236 SELECTED SUMMARIES

provide insight into the role of ICAM-1 in trafficking between the peripheral blood and the lamina propria, as well as in re- lation to other integrins. The increase in p7 and a d expression in ISIS 2302-treated patients relative to placebo was based mostly on an early drop in CD3+ cell expression of these mol- ecules in placebo-treated patients. ls this a reflection that in patients with active Crohn's disease there is a tendency for cells bearing p7 or ad to egress from the blood into the tissue'? Does the interference with ICAM- I expression lead to upregulation of integrins such as p7 or a d that rely on other endothclial ligands? It is curious that CD3+ cell expression of CDS4 (ICAM-I) was unchanged between the two groups. The inves- tigators offcr the explanation that expression of ICAM-I is primarily reduced in the tissue aRer ISIS 2302, and perhaps cells expressing this ligand or cells that use it as a receptor are released from tissue and enter the circulation.

That ISlS 2302 prolongs the aPTT apparently by inhibition of intrinsic tenase complex raises an interesting possiblc expla- nation regarding the therapeutic efficacy of ICAM- 1. The pro- duction of other adhesion molecules such as selectins may be critical in the generation of thrombosis (G Shaw. Therapeutic potential of recombinant soluble PSGL-1. In: Molecular Mechanisms of Leukocyte Traficking. Keystone Symposium, March, IYYX). Blocking thrombosis may be of value, much like heparin, which may have some efficacy in treating ulcerative colitis (Am J Gustroenrerol 1995;90:220-3). This also fits within the paradigm of the vascular activationlmicrothrombosis hypothesis of Crohn's disease (Can J Gastroenterol 1994;R: 70-4). Yacyshyn and colleagues have introduced us to a novel "antistick," antithrombosis treatment for Crohn's disease. We have come to learn that some of our old favorite immunomodu- latory therapies, such as corticosteroids and methotrexate may function to diminish cell adhesion (Proc Nut1 Ac-ad Sci USA 1992;88:9991-5; Gastroenterology 1993;104:31-7), and so a more specific antisense, antiadhesion approach with ISIS 2302 makes sense in Crohn's disease. The challenge for these inves- tigators will he to prove its efficacy in the large multicenter trial that is ongoing, to find a way to limit the frequency of systemic administration or ultimately to develop vehicles that allow for oral drug administration.

Charles N. Bernstein, M.D. I1tziver.s i l y OJ Mutzitoba

InJummcitory Bowel Disease Clinical and Research Centre Winnipeg, Mcinitobu. Canada

SHOULD WE THROW FAT ON THE FIRE?

Distal proctu-colitis, natural cytotoxicity, and essential fatty acids. Alniallah YZ, Richardson S, O'Hanrahan T, Mowat NAG, Brunt PW, Sinclair TS, Ewen S, Heys SD, Eremin 0. Am J Gastroenterol I998:93:804-9.

This pilot study was performed in a randomized, double- blind, placebo-controlled fashion in patients with active ulcer- ative colitis (UC). The aim of the study was to investigate whether dietary supplementation for 6 months with essential fatty acids (EFA), eicosapentaenoic acid (EPA), and docosa- hexaenoic acid (DHA) can modulate disease activity and im- mune reactivity in patients with distal proctocolitis. The pd- tients were randomizcd into two groups. Each patient received

either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and endoscopic scores) and histologic evaluation of mucosal biopsies were carried out. The circulating levels and activities of natural killer (NK) and lymphokine-activated killer (LAK) cells, using flow cytometric analysis (CD16+ CD56+) and in vitro "Cr release assays (K562), respectively, were monitored. At 6 months, supplementation with EFA resulted in the im- provement of the clinical activity compared with pretreatment evaluation. There was a significant reduction in the endoscopic and histological scores in the in the EFA group compared with the placebo group. EFA supplementation for 6 months also induced significant reduction in the circulating numbers of C016+ and CD56+ cells and the cytotoxic activity of N K cells, compared with the placebo group. Comment: EFA are a group of polyunsaturated fatty acids that are present in food and cannot be synthesized in the body. They are composed of two main types, the omega-6 (w-6) and omega-3 (w-3) series. It has been shown that patients with UC have an altered natural cytotoxicity mediated by NK and LAK cells. Dietary enrichment with EFA (EPA and DHA) results i n inhibition of natural cytotoxicity ( N Engl J Med 1985;312: 1217-24). However, the precise mechanism of action by which the EFA suppresses the inflammatory process in patients with UC is not clear. The number of studies published to date are

cult to interpret. This trial demonstrates that the administration of EFA for a period of 6 months results in inhibition of natural cytotoxicity (NK, LAK cells) and a reduc- tion in both the number and function of blood N K cells.

Although the etiology of UC is unclear, active disease is characterized by marked infiltration and accumulation of neu- trophils in the colonic mucosa and enhanced production ot' inflammatory mediators derived from arachidonic acid (AA), notably, leukotriene B, (LTB,), and two-series prostaglandins, such as prostaglandin E2 (PGE,) and thromboxane A, (TxA2). Furthermore, polymorphonuclear neutrophils (PMNs) in pa- tients with UC release more LTB, for a given amount of AA than normals. Diets containing high levels of w-3 fatty acids, such as EPA and DHA, are known to modify leukotriene pro- duction ( N Engl J Med 1985;312:1217-24). Several small pre- liminary crossover studies have claimcd clinical benefit (Am J Gastroenterol 1992;87:432-7). In a large 12-month prospcc- tive, placebo-controlled trial in patients with UC, the long-term use of EPA was safe and resulted in a significantly sustained increase in the membrane EPA levels, enhanced synthesis or LTB,, and a 50% reduction in LTB, levels (Gut 1992;33:922- 8). However, despite a modest steroid-sparing effect in activc disease noted in this study, EPA showed no benefit in mainte- nance o f remission in UC. The clinical benefit must be inter- preted with caution and should not solely be attributed to in- hibition of leukotriene synthesis. There is also evidence that EFA may result in a number of other antiinflammatory actions, including suppression of a range of cytokines, platelet activat- ing factor, free radical scavenging, and alteration of membrane fluidity and inhibition of platelet aggregation.

On the contrary, one study failed to demonstrate a beneficial effect of w-3 fatty acids on UC (J Intern Mecl 1989;22S(suppl 1):225-32). while in another study, EPA supplementation re- duced rectal dialysate levels of LTB, and showed only a mod- est improvement in rectal histology (Ann Intern Med 1992; I 16: 609-14). The lack of major benefit from 0-3 fatty acids may

SELECTED SUMMARIES 23 7

have several explanations. First, the duration of treatment and wash-out periods may have been too short. Second, the dose may have been too low. Third, the increase in inflammatory mediators in UC may be more of an epiphenomenon than an essential link in the chain of events. Lastly, olive oil may not have been an ideally inert placebo. In any trial of therapy in UC, one must recognize the inherent placebo response. An analysis of 12 placebo-controlled trials in active UC revealed a mean clinical response of 25% to placebo therapy ( J Clin Gas- troenterol 1989;11:33-7).

In conclusion, this pilot study has demonstrated that w-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with active, distal proctocolitis. In our view, a large multicenter, prospective, randomized double-blind trial should be conducted to confirm the clinical benefits of’ EFA in the management of UC. Long-term follow-up is also needed to study the duration of remission and to define an effective dos- ing schedule.

Aijaz Ahmed, M.D. George Triadafilopoulos, M.D.

Stanford University School of Medicine Stanjixd, California, U.S.A.

ARE SEROLOGICAL TESTS FOR IBD USEFUL TO CLINICIANS?

Anti-Saccharomyces cerevisiae mannan antibodies com- bined with antineutrophil cytoplasmic autoantibodies in in- flammatory bowel disease: prevalence and diagnostic role. Quinton JF, Sendid B, Reumaux D, Duthilleul P, Cortot A, Grandbastien B, Chamer G, Targan SR, Colombel JF, Poulain D. Gut 1998:42:788-91.

Perinuclear antineutrophil cytoplasmic autoantibodies (pANCA) have become established as a marker of ulcerative colitis (UC). More recently, antibodies to oligomannosidic epi- topes of the yeast Saccharomyces cerevisiae (ASCA) have been the focus of much interest as a marker of Crohn’s disease (CD). The authors assessed the diagnostic value of detecting pANCA and/or ASCA for the diagnosis of UC and CD. The study population consisted of 100 adult patients with CD, 101 with UC, 27 with various other diarrheal disorders, and 163 healthy controls. The combination of a positive pANCA and nega- tive ASCA tests yielded a sensitivity, specificity, and positive predictive values of 57, 97 and 92.5%, respectively, for UC. The combination of a positive ASCA and negative pANCA tests yielded 49, 97, and 92.5% for the same parameters. Using multi- variate analysis, ASCA in CD was found to be associated with small bowel involvement. The authors concluded that ASCA and pANCA are strongly associated with CD and UC, respectively.

Comment: The article by Quinton et al. raises the question as to the clinical usefulness and role for serological tests in IBD. Most clinicians would argue that they are certainly capable of diagnosing IBD using the gold standard combination of radio- logical, endoscopic, and histologic criteria. What then is the place for these antibody assays?

There is no doubt that in many cases, especially those that are the most severely affected, an experienced clinician can make a diagnosis of IBD on the basis of the history and physi-

cal examination alone. In such instances, we carry out colo- noscopies and barium studies to provide histological confirma- tion and for determining the extent of involvement. Do expe- rienced clinicians need serological assays in their diagnostic armamentarium? In my opinion, I would say yes.

The answer to my rhetorical question is based on the diag- nostic accuracy of the tests in question. In UC, pANCA have been reported to be present in 4040% of cases, with a high degree of disease specificity (Gastroenterology 1991 ; 100: 1590-6; Gastroenterology 1998 -9). Similarly, ASCA has been reported to be 64% s and 77% specific for discriminating CD from UC and 89% specific for distinguish- ing CD from controls ( C h Diag Lub Immunoi 1996;3:219- 26). The results of the present study thus confirm previous reports. A recent study found similar results for the diagnostic accuracy of ASCA and pANCA in pediatric IBD patients (Gus- troenterology 1998;115:822-9). In the present and the pediatric study, the sensitivity of ASCA in patients with CD restricted to the colon was 45 and 47%, respectively. However, in the latter study, “double ASCA positivity” (IgG and IgA titers) was 100% specific for CD (Gastroenterology 1998; 1 1 S:822-9). In the above study by Quinton and colleagues, it is not clear whether ASCA positivity related to IgG only, or to other isotypes as well.

These findings have important clinical implications with re- spect to differentiating CD from UC in patients with colitis, or for cases of “indeterminate colitis.” CD patients with a “UC- like” presentation are often pANCA positive (Gastroenterology 1996; 1 10: 18 10-9). Therefore, only the presence of ASCA can truly be considered specific for CD. In the above study by Quinton et al., pANCA negative/ASCA positive results were 97% specific and had a 96% positive predictive value for CD, whereas pANCA positive/ASCA negative assays were 97% specific and 92.5% predictive value positive for UC. In view of the disparate prognosis after colectomy in UC vs. CD, the data thus suggest that ASCA and pANCA testing should be camed out prior to elective “curative” surgery for UC.

In many cases, the diagnosis of IBD is delayed due to non- specific presenting complaints. Reliable screening tests would be potentially helpful in these circumstances, allowing the cli- nician to expedite the diagnosis. Furthermore, a high negative predictive value of serological tests would potentially avoid unnecessary, more-invasive and costly testing. In the study by Quinton et al. the negative predictive value of ASCA for CD was 94.5%. However, it is not at all clear that the study was carried out prospectively. Nor did all patients have symptoms potentially consistent with IBD. On the contrary, all but 27 of the 190 non-IBD control patients were healthy individuals who had no gastrointestinal symptoms or family history of IBD. Furthermore, the clinical value of any test is overestimated when the prevalence of the disease in the population studied is artificially high, such as in the above report (201 of 39 1 patients studied had IBD). Further prospective studies using ASCA thus need to be carried out in patients with gastrointestinal com- plaints so that the true diagnostic accuracy of this very prom- ising test can be established.

Ernest G. Seidman, M.D. Division of Gastroenterology & Nutrition

Ste-Justine Hospital Department of Pediatrics

University of Montreal Montreal, Quebec, Canada

Inflammatory Bowel Diseasesa, Val. 5, No. 3, August 1999