Gut 1996; 39: 846-851

Collagenous colitis: a retrospective study ofclinical presentation and treatment in 163 patients

J Bohr, C Tysk, S Eriksson, H Abrahamsson, G Jamerot

AbstractBackground-Data on collagenous colitishave been based on a limited number ofpatients.Aims-To obtain more information onthis disease from a register set up atOrebro Medical Center Hospital.Patients and methods-Twenty fiveSwedish hospitals have contributed to thispatient register, which comprises 163histopathologically verified cases. Clinicaldata were retrospectively analysed.Results-Collagenous colitis followed achronic intermittent course in most cases(85%) with a sudden onset in 42%. Symp-toms were chronic watery diarrhoea, oftennocturnal (27%), abdominal pain (41%),and weight loss (42%). Sixty six patients(40%) had one or more associated diseases.Routine laboratory data were mostlynormal. The median age at diagnosis was55 (range 16-86) years, but 25% of thepatients were younger than 45 years. Sevenpatients died of unrelated diseases. Theresponse rate for sulphasalazine was 59%,and 50% and 40% for mesalazine andolsalazine. Prednisolone was most effectivewith a response rate of 82%/ but therequired dose was often high and the effectwas not sustained after withdrawal. Anti-biotics were efficient in 63%. Cholestyra-mine and loperamide had response rates of59% and 71% respectively.Conclusions-Collagenous colitis followsa chronic continuous course. Symptomscan be socially disabling, but the diseasedoes not seem to have a malignantpotential. A plan for the treatment of anewly diagnosed patient with coliagenouscolitis is proposed.(Gut 1996; 39: 846-851)

Keywords: collagenous colitis, clinical data, treatment.

Collagenous colitis, described in 1976 byLindstrom,l is characterised clinically bychronic watery diarrhoea, and histopatho-logically by a thickened subepithelial collagenlayer adjacent to the basal membrane,infiltration of the lamina propria with inflam-matory cells, epithelial lesions, and infiltrationof the epithelium with lymphocytes.2 Today,collagenous colitis is widely accepted as anentity of its own, and by the end of 1992, 446patients with collagenous colitis had beendescribed in the medical literature (CGLindstrom, personal communication).The clinical features and treatment of the

disease are mainly based on case reports or

small uncontrolled series. Only one controlledstudy has been undertaken, on corticosteroidtreatment,3 as the few patients at each hospitalhave limited larger controlled trials ontreatment.At our hospital, a register of patients with

collagenous colitis has been established duringthe past six years. The present study presentsretrospectively evaluated data on clinicalfeatures and medical treatment.

Methods

PATIENTSA register of patients with collagenous colitiswas established in 1989 at Orebro MedicalCentre Hospital. At first it was limited topatients diagnosed in this hospital, but since1992 records from other hospitals have beenincluded after consent of the patients. Twentyfour hospitals submitted the medical records oftheir patients with collagenous colitis to us, orallowed us to scrutinise the notes at thehospital. Registration of data for this study wasconcluded by December 1995. The registerwas approved by the Swedish Data InspectionBoard.

DIAGNOSTIC CRITERIAAll biopsy material was re-evaluated by one ofus (SE), and the following histopathologicalcriteria in a van Gieson stained specimen hadto be fulfilled: (1) a subepithelial collagen layerwith a thickness of at least 10 ,um on a welloriented section of the mucosa - that is, asection where at least three adjacent cryptswere cut in their vertical plane; (2) the presenceof lymphocytic infiltration in the epithelium orlesion in the form of detachment, flattening, orvacuolisation of the epithelium; (3) inflam-mation of the lamina propria with infiltrationof predominantly plasma cells and lympho-cytes.2These histopathological features, together

with the main symptom - chronic waterdiarrhoea - constituted the diagnostic criteria.

CLINICAL DATAAll clinical data were evaluated retrospectively.The age of the patient at the time of histo-pathological diagnosis and at the time of onsetof the disease were registered. Whether theonset of diarrhoea was sudden (within a fewdays) or insidious and stool frequency werenoted at the time of the diagnosis. Any historyofabdominal pain was registered, but this couldnot be specified regarding location or intensity.

Department ofMedicine, Division ofGastroenterologyJ BohrC TyskG Janerot

Department ofPathology, OrebroMedical CentreHospital, Orebro,SwedenS Eriksson

Department ofMedicine, Division ofGastroenterology,Sahlgrenska UniversityHospital, Goteborg,SwedenH AbrahamssonCorrespondence to:Dr J Bohr,Department of Medicine,Orebro Medical CenterHospital, S-701 85 Orebro,Sweden.Accepted for publication22 July 1996

846

Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients

Weight loss, quantified if possible, and symp-toms of fatigue were noted. The longtermcourse of the disease was evaluated individuallyas single episode, chronic intermittent, orchronic continuous. Disease activity duringpregnancy and associated diseases of inflam-matory or autoimmune origin were registered.

LABORATORY DATA

Blood tests were recorded if taken within twoweeks of the date of diagnosis. The followingvariables were recorded with normal rangesgiven in parentheses: erythrocyte sedimen-tation rate (women 2-15 mm, men 2-10 mm)and haemoglobin (women 115-140 g/l, men135-165 g/l). Serum albumin (37-46 g/l),alkaline phosphatases (2.0-5.0 ,ukat/l), ala-nine transaminase and aspartate transami-nase (0.2-0.8 ,ukat/l), platelet concentration(180-350X109/1), and creatinine (60-115jimol/l). A retention on day 7 of less than 10%of the administered doses of radioactivity wasconsidered diagnostic for bile salt malabsorp-tion when testing with the selenium-75-homocholic acid taurine test (SeHCATtest).

ENDOSCOPYThe macroscopic appearance of the mucosaduring colonoscopy or sigmoidoscopy wasregistered.

TREATMENT

Medication given for collagenous colitis wasevaluated, as well as medication possiblyinfluencing the disease - namely, non-steroidalanti-inflammatory drugs (NSAIDs) andcytostatic treatment. The effect was evaluatedretrospectively, and relied on the change orlack of change in the stool frequency. If themedication improved the patients' diarrhoea, itwas registered as having an 'effect'. If themedication did not have any impact on thepatients' diarrhoea, it was registered as having'no effect'. If side effects (nausea, abdominalpain, diarrhoea, taste sensation) or idio-syncrasies (fever, skin rash, agranulocytosis)occurred, they were registered as 'adverseeffects'. If the effect was not mentioned, orthere was any doubt of the outcome, or mixedmedication was given, the drug was notincluded in the analysis.Data on surgical treatment in nine patients

with medically intractable diarrhoea have beendescribed earlier.4

STATISTICS

Clinical data are presented as medians (range);laboratory data are presented as means. Inretrospective studies not all information isavailable in all medical notes. Therefore, thepercentages in various respects have beencalculated from the number of patients forwhom medical notes confirmed or denied theoccurrence of a sign or symptom. This explainsthe varying numbers in different Tables.

Results

PATIENTS

Histopathological specimens from 196 patientssuspected ofhaving collagenous colitis were re-evaluated. A total of 163 patients fulfilled theabove mentioned criteria, and 33 wereexcluded. Twenty of these 33 cases had someother form of microscopical colitis, six hadunspecific colitis, one had acute colitis andSalmonella species in faecal culture, and six hadnormal colonic mucosa.

CLINICAL DATA

Age and sex ratioThe median age at the time of diagnosis was55 (18-87) years, equal for men and women.Of the 163 patients, 142 were women and 21were men, yielding a female:male ratio of6-8: 1. The Figure shows the age distribution atthe time of diagnosis. Forty patients (25%)were diagnosed before the age of 45. Themedian age at the time of onset of symptomswas 48 (16-86) years. The duration of symp-toms from onset to diagnosis varied consider-ably (median 47 (1-421) months). Themedian follow up time was three (0-16) years.

Mode of onset and clinical course (Table I)For 48 patients a sudden onset was mentioned;66 had an insidious onset and for 49 patients themode of onset was not specified in the records.Two patients have so far only had a singleepisode - that is, longlasting remission wasobtained within three months. One experiencedremission spontaneously and one after treatmentwith metronidazole. Ninety patients had achronic intermittent course and 14 patientsexperienced a chronic continuous course; in 57patients the course was not described.

Symptoms (Table I)All patients had diarrhoea. In 131 of 163patients the stool frequency was reported at thetime of diagnosis. The median value was six

40W WomenM Men

30

200o

11-20 31-40 51-60 71-8021-30 41-50 61-70 81-90

Age at diagnosis (y)Distribution ofpatients in relation to age at diagnosis.

847

Bohr, Tysk, Eriksson, Abrahamsson, Jdrnerot

TABLE I Clinical data in 163 patients with collagenouscolitis

n (%)

Onset (n=1 14):Sudden 48 (42)Insidious 66 (58)

Course (n=106):Single episode 2 (2)Chronic intermittent 90 (85)Chronic continuous 14 (13)

Symptoms (n= 153):Weight loss* 64 (42)Abdominal pain 62 (41)Nocturnal diarrhoea 41 (27)Fatigue 21 (14)Meteorism 12 (8)

Stools per day (n= 131):<3 16 (12)4-9 86 (66).10 29 (22)

*Median value 6 kg, range 3-20 kg. n=Number of patients onwhom information is available.

(1-23) stools per day. Sixteen patients had <3stools per day, 86 patients had four to nine, and29 patients had 10 or more. Forty one patients(27%) had nocturnal diarrhoea.Recordings regarding symptoms other than

diarrhoea were available in 153 cases. Un-specified abdominal pain was experienced by 62patients, fatigue occurred in 21, and meteorismin 12. Weight loss was registered in 64 cases,and quantified in 40 (median 6 (3-20) kg).

Disease activity duringpregnancyFive women became pregnant after the diag-nosis ofcollagenous colitis. All experienced clini-cal remission during pregnancy and remained inremission some months after delivery.

Associated diseases (Table II)Sixty six patients (40%) had one or moreassociated diseases of inflammatory or auto-immune origin. The four most frequent wererheumatoid arthritis (n=16), thyroid disorders(n= 14), coeliac disease (n= 13), and diabetesmellitus (n=9). Four patients had a concomi-tant inflammatory bowel disease, which washistopathologically in remission at the time of

TABLE II Associated diseases in 163 patients withcollagenous colitis

n (%)Rheumatoid arthritis

SeropositiveSeronegativeSerum not examined

Thyroid disordersHyperthyroidismHypothyroidismGoitre

Coeliac diseaseAsthma/allergyDiabetes mellitus

Insulin dependentNon-insulin dependent

Chronic gastritisCrohn's diseaseUlcerative proctitisSjogren's syndromePsoriasisRaynaud's diseasePolymyalgia rheumaticaDermatitis herpetiformisMb BechterewSarcoidosisAlopeciaSystemic lupus erythematosus

16 (10.0)655

14 (8-6)84213 (8-0)10 (62)9 (5-5)634 (2-5)3 (1.9)1 (0-6)3 (1.9)3 (1.9)3 (1.9)2 (1-2)2 (1.2)2 (1.2)1 (0-6)1 (0-6)1 (0-6)

the diagnosis of collagenous colitis. Three hadCrohn's disease diagnosed one, four, and 32years before the diagnosis of collagenous colitison resected specimens from the colon (n=2) orileum (n=l) with typical findings such as

granulomas and transmural inflammation. Onepatient had ulcerative proctitis diagnosed eightyears before collagenous colitis.Of the 66 patients with associated diseases,

48 patients had one associated disease, 15patients had two, two patients had three, andone patient had four.

MortalitySeven patients had died at a median age of 66(55-79) years of diseases not related tocollagenous colitis. These were pulmonaryfibrosis with respiratory insufficiency (n=2),myocardial infection (n=2), cerebrovascularlesion (n= 1), lung cancer (n= 1), and relapse ofacute lymphatic leukaemia (n= 1).

LABORATORY DATA

The erythrocyte sedimentation rate wasrecorded for 44 patients. The mean for womenand men was 25 and 12 mm respectively. Themean concentrations of haemoglobin, serum

albumin, alkaline phosphatases, alanine trans-aminase, aspartate transaminase, platelet con-centration, and creatinine were normal. Fifteenof the patients treated with cholestyraminewere tested with the SeHCAT test. Ten hadbile salt malabsorption.

ENDOSCOPY

In 105 patients (71%), normal appearingcolonic mucosa was reported, and in 42patients (29%), non-specific abnormalitiessuch as oedema, erythema, or abnormal vesselpatterns were seen, while in 16 patients themacroscopic appearance was not reported.

TREATMENT

Table III shows the data on treatments. In mostpatients more than one treatment regimen wastried. Adverse reaction to sulphasalazine oc-curred in 45 of 108 (42%) treatments. Treat-ment with prednisolone often resulted in promptimprovement, but relapse usually occurred onlydays after treatment was discontinued. Two

TABLE III Retrospective evaluation of treatment incollagenous colitis

No of No Adversepatients Effect effect effects

Sulphasalazine 108 37 26 45Mesalazine 16 8 8 0Olsalazine 15 4 6 5Prednisolone 39 32 6 1Budesonide* 2 2 0 0Metronidazole 44 24 16 4Erythromycin 15 10 4 1Penicillin 8 8 0 0Cholestyramine 44 26 17 1Mepacrine 19 10 7 2Loperamide 69 49 18 2

*One controlled ileal release and one controlled colon release.

848

Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients

patients received budesonide, one withcontrolled ileal release and one with controlledcolonic release; both had relief from symptomson this treatment. Relapse was also noticed inresponders after treatment with antibiotics, butthe interval between discontinuation and relapsewas usually longer than after treatment withcorticosteroids (weeks rather than days). Of the26 patients who responded to cholestyraminetreatment, 10 had a pathological and five anormal SeHCAT test. Loperamide often had tobe given at high dosage (4 mg thrice daily ormore) to be effective.One patient with pulmonary cancer and

one with breast cancer were treated withfluorouracil alone or in combination withmitoxantrone and folic acid. Two patientsreceived low dose methotrexate for rheumatoidarthritis. Clinical improvement in collagenouscolitis was seen in all four patients during thesetreatments.

Information on treatment with NSAIDswere available in 104 patients. Thirty five ofthese had taken NSAIDs regularly or forlimited intervals.

DiscussionOnly a few larger studies of patients withcollagenous colitis have been presented up tonow. The latest published review, ofThe JohnsHopkins Collagenous Colitis Registry, con-tains 107 patients.5 Pierrugues et al reviewed in1989 their experience of 40 patients,6 and Zinset al have recently presented some data from172 patients.7The median age at diagnosis in our study of

55 years and the sex ratio of 6.8:1 is in accor-dance with the Johns Hopkins experience.5However, 40 (25%) of the 163 patients werediagnosed before the age of 45 years. It isusually not well known that substantialnumbers of patients who acquired collagenouscolitis are young, but our findings clearlyillustrate that collagenous colitis must beconsidered also in young people with chronicwatery diarrhoea.The onset of collagenous colitis might be

sudden. Forty eight patients described it assuch: some could even mention the exact date,similar to the onset of an infectious gastro-enteritis. The type of onset was described by114 patients, implying sudden onset in 48 of114 (42%). However, this must be regarded asa maximum percentage, as a sudden onset ismore likely to be mentioned than an insidiousone. If none of the 49 patients with anunknown type of onset had a sudden type, thefrequency would be 48 of 163 (29%), whichwould be the minimum percentage.

In two patients longlasting remission wasacquired within three months of onset. Most(85%), however, had a chronic intermittentcourse. Watery diarrhoea is regarded as theprimary symptom in collagenous colitis, andonly one case with chronic obstipation has beenreported.8 As all patients in our survey wereinvestigated because of chronic waterydiarrhoea we cannot comment on this point.Nocturnal diarrhoea was fairly common in our

patients (27%), but a more frequent occurrence(680/o), was reported in a study of 19 patients.9Weight loss occurred in 42% of the patients,

and it was occasionally pronounced (onepatient lost more than 20 kg). Evidence ofmalabsorption in the form of steatorrhea hasbeen reported,'° 1' and could be one of theexplanations for the weight loss. Otherwise thecause is unknown. Serious dehydration wasseen in one patient only, although 22% hadmore than 10 watery stools per day. De-hydration has been reported as a possible con-tributing factor in a patient who died,'2 but thisseems to be a rare complication. Abdominalpain is common.5 '3 In our study 41%, and inanother recent study9 79%, had abdominalpain. Schub et al who studied motility incollagenous colitis, found that abdominal painwas not due to increased motility in thecolon.'4 In the present study 21 patients (14%)complained of fatigue; 67% of these patientshad either some associated systemic disease ornon-specific arthralgias, which might at leastpartly explain their fatigue.The variation in duration of symptoms from

the onset of the disease to the time of thehistopathological diagnosis was very large: onemonth to 35 years. We have shown in aprevious study that this interval decreased con-siderably in our catchment area during1984-93, most probably because of anincreased awareness of collagenous colitis andan increased biopsy rate during endoscopy.'5

Five patients experienced remission duringpregnancy and even some months afterdelivery. Collagenous colitis is more commonin women than men which, together with theeffect of pregnancy on symptoms, indicatesthat hormonal changes may influence thecourse of the disease and perhaps are of patho-genetic importance. Sex hormones and preg-nancy have been shown to have a modifyingeffect on the immune system and autoimmunedisease; thus collagenous colitis may be anexample of the greater female susceptibility toautoimmune diseases.'6 17

No patient in our register had died fromcollagenous colitis and it does not seem to havea malignant potential.5 The course in mostcases is chronic, and often troublesome, butbenign.

Laboratory tests were normal. Earlier studieshave come to the same conclusion, except thatpatients might have a slightly raised erythrocytesedimentation rate, mild anaemia, or peri-pheral eosinophilia.5 18 The mean erythrocytesedimentation rate in our study was 24 mm.For clinical purposes this has little relevance.In earlier studies we found that the serum IgMconcentration was significantly increased incollagenous colitis and the serum concen-tration of P-III-NP, a product of collagen IIIsynthesis, did not alter.'9 20 As in most series ofmicroscopical colitis no endoscopic changeswere noted in most patients. Changes, alwayssubtle were reported in only 29% thus the onlymeans of diagnosis for collagenous colitis iscolonoscopy biopsies, although an increasedconcentration of IgM might be an indicator ofthe disease.

849

Bohr, Tysk, Eriksson, Abrahamsson, _irnerot

Patients with collagenous colitis oftenhave concomitant diseases of autoimmuneorigin.6 16 21 22 In our study 66 patients (40%)had one or more associated diseases. The factthat the disease is associated with otherdiseases of autoimmune or suspected auto-immune origin, is another indication forcollagenous colitis being an autoimmunedisease itself.23 24 The association betweencoeliac disease and collagenous colitis has beennoted, but a common aetiology is ques-tioned.2 7 25 However, if a patient withcollagenous colitis responds poorly to treat-ment, it is important to exclude coeliac diseaseas a cause of treatment failure. Three of thepatients in our register had Crohn's diseasediagnosed before the diagnosis of collagenouscolitis. Two earlier reports have described thedevelopment of Crohn's disease before or aftercollagenous colitis.26 27 The association be-tween the two diseases might be coincidental.

Retrospective assessment of the efficacy oftreatment has several limitations and cannot becompared with clinical trials. Therefore ourresults must be interpreted with caution.

Sulphasalazine was the most often prescribedtreatment. Side effects to sulphasalazine seemedto occur more often than when treating ul-cerative colitis. However, 59% of those whotolerated the drug had benefit from it. Earlierreports on the effect of treatment with sulpha-salazine have been based on small numbers,with response rates between 25% and75%.9 10 18 28 29 Mesalazine and olsalazine seemto be somewhat less efficient. The responserates in our study were 50% and 40% respect-ively. Both have been tried previously in smallseries and case reports, with varying results.29-33

Prednisolone was the most effective treat-ment, which is also supported by otherreports.3 9 Thirty two patients (82%)responded to prednisolone. However, theeffect was not sustained. Relapse oftenoccurred early after withdrawal, and the doserequired to maintain remission was oftenunacceptably high, at more than 20 mg perday. Oral budesonide, with its lesser systemiceffects, may be an alternative. Our experienceis limited to two patients, both of whomresponded.

Various antibiotics and mepacrine hydro-chloride seem to be helpful in collagenouscolitis, and generally with very few side effects.Metronidazole and erythromycin were themost often prescribed drugs, and most patients(55% and 67%, respectively) responded well.Penicillin G was effective in all eight patientstreated. Half of the patients showed benefitfrom treatment with mepacrine hydrochloride.Mepacrine has both antibiotic effect and aninhibiting effect on arachidonic acid syn-thesis.34 31 Effects of antibiotics and mepacrinein collagenous colitis have been reported,7 34 35

supporting the hypothesis that collagenouscolitis might be a disease initiated by a micro-biological agent. The effect of sulphasalazinemight also partly depend on its antimicrobialproperty via the sulphur moiety. The suddenonset of collagenous colitis in some casessupports the theory of infection.

Cholestyramine was effective in 26 (59%)patients, and was generally well tolerated.Cholestyramine binds various substances - forexample, bile salts and bacterial toxins - whichboth could be of pathophysiological im-portance in collagenous colitis. The involve-ment of bile salts as part ofthe pathophysiologyhas been suggested by two groups whoreported on bile salt malabsorption in patientswith collagenous colitis,'0 36 but this wasquestioned by a third group.37 In our study, 15of the patients who responded to cholestyra-mine had been examined by the SeHCAT testand 10 had signs of bile salt malabsorption.Thus five patients responded to cholestyra-mine without having signs of bile salt mal-absorption. In such cases the effect of choles-tyramine could be due to absorption orinactivation of bacterial toxins. This mechan-ism has been suggested in a case report.38 Ourfinding that faecal stream diversion incollagenous colitis induces clinical and histo-pathological remission supports the view thata luminal factor may be of aetiologicalimportance.39Loperamide was prescribed to 69 patients in

this study. Seventy one per cent benefited fromthis, and serious side effects were not reported.In some earlier reports loperamide had noeffect,40 41 but in two recent reviews ofcollagenous colitis non-specific antidiarrhoealmedication is recommended as the primarytreatment.5 18 Our results support this view.

In four patients cytostatic treatment wasgiven for concomitant diseases. In two patientsdiarrhoea disappeared after treatment withmethotrexate for rheumatoid arthrtitis. Aclinical effect of methotrexate in inflammatorybowel di'sease has been suggested earlier.42 Thetwo patients who received treatment withfluorouracil with or without mitoxantrone andfolic acid for malignant disorders also had aclear improvement of the bowel symptoms.The clinical implication is not obvious, but theeffect of cytostatic treatment in collagenouscolitis is of interest.

Thirty five of 104 patients with collagenouscolitis (34%) had regular or sporadic treatmentwith NSAIDs. It has been claimed thatNSAIDs could be an aetiological factor incollagenous colitis,43 44 but this idea wascontradicted by others.45 46 NSAIDs areusually prescribed for associated arthritis orarthralgia, which makes it difficult to concludewhether NSAIDs cause or are the consequenceof collagenous colitis. Obviously, most patientswith collagenous colitis do not use NSAIDs,and therefore it can only be one of severalaetiological factors.On the basis of this retrospective study we

suggest that the following treatments should betried in a newly diagnosed patient withcollagenous colitis:(1) Antidiarrhoics - for example, loperamide (adose of 4 mg thrice daily may be required forloperamide).If no response:(2) Sulphasalazine: it might be wise to titratethe dose for one or two weeks to reduce adverseevents. In cases of intolerance to sulphasala-

850

Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients 851

zine, mesalazine and olsalazine are otheroptions.If still no response:(3) Cholestyramine: supplement with vitaminmay be needed during longterm treatment.If still no response:(4) Prednisolone: this drug usually has aprompt effect but symptoms reappear soonafter withdrawal, and often a daily dose of ¢20mg is needed. It is possible that budesonidewith its lesser systemic side effects is analternative.If still no response:(5) Antibiotics such as metronidazole, erythro-mycin, or penicillin G or mepacrine oftenrelieve symptoms for some weeks, but seldomgive a longlasting effect.(6) Immunosuppressant therapy such asmethotrexate might have an effect. However,these drugs have potentially serious side effectsand a split ileostomy is the recommendedoption in medically resistant cases.

In patients resistant to treatment it isimportant to exclude concomitant causes ofdiarrhoea - for example, coeliac or thyroiddisease.

The following colleagues have generously submitted patientrecords for this study: Anders Ronnblom, Boden; LasseCarling, Bollnas; Lars Weywadt, Boras; Gudrun Schumacher,Danderyd (Stockholm); Hans Tanghoj, Eskilstuna; KjellFurugard and Marie Felike, Falun; Anders Danielsson andDan-Axel Hallback, Kariskoga; Ebbe Lyrenas, Karlskrona; LarsBergman, Lars-Krister Enander and Jesper Persson, Karistad;Lars Blomquist and Jan Bjork, Karolinska (Stockholm); DanHegewald, Katrineholm; Jan Bergman, Lindesberg; G6ranBodemar and Magnus Strom, Linkoping; Bernard Jaup,Lundby (Goteborg); Ake Kjellmert, Mora; Sven-PetterFallstrom and Lars Nilsson, Molndal; Christer Granno,Jonkoping; Henry Nyhlin, Skovde, Olle Brostrom and PerKarlen Sodersjukhuset (Stockholm); Thomas Ericson, Udde-valla, Xke Danielsson, Umea; Lars Lo6f and Yesuf Taha,Uppsala; Franz Riucker, Visby; Einar Thorhallsson, Vaxjo.JB was financially supported by Orebro County Research

Committee, Orebro Medical Centre Research Foundation,Orebro Lakaresallskap, Pharmacia AB, the Nanna Svartz grant,and Glaxo AB; this is gratefully acknowledged.

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