cytotoxic drugs in rheumatoid arthritis

3
1231 Prophylactic Antibiotics THE LANCET FEW subjects are more contentious than the use, more often the abuse, of antibiotics for prophylactic purposes. The temptation to " sterilise " the suscept- ible patient is clinically attractive, but both clinically and microbiologically mistaken. " Sterilisation " of patients simply cannot be achieved, and the unwise use of prophylactic antibiotics may often lead to a higher rather than a lower rate of infection. Further- more, when infection does arise in those receiving prophylactic antibiotics it will, of course, be caused by antibiotic-resistant organisms which may pose great therapeutic difficulties. The article by Mr. PRICE and Dr. SLEIGH on page 1213 again draws attention to this danger, this time to an increase in the isolation-rate of Klebsiella aerogenes when antibiotics were used in an intensive-care unit, and the reverse-namely, the disappearance of those bacteria when the use of all antibiotics was severely restricted. The same sort of reduction in isolation of Staphylococcus aureus and Candida albicans has been repeatedly reported after restriction in the use of antibiotics.1-5 But it must be emphasised (and PRICE and SLEIGH make the point) that the mere isolation of gram-negative bacteria, particularly from sputum and even from purulent sputum, does not necessarily indicate infection nor the need for anti- biotic treatment. In 76 patients studied by EYKYN,6 . from all of whom a heavy growth of Pseudomonas aeruginosa was obtained from various sites, no less than 64% had been receiving broad-spectrum anti- biotics, but less than a third of these patients appeared, on clinical criteria, to be suffering from an actual infection with this organism. PRICE and SLEIGH’S findings highlight another problem-namely, ignorance of the sources, reser- voirs, and modes of spread of gram-negative bacteria. In their investigation, typing of K. aerogenes by anti- biotic pattern, klebecine, and phage indicated a large number of different types, pointing to multiple rather than single sources. Perhaps each patient was colon- ised or infected with his own type of klebsiella. The same thing has been seen in another intensive-care unit, when, during a period of nine months, many different types of Ps. ceruginosa were found, but more recently in this same unit a predominant type of 1. Barber, M., Dutton, A. A. C., Beard, M. A., Elmes, P. C., Williams, R. Br. med. J. 1960, i, 11. 2. Ridley, M. in Therapeutic Uses of Antibiotics in Hospital Practice (edited by M. Ridley and I. Phillips); p. 11. London, 1966. 3. Ridley, M., Barrie, D., Lynn, R., Stead, K. C. Lancet, 1970, i, 230. 4. Bulger, R. J., Sherris, J. C. Ann. intern. Med. 1968, 69, 1099. 5. Molloy, P. J. in Bacterial Endocarditis: Proceedings of a National Symposium held at the Royal College of Physicians, London, 1969 (edited by P. B. Beeson and M. Ridley); p. 108. 6. Eykyn, S. Personal communication. pseudomonas has appeared,’ indicating possible cross-infection by a route or routes as yet undeter- mined. Despite increasing research, very little is known about the mode of spread and even the origins of gram-negative bacteria that cause infections or colonise patients. One thing is clear, however, the unwarranted use of antibiotics and particularly broad-spectrum antibiotics in a mistaken prophyl- actic attempt is a sin and it would be wise to " avoid not only the sin but also the occasions of sin " by better understanding of the epidemiology of gram- negative bacteria and the application of aseptic and other methods designed to prevent these bacteria colonising or infecting patients. The trouble is, as Sir JAMES HowiE said at the height of the hospital staphylococcal troubles, " none of us knew quite enough bacteriology, pathology and pharmacology to avert the inevitable disillusionment that descended and lay heavily upon us throughout the 1950s. We forgot the versatility of bacteria." The same dis- illusion ment is with us now, but the emphasis has shifted from the staphylococcus to apparently ubiquitous gram-negative bacteria and other oppor- tunist microbes. There are, of course, clear and concise indications for antibiotic prophylaxis in such situations as the prevention of bacterxmia after tooth extraction, of recurrence of rheumatic fever, and of gas gangrene after the amputation of lower limbs. In most of these well-established and successful applications of anti- biotic prophylaxis the drug is aimed with precision at a particular organism or group of organisms. All other attempts at more general prophylaxis with antibiotics should be discussed in detail by clinician and microbiologist, for so often the clinician’s good intentions are thwarted by the infinite variability of microorganisms and the selection of antibiotic- resistant bacteria, once the soil is prepared by the removal of antibiotic-sensitive and often harmless commensals. Cytotoxic Drugs in Rheumatoid Arthritis IN rheumatoid arthritis, it has been suggested, immunological mechanisms are important in the pathogenesis of joint inflammation,9-12 arteritis, 13 and interstitial pulmonary fibrosis.14 In the absence of any obvious cause, curative treatment is impossible, and an attractive prospect is to be able to destroy the underlying immunological mechanisms respon- 7. Phillips, I. Personal communication. 8. Howie, J. W. Lancet, 1962, i, 1137. 9. Hollander, J. L., McCarty, D. J., Astorga, G., Castro-Murillo, E. Ann. intern. Med. 1965, 62, 271. 10. Rawson, A. J., Abelson, N. M., Hollander, J. L. ibid. p. 281. 11. Restifo, R. A., Lussier, A. J., Rawson, A. J., Rockey, J. H., Hollander, J. L. ibid. p. 285. 12. Hollander, J. L., Rawson, A. J. Bull. rheum. Dis. 1968, 18, 502. 13. Baum, J., Stastny, P., Ziff, M. Arthritis Rheum. 1962, 5, 101. 14. Tomasi, T. B., Fudenberg, H. H., Finby, N. Am. J. Med. 1962, 33, 243.

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Page 1: Cytotoxic Drugs in Rheumatoid Arthritis

1231

Prophylactic Antibiotics

THE LANCET

FEW subjects are more contentious than the use,more often the abuse, of antibiotics for prophylacticpurposes. The temptation to

" sterilise " the suscept-ible patient is clinically attractive, but both clinicallyand microbiologically mistaken. " Sterilisation "

of patients simply cannot be achieved, and the unwiseuse of prophylactic antibiotics may often lead to ahigher rather than a lower rate of infection. Further-

more, when infection does arise in those receivingprophylactic antibiotics it will, of course, be causedby antibiotic-resistant organisms which may posegreat therapeutic difficulties. The article by Mr.PRICE and Dr. SLEIGH on page 1213 again drawsattention to this danger, this time to an increasein the isolation-rate of Klebsiella aerogenes whenantibiotics were used in an intensive-care unit,and the reverse-namely, the disappearance of thosebacteria when the use of all antibiotics was severelyrestricted. The same sort of reduction in isolation of

Staphylococcus aureus and Candida albicans has beenrepeatedly reported after restriction in the use ofantibiotics.1-5 But it must be emphasised (andPRICE and SLEIGH make the point) that the mereisolation of gram-negative bacteria, particularly fromsputum and even from purulent sputum, does notnecessarily indicate infection nor the need for anti-biotic treatment. In 76 patients studied by EYKYN,6 .from all of whom a heavy growth of Pseudomonasaeruginosa was obtained from various sites, no lessthan 64% had been receiving broad-spectrum anti-biotics, but less than a third of these patients appeared,on clinical criteria, to be suffering from an actualinfection with this organism.PRICE and SLEIGH’S findings highlight another

problem-namely, ignorance of the sources, reser-voirs, and modes of spread of gram-negative bacteria.In their investigation, typing of K. aerogenes by anti-biotic pattern, klebecine, and phage indicated a largenumber of different types, pointing to multiple ratherthan single sources. Perhaps each patient was colon-ised or infected with his own type of klebsiella. Thesame thing has been seen in another intensive-careunit, when, during a period of nine months, manydifferent types of Ps. ceruginosa were found, but morerecently in this same unit a predominant type of1. Barber, M., Dutton, A. A. C., Beard, M. A., Elmes, P. C., Williams,

R. Br. med. J. 1960, i, 11.2. Ridley, M. in Therapeutic Uses of Antibiotics in Hospital Practice

(edited by M. Ridley and I. Phillips); p. 11. London, 1966.3. Ridley, M., Barrie, D., Lynn, R., Stead, K. C. Lancet, 1970, i, 230.4. Bulger, R. J., Sherris, J. C. Ann. intern. Med. 1968, 69, 1099.5. Molloy, P. J. in Bacterial Endocarditis: Proceedings of a National

Symposium held at the Royal College of Physicians, London, 1969(edited by P. B. Beeson and M. Ridley); p. 108.

6. Eykyn, S. Personal communication.

pseudomonas has appeared,’ indicating possiblecross-infection by a route or routes as yet undeter-mined. Despite increasing research, very little isknown about the mode of spread and even theorigins of gram-negative bacteria that cause infectionsor colonise patients. One thing is clear, however,the unwarranted use of antibiotics and particularlybroad-spectrum antibiotics in a mistaken prophyl-actic attempt is a sin and it would be wise to

" avoidnot only the sin but also the occasions of sin " bybetter understanding of the epidemiology of gram-negative bacteria and the application of aseptic andother methods designed to prevent these bacteria

colonising or infecting patients. The trouble is,as Sir JAMES HowiE said at the height of the hospitalstaphylococcal troubles, " none of us knew quiteenough bacteriology, pathology and pharmacologyto avert the inevitable disillusionment that descendedand lay heavily upon us throughout the 1950s. Weforgot the versatility of bacteria." The same dis-illusion ment is with us now, but the emphasis hasshifted from the staphylococcus to apparentlyubiquitous gram-negative bacteria and other oppor-tunist microbes.There are, of course, clear and concise indications

for antibiotic prophylaxis in such situations as the

prevention of bacterxmia after tooth extraction, ofrecurrence of rheumatic fever, and of gas gangreneafter the amputation of lower limbs. In most of thesewell-established and successful applications of anti-biotic prophylaxis the drug is aimed with precision ata particular organism or group of organisms. Allother attempts at more general prophylaxis withantibiotics should be discussed in detail by clinicianand microbiologist, for so often the clinician’s goodintentions are thwarted by the infinite variability ofmicroorganisms and the selection of antibiotic-resistant bacteria, once the soil is prepared by theremoval of antibiotic-sensitive and often harmlesscommensals.

Cytotoxic Drugs in RheumatoidArthritis

IN rheumatoid arthritis, it has been suggested,immunological mechanisms are important in the

pathogenesis of joint inflammation,9-12 arteritis, 13 andinterstitial pulmonary fibrosis.14 In the absence of

any obvious cause, curative treatment is impossible,and an attractive prospect is to be able to destroythe underlying immunological mechanisms respon-7. Phillips, I. Personal communication.8. Howie, J. W. Lancet, 1962, i, 1137.9. Hollander, J. L., McCarty, D. J., Astorga, G., Castro-Murillo, E.

Ann. intern. Med. 1965, 62, 271.10. Rawson, A. J., Abelson, N. M., Hollander, J. L. ibid. p. 281.11. Restifo, R. A., Lussier, A. J., Rawson, A. J., Rockey, J. H.,

Hollander, J. L. ibid. p. 285.12. Hollander, J. L., Rawson, A. J. Bull. rheum. Dis. 1968, 18, 502.13. Baum, J., Stastny, P., Ziff, M. Arthritis Rheum. 1962, 5, 101.14. Tomasi, T. B., Fudenberg, H. H., Finby, N. Am. J. Med. 1962, 33,

243.

Page 2: Cytotoxic Drugs in Rheumatoid Arthritis

1232

sible for the progression of the disease. The poten-tial value of cytotoxic drugs in rheumatoid arthritisis now recognised by most rheumatologists.l6 Butrheumatoid arthritis is a benign disease with remis-sions and relapses, and intensive conservativetreatment (bed rest, physiotherapy, and anti-

inflammatory drugs) will induce remissions in mostpatients.16 Patients unresponsive to these measuresshould be treated with corticosteroids or gold,17 andonly the few who are refractory to this regimen shouldbe considered for cytotoxic therapy.

Cytotoxic drugs have been used for many years inthe treatment of rheumatoid arthritis,18-23 yet, becauseadequate experimental control was lacking, itremained uncertain whether or not they were bene-ficial. But better-controlled trials have lately beenreported. FOSDICK et al.24 gave cyclophosphamideover periods of from six months to three years to38 patients with severe rheumatoid arthritis. The

patients acted as their own controls by being closelyobserved for six months before they had cyclo-phosphamide. Only patients who deteriorated

despite intensive conventional therapy were judgedsuitable for the trial. 2 patients with malignantrheumatoid arthritis were observed for two months

only. At the start 50 mg. of cyclophosphamide wasgiven daily, and the dose was gradually increased tomaintain the white-cell count between 2000 and4000 per c.mm. Regular subjective and objectiveassessments of disease activity were recorded, andincluded clinical examination, erythrocyte-sedimen-tation rate (E.s.R.), latex titre, and joint X-rays.Complete remission was said to be achieved whenboth subjective and objective assessment failed toshow any disease activity, and this was the situationin 10 patients. Other drugs, such as corticosteroids,gold, and salicylates, were able to be withdrawn, and,if cyclophosphamide was discontinued, relapse didnot follow. 1 patient remained in remission foreighteen months after cyclophosphamide was with-drawn before the disease became active again. Partialremission was achieved in 19 patients, but, althoughthey felt much better, the laboratory evidence wasthat the disease was still active, though less so thanbefore treatment. Most of these patients could bewithdrawn from corticosteroid or gold, but whencyclophosphamide was withdrawn in 2 patients,relapse soon followed. 4 patients, subjectivelyimproved, failed to show any change to laboratory15. Baum, J., Vaughan, J. Ann. intern. Med. 1969, 71, 202.16. Duthie, J. J. R., Brown, P. E., Truelove, L. H., Baragar, F. D.,

Lawrie, A. J. Ann. rheum. Dis. 1964, 23, 193.17. Nuki, G., Dick, W. C. Br. J. Hosp. Med. 1969, 2, 1962.18. Jiménez-Díaz, C., López Garcia, E., Merchante, A., Perianes, J.

J. Am. med. Ass. 1951, 147, 1418.19. Lorenzen, I., Videbaek, Aa. Lancet, 1965, ii, 558.20. Myles, A. B. Ann. rheum. Dis. 1965, 24, 179.21. Enderlin, M., Gross, D. Z. Rheumaforsch. 1967, 26, 26.22. Corley, C. C., Lessner, H. E., Larsen, W. E. Am. J. Med. 1966, 41,

404.23. Philips, V. K., Bergen, W., Rothermich, N. O. Arthritis Rheum.

1967, 10, 305.24. Fosdick, W. M., Parsons, J. L., Hill, D. F. ibid. 1968, 11, 151.

testing, and 5 continued to have active diseasewithout any subjective or objective changes. 3 ofthe 5 patients with no evidence of remission hadcyclophosphamide stopped because it had failed, andexacerbation of the disease was immediate, 1 patientdeveloping rheumatoid pneumonitis. The latextitre fell in most patients, but the E.s.R. seemed to bemore closely related to the activity of the disease.No bone-marrow depression was observed; and nopatient died during the trial; 4 died later 25-2 ofHong Kong influenza and 2 of coccidioidomycosis-infections which may have been attributable to thedrug. Superficially these results are impressive, butfailure to control the trial double-blind leaves the

possibility that spontaneous remission may haveaccounted for the clinical improvement. 26Another controlled trial of cyclophosphamide has

just been reported. 27 Of 48 patients, 20 had a highdose (up to 150 mg. daily) and 28 a low dose (up to15 mg. daily); and the high-dose patients did betteras judged by five out of six measures of disease

activity and as assessed by both physicians and

patients. But unwanted effects arose in 90% ofhigh-dose patients and in 40% of low-dose patients.Herpes zoster, cystitis, and severe loss of hair werevirtually confined to the high-dose group.The London Hospital group 28 reported their

experiences with azathioprine in a dose of 2-5 mg.per kg. per day in a double-blind trial. All patientshad definite rheumatoid arthritis with a latex titre

greater than 1/40, and all had had prednisolone, atleast 5 mg. daily for a minimum of six months beforeentering the trial. Prednisolone was reduced to theminimum dose which controlled symptoms, and thisdose had to be stable for at least two months beforea patient joined the trial. All analgesic drugsexcept paracetamol were withdrawn for a monthbefore azathioprine began. The " corticosteroid-

sparing effect " of azathioprine was used as the drug’stherapeutic index. In the azathioprine-treated groupthe mean daily corticosteroid requirements fell by36% of the mean daily starting dose, whereas it wasunchanged in the control group. Although the

severity of corticosteroid side-effects was reduced, itis hard to draw conclusions about therapeutic benefit,but the reduction in mean daily prednisolone dosagefrom 11 mg. to 7 mg. suggests that azathioprine mayhelp these patients.Although cytotoxic drugs have been found to

suppress immune responses in laboratory animals,29,30it has been shown 3.1 that in patients with rheumatoid

25. Fosdick, W. M., Parsons, J. L., Hill, D. F. ibid. 1969, 12, 663.26. O’Brien, W. M. ibid. 1968, 11, 698.27. Cooperating Clinics Committee of the American Rheumatism

Association. New Engl. J. Med. 1970, 283, 883.28. Mason, M., Currey, H. L. F., Barnes, C. G., Dunne, J. F.,

Hezleman, B. L., Strickland, I. D. Br. med. J. 1969, i, 420.29. Aisenberg, A. C. New Engl. J. Med. 1965, 272, 1114.30. Tripathy, S. P., MacKennas, C. B. J. exp. Med. 1969, 130, 1.31. Denman, E. J., Denman, A. M., Greenwood, B. M., Gall, D.,

Heath, R. B. Ann. rheum. Dis. 1970, 29, 220.

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arthritis treated with either azathioprine or cyclo-phosphamide cellular and humoral immune responsesare normal when tested with purified proteinderivative, streptokinase, influenza vaccine, tetanustoxoid, and brucella vaccine. In-vitro transformationof peripheral blood lymphocytes in response to

phytohaemagglutinin and the various immunisingantigens was also normal, and in a few patientstreated with cytotoxic drugs in-vitro lymphocytetransformation to these antigens was enhanced.Insufficient data were available for statistical appraisal.Despite the fact that immune responses were notimpaired by cytotoxic drugs, serum-immuno-

globulin levels, rheumatoid-factor titres, E.S.R., andperipheral blood lymphocyte counts all fell, com-pared with control patients, although the clinicalcondition of most treated patients did not alter

greatly. These findings suggest that azathioprineand cyclophosphamide are not acting as immuno-suppressants in patients with rheumatoid arthritis,and, in some way, despite a striking lymphopenia inthe peripheral blood, antigen-sensitive and antibody-producing cells seem to avoid inactivation. Of the20 patients included in the study, 4 died; 3 of thesedeaths may have been attributable to cytotoxictherapy. In addition, in 3 other patients bone-marrow depression was noted.Thus, the position of cytotoxic drugs in the

treatment of severe rheumatoid arthritis is stilluncertain. They seem to do some good, but side-effects are common and may be dangerous. And

dangerous side-effects to a treatment for a non-lethaldisease are a heavy disadvantage.

The General Medical Council:a New Look

LAST week the General Medical Council madeknown the text of its new pamphlet on professionaldiscipline which will be published in January. Inan address last month the President explained that anew pamphlet was necessary because the DisciplinaryCommittee had been given by the Medical Act 1969the power to order suspension, in addition to that oferasure; and a general leaflet on the Council’s workhad lately been introduced which superseded partsof the old pamphlet. A suggestion emerges " of someother changes in the Council’s disciplinary powersand in the formulation of the list of professionaloffences ". The President referred to certain criti-cisms of the Council-namely, insufficient concern" with doctors who disregard their personal responsi-bilities to patients ", " excessive attention to caseswhere a doctor is found to have committed adulteryor behaved improperly with a patient", and " thatthe Council is excessively active in suppressingadvertising ". Concerning this last criticism, thePresident said: " The revised draft makes it clear

that the Council regards advertising by medical

practitioners as something which is capable of beinga source of danger to the public as well as being in-compatible with the principles which should governrelations between members of a profession."An examination of part 11 of the new pamphlet

shows that the " abuse of professional confidence "has been included in the examples of

" convictionsand forms of professional misconduct which maylead to disciplinary proceedings". The examples nownumber twelve, their order in the list has been varied,and the section dealing with advertising has been inpart rephrased and expanded. Under " inquiriesbefore the disciplinary committee ", there is a

reminder that in cases of conviction (by a criminalcourt) the Disciplinary Committee " is bound to

accept the fact that a doctor has been convicted asconclusive evidence of his guilt ", whereas in cases ofconduct allegations denied by a doctor " must bestrictly proved by evidence ". A welcome inclusionis the warning: " It may therefore be unwise for adoctor to plead guilty in a Court of Law to a charge towhich he believes that he has a defence."

Many members of the profession will not quarrelwith the Council for putting in first place in the listof disciplinary offences the disregard of personalresponsibilities to patients ", though some practi-tioners believe that there may be offences in this

category, such as breaches of a general practitioner’sterms of service, which might be more appropriatelyreferred to the Tribunal of the National HealthService. These doctors seldom understand whysubstantially the same charges may be heard by twodisciplinary bodies and two

"

punishments " inflictedfor the same offence. " Improper association " andadultery cases are now in fifth place and attract amore succinct comment than formerly.

Despite the rephrasing and expansion of the para-graphs concerned with advertising and depreciationof other doctors, the criticism of the Council’s atti-tude does not seem to be met by anything morespecific than the view that advertising " could be asource of danger to the public ". Nowhere, indeed,does the pamphlet answer the points made1 after adoctor was found guilty of advertising (subject to

appeal), when the decision was seen as throwing" into dismal relief the mechanism by which doctorsdiscipline their fellows ". In fact, on appeal thePrivy Council altered the penalty of erasure to sus-pension, but that half-hearted reversal of the Discip-linary Committee’s decision did not serve to illuminethe " mysterious justice"1 which was apparentlyoperating.

It seems a pity that the new pamphlet and thePresident’s address give no indication that the presentsystem might one day be recast. The wide range ofcases, their complexity, and a public better informedand interested in such matters give the Disciplinary1. Lancet, 1969, ii, 305.