## Fish Oil for the Treatment of Crohn’s Disease

Heard about fish oil? This ill defined substance has gotten play in the popular health literature, but now there has been a study in Crohn’s disease published in the New England Journal of Medicine . The study showed that the preparation, Purepa, is effective. It should be available in a few years in the US.

There has been a fair amount of interest in fish oil as an antiinflammatory medicine over the years. In part this is driven by fish oil being “natural”. The scientific reason is that oils in the diet are the building blocks for certain chemicals the body makes, some of which are immune modulators. Fish oils contains a group of oils known as omega-3 fatty acids (chemically a double bond is present 3 down from the end of the carbon chain of the fat molecule). These oils are able to prevent the production of certain inflammatory molecules in the human body.

Fish oil per se is not a defined substance. There is the matter of variation of the fish, whether the oils is taken from whole fish sqeezings or just the fillets, and what processing is done. The whole fish issue is important because toxins (or perhaps useful drugs) are concentrated in fish livers. Processing is important because of stability. As with all supplements marketed as foods, the natural food pushers do not want regulation to be exerted upon them as it would add all sorts of complexities to their lives. As I see it, if they are going to push their own products, the consumer should be assured that the manufacturer can trace the source of raw material, have a regular way of making the stuff, keeps records of quality control, and does assays of the important ingredient(s). Additionally, the studies, if any, used to support the use of natural products often are used to recommend products different from those in the study. With something as unregulated, unassayed, and undefined as health food store products, who knows whether the health food store drug will do any good.

With this background, now comes a drug which is a fish oil preparation. Researchers in Italy used a fish oil preparation called Purepa, manufactured in Sweden, and coated the capsules with an enteric coating called Eudragit NE 30D. It is well defined and manufactured with the care a drug company takes. A study in the New England Journal of Medicine (NEJM 334(24):1557-1560, 13 June 1996) reported that patients with Crohn’s disease had less relapses when taking the medicine than did those taking placebo. The study was well done. It used a group of patients randomly assigned to either drug or placebo. Patients were not able to tell which drug they were on. (Which also implies that enteric coated Purepa does not have the nasty fish taste which can make fish oil hard to take.) The patients who were asked to participate were known to have a high chance of flares of the disease, based on their having all been in remission less than 2 years, with serum alpha 1-acid glycoprotein concentration > 130, alpha 2-globulin > 0.9, or a sed rate > 40. The findings were remarkable. The patients on drug had a relapse rate of only 41% compared to controls who had a relapse rate of 74% over the one year of followup. Diarrhea was a side effect in 4 of 39 fish oil treated patients vs 1 of 39 placebo patients. The diarrhea did not resolve when the drug was stopped in experimental or control subjects. The dosage of fish oil was 9×500 mg capsules per day, = 4.5 grams of fish oil per day. Interestingly, all relapses occurred within 7 months in both groups. Also, the fish oil group had improvement in all three serum measurements made, while the placebo group all had worsening of the measures.

The problems with the study concern whether the drug will be effective in all patients with Crohn’s, or only those patients like those in the study. This is a real issue – Crohn’s disease is a heterogeneous group, and the Italian group that published this may have selected a subset of Crohn’s that would respond differently. Also, this study was done in Italy. The Italian diet differs from a typical American diet, not to mention Scottish, New Zealand, Chinese, Dutch, Polish, German, French, or any cuisine that you may wish to identify. Italians also are heterogeneous in their diet, varying greatly from North to South, and inland vs seacoast. The study did not subgroup its results by region of Italy where subjects were born or lived, which would have been interesting.

It looks like this will be effective, however. Given the safety of the preparation it will be a welcome addition to treatment of Crohn’s. The variation in fish oil preparations available, along with the history of previous negative studies with fish oils, leads me to conclude that until a particular preparation is studied it will not be possible to say whether any particular fish oil preparation will work in Crohn’s. It is interesting that both placebo group and Fish Oil group had no more relapses after 7 months. It would be nice to know if the changes in any of the blood measures predicted who would relapse. The relapse curves also raise the question whether patients only need to be on the drug for 7 months to get the full benefit.

Stephen Holland, M.D.
University of Illinois College of Medicine at Urbana-Champaign

## cA2 in Crohn’s disease

What is the “cure” for Crohn’s that has been reported in the news? There have been reports of an antibody that can treat Crohn’s disease. While not a cure, it may represent a new treatment that will more rapidly bring flares of Crohn’s under control.

[ The IBDPage has been around for a long time. Remicade (infliximab | Janssen) was the first anti-TNF drug available. Take this post as an interesting post from long ago – Ed.]

cA2 in Crohn’s disease

A fair amount of press has recently been seen about a new cure for Crohn’s disease. Unfortunately, this was very poor reporting. The drug that has garnered all this attention was called cA2, and now is named Infliximab. This drug is an antibody that binds an immune chemical called TNF-alpha. Antibodies are large proteins that can only be administered intravenously.The reports at the Digestive disease week meeting in San Francisco lastMay (May 1996) basically showed that in patients with severe Crohn’s disease,65% percent had an excellent response to administration of cA2. Patientswith Ulcerative colitis were not helped. Patients relapsed as the drugwore off.

Thus, while not a cure, cA2 will probably be an important drug in the treatmentof Crohn’s disease. It will probably find its role in the treatment ofpatients with Crohn’s who are hospitalized for a severe flare. In thesepatients, the drug will probably allow faster control of the inflammation.The patients will still be treated with steroids, but the cA2 will allowfaster discharge. Interestingly, a lot of patients getting the drug at this time are patients who have been maintained as an outpatient who havebeen doing poorly with chronic fistulas or inflammation that has nevercome under control.

One aspect which has cause a lot of excitement in the scientific communityabout this drug is that it is one of the first success stories for immunologyresearch predicting clinical results. TNF-alpha is an early player in theimmune response, so blocking it should be effective. However, studies ofUlcerative Colitis patients showed that they do not have elevated levelsof TNF-alpha, while Crohn’s patients do. Thus, the effectiveness of cA2in Crohn’s but not in UC confirmed the immune studies in those patients.The research into what causes the lack of response in 35% of the Crohn’spatients will be interesting to follow.

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria

## Salmonellosis Associated with a Thanksgiving Dinner

Many will enjoy eating turkey on Christmas. (Perhaps some on Hanukah – is turkey Kosher?) Some tips from the CDC on cooking can be found in this chilling report on a family that had a bacterial infection from Thanksgiving dinner.

The turkey can kill you.

The following is from the CDC’s MMWR publication. The MMWR can be downloaded from ftp://ftp.cdc.gov/pub/Publications/mmwr/wk/

### Salmonellosis Associated with a Thanksgiving Dinner

MMWR Morb Mortal Wkly Rep. 1996 Nov 22;45(46):1016-7.

On November 28, 1995, the county coroner’s office notified the ClarkCounty Health District in Las Vegas, Nevada, about a death suspected tohave resulted from a food-borne disease. This report summarizes the investigationof the outbreak of gastroen-teritis among persons who attended a Thanksgivingdinner. The investigation documented Salmonella serotype Enteritidis (SE)infection associated with eating improperly prepared turkey and stuffingcontaining eggs and emphasizes the need to use a meat thermometer to ensurecomplete cooking of turkey and stuffing.

During November 25­-28, 1995, all six persons who attended a Thanksgivingdinner at a private home on November 23 and a seventh person who on November25 ate food remaining from the dinner had onset of abdominal cramps, vomiting,and diar-rhea. Two persons were hospitalized because of dehydration; athird person was found comatose at home and died from severe dehydrationand sepsis. Stool cultures obtained from three persons, including the decedent,yielded SE phage type 13a. Turkey and stuffing were the only foods eatenby all seven ill persons. No leftover food was available for culture.

The Clark County Health District interviewed the ill persons (includingthe cook) to obtain details about the preparation and cooking of the turkeyand stuffing. On No-vember 22, a 13-pound frozen turkey was thawed for6 hours in a sink filled with cold water. After thawing, the packet ofgiblets (heart, liver, and gizzard) was removed, and the turkey was storedin a refrigerator overnight. However, on November 23, parts of the turkeywere noted to be frozen. The turkey was filled with a stuffing made frombread, the giblets, and three raw eggs, and then placed for 1 hour in anoven set at 350 F (177 C). The setting was lowered to 300 F (149 C) whilethe turkey cooked for an estimated additional 4 hours. The turkey was removedfrom the oven when the exte-rior had browned. A meat thermometer was notused. The stuffing was removed im-mediately and was served with the turkey.After the outbreak, health officials tested the oven set at 300 F (149C) and found the temperature to be 350 F (176 C).

Reported by: O Ravenholt, MD, CA Schmutz, LC Empey, DJ Maxson, PL Klouse,AJ Bryant, Clark County Health District, Las Vegas; R Todd, DrPH, StateEpidemiologist, Nevada State Health Div. Foodborne and Diarrheal DiseasesBr, Div of Bacterial and Mycotic Diseases, National Center for InfectiousDiseases, CDC.

Editorial Note: An estimated 2­4 million cases of salmonellosisoccur each year in the United States, resulting in at least 500 deaths( 1 ). Approximately 40,000 of these infections are culture-confirmed, serotyped, and reported to CDC through the National Salmonella SurveillanceSystem. In 1995, SE was the most common serotype reported, accounting for25% of the 40,720 serotyped culture-confirmed cases. Salmonellosis is frequentlyassociated with eating undercooked eggs and poultry. Undercooked eggs area particularly common source of SE infections.

During 1988­ 1992, among foodborne disease outbreaks of salmonellosisreported to CDC in which a single food item was implicated, consumptionof turkey and eggs accounted for 4% and 14% of cases, respectively. Inaddition, eggs or foods containing eggs as a princi-pal ingredient caused64% of the SE outbreaks ( 2 ). Factors probably associated with the outbreakdescribed in this report included inadequate thawing, use of raw eggs inthe stuffing, and undercooking; in addition, the browned color of the turkeymay have caused the cook to believe that the turkey andstuffing were thoroughlycooked. Although the original source of the Salmonella is unknown, theraw eggs used in the stuffing probably contained SE, and these eggs probablywere incompletely cooked; undercooking may occur more commonly in tur-keysthat contain stuffing (J. Carpenter, Ph.D., University of Georgia, personalcommu-nication, 1996).

Each year, an estimated 45 million turkeys are eaten in the United Statesat Thanks-giving (J. DeYoung, National Turkey Federation, personnel communication,1996). Salmonella infection may result from eating improperly cooked turkeyand stuffing ( 3,4). This risk for infection can be reduced by cookingstuffing outside the turkey. Guidelines prepared by the U.S. Departmentof Agriculture (USDA) for persons who choose to cook stuffing inside theturkey recommend preparing the stuffing immediately before it is placedinside the turkey, stuffing the turkey loosely, inserting a meat thermometerinto the center of the stuffing, and ensuring that the thermometer attainsa temperature of at least 165 F (74 C). Additional recommendations forsafely preparing and cooking a turkey include thawing the turkey completelybefore cooking, cooking in an oven set no lower than 325 F (163 C), andusing a meat thermometer to ensure that the innermost part of the thighattains a temperature of 180 F (82 C). Although the set temperatureand cooking time can be used as guides to determine whether food is completelycooked, inaccuracies in the actual temperature and incomplete thawing beforecooking can lead to undercooking. Use of a meat thermometer provides amore accurate determination of thorough cooking. Further advice on cookingturkeys and stuffing is available from USDAÕs Meat and Poultry Hotline,telephone (800) 535-4555.

References

1. Cohen ML, Tauxe RV. Drug-resistant Salmonella in the United States:an epidemiologic perspective. Science 1986;234:964­9.

2. Bean NH, Goulding JS, Loa C, Angulo FJ. Surveillance for foodborne-diseaseoutbreaks United States, 1988­-1992. In: CDC surveillance summaries(October). MMWR 1996;45(no. SS-5).

3. CDC. Foodborne nosocomial outbreak of Salmonella readingÑConnecticut.MMWR 1991;40: 804­6.

4. CDC. Restaurant outbreak of salmonellosis due to undercooked turkey Washington. MMWR 1978;27:514,519.

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria

## Heparin in IBD

Here is an overview and several abstracts about heparin in IBD

One of the oddest treatments to come along in quite some time is the use of a medicine called heparin in the treatment of IBD. The reason this is so odd is that heparin is one of a number of drugs known as anticoagulants. In someone with a disease that causes bleeding it is surprising that ananticoagulant would not make things worse.

Historically, the main drug used in ulcerative colitis was discoveredaccidentally. Sulfasalazine (aka Azulfidine) was initially designed asan antiarthritis drug. It is a molecule of 5-ASA and sulfa antibiotic joinedby a covalent bond. The initial thinking was that the drug would be absorbedand the combination of antibiotic and antiinflammatory would be good forrheumatoid arthritis, a disease that back then was thought to be due toan infection and inflammation. A few patients with UC and arthritis wereseen to do quite well in regards to their colitis. It didn’t work verywell against the arthritis. Turned out that the drug is not well adsorbed,and that in the colon the drug was broken down by bacteria (hooray forbacteria) and locally liberated the antiinflammatory drug 5-ASA.

History seems to have repeated itself with heparin. A patient with UCwas being treated for a blood clot in the leg. Their intrepid physician,knowing that DVT’s could be life threatening, went ahead and used heparin.The patient’s UC improved. Thus the use of heparin in UC had its beginnings.

Further support for the use of heparin in UC is that the microscopicappearance of the tissue is that of multiple tiny blood clots in the vesselsof the injured colon. This was thought to represent coagulation in responseto the inflammation, and perhaps was even protective since clotting mayhave represented the prevention of further bleeding. Well, with the improvementthat was seen, it was only natural to wonder whether the improvement seenin the patients with UC might have been due to better blood flow to theinjured tissue.

A number of patients have now been given heparin during attacks of UC.It seems to work. The abstracts below describe the responses that patientsseem to have. Interestingly, one of the described uses is in patients withextraintestinal complications of IBD, such as erythema nodosum. These complicationscan be very slow to respond to conventional therapy. Bleeding does ometimeshappen, but it does not seem to be uncontrollable. Heparin has no toxicity,and only occasionally has poor outcomes, though as more patients are treatedwe may see injuries occur (massive GI or pulmonary bleeding, strokes).

Below I have reproduced the abstracts from the 1996 DDW meeting thatreferred to heparin in treatment of IBD. They are copyright DDW.

Remember that these are early studies, and a number of treatment forIBD have been found to be worthless over the years. Even if correct, thestudies were small, and did not have controls. There is no data on whatthe optimal dose or duration of treatment is. Even simple things, liketaking advantage of what is known about the histology of UC and checkingwhether the presence of microthrombi predicted whether patients would benefit was not done. Most patients seem to be helped, but a few seem to bleedmore. Can we predict who those will be? These questions will need to beaddressed before heparin moves into the mainstream of treatment of IBD.

TITLE: [65] HEPARIN THERAPY IN REFRACTORY ULCERATIVE COLITIS – AN UPDATE.

AUTHORS: P.R. Gaffney, A. Gaffney. Dept. of Surgery, Mallow GeneralHospital, Mallow, Co. Cork, Ireland.

BODY: Aims and Methods: At the 1993 meeting of the AGA we reported a beneficial effect associated with heparin therapy in nine of ten cases with refractory UC. As a number of initially promising treatments for IBD have subsequently proved disappointing, we decided to review (a) the outcome of the patients in our pilot study, (b) unpublished case reports of further patients treated with heparin, and (c) recent publications on heparintherapy in refractory UC.

Results: (a) Five of the nine patients who went into remission on heparin had a recurrence off heparin; four of these responded to further heparin treatment. Three patients had colectomies (for cancer; obstruction; pseudopolyps). All three were in clinical remission at the time ofsurgery. (b)Seven further patients with refractory UC were treated at our hospital. Three had fulminant and four moderate disease. All went into remissionon i.v. heparin with sulphasalazine, two having initially failed to respondon s.c. heparin. We received reports of nine cases of UC treated with heparin at other centers here and abroad, seven of whom had a favorable response. (c)an open pilot study of heparin in nine cases of refractory UC reports remission in seven cases, with one relapse[1]. A case study [2] reportsthe rapid and sustained resolution of pyoderma gangrenosum and refractoryUC on
i.v. heparin. Conclusions: Heparin, used i.v. and with sulphasalazine, appears to be effective in the treatment of refractory UC, and warrants larger controlled trials.

1. Evans RC, Rhodes JM.Treatment of corticosteroid resistant ulcerative colitis with heparin -a report of nine cases (abstract). Gut 1995;37(supp1 2);A49.

2. Dwarakanath AD, Yu LG, Brookes C, Rhodes JM. ‘Sticky’ neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis. Gut 1995;37:585-588.

TITLE: [65] TREATMENT OF ULCERATIVE COLITIS WITH HEPARIN

AUTHORS: F. Brazier1, T. Yzet1, A. Boruchowicz , J.F. Colombel , J.C.Duchmann1, J.L. Dupas1. Department of Gastroenterology, University Hospital,Amiens1, Lille , France

BODY: Activation of procoagulant factors and high incidence of
thromboembolic events observed in ulcerative colitis (UC) suggest thata disorder of coagulation may contribute to the pathogenesis of thisdisease. Preliminary studies have shown that clinical remission may be obtainedby heparin treatment in UC.

The aim of this study was to evaluate on a small group of patients,the efficacy of heparin in active UC.

Methods: 6 patients (2 F, 4 M; age 20-43 yr) with active UC were included in this open label study. Disease activity was established at entryby clinical and colonoscopic criteria. Disease extent was left-sided in 3 patients and extensive to the entire colon in the 3 other patients. UC was moderately active in 4 patients and severe in 2 patients ;3 patients failed to respond to corticosteroids given for at least 2 weeks. Patients were administered heparin, either intravenously (IV) 3000u/4hrs for 1 weekand subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for the 3 following weeks (n=3), or SC 0.1ml/10kg b.i.d. for 4 weeks (n=3). Concomitant treatment with other drugs was not allowed during the study.
Patients were clinically evaluated daily.

Results: 4 patients reported significant clinical improvement: rectal bleeding stopped within the first 3 days and a remarkable decreasein bowel movements was observed in less than 10 days. One patient did not improve and proceeded to colectomy after 1 week. In the last patient heparin treatment was discontinued after 5 days because of a skin allergic reaction. Colonoscopy performed after 4 weeks in the 4 responders showed a complete healing of mucosal damages in 3 patients but persistent superficial erosions in one. Three of these 4 patients were still in clinical remission 4 weeks after the end of heparin treatment.

Conclusion: These preliminary results indicate that heparin treatmentmay be effective in acute UC.

TITLE: [65] EFFECT OF HEPARIN TREATMENT ON EXTRAINTESTINAL MANIFESTATIONSASSOCIATED WITH INFLAMMATORY BOWEL DISEASES.

AUTHORS: F. Brazier, T. Yzet, J.C. Duchmann, F. Iglicki, J.L. Dupas.Department of Gastroenterology, University Hospital, Amiens, France

BODY: Extra-intestinal manifestations occurring in patients with Crohn’s disease (CD) or ulcerative colitis (UC) are related to the activityof the bowel disease. Microvascular inflammation and hypercoagulable statemaycontribute to the pathogenesis of active inflammatory bowel disease(IBD).Preliminary studies have suggested that heparin, acting by anti-inflammatoryand anticoagulant properties, may be effective in the treatment of activeUC. The aim of this study was to evaluate the efficacy of heparin treatmenton extra-intestinal manifestations associated with active IBD. Methods:Thestudy was undertaken in 7 patients (5 F, 2 M, age 25-35 yr) with activeIBD(6 CD, 1 UC) and one (n=5) or more (n=2) extra-intestinal manifestations(erythema nodosum n=4, pyoderma gangrenosum n=1, peripheral arthritis n=3, apthous stomatitis n=1). These manifestations were associated with flare ofbowel disease in 6/7 patients. Three patients had chronic active CD treatedby prednisolone (20-35 mg/d) for at least 3 months; prednisolone doses werenot altered in the 3-weeks period before and were to be maintained at thesestable doses throughout the 4-weeks study period. Patients wereadministered heparin, either intravenously (IV) 3000u/4hrs for 1 week and subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for thefollowing 3 weeks (n=2), or SC 0.1ml/10kg b.i.d. for 4 weeks (n=4).Concomitant treatment with other drugs was not allowed during the study.Clinical evaluation was performed every week during the treatment,andevery 2 weeks for 3 months after the end of heparin treatment. Results:Extra-intestinal manifestations vanished completely in 5/7 patients withinthe first 2 weeks. In 1 patient erythema nodosum improved but did notvanish completely; for one patient with pyoderma gangrenosum, heparin treatment had to be discontinued after 5 days because of a skin allergic reaction. In 2 responders, erythema nodosum recurrence was observed within2 weeks after the end of heparin treatment. In the 5 responders, the meanC-reactive protein level remarkably decreased from 108 mg/l beforetreatment to 31 mg/l after 1-week treatment. Conclusions: These resultsindicate that heparin may be a potential therapeutic drug forextra-intestinal manifestations in the treatment of active IBD.

TITLE: [65] TREATMENT OF ACTIVE CROHN’S DISEASE WITH HEPARIN

AUTHORS: J.L. Dupas, F. Brazier, T. Yzet, B. Roussel, J.C. Duchmann,F. Iglicki, Department of Gastroenterology, University Hospital, Amiens,France

BODY: It has been suggested that microvascular thrombosis related to vasculitis and procoagulant factors activation may contribute to the pathogenesis of Crohn’s disease (CD). Anticoagulant and anti-inflammatory properties of heparin may be useful in the treatment of active inflammatory bowel diseases. The aim of this study was to investigate the potential efficacy of heparin in the treatment of active CD. Methods: 13 patients(9F, 4 M; age 16-31 yr) with active CD (Crohn’s disease activity index,CDAI> 200) were included in the open-label study. Disease activity was clinically and endoscopically assessed before treatment. Disease extended only to the colon in 3 patients and to the colon and terminal ileum in the10 other patients. Eight patients had chronic active CD treated by azathioprine and/or prednisolone for at least 3 months; drug doses were not altered in the 3 weeks period before and were continued at the dose used at entry, throughout the 4-weeks study period. Patients were administered heparin, either intravenously (IV) 3000u/4hrs for 1 week and subcutaneously(SC) (calcium heparinate) 0.1 ml/10kg b.i.d. for the following 3 weeks(n=7), or SC 0.1 ml/10kg b.i.d. for 4 weeks (n=6). Concomitant treatment with other drugs was not allowed during the study. All patients were clinically and biologically evaluated every week for the 4-weeks treatment period and followed up every 2 weeks for 2 months after the end of heparin treatment. Results: After 4-weeks treatment, 7/13 patients (54 %) fulfill the remission criteria (CDAI < 150) and 3 other patients reported significant clinical improvement ([Delta-bar] CDAI>100); 3 patients failed to respond. The mean CDAI decreased from 315 (95%CI:260-369) before treatment to 165 (95%CI:107-222) at the end of heparin treatment (p<0.004).The mean C-reactive protein decreased from 80.5 mg/l (95%CI:45-115) before treatment to 35 mg/l (95%CI:18-52) (p<0.007) after 1-week treatment.Slight increase of rectal bleeding due to overdosage of heparin was observed in 2patients leading to discontinuation of treatment in one of them. Among responders, 6 patients were still in remission 3 months after the end of treatment and 1 patient had a relapse at week 6. Conclusions: These results suggest that heparin treatment may be effective in patients with active CD.

TITLE: [65] EFFECT OF HEPARIN ON INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-alpha SERUM LEVELS IN INFLAMMATORY BOWEL DISEASES.

AUTHORS: F. Brazier1, T. Yzet1, C. Dessaint , J.C. Duchmann1, L. Prin, J.L. Dupas1. Departments of Gastroenterology1, Immunology, University Hospital, Amiens, France.

BODY: It has been suggested that pro-inflammatory cytokines interleukin-6(IL-6) and tumor necrosis factor – alpha (TNF-alpha) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). In a preliminary study conducted to evaluate the effectiveness of heparin treatment in IBD,we obtained a clinical remission (CDAI<150) in 7/13 (54 %) patients and a significant improvement ([open square]CDAI>100) in 3/13 (23 %) patients with Crohn’s disease (CD) as well as a clinical remission in 4/6 patients with acute ulcerative colitis (UC).

The aim of this study was to evaluate the effect of heparin treatmenton IL-6 and TNF-alpha serum levels in IBD.

Methods: IL-6, TNF-alpha (ELISA) and C-reactive protein (CRP) serum levels were measured before and after 1-week heparin treatment in 12 patients with active IBD (8CD, 4 UC). Patients received heparin, either intravenously 3000u/4hrs or subcutaneously (calcium heparinate) 0.1 ml/10kg b.i.d.

Results: table shows mean values and the results of paired comparison of CRP, IL-6 and TNF-alpha serum levels for the 12 patients:

             normal   before     after   p-value
treatment   1 week
CRP mg/l      < 5      79         36     <0.02
IL-6 pg/ml  3-8.5    74.3       42.0     <0.02
TNFα pg/ml  3-20     40.8       27.9     <0.15


Conclusion: High values of IL-6, and TNF-alpha serum levels are observed in acute IBD. IL-6 but not TNF-alpha decreases significantly after 1-week heparin treatment.

TITLE: [65] HEPARIN IN THE TREATMENT OF HIGHLY ACTIVE INFLAMMATORYBOWEL DISEASE (IBD).

AUTHORS: C. Folwaczny, M. Spannagl, W. Wiebecke*, M. Jochum#, W. Heldwein,K. Loeschke. Medizinische Klinik, Klinikum Innenstadt, Pathologisches Institut*,Abteilung für klinische Biochemie#, Ludwig-Maximilians University,Munich, Germany

BODY: Recently (Gaffney et al., Am. J. Gastroenterol. 1995, 90: 220) unfractioned heparin (UH) was reported to be clinically helpful in 10patients with steroid-resistant ulcerative colitis (UC). It is not known whether this beneficial effect is mediated by anti-coagulatory or anti-inflammatory properties of UH. Therefore, we started an openun controlled trial to investigate the clinical and antiinflammatory effects of UH in patients with highly active IBD. Patients and methods: So far 6 UC patients and 1 patient with Crohn’s disease (CD) (2 women, 5 men; mean age:31+-3 y; mean duration of the disease: 10+-4 y) were studied. At entry UC patients had a mean clinical activity index (CAI, according to Gomeset al.) of 17+-3 points and the CD patient had a Crohn’s disease activity index(CDAI, according to Best at al.) of 425 points. The mean follow-upper iod was 5 weeks. The protocol includes PTT-effective i. v. application of UH(>60 sec.) for 2 wk followed by s. c. UH (12.500 I. E. BID) for another6wk. In addition, sulfasalazine (1 g/TID) was given orally. Prednisolone in the 6 UC-patients could be tapered from 38+-7 mg/day at study entry to 26+-10mg after 4 wk. Erythrocyte-sedimentation rate (ESR), C-reactive protein(CRP), white-blood cell (WBC) and platelet count (PC), \alpha_1 and\alpha_2-globulin and fibrinogen were monitored weekly. Results: All patients showed marked clinical improvement. After 2 and 4 wk the CAI decreased to a mean of 5+-1 points and 5+-1 points (p<0,01), resp. and the CDAI decreased to 229 and 250 points, resp. Rectal bleeding stopped in all patients within 4 wk.

The laboratory values at study-entry, after 2 and 4 wk resp. were asfollows:

       baseline         2wk                 4wk
ESR:    77+-8       43+-6   (p<0,01)  47+-9 mm/2h   (p<0,01)
CRP:    12+-4        2+-1   (p<0,01)   2+-0,5 mg/dl (p<0,01)
WBC:  14.0+-2.0   10.0+-1.2 (p<0,01) 9.0+-1.3/ l    (p<0,01)
PC:    448+-34     387+-47  (p<0,01) 330+-44/ l     (p<0,01)
\alpha_1-globulin:
5,3+-0,9    3,8+-0,6 (p<0,01) 5,0+-0,6%
fibrinogen:
379+-12     290+-37  (p<0,01) 317+-32 mg/dl

The CD patient refused corticosteroids and arthritis resolved after 6 wk. In 1 UC-patient UH treatment was stopped at day 11 because of sudden worsening of the rectal bleeding (PTT at this time <60 sec.) necessitating blood transfusions. Because the patient noticed a decrease in bowel movements i. v. UH was restarted after 2 days, resulting in continuing improvement with no further bleeding. No other unwanted effects were seen, apart from a minor reversible increase in ALT-activity in 3 patients. Conclusions: These preliminary data confirm that UH could be useful in highly active IBD. This effect may in part be due to anti-inflammatory properties of UH. However, controlled trials have to be awaited before routine use of UH can be recommended.