PEPTIC ULCER, NONSTEROID ANTI-INFLAMMATORY DRUGS AND THE RHEUMATIC DISEASES

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1 330 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXV NO Lindahl BIB, Allander E. Problems in the classification of cause of death diagnoses affecting the reliability of mortality statistics for rheumatoid arthritis. J Chron Dis 1985;38: Lawrence JS. Rheumatism in populations. London: Heinemann, Wood JW, Kato H, Johnson KG, et al. Rheumatoid arthritis in Hiroshima and Nagasaki, Japan: prevalence incidence and clinical characteristics. Arthritis Rheum 1967;10: Kato H, Duff IF, Russell WJ. Rheumatoid arthritis and gout in Hiroshima and Nagasaki, Japan: a prevalence and incidence study. / Chron Dis 1971^3: Linos A, Worthington JW, O'Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence and mortality. Am J Epidemiol 1980;lll: Royal College of General Practitioners. Weekly returns: Notification of newly diagnosed episodes: 4 weekly summary (reports) Birmingham: R.C.G.P. Research Unit. 12. R.C.G.P., O.P.C.S., D.H.S.S. Morbidity statistics from general practice: second national morbidity survey [Studies on medical and population-subjects No. 36]. London: H.M.S.O., Kelsey JL. Epidemiology of musculo-skeletal disorders. New York: Oxford University Press, Wood PHN. Age and the rheumatic diseases. In: Bennett PH, Wood PHN, eds. Population studies of the rheumatic diseases. Proceedings of the third international symposium. Amsterdam: ExerptaMedica, Bachman DM. Survey of rheumatoid arthritis in Oregon [Abstract]. Arthritis Rheum 1963; 6: Wingrave S, Kay CR. Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet 1978;i: Vandenbroucke JP, Valkenburg HA, Boersma JW, et al. Oral contraceptives and rheumatoid arthritis: further evidence for a protective effect. Lancet 1982;U: Linos A, Worthington JN, O'Fallon WM, Kurland LT. Case control study of rheumatoid arthritis and prior use of oral contraceptives. Lancet 1983;i: del Junco DJ, Annegers JF, Luthra HS, Coulam CB, Kurland LT. Do oral contraceptives prevent rheumatoid arthritis? JAMA 1985; 254:1938-^ Esdaile J, Horwitz R. Resolving contradictory results in epidemiologic studies of oral contraceptives and rheumatoid arthritis. Clin Res 1984;32:462A. PEPTIC ULCER, NONSTEROID ANTI-INFLAMMATORY DRUGS AND THE RHEUMATIC DISEASES A RELATIONSHIP between nonsteroid anti-inflammatory drugs (NSAIDs) and serious gastric pathology has been much studied clinically and experimentally and still continues to arouse interest and controversy. The clinical evidence implicating NSAIDs as a cause of peptic ulcer has been acquired in several different ways: 1. Patients with rheumatic diseases taking NSAIDs are assessed for gastric symptoms and by gastroscopy and faecal occult blood testing. Studies of this type are an essential part of evaluation of new NSAIDs, but may be misleading if too few patients are studied for too short a period of time. It is essential to have a suitable control group and a clear distinction must be made between prevalence and incidence. These problems have been well reviewed [1]. 2. The drug history of patients presenting to hospital with serious gastric problems, especially haemorrhage and perforation, is compared with that of a suitable control group of subjects. In one recent study of perforated peptic ulcer [2], there was a highly significant excess consumption of NSAIDs in patients with perforation over the age of 65 years. There was also a significant correlation between the annual number of older patients with perforation and the annual prescription rate of NSAIDs in the region. The drug history of 230 patients over the age of 60 presenting with acute bleeding from peptic ulcer has recently been compared with that of both hospital and community control groups [3]. Non-aspirin NSAIDs were taken more than twice as often by the patients as by the controls and an attributable risk of 22% was calculated (i.e. NSAIDs were considered to be responsible for 22% of the bleeding episodes). 3. Adverse reactions to drugs are reported to the Committee on Safety of Medicines (CSM), who have recently published their observations

2 EDITORIAL 331 relating to NSAIDs and serious gastric adverse reactions, based on reports collected over the last 20 years [4, 5]. Haemorrhage and perforation are frequently reported especially in the older age groups and certain drugs are considered to be more dangerous than others, if adverse reactions are related to the total numbers of prescriptions. The most dangerous drugs in this respect (indoprofen and Osmosin) have already been withdrawn and the safest appears to be ibuprofen. There are clearly major problems of under-reporting, inaccurate reporting, multiple drug usage and different dosages and durations of prescriptions. 4. Very indirect evidence can be based on epidemiological studies. Recent evidence has shown that, against a striking fall in hospital admissions for peptic ulcer during the last 25 years, there has been an increase in the admission rate for perforated peptic ulcer in women over 65 years of age [6]. This has coincided with a huge increase in the prescription of NSAIDs for females in this age group. During this period there has also been a marked increase in NSAID prescribing for men and for middle-aged females, who do not show the same trend in perforation rate. Deaths from peptic ulcer are now relatively infrequent but, in a recent study based on an incomplete postal questionnaire in Hampshire, almost 50% of those dying had been taking NSAIDs [7]. Against this background it is difficult to avoid the conclusion that NSAIDs can adversely affect the stomach and that elderly women are especially susceptible. Three recent articles in this journal shed some light on other aspects of this intriguing problem. In this issue, Malone et al. [8] show that the prevalence of peptic ulcer disease based on retrospective evidence is similar in patients with rheumatoid arthritis and osteoarthritis. These patients were all ill enough to be admitted to hospital and had nearly all taken NSAIDs, whereas only a minority had received aspirin or corticosteroids. Approximately 16% of each group had definite or probable evidence of peptic ulcer at some stage in their lives. No attempt was made to relate the use of the drugs to the development of peptic ulcer and the temporal relationships are not described. Nevertheless, the observations strongly suggest that patients with rheumatoid arthritis do not have a peculiar susceptibility to peptic ulcer or a gastric mucosa that is especially sensitive to the adverse consequences of NSAIDs. Indeed in the big Nottingham study mentioned above [3] the vast majority of patients whose bleeding was ascribed (at least in part) to NSAIDs had osteoarthritis rather than rheumatoid arthritis. In a study recently reported from Bath [9] the referral pattern of rheumatological patients for gastroscopy was compared with the symptoms and findings among non-rheumatological patients attending an endoscopy clinic. The rheumatological patients were more likely to have anaemia from frank or occult bleeding than dyspepsia or pain and more commonly had endoscopic abnormality, especially gastric or duodenal ulcer. Although the two groups were said to be matched for age and sex (details not given), the rheumatological patients were in-patients and some had presumably been admitted for gastro-intestinal haemorrhage, whereas the control group were mainly outpatients in whom one would expect pain/dyspepsia to be the main reason for referral. Never-.theless, there is a suggestion that ulcers in rheumatological patients may be relatively painless prior to bleeding or that rheumatologists are reluctant to enquire about dyspepsia or refer their dyspeptic patients for endoscopy (which seems unlikely!). In the study of peptic ulcer deaths [7], the majority of patients on NSAEDs were not known to have had a previous history of peptic ulceration, suggesting that serious complications are often not preceded by pain. Finally, there is surprisingly little evidence available about the healing of peptic ulcer in response to cimetidine and other drugs during the continued use of NSAIDs. Another study from the same group in Bath [10] concluded that cimetidine was no better than placebo in promoting the healing of peptic ulcer (gastric or duodenal) in patients who continue to take NSAIDs. It must be said that the numbers were very small and that the healing rates after six weeks on placebo were surprisingly high (60%, but only six ulcers in 10 patients). It would not be surprising if cimetidine were found to be relatively ineffective, because gastric ulcers in the older age groups are usually associated with low gastric acid secretion and the adverse effects of NSAIDs are on the gastric mucosal barrier. Mucosal protective drugs, such as De Nol (tripotassium di-citrato-bismuthate) and sucralfate, would seem a more obvious choice, and clearly much more work is required on this important problem. In conclusion NSAIDs must be used with cir-

3 332 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXV NO. 4 cumspection especially in older females. Major gastroduodenal complications tend to occur without prior warning in the form of dyspepsia and one cannot rely on the simultaneous use of cimetidine or other drugs to reduce the complication rate. The first two points are only too familiar to all rheumatologists; the last point has been inadequately assessed to date by controlled clinical trial. Gastroenterology Unit, Guy's Hospital, London SE1 9RT, UK. G. SLADEN REFERENCES 1. KurataJH,ElashoffJD, Grossman MI. Inadequacy of the literature on the relationship between drugs, ulcers and gastrointestinal bleeding. Gastroenterology 1983;82: Collier DSU, Pain JA. Non-steroidal antiinflammatory drugs and peptic ulcer perforation. Gut 1985^6: Sommerville K, Faulkner G, Langman M. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet 1986;i: CSM Update. Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions 1. Br Med J 1986;292: CSM Update. Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions 2. Br Med J 1986;292: Walt R, Katschinski B, Logan R, Ashley J, Langman M. Rising frequency of ulcer perforation in elderly people in the United Kingdom. Lancet 1986;i: Catford JC, Simpson RJ. Confidential enquiry into deaths from peptic ulcer. Health Trends 1986;18: Malone DE, McCormick PA, Daly L, et al. Peptic ulcer in rheumatoid arthritis intrinsic or related to drug therapy? Br J Rheumatol 1986;25: Collins AJ,DaviesJ,Ducon ASU. Contrasting presentation and findings between patients with rheumatic complaints taking nonsteroidal anti-inflammatory drugs and a general population referred for endoscopy. Br J Rheumatol 1986^5: Davies J, Collins AJ, Dixon ASU. The influence of cimetidine on peptic ulcer in patients with arthritis taking anti-inflammatory drugs. Br] Rheumatol 1986;25:54-8.

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5 Worldwide opinion Extensive worldwide assessment and the most exhaustive investigation ever undertaken by the FDA 1 on an NSAID in the elderly, together confirm the position of Feldene as appropriate therapy 1 " for patients with chronic arthritis. No other NSAID has received as much recent independent investigation. No other once-daily preparation is prescribed in over 100 countries and supported by the evidence of 2.5 billion patient days. fine usual precautions regarding the use of any NSAID should of course be observed. Feldenef piroxicam in chronic arthritis Independently assessed, internationally prescribed Prescribing Information: Indications: Rheumatoid arthritis, osteoarthrius. ankylosing spondylitis, acute gout and acute musculoskeletal disorders. Dosage: Rheumatoid arthnti osteoarthritis and ankylosing spondylitis. Normal starting and maintenance dosage 20 mg once daily Acute gout - 40mg daily in single or divided doses for up to 7 days. Acute musa loskeletai disorders - 40mg daily, in single or divided doses, for the first 2 days. 2Cmg daily for the remaining ~ to 14 days treatment. Feldene suppositories 20mg once dail) Contra-indications: Active peptic ulcerauon or history of recurrent ulceration. Hypersensitivity to Feldene. aspirin or other NSAIDs. Suppositories - patients with a history c inflammatory lesions or bleeding of the rectum or anus Warnings: Pregnancy, lactation. As with other agents, elderly patients should be closely supervised. Not recommended fo use in children Side-Effects: Gastro-intestinal symptoms: if peptic ulceration or gastro-intestinal bleeding occurs withdraw Feldene. Oedema, mainly of the ankle. Skin rashe Basic NHS Cost: Capsules lomg coded FEL 10. pack of 6C 9.00 IPLOO57/0145) and capsules 20mg coded FEL 20. pack of 30 9 X (PL0057,'0146t dispersible cablets lomg code FEL 10. pack of fpl0057/024ot dispersible tablets 20mg coded FEL 2C. pack of 3C 9.9C DPL0057/0242I: suppositories 20mg. pack of IPL0057/0219L v,,n.^t^r^^^r. ^, P ^, c, ^Pfrrrnrr.i p,mt n-i^r H3f-,nn of rh^ Omer fnr Drue? and Riolocics Food and Drue Administration. 14ch Mav 'Trade Ma: > rnzer Limit ea. Sandwich. Kenl