8/13/2019 klouy

1/6

286

Immune manipulationsThe identity ofthe original antigenic stimulus isunknown

but a theoretical view of how such a model operates is

possible to derive. Type II collagen, a physically restricted,major structural component of cartilage, is arthritogenic inseveral animal species, including certain primates 4

Autoimmunity to type II collagen is frequentlydemonstrable within the joints of patients with rheumatoidarthritis .14,15,26 Not only does Epstein-Barr virus (EBV)possess homologous HLA-DR? chain epitopes implicatedin rheumatoid arthritisbut it also shares with type II

collagen a homologous a 1 (II) chain epitope.27Accordingly,anti-collagen reactivity could arise in a HLA-susceptiblehost after EBV infection through molecular mimicry.Models of autoimmune disease, including experimentalallergic encephalomyelitis and adjuvant arthritis, can besuppressed by feeding animals the relevant antigen, myelinbasic protein and type II collagen, respectively.28 Thesimplicity and safety of this approach, designated oral

tolerance,has led to the

inceptionofclinical trials in

multiplesclerosis and rheumatoid arthritis using these candidate

proteins.29REFERENCES

1. Cush J, Lipsky PE. Cellular basis for rheumatoid inflammation. ClinOrthopaedics Rel Res 1991; 265: 9-12.

2. Harris ED Jr. Rheumatoid arthritis: pathophysiology and implicationsfor therapy. N Engl J Med 1990; 322: 1277-89.

3. Panayi GS, Lanchbury JS, Kingsley GH.The importance of the T cell in

initiating and maintaining the chronic synovitis ofrheumatoid arthritis.Arthritis Rheum 1992; 35: 729-35.

4. Breedveld FC, Trentham DE. Progress inthe understanding of induciblemodels of chronic arthritis. Rheum Dis ClinNAm 1987; 13: 531-44.

5. Roudier J, Petersen J, Rhodes GH, et al. Susceptibility to rheumatoidarthritismaps to a T-cell epitope shared by the HLA-Dw4DR beta-1chain and the

Epstein-Barrvirus

glycoprotein gp110. Proc NatlAcad

Sci USA 1989; 86: 5104-08.6. Iwakura Y, Tosu M, Yoshida E, et al. Induction of inflammatory

arthropathy resembling rheumatoid arthritis in mice transgenic forHTLV-I. Science 1991; 253: 1026-28.

7. Pitzalis C, Kingsley GH, Haskard DO, Panayi GS. The preferentialaccumulation of helper-inducer T lymphocytes in inflammatorylesions: evidence for regulation by selective endothelial and homotypicadhesion. Eur J Immunol 1988; 18: 1397-404.

8. Hemler ME, Glass D, Coblyn JS, Jacobson JG. Very late activationantigens on rheumatoid synovial fluidT lymphocytes: association with

stages ofT cell activation. J Clin Invest 1986; 78: 696-702.9. Solinger AM, Hess EV. HIV and arthritis.Arthritis Rheum 1990; 17: 562.

10. Pitzalis C, Kingsley GH, Lanchbury JSS, Murphy J, Panayi GS.

Expression of HLA-DR, DQ and DP antigens and IL-2 receptor on

synovial fluid T lymphocyte subsets in rheumatoid arthritis: evidencefor a "frustrated" activation. J Rheumatol 1987; 14: 662-66.

11. Bacha P, Forte SE, Perper SJ, Trentham DE,Nichols

JC.Anti-arthriticeffects demonstrated by an interleukin-2 receptor-targeted cytotoxin(DAB486IL-2) in rat adjuvant arthritis. Eur J Immunol 1992; 22:1673-79.

12. Sewell KL, Trentham DE. Rapidimprovementin refractory rheumatoidarthritis by an interleukin-2 receptor targeted immunotherapy. ClinRes 1991; 39: 314A (abstr).

13. Brahn E, Trentham DE. Experimental synovitis induced by collagen-specificT cell lines. Cell Immunol 1989; 118: 491-503.

14. Watson W, Tooms R, Carnesale P, Dutkowsky J. Subchondral bone andthe erosive autoimmune origins of rheumatoid arthritis. ArthritisRheum 1992; 35: S59 (abstr).

15. TarkowskiA, Klareskog L, Carlsten H, Herberts P, Koopman WJ.Secretion ofantibodies to type I and type II collagen by synovial tissuecells in patients with rheumatoid arthritis.Arthritis Rheum 1989; 32:1087-92.

16. JasonHE,Taurog JD. Mechanisms ofdisruptionofthe articular cartilage

surface in inflammation: neutrophil elastase increases availability ofcollagen type II epitopes for binding with antibody on the surface ofarticular cartilage.J Clin Invest 1991; 87: 1531-36.

17. Trujillo PE, Mannik M. IgG is bound by antigen-antibody bonds and

18. Wooley PH, Luthra HS, Singh SK, HuseAR, Stuart JM, David CSPassive transfer of arthritis to mice by injection ofhuman anti-typecollagen antibody. Mayo Clin Proc 1984; 59: 737-43.

19. Firestein GS, Zvaifler NJ. How important are T cells in chronrheumatoid synovitis?Arthritis Rheum 1990; 33: 768-73.

20. Firestein GS, Xu WD, Townsend K, et al. Cytokines in chron

inflammatory arthritis. I. Failure to detect T cell lymphokin(interleukin 2 and interleukin 3) and presence of macropha

colony-stimulating factor (CSF-1) and a novel mast cell growth facin rheumatoid synovitis.J Exp Med 1988; 168: 1573-86.21. KockAE, Polverini PJ, Leibovich SJ. Stimulation ofneovascularizati

by human rheumatoid synovial tissue macrophages.Arthritis Rhe1986; 29: 471-79.

22. WilliamsWV, Fang Q, Demarco D, Vonfeldt J, ZurierRB, WeinerDRestricted heterogeneity ofT cell receptor transcripts in rheumatosynovium. J Clin Invest 1992; 90: 326-33.

23. Weyand CM, Oppitz U, Hicock K, Goronzy JJ. Selection of Treceptor V&bgr; elements by HLA-DR determinants predisposingrheumatoid arthritis.Arthritis Rheum 1992; 35: 990-98.

24. Paliard X, West SG, Lafferty JA, et al. Evidence for the effects osuperantigen in rheumatoid arthritis. Science 1991; 253: 325-29.

25. Moss PAH, Rosenberg WMC, Bell JI. The human T cell receptohealth and disease.Annu Rev Immunol 1992; 10: 71-96.

26. Londei M, Savill CM, VerhoefA, et al. Persistence of collagen tII-specific T-cell clones in the synovial membrane of a patient w

rheumatoid arthritis. Proc NatlAcad Sci USA 1989; 86: 636-40.27. Birkenfeld P, Haratz N, Klein G, Sulitzeanu D. Cross-reactivity betw

the EBNA-1 p.107 peptide, collagen, and keratin: implications forpathogenesis of rheumatoid arthritis. Clin Immunol Immunopat1990; 54: 14-25.

28. Zhang ZJ, Lee CSY, Lider O, Weiner HL. Suppression of adjuvarthritis in Lewis rats by oral administration of type II collaJ Immunol 1990; 145: 2489-93.

29. Marx J. Testing ofautoimmunetherapy begins. Science 1991; 252: 27

Clinical management ofrheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory dis

affecting joints and other tissues, which has an annincidence of between 2 and 4 per 10 000 adult populatioThe disease mainly involves the synovial joints but virtuevery tissue in the body can be affected by the inflammatprocess. Rheumatoid arthritis may present clinicallseveral ways, the most common being an insidious owith symptoms developing over months.A few patipresent with an acute onset of polyarthritis or disease

develops over a few weeks .2 Patients with rheumatarthritis tend to follow one of three courses (table I). M

patients, however, will have progressive diseasesubstantial morbidity and mortality. The diminisurvival ofthese patients is similar to that seen for diabeHodgkins disease, and three-vesselcoronary artery disethe median life expectancy is reducedby seven years forand three years for women.3 For instance, a patientrheumatoid arthritis attendingan outpatient clinichas aa one in three chance of being severely disabled at 20 ywhile those requiring inpatient care have approximatel80% chance. After 10 years of disease, fewer than 50

patients can continue to work4 contributing to anannualofrheumatoid arthritis in the USA of over$1 billion.

Since the exact cause and pathogenesis of rheumaarthritis are

unknown,our

therapiesmust be dir

against the various components ofthe chronic inflamma

ADDRESS: Department of Medicine St Vincents Hosp

8/13/2019 klouy

2/6

28

TABLE I-CLINICAL COURSE OF RHEUMATOIDARTHRITIS

Progressive Chronic disease with remissions andexacerbations but continuing disease activity(about 70%)

Intermittent Brief attacks with intermittent remissionswith no disease activity (25%)

Malignant Severe disease with extra-articular

manifestations, especially vasculitis

response. Many drugs thatwe might usehave severeadversereactions and it is, therefore, important to try to ascertainwhich patients have a poor outlook. The predictors ofpoorprognosis in rheumatoid arthritis are summarised intable 11.4 Of importance in changing our approach to the

management of rheumatoid arthritis is an appreciation that

joint erosions, which are closely linked to long-termdisability, develop within the first two years of diseaseonset.5

Strategiesfor treatment

Treatment of rheumatoid arthritis demands a

multidisciplinary approach. Although pharmacologicalcontrol ofinflammation,with combinations of non-steroidal

anti-inflammatory drugs (NSAIDs) and slow-actingantirheumatic drugs (SAARDs), provides the basis fortreatment, physical therapies, including general and specificexercises, educational programmes, and attention topsychological factors, are all important in improving the lifeof patients with rheumatoid arthritis.WhileNSAIDsprovide somesymptomatic relief, they do

nothing to suppress the rate ofcartilageerosion or to alterthecourse of the disease. Rheumatologists now advocate

SAARDs early in the disease process before erosions occurand certainly in all patients with persisting synovitis despiteadequateNSAID therapy.2 Long-term studies are requiredto determine exactly what the impact of early SAARDtreatment is, but there is no doubt that the rate offunctionaldeterioration is reduced by these drugs,6although the

changes may only be modest .7 Fries8 has suggested a moreformalised approach to drug treatment by commencingSAARDs at the time of diagnosis and reviewing disabilityand other outcome variables at regular intervals to assessdisease progression. In this "saw tooth" strategy, a ceiling isset in terms of disability, which will indicate a subsequentdecision point to trigger a change ofSAARD in an effort to

maintain disease suppression. Whether this approach ishelpful in the long term remains to be tested.

NSAIDs

NSAIDs areone ofthemostcommonly prescribed groupofdrugs world wide, with up to 20% of people admitted tohospital taking an NSAID.9,10Although the principlemechanism of action ofNSAIDs is that of interfering withprostaglandin production, many other cellular processes are

TABLE 11-PREDICTORS OFA POOR PROGNOSIS IN

RHEUMATOIDARTHRITIS

Male with disease onset before age 50> 20 affected jointsFunctional disability within one year ofonsetExtra-articularinvolvement

TABLE III-PROCESSES INFLUENCED BY NSAIDs

Prostaglandin productionLeukotriene synthesisSuperoxide generationLysosomal enzyme releaseNeutrophil aggregation and adhesionCell-membrane functions

Enzyme activity(NADPH oxidase, phospholipase C)Transmembrane anion transportOxidative phosphorylationUptake of arachidonate

Lymphocyte functionRheumatoid factor productionCartilage metabolism

modified by these drugs (table in). NSAIDs come froseveral chemical classes and are invariably weak acids; thi

helps in their preferential sequestration to inflamed jointsbut also leads to accumulation in the kidney and the gu(important sources of adverse drug reactions).Althougsome studies have suggested that there are individua

differences in response to NSAIDs,ll whether these argreater than the well known fluctuations in the disease itse

are unclear. Individual differences in pharmacokinetics anin side-effect profiles occur between NSAIDs and thesmust be taken into account when prescribing a particulaNSAID to a given individual. NSAIDs may bdifferentiated on the basis of plasma half-life (table iv). Ishould be remembered, however, that synovial fluiconcentrations are lower than concentrations in plasma buthe drug remains in the synovial fluid for a substantialllonger time. 12 Thismeans thatmany short half-lifeNSAIDcan be given on a twice-daily basis without interfering witpain relief over a 24 h period.

Adverse reactions to NSAIDs

NSAIDs are one of the most common causes of advers

reactions reported to drug regulatory authoritiesgastrointestinal effects being the most common followed b

TABLE IV-MEAN (SD*) PLASMA HALF-LIVES OF I31FFERENT NSAIDs

Drug Hatf-tlfe (h)

Short half-life

Aspirin 0-25(0-03)Diclofenac 1-1(02)

Etodotac 3-0; 65 (0-3)tFenoprofen 25(0-5)Flufenamic acid 1-4; 9 Of

Flurbiprofen 3-8 (1-2)Ibuprofen 21 (03)Indomethacin 4-6 (0-7)Ketoprofen 1-8 (0-4)Pirprofen 3-8,681Tiaprofenic acid 3-0 (0-2)Tolmetin 1-0 (0-3); 5-8 (l5}t

Long half-lifeAzapropazone 15 (4)Diflunisal 13(2)Fenbufen 11-0

Nambumetone 26 (5)

Naproxen 14 (2)Oxaprozin 58 (10)Phenylbutazone 68 (25)Piroxicam 57 (22)Salicylate 2-151S ti d ( lfid ) 14 (8)

8/13/2019 klouy

3/6

288

TABLE V-SLOW-ACTINGANTIRHEUMATIC DRUGS

PMN, polymorphon uclear leucocyte.

renal damage, skin reactions, blood dyscrasias, headaches,and nausea.13 Since prostaglandins have an important role in

maintaining normal gastrointestinal physiology, it is notsurprising that drugs which interfere with prostaglandinsynthesis cause abnormal gastrointestinal function.NSAIDs are associated with gastric erosion, peptic ulcerformation, and haemorrhage, as well as producinginflammation in the small and large intestine.10 Estimates ofthe absolute risk of a serious gastrointestinal adverse eventvaries from about 2 cases per 10 000 person-months ofprescription to a seven-fold increase in the risk ofhospitalisation in patients with rheumatoid arthritis .14 Todate there is no clear evidence differentiating equipotentanti-inflammatory doses of one NSAID from another withrespect to the risk of serious upper gastrointestinal side-

effects. However, patients taking corticosteroids andNSAIDs have a greater risk of peptic ulceration.15 Otherrisk factors for serious gastrointestinal side effects in patientswith rheumatoid arthritis include previous gastrointestinaladverse reactions, disability, age, and co-morbidity.16

Patients who develop peptic ulceration while taking anNSAID may be treated in the following ways. If theNSAID can be stopped by substitution of pure analgesicagents, such as paracetamol or even corticosteroids for ashort time, this manoeuvre is likely to speed ulcer healing.The ulcer should then be treated withhistamineH2 receptorantagonists, sucralfate, prostaglandins, or omeprazole.17Prophylaxis with H2 antagonists or prostaglandins mayreduce ulcer formation in those patients at risk, but whether

they reduce complications remains unknown.Since prostaglandins also regulate renal blood flow,

NSAIDs may cause reversible impairment of glomerular

Although individual variation betweenNSAIDs may ethere is general agreement that noNSAID is absolutelywith respect to renal adverse effects. NSAIDs mayinterfere with the effects of antihypertensive and diuragents and care should be taken when these are prescrtogether. Since many patients with rheumatoid arthhave comorbidity and are elderly, the potential forinteractions is high. These interactions include

anticoagulants, lithium, oral hypoglycaemic agphenytoin, methotrexate (in high dose), probeneantihypertensive agents, diuretics, and antacids.9The choice of NSAID in an individual patient

rheumatoid arthritis will be determined by the prevexperiences of the physician and the patient,9 the seleremaining inpartmore ofan art than a science. Doses sh

be increased to the recommendedmaximumoverone tweeks and, if results are disappointing, an alternNSAID should be tried. Dose of NSAID can be ti

against symptoms by the patient and concurrent uon-demand or regular analgesics, such as paracetamol,reduceNSAID requirements. Ifa patient with rheumaarthritis has significantsymptoms and signs ofinflammaafter a short time on optimum NSAID therapy, aacting drug should be considered.

Slow-acting drugsThese drugs alter disease outcome in rheuma

arthritis, although the extent to which they do so is uncThe demonstrationthat drugs such as sulphasalazine, w

has fewer potentially serious adverse reactions thanSAARDs, slow erosion rates in early arthritis20 has helpromote earlier use of SAARDs. The main SAARD

8/13/2019 klouy

4/6

long-term are those of side-effects and flares in disease

activity despite initial control. Wolfe et al22 have shown thatpatients remain on SAARDs for 15-2 years, except formethotrexate (4 years). Meta-analyses of randomisedcontrolled trials of SAARDs23 show little difference in

efficacy between methotrexate, injectable gold,

D-penicillamine,and

sulphasalazine. Auranofinand

hydroxychloroquine, however, were significantly lesseffective, although at least 170 patients would be requiredper treatment group to differentiate between SAARDs.

Antimalarials are given early in rheumatoid arthritis butare not as effective as other SAARDs. The main concern is

retinopathy, although severe retinal toxicity is extremelyrare at currently recommended doses (7-5 mg/kg per dayhydroxychloroquine).24 Enteric-coated sulphasalazine canbe given safely in early rheumatoid arthritis 20 the mostcommon adverse reactions being skin rashes and hepaticenzyme abnormalities within the first four months oftreatment25 after which the frequency of blood tests may be

reduced. Gold compounds (both injectable and oral)are

stillextensively prescribed. Injectable gold is given in dosesbetween 10 mg and 50 mg per week until a total dose of 1 ghas been reached or significant remission takes place.At thisstage, the frequency of injections is reduced, althoughceasing gold completely usually leads to an early relapse indisease. Oral gold (auranofin) is significantly weaker thanother SAARDs,23 although adverse reactions are lessfrequent except for diarrhoea. In a recent survey of goldsefficacy, Champion et al concluded that doses ofintramuscular gold in the range of 10-50 mg/week for one totwo years are more effective than placebo; a dose-responserelation in the region of 10-150mghad not been established

and excellent clinical responses occur in 20-35 % ofpatientsand peak at 6-12 months, but only half of these patientsmaintain their response after 12 months.26A recent study byEpstein et al27 failed to show any significant effect ofintramuscular gold on the course of rheumatoid arthritisover a five-year interval.

Although D-penicillamine was used extensively in theearly 1980s, poor long-term efficacy and a high incidence ofside-effects have reduced the enthusiasm for this drug.Methotrexate, given as a single weekly oral dose, is rapidlybecoming the most commonly prescribed SAARD. Its easeof use, rapid onset of action, and low incidence ofside-effects, at least in the short term, have helped its

acceptance.28The long-term effect of methotrexateon

liverfunction still remains a concern29 and patients must beadvised to have minimum alcohol and be warned not to take

antibiotics such as trimethoprim-sulphamethoxazole. Theissue of if and/or when liver biopsy should be done inpatients on methotrexate has still not been clarified but it is

certainly not required before treatment in patients withoutrisk factors such as previous liver damage. Although fullblood count and liver function tests are regularlymonitored,they do not correlate with histological changes.Azathioprine, cyclophosphamide, and chlorambucil are

still used in some patients with severe rheumatoid arthritisand especially in those with extra-articular manifestations.With these

drugsthere is a substantial risk of

long-termtoxicity, especially an increased incidence of neoplasia.Patients treated with azathioprine have an increased rate ofl mphoproliferati e disorders and other li i 30

better to give intermittent pulse therapy rathercontinuous daily treatment since this regimen reducestotal dose ofcyclophosphamide administered and hence

potential for malignant disease.Several studies support cyclosporin in the managemen

rheumatoid arthritis.28 However, cyclosporin invaricauses some

reductionin renal

functionand a rise in

bpressure, and although these changes invariably returnormal once the drug is ceased, they raise concerns ab

long-term safety in patients with a chronic relapdisorder.

Corticosteroids are still prescribed extensively to patiwith chronic arthritis. They tend to be given as continubackground therapy, in short oral courses of rapdecreasing dose for disease flares, or as oral, intramuscuor intravenous high-dose regimens during a flare or attime of commencement of other SAARDs.21 Doses be

7-5 mg dailyare well tolerated but there is still concern ablong-term corticosteroid therapy (skin fragility

increased susceptibilityto

infection) and steroid doshould be kept to a minimum. Combinations of sterwith other SAARDs or at the time of beginning SAARsuch as gold3 may also be beneficial.Although combinations ofSAARDs arenow being gi

to patients with rheumatoid arthritis in the hope that lodoses of each might provide added efficacy withincreased side-effects, few well-controlled trials have bdone with combinations.Available data have not sh

significant benefit of a combination therapy over siagents.32 This approach needs to be pursued with carefdesigned clinical trials.The next decade is likely to bring several new treatme

for rheumatoid arthritis including monoclonal antibodiesT-cell vaccination,34 and cytokines and cytokinhibitors.35 These compounds, together with drugs suctenidap and mycophenolic acid,36 should provide us witrange oftreatments to suppress inflammation and to red

long-term disability.The pharmacological treatment ofrheumatoid arthriti

reaching an exciting stage but, since cure is currentlypossible, every method of reducing pain should be pursin each patient. Teaching patients about their diseasereduce pain and increase function37 and maximumshould be made of patient support groups. Sensible dietadvice is commonly sought by patients. While there is li

evidence that most patients with rheumatoid arthritis hspecific food allergies,38 a few patients respondelimination of milk products or fasting.39Addition of foils and/or evening primrose oil may also provideadditional reduction in pain and joint swelling by reducinflammatory mediator production.40 These strategithough useful, have not been shown to influence dise

progression in the long term.The challenge in managing a patient with rheumato

arthritis is to produce maximum suppression of synoviwithout serious adverse drug reactions. Damage (ofreversible) to cartilage occurs early and if pharmacologicontrol is inadequate, then thought should be given

surgicalmeasures such as

synovectomy or,at a la

stage when cartilage has been destroyed, total joreplacement. These operations, especially total jo

l t id substantial i relief and incre

8/13/2019 klouy

5/6

290

promoted. Few patients (if any) can be cured, but most canbe helped with this multidisciplinary approach.

REFERENCES

1. Spector TD. Rheumatoid arthritis. Rheum Dis ClinNA 1990; 16: 513-37.2. ScottDL, Huskisson EC. The course of rheumatoid arthritis. Baillires

Clin Rheum 1992; 6: 1-21.

3. Vandenbroucke JP, Hazevoet HM, CatsA. Survival and death inrheumatoid arthritis: a 25 year prospective follow up. J Rheumatol1984; 11: 158-61.

4. Markensen JA. World wide trends in the socioeconomicimpact and longtermprognosisofrheumatoid arthritis. SeminarsArthritis Rheum 1991;212 (suppl 1): 4-12.

5. BrookA, Corbett M. Radiographic change in early rheumatoid disease.AnnRheum Dis 1971; 36: 71-73.

6. Wolfe F. 50 years of antirheumatic therapy: the prognosis of rheumatoidarthritis.J Rheumatol 1990; 22 (suppl): 24-32.

7. Capell HA, Brzeski M. Slow drugs, slow progress: use of slow actinganti-rheumatic drugs (SAARDs) in rheumatoid arthritis.Ann RheumDis 1992; 51: 424-29.

8. FriesJF. Evaluatingthe therapeutic approach to rheumatoid arthritis: thesawtooth strategy. J Rheumatol 1990; 22 (suppl): 12-15.

9. Champion GD. Therapeutic usage of non-steroidal anti-inflammatorydrugs. Med JAust 1988; 149: 203-13.

10. Brooks PM, Day RO. Non-steroidal anti-inflammatory drugs-differences and similarities. N Engl J Med 1991; 324: 1716-25.

11. Huskisson EC, Woolf DL, Balme HW, Scott J, Franklyn S. Four newanti-inflammatory drugs: responses and variations. BM J 1976; i:1048-49.

12. DayRO,Graham GG, WilliamsKM. Pharmacokinetics ofnon-steroidal

anti-inflammatory drugs. Baillires Clin Rheumatol 1988; 2: 363-93.13. OBrien WM, Bagby GF. Rare adverse reactions to non-steroidal

anti-inflammatory drugs. J Rheumatol 1985; 12: 13-20, 347-53,562-67, 785-90.

14. Langman MJS. Epidemiologic evidence on the association between

peptic ulceration and anti-inflammatory drug use. Gastroenterology1989; 96 (suppl 2): 640-46.

15. Piper JM, RayWA, Daughery JR, Griffin MR. Corticosteroid use and

peptic ulcer disease: role of non-steroidal anti-inflammatory drugs.Ann Intern Med 1991; 114: 735-40.

16. Fries JF.NSAID gastropathy: the second most deadly rheumatic disease

epidemiology and risk appraisal. J Rheumatol 1991; 18 (suppl 2): 6-10.17. Howard JM,LeRicheNGH. The management ofNSAID gastropathy.

Baillires Clin Rheumatol 1990; 4: 269-91.18. Clive DM, Stoff JS. Renal syndromes associated with non-steroidal

anti-inflammatory drugs.N Engl J Med 1984; 310: 563-72.19. Tonkin AL, Wing LMH. Interactions of non-steroidal anti-

inflammatory drugs. Baillires Clin Rheumatol 1988; 2: 455-83.20. Van der Heijde D, Van Riel P, Nuverzwart I. Effects of

hydroxychloroquine and sulphasalazine onprogression ofjoint damagein rheumatoid arthritis. Lancet 1989; i: 1036-39.

21. Brooks PM. Medical management of rheumatoid arthritis: slow actingdrugs. RheumatolRev 1992; 1: 137-45.

22. Wolfe R, Hawley DJ, Lathem MA. Termination of slow actingantirheumatic therapy in rheumatoid arthritis: a 14 year prospectiveevaluationof 1017 consecutive starts.J Rheumatol 1990; 17: 994-1002.

23. Felson DT,Anderson JT, Meenan RF. The comparative efficacy andtoxicity of second-line drugs in rheumatoid arthritis.Arthritis Rheum

1990; 33: 1449-61.24. Tett S, CutlerD,DayRO.Antimalarials inrheumatic diseases. Baillires

Clin Rheumatol 1990; 4: 467-89.25. Donovan S, Hawley S, MacCarthy J, Scott DL. Tolerability of enteric

coated sulphasalazine in rheumatoid arthritis: results of a co-operativeclinical study. Br J Rheumatol 1990; 29: 201-04.

26. Champion GD, Graham GG, Ziegler JB. Thegold complexes. BailliresClin Rheumatol 1990; 4: 491-534.

27. Epstein WV, Henke CJ, Yelin EH, Katz P. Effect of parenterallyadministered gold therapy on the course of adult rheumatoid arthritis.Ann InternMed 1991; 114: 437-44.

28. Brooks PM. Current issues ofmethotrexate and cyclosporin. Curr OpinRheumatol 1992; 4: 309-13.

29.Ahern MJ, Kevat S, Hill W, Hayball PJ, Harvey H, Hall P de la M.

Hepatic methotrexate content and progression of hepatic fibrosis:

preliminary findings.AnnRheum Dis 1991; 50: 477-80.30. Matteson EL, HickeyAR, Maguire L, et al. Occurrence of neoplasia in

patients with rheumatoid arthritis enrolled in a DMARD registry.J Rheumatol 1991; 10: 809-14.

31. Corkhill MM, Kirkham BW, Chikanza IC, Gibson T, Panayi GS.Intramuscular depomethylprednisolone induction of chrysotherapy in

32. Boers M, Ramsden M. Long acting drug combinations in rheumatoidarthritis: a formal review. J Rheumatol 1991; 18: 316-24.

33. Burmester GR, Horneff G, Emmrich F. Intervention with

immunomodulatory agents: monoclonal antibody therapy. BaillireClin Rheumatol 1992; 6: 415-34.

34. Kingsley G, Panayi GS. Intervention with immunomodulatory agentsT-cell vaccination. Baillires Clin Rheumatol 1992; 6: 435-54.

35. Dayer JM, Fenner H. The role of cytokines and their inhibitors iarthritis. Baillires Clin Rheumatol 1992; 6: 485-516.

36. Veys EM, Mielants H, Verbruggen G, De Keyser F. Intervention witimmunomodulatory agents: new pharmacological developmentsBaillires Clin Rheumatol 1992; 6: 455-84.

37. Lindroth Y, BaumanA, Barnes C, McCredie M, Brooks PM.controlled evaluation of arthritis education. Br J Rheumatol 1989; 27-12.

38. Buchanan HM, Preston SJ, Brooks PM, Buchanan WW. Is di

important in rheumatoid arthritis? Br J Rheumatol 1991; 30: 125-3439. Kjeldsen-Kragh J,Haugen M, Borchgrevink CF, et al. Controlled trial

fasting and one year vegetarian diet in rheumatoid arthritis. Lanc1991; 338: 899-902.

40. ClelandLG, French JK, BettsWH, Murphy GA, Elliot MJ. Clinicalabiochemical effects of dietary fishoil supplements in rheumatoarthritis.J Rheumatol 1988; 15: 1471-75.

VIEWPOINT

Measles control in young infants

where do we go from here?

The withdrawal of the recommendation to use high-timeasles vaccines at 6 months old in countries where meas

mortality is high before the age of 9 months, has dela

availability of a tool that has been considered vital measles contro1.2 However, implementation of measvaccination policies needs to be greatly improved befcurrent vaccines can be deemed to have failed.

Vaccination programmes that have achieved

sustained high coverage with Schwarz vaccine at agmonths have substantially reduced measles incidence

mortality.3 Measles vaccine was introduced only receinto many vaccination programmes, particularlySoutheast Asia (fig 1). In theAmericas, several count

reported coverage rates under 60% for measles vaccinlate as 1989 (fig 2). In the World Health Organizat(WHO)African region, average coverage ofmeasles vacin 1990 was

only 54%,and the three most

populcountries in the region-Nigeria, Ethiopia, and Zaireported coverages of 54%, 37%, and 44%, respecti(WHO Expanded Programme on Immunization [Eunpublisheddata). In addition to the need forhigh covervaccination should be timely. Surveys inAfrica,Asia,LatinAmerica in 1986 to 1989 found that in only 8 ocountries were more than halfof measles vaccinations gbefore 12 months of age.4 The major reason formortality and morbidity from measles is failure of hservices to achieve and sustain high vaccine coverage arecommended age, both in developing and develcountries.5

To determine the need for earlier vaccination, prospe

community-based data on incidence and complication

ADDRESS Communicable Disease Epidemiology Unit, Sf i d i l M di i l S L

8/13/2019 klouy

6/6

Reproducedwithpermissionof thecopyrightowner. Further reproductionprohibitedwithoutpermission.