor B. Reiter s syndrome: long-term follow-up data. Ann Rheum Dis 1979;38(Suppl): to prevent the evolution because all patients evolving 11. Leirisalo-Repo M, Suoranta H. Ten-year follow-up study of patients with Yersinia arthritis. Arthritis Rheum 1988;31:533 to IBD were treated with SASP. However, a favorable influence on the evolution cannot be excluded because Bremell T, Bjelle A, Svedhem A. Rheumatic symptoms following no data are available about the natural evolution in unan outbreak of Campylobacter enteritis: a five year follow-up. Ann treated patients with SpA. Rheum Dis 1991;30: In conclusion, our data support the hypothesis that 13. Lindholm H, Viskorpi R. Late complications after a Yersinia enterocolitica epidemic: a follow-up study. Ann Rheum Dis 1991;50: the gut plays a role in the etiopathogenesis of more than half of patients with SpA. They show the existence of a 14. Herrlinger JD, Asmussen JU. Long-term prognosis in Yersinia arthritis: subclinical gut inflammation in patients with SpA as the clinical and serological findings. Ann Rheum Dis 1992; 51: only manifestation of IBD and describe a chronic gut 15. Carette S, Graham D, Little H, Rubenstein J, Rosen P. The natural inflammation as the earliest IBD lesion. Finally, they disease course of ankylosing spondylitis. Arthritis Rheum 1983; show that SASP has a beneficial effect on the evolution 26: of AS most probably by way of the elimination of the 16. Mau W, Zeidler H, Mau R, Majewski A, Freyschmidt J, Stangel W, Deicher H. Clinical features and prognosis of patients with initiating gut inflammation; however, SASP is unable to possible ankylosing spondylitis. Results of a 10-year follow-up. prevent the evolution to IBD. J Rheumatol 1988;15:

8 June 1996 GUT INFLAMMATION IN SPONDYLOARTHROPATHY Kennedy LG, Edmond L, Calin A. The natural history of ankylosing 23. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazin spondylitis. Does it burn? J Rheumatol 1993;20: is active in rheumatoid arthritis. Br J Rheumatol 1985;290: 18. Schorr-Resnick B, Brandt LJ. Selected rheumatologic and derma tologic manifestations of inflammatory bowel disease. Am J Gashistocompatibility 24. Cuvelier C, Mielants H, De Vos M, Veys EM, Roels H. Major troenterol 1988;83: class II antigen (HLA-DR) expression by ileal 19. Haslock I. Arthritis and Crohn s disease a family study. Ann epithelial cells in patients with seronegative spondylarthropa- Rheum Dis 1973;32: thies. Gut 1990;31: Gravallese EM, Kantrowitz FG. Arthritic manifestations of in- 25. Cuvelier C, Quatacker J, Mielants H, De Vos M, Veys E, Roels flammatory bowel disease. Am J Gastroenterol 1988;83:703 HJ. M-cells are damaged and increased in number in inflamed 709. human ileal mucosa. Histopathology 1994;24: Bjarnasson I, Hayllar J, MacPherson AJ, Russel AS. Side effects of nonsteroidal antiinflammatory drugs on the small and large Received May 12, Accepted January 26, intestine in humans. Gastroenterology 1993;104: Address requests for reprints to: Martine De Vos, M.D., Ph.D., 22. Altomonte L, Zoli A, Veneziani A, Mirone L, Santacesaria G, Chiarelli Department of Gastroenterology, University Hospital Ghent, De Pintory C, Federico F, Massi G, Magaro M. Clinically silent inflamma- telaan 185, B-9000 Ghent, Belgium. Fax: (32) gut lesions in undifferentiated spondyloarthropathies. Clin Presented in part at the plenary session of the 1994 annual meet- Rheumatol 1994;13: ing of the American Gastroenterological Association.