PR ACTI CAL TH ER AP E UTI C S

_.

DI'I' p f 3 l/l~ 8f9-163,

1 ~2

OO I 2~1~2/OXlf>-0849J101.~

C 40:1 .. Inln'ftalional Lim ilo:d. " II riV"~ rnnwd .

Pharmacological M anagement of Juvenile Rheumatoid Arthritis Carlos D. Rose and Robert A. Doughty Division of Pedia tric Rheumatology, Alfred I. du Pont Inst it ute, Wilm ington, Delaware, and the Jefferson Medica l College. T homas Jefferson University, Philadelph ia. Pennsylvania. USA

Contents 84'1 850 850 852 8B 8B 854 8.~4

855 857 857 858 858 858 859 859 860 860 861

S ummary

Sum mary I. Nonste ro idal Anti.l nflamma tory Drugs 1.1 Aspirin 1.2 Oth er NSAIDs 2. Cort icosteroid s 2.1 Oral Adminislrati on 2.2 Intra venous Meth ylpredn isolone Pulse 2.3 Intra-Articular Administration 3. Methot~ute 4. Gold SalIS 4.1 Sodium Auroth iomal ate 4.2 Auranofin S. Sulfasalazine 6. Hyd roxychlorcq ume 7. Pen icillam ine 8. Immunosupressams 9. Gammaglobu hn and Monoclonal Anti bod ies 10. Furt her Clinical Considerations II. Conclusions

The goals of pharmacotherapy in juvenile rheum atoid arthritis (JRA) are to suppress chronic synov itis which causes poten tial cartilage dest ruction and deformities. 10 control the systemic effects of inflammat ion (includ ing growth retardation and nutritional deficits), relieve pain and limit psychological impact of disease. Curren tly ava ilab le met hods include nonstero idal an ti-inflamm atory d rugs (NSAIDs ) such as aspiri n. salicylate$. naprc xen. tormeun . ibuprofen and indo methacin; disease modi fying antirheumatM: drugs (DMARDs) such as oral and injectabl e gold salts. hydroayehloroq uine. penicillam ine. oral and injecta ble methotrexate, and sulfasalazine; oral Idaily or on alternate days). intra venous pulse or intra-articular corticosteroids ; immunosupressams, includinJ cyclophospham ide. chlorambucil, cydosporin. and azathi opri ne; and pmmaglobulin and other experimental therapies . Over the past 10 years. rheumatologists ha ve adop ted more aggressi\'e phamacologicaltreatment of JRA . As time progresses and the safety of certain drugs such as methot reJlale and

Drugs 43 (6) /992

850

sulfasalazine becomes clearer , wider and earlier use of these agents can be expected. Still the approach 10 treat ment is a 'step by step' one, staning with the classical NSAIDs and ending with the DMARDs as needed.

Ju venile"rheumatoid arthritis (JRA ) should be viewed as a heterogeneous group of clinically defined condi tio ns with d ifferent functional outcom e. Subsets include systemic onset JRA , earl y onset pauciarticula r (i.e. < 5 joints involved ) JRA , late o nset pa udartic ular JRA , and polyarti cular JRA ( > 5 joints involved). Th e prognosis is highly depende nt upon the subset (Schaller 1977). A recent rev iew of 147 JR A patients showed syste mic onset JRA has a 50% remission rate at 5 years and 57% at 10 (Ansell 1987). Child ren with the polyarticular rheumatoid factor-positive fonn had 0% remi ssion at 10 years, while 60%of seronegative children were in remission at 10 years . Early onset pauciarticul ar remits in 70% of the cases at 10 years and the late onset pauciarticular form on ly in 55%. The impact of d rug therap y on function al outcome is difficult to establi sh given the lack of control group s. In general, arti cular inflammation can be controlled in 50% of JR A patients with the use of nonsteroidal anti- inflammatory dru gs (NSAIDs ) [Gi annini et al. 1990], b ut this figure varies amo ng the d ifferen t subsets. Over the last 15 years, rheumatologists have become more aggressive in treat ing ad ult and ju venile rheumatoid arthritis. The classic pyramidal mod el has been challenged, and a trend toward the early use of disease mod ifying a ntirheu matic dru gs is seen not only am ong ad ult but also paediatric d isease therapy. In the past, child ren with JRA were initially treated with NSAIDs, and on ly after I year of active disease and/or bon y erosions were disease modifying agent s considered. Nowadays such patent dru gs are often initiated after period s as sho rt as I to 3 mon ths: In adults eve n more aggressive simulta neous therapy of up to 5 disease modifying agents has been suggested (Wilske & Healey 1989). The actual efficacy of an y dru g regimen is difficult to evaluate because even when satisfactory results are achieved, spontaneous remi ssion may have been respon sible for the improvement . Therapy is generally aimed at helping to control synovi tis until

'spontaneous remission' occurs in the hope that this will diminish cartilage destruction and prevent deform ities.

1. Nonsteroidal Anti-Inflammatory Drugs 1.1 Aspirin

The analgesic action of the leaves, bark and roots of the willow has been known for cen turies. Their antipyretic action was confirmed d uring the eighteenth century, and the active ingredient (salicin) identified in the nineteenth century. In 1876 Maclagan used salicine to treat acute rheum atism [Ma clagan 1876). Aspirin was first synthesised for commercial produ ction by Hofman for Bayer in 1893, and was the only commercially ava ilable antiinflammatory compo und until 1949. Aspirin is still the most widely used, least expen sive and best known NSAID. A therapeut ic serum concentration of 1 to 24 srnc l/L (15 to 30 mg/dl ) is usually achieved after I week of treatment. Dosage increments should be done carefully with d oses above 100 mgykgyday in child ren (or 3 g/day for adolescents and adults; table I), since even small increases can be associated with significant changes in aspirin blood co ncentrations. The dru g can be butTered without interference with absorplion and the maximal antiarthritic action is generally achieved in 2 to 4 weeks, with some extra benefit obtain able up to the thi rd month. Aspiri n (and indeed other NSAID) therapy in childre n with JRA should be monit ored because of the possibility of adverse reactions (table II). In sma ll children a norexia is the most specific symptom caused by salicylate-indu ced gastritis. At every ph ysician visit parents should be q uestioned about their child's eating hab its, abd omi nal pain or diarrhoea. G uaiacolate card s can be mailed to families when gastrointestina l symptoms are reponed. Subclinical gastrointest inal bleedin g is very common (up to 70%) in ad ults with rheuma toid arthri tis (Fries et al. 1990) but its prevalence and signifi-

Management of Ju venile Rheumatoid Arthr itis

85'

cance among children is not known. Self-limiting transaminase elevation is common in children receiving aspirin (table III), If the transaminase elevation is asymptomatic. dosage adjustment or discontinuation should sufffice, but if neurological symptoms develop, an investigation (serum ammonia. amino acid profile) for Reye's

syndrome may be indicated. Aspirin should be dis-continued after exposure to chickenpox (in previously unexposed patients) or influenza-like illness. Increased shin bruising is commonly seen and is considered benign. Epistaxis. if recurrent, may require drug discontinuation. Less common side effects of salicylates include peptic ulcer, severe

Tabl a I. Dosage 01 a1ltimaumatic drugs in children Drug

Fraqua nty and rou te

Do. ., .

Com mant

Asp irin

PO qid

75 -100 mg/kg/day ; 8-12 3SOmg

Initial treatment;

tabl ets in old er (> 40 kg) children 10-30 mg/kg /day : max: 1800 mgfday 2-4 mgJkg/day 1 mg/kg

ine~pen sive

Toi metin

PO tid

Indomathacin

PO tid mane

lbupr ote n

PO tid-qid PO bid-t id PO: qd , mane, alt d ;

30-40 mg/kgfday 10-1 5 mg/kg /day

PO: tid-qid

1-2 mg/kg /day

IV (methyl-

30 mg/kg : max : 1-1.59g

predn isolor1e): qd for 1-3 days IA (triamcinolone): pm PO weekly 1M weekly

0.2-0 .8 mg/kg

10-20 mg/m 2 0.5·1 mg/kg·

Persist ent; useful for isolated joints For severe or prog ress ive disesse Used in patients unrespon sive to oral

Sodi um auroth ioma late Aur al'lOfin

1M weekly

Max : 1 rT\9Jkg

For savere or progressive disease

POqd

0.1 mg/ kg

Sull aulazine

1-2 .5 g/day 5-7 mg /kg

Penicillamine

PO bid PO q PO qd

Gam maglobulin

IV every 2-4

1-1.5 gJkg

For severe or prog ressive disease: alternate with other disease modifying agents For severe or prog ress ive dis ease Only mild ly active For severe or progressive disesse and disease unraspon sive to multiple disesse· modif ier therapy : relatively high tox icity For systemi c disease: experimental

Napro~en

ccrtcestercros

Methot re~ate

0.1-1 mg/kg /day

As lor aspirin, plus low GI lO~icity Potent, higher to~icity profile For momin g stilfnass; spond yloartllropathy Init ial trea tmant; OTC Initial treatment Therapeutic bridge: syst emic side affects Maintenance: severe compl ication s Therapeutic bridge: uncontrollable: severe systemic complications

methotre~ate

Hydro~ychloroqu ine

-"

5-10 rT\9/kg

a No studies published yet . Abbrevietions: PO _ by mouth; 1M • intramuscular ; IV - jntravenous: mane - in the morning; alt d - on altemate days; qd - daily: bid · tw ice daily; tid · 3 times daily; qid • 4 times daily.

852

Drugs 43 (6) /992

Table II. Dr ug toxicity moni toring in patients w ith J RA Dr ug

aasesre tests

NSAIDs Me thotrex ate

cec. AST, ALT, creatine

NO! needed il asymptom atic

cec or plal a' sl count. AST. ALT, creatinine , urine analysis

Sodium e wouuomatete

c ee or pla telet cou nt, creatinine, urine analysis

e sc or platelet cou nt. AST. ALT, weekly for 3 we eks. then month ly Repeat every 2 week s

Hydr ox ychlor oq uine Penicillamine

Eye test

Repeat every 6 months

esc or platelet count creatinine,

c ee or platelet cou nt . urine analysis mont hly ; CPK every 6 months Repea t monlt1ly

urine analysis

Sunasatazire

cac

FOllow-up tests

Ab brevia tions: cee • complete blood count: AS1 • aspartate am ino transferase: ALI · alan iJ'le amino tra nsferase : CPK • cre atine

phosphokinase.

bleeding, disseminat ed intravascular coagulation (mainly in systemic JRA), Reye's syndrome, nephropathy, urticaria , asthma, and salicylism (i.e . salicylate intoxicat ion). In patients with chronic salicylate overdose the first symptom is tinnitus in the older a nd behavioural changes in the younger child. Salicylates are contraindicated in children with glucose-o-diphosphate deficiency, pyruvate kinase deficiency, haemophilia, von Willebrand 's disease (angiohaemophilia) and in those receiving anticoagulant therapy. Nonacetvlated salicylates are theoretically less toxic to the gastrointestinal tract and are a conceivable option in aspirin-sensitive individuals. Experience with these agents is however limited, and data on efficacy and toxicity are anecdotal for children with JRA. A frequently overlooked problem with aspirin is compliance. Data from adults show an overall compliance rate of 50%. The figure for children with JRA is probably similar, but adolescent compliance may be significantly worse. Serum aspirin concentrations shou ld be determined after 5 to 10 days and later they should be checked if clinical response seems inadequate, if there are toxic symptoms or if there is concern about compliance.

1.2 Other NSAlDs For years the only anti-inflammatory mechanism of NSAIDs was attributed to the inhibition of prostaglandin synthesis. However, the antirheumatic action of the NSAIDs has recently been re-

viewed (Abramson & Weissman 1989). It is now clear that low dose NSAIDs can affect prostaglandin-mediated interleukin-l-induced systemic effects. At higher doses, they probably affect neutrophil activati on directly. Although gastrotcxicity is partly caused by direct epithelial damage via a prostaglandin-independ en t mechani sm, prostaglandin inhibiti on remains as the most significant mechanism. Platelet function inhibition is also mediat ed by prostaglandin inhibition. In recent years NSAID-mediated toxicity has become a highly prominent issue. Dram atic data generated by the ARAMIS (American Rheumatism Association Medical Informat ion System) showed that NSAID gastroto xicity may be responsible for as many as 20 0Cl0 admissions and 2400 death s each year in the United States. The risk is increased by age, female gender and concomitant use of corticosteroids (Fries et al. 1989). Paediatri c data are limited however, and it seems that this problem is less common and/or less severe in children . NSAID-induced peptic disease can be minimised using dietary measures or drug therapy where appropriate (table IV). Renal toxicity is seldo m a clinically significant problem in children. Nevertheless, it is advisable to stop NSAlDs durin g episodes of hypovolaemia because of potential inhibition of prostaglandinmediat ed renal function. Tubular dysfunction appears to be common in JRA and the role of NSAIDs in its pathogenesis is still unclear. Although not clear ly related to prostaglandin in-

Management of Juvenile Rheumatoid Arthritis

853

hibition, a very common complaint among children receiving NSAIDs is CNS toxicity manifested as headaches and behavioural changes. These are the paediatri c counterpart of lightheadedness and dizziness commonly seen in adults. Many NSAIDs other than salicylates are currently ava ilable, but only totmeun, naproxen, ibuprofen and indomethacin have been studied in children with rheumatic disease. Occasionally other NSAIDs can be used when intolera nce or lack of efficacy occur. Safety and efficacy for drugs such as diclofenac, piroxica m, fenoprofen and sulindac in children are not completely understood. Tolmetin has been in the market for many years and is widely used in children with JR A. It is a potent and relatively well tolerated drug (tables I and III). False positive sulfosalicylic urine test for proteins may be seen in patients taking the drug, possibly leading to unnecessary investigation for renal impairmen t. Naproxen is also well tolerated and is available as a liquid form ulation, but more significantly it is effective with twice daily administrat ion (table I). The latter is important when morning stiffness is a problem and a long-acting night dose can be given to correct the morning symptoms. Its tolerability, pleasant taste, and dosing frequency make naproxen liquid a good choice for early onset pauciarticular JR A. Idiosyncratic reactions, particularly skin rash and more recently pseudopc rphyria. have been reported (Suarez et al. 1990). The relatively high price of naproxen is a disadvantage. Ibuprofen has an excellent gastrointestinal tolerance (tab le III) and its liquid form ulation is well accepted by children. Like other NSAlDs given 3 times daily, the second dose can be given after

school instead of at lunchtime, thus limiting the stigma of a child needing to take medication at school. Another advantage of ibuprofen is its ava ilability as an over-the-counter drug. Indomethacin is a very potent NSAID but its tolerability is a limiting factor (tables I and III). Its particular advantages are control of morning stiffness and systemic symptoms (fever and rash). Some rheumatologists prefer indomethacin for spondyloarthropat hies, although data to support this approach are limited.

2. Corticosteroids 2. 1 Oral Administration Oral corticosteroids in J RA synovitis are commonly used as a therapeutic 'bridge' to cover for the latency of action of a selected disease modifying dr ug. Thus, both are usually prescribed sim ultaneous ly. Predn ison e, predni solon e or methylprednisolone are the most often used. Corticosteroids are also indicated to treat extra-articular manifestations of JR A including uveitis refractory to topical treat ment, fever and other systemic manifestations of JR A such as pleuropericarditis, vasculitis and disseminated intravascular coagulation (table I). While efficacy with corticosteroids is obtained quickly using a generous dose (e.g. 1.5 to 2 mg,lkg,l day in th ree divided doses), maintenance and reducing doses can be planned early in the treatment and a tapering calendar may be designed. The goal is an alternate regimen a nd/or a low daily dose given in the morning. A concomitant steroid-sparing agent (e.g. NSAID or disease modifier) is desirable to facilitate tapering. A maximum effect is

Teble 111. Relative tolerability of some NSAIDs used in JRA Reaction

Aspirin

Tolmetin

Naproxen

Ibupro fen

Indomethacin

Gastritis eNS Trans aminase elevati on

+ + ++

+ +

+ +

+ +

+++ +++ ++

Symbols:

+ .. mild; ++ .. moderate ; +++ .. severe ; -

.. absent.

Drugs 41 (6) J991

854

T.blll IV. Man agement and prevention 01 NSAID-induced peptic dam age

Treatment Preve ntion

Dietary rreasures

Antacid

Cimetidine

Sucralf ale

++ +++

+++

+++

+' +++

a Duodena l ulceration. Symbols: + .. limi ted eHicacy :

++ .. moderate

etticacy :

+++ .. high

achi eved by 2 mg/kg/day in a 3-times-daily schedule. Unfortunately, toxicit y is also commonly seen with thi s regimen . Consolidation to a single daily d osage equal in magnitude to the total divided dosage is often associated with clinical flares in disease activity and ma y require a few days to implement. An example of a consolidating regimen would be IOmg three times daily, and then I Smg twice daily, and finally 30mg once daily . When given as a single do se corticosteroids should be provid ed in the early morning to minimise pituitary inhibition. Following consolidation, a tapering of the dail y dose (e.g. by 10% every 10 days) or an alt ernate dail y dose ca n be att empted according to clini cal response. Tapering may need to be don e slowly to avoid clinical rebound, particularl y in systemic JRA ; as much as 3 to 6 months ma y be needed to complete the weaning. The tapering process is more an art than a science. T o aid compliance, tabl ets can be crushed and mixed with food rather than using liquid preparation s. Prednisone and methylprednisolone can be used. The latt er bypasses hepatic acti vation and is felt to be especially useful in the presence of liver di sease. Dexameth asone and other long-acting fluorinated oral preparations are contraindicated in JRA due to the high incidence of myopath y associated with th em. It is un pred ictable which pati ents will develop cushingoid symptoms but there is a clear relati onship with d ose and length of therapy. Normal linear growt h ma y be affected with as little as 5 mg/ m 2 dail y for a month. The mechanism is likely to be peri pheral resistan ce to somatomed in. The beginning of recovery from growth retardation can be seen 4to 6 weeks after discontinuation of the drug. Alternate-da y regimens are associated with less

erfi C8C:Y : - .. no valuE!.

growth retardation . Th e ability to exhibit 'catch up' growth is inversely related to age. Th e other multiple side effects of corticosteroids are well defined in sta ndard paediatric textbo oks (Cassidy & Petty 1990). The Food and Drug Administration have recently recommended that children receiving long term or high dose corticosteroids (e.g. those with JRA) should avoid exposure to chickenpo x and measles, since immunosuppression can lead to severe infection or death. 2.2 Intravenous Meth ylprednisolone Pulse Very large doses of steroids ma y be indi cated in patients with severe persistent disea se or in those with potentially life-threat ening complications. Meth ylpredn isolone 30 mg/kg per dose (maximum 19) ma y be given intravenously for 3 consecutive days (tabl e I). Thi s is clearly less toxic in the long term than dail y oral the rapy and provides maximum prompt anti-inflammatory action. Intravenous methylpredn isolon e pulse ma y be ad ministered on an out patient basis. Its effect lasts 3 to 6 weeks which allows its use as a therapeutic bridge (see section 10). 2.3 Intra-Articular Adm inistration Th e indi cati on for intr a-arti cular inject ion is the presence ofone or a few inflamed jo ints which have been unrespon sive to more conserva ti ve noninvasive therapy. Intra-articular steroid injections are very effective and the therapeutic effects ma y persist for prolonged periods. A frequentl y chosen drug is triamcinolone hexacetonide which has high patency, is relativel y insoluble and its effects ma y last for weeks or even month s. Recurrent injection s

Man agement of J uvenile Rheumatoid Arth ritis

however may result in infection, crystal-ind uced synovitis, calcification and osteoporosis. Sparling et al. (1990) recently report ed excellent outcome with multiple joint injections in a large number of J RA patien ts, although the multijoint injection proced ure requi red general anaesthesia with its associated risks.

3. Methotrexate Methotrexate is a folic acid analogue with a potent inhibitory binding to the enzyme dihydrofolic reductase. This binding is readily reversed by adding low concentrations of the substra te dihydrofolic acid (White 1979) which permits ' rescue' therapy when toxicity occurs. Reduction of dihydro folic acid to tetrahyd rofolate is req uired in the synthesis of thymidine mono phosphate, purines, and serine from methioni ne, which are crucial pathways in the synt hesis of DNA, RNA and proteins, respectively. Methotrexate functio ns as a n a ntiprcliferative agent and this may relate to its ant i-inflammatory action (Stewart et al. 199 1). Methotrexate has shown variable degree of inhibition of proliferation and mitogen response in T and B lymphocytes, but the suppression of rheumatoid factor production is striking (Alarco n et al. 1990; Olsen et al. 1987). Olsen and Murra y (1989) a lso demonstrated a dr amatic antiproliferat ive effect on peripheral blood mononuclear cells of patient s with rheumatoid arthritis. Methotrexate also has a folate-dependent inhibitory action on interleukin-l action, a potent mediator of local and systemic inflam mat ion. Furthe rm ore, met hot rexate potent ly inhibits interleukin-l-induced interleukin-Z synt hesis and proliferation of T cells in vitro when added to peripheral blood mo nonuclear cells. Thi s mechanism is reversible by the .addit ion of calcium folinate (leucovo rin) [Segal et at 1989, 1990]. Other mechanisms of action of methotrexate have been proposed. Sperling et al. (1990) showed an effect of methot rexate on neutrophil leukotriene B productio n in the hpo xygcnase pat hway, and Hu et at ( 1988) showed that it led to dimin ished expression of immune associated antigens in the

855

surface of peritoneal macrophages of rats with adjuvant arthritis. Nesher and Moore (1990) postulated that the inh ibition of folate-dependent regeneration of meth ionine from homocysteine by methotrexate is responsible for its ant iproliferative actio n on lymphocytes (Hine et aJ. 1990) because of interference with the synthesis of polyamines (spermidi ne a nd spermine) which are essential for DNA synt hesis and hence cell proliferation, and synthesis of proteins such as imm unoglobulins, rheumatoid factor and interleukin-2. In summa ry, several mechanisms involving folate-dependent pathways affecting the reactivity of imm une response and inflammatory cells have been suggested to account for the efllicacy of methotrexate in rheumatoid arthritis. These effects are obtained by more of a n inhibitor rather than a cytotoxic mechanism. G ubner et al. (1951) were the first to report on the efficacy of a folic acid antagonist (aminopterin sodium) in contro lling rheum atoid art hritis. During the 1980s a number of placebo-controlled clinical trials involving over 200 patients (weinblatt et al. 1985; Williams et al. 1985) demonstra ted the benefits of methotrexate in controlling disease activity. However, in another controlled study, radio logical progression was shown not to be suppressed (Nordstrom et al. 1987). In 1986, methotrexate was reported to be useful in J RA (Truckenbrodt & Hafner 1986) and this was followed by other reports with similar findings (Danao et a!' 1989; Rose et at. 1989, 1990a,b; Wallace et at 1989). The first multice ntre dou ble-blind placebo-contro lled trial cond ucted by the Pediatric Rheumatology Co llabo ra t ive Study G ro up (PRCSG) showed methotrexate superiority at 2 different dosage schedules, 5 and 10 mg,lm 2/week (Gian nini & Brewer 1989). Oral methotrexate adm inistratio n is preferred but parentera l (intramuscular ) therapy may be used for oral treatm ent failures. In fact, some patients show a favourable init ial response but then develop a plateau or flare while on methotrexate. These patients can be treated with larger pare nteral doses (0.5 to I mg; kg/week). No studies appear to have been published on parenteral methotrexate for JR A therapy.

'56

Mon itoring of serum methotrexate concent rations is not needed on a regular basis. Clinical effficacy has not been corre lated with methotrex ate concentrat ion s, and toxicity has been seen within the range of-safety' (Wallace et aJ. 1989). Typical cand idates for methotrexate are pat ients with systemic or polyart icular forms of JRA who ha ve persistent or progressive disease (morn ing st iffness, jo int wa rmth , swelling/thickening, flexion contract ures) despite an adequate trial ofNSAIDs. As no ted earlier there is controversy as to whether this should be done ear ly (e.g. 4 weeks) into NSAID th erap y or after a prolonged (6 to 12 mon ths) trial. Th is decision sho uld be based on the sever ity and/or aggressiveness of the indi vidual pat ient's disease. A 3-day cou rse of intravenous meth ylpredni solon e 30 mg/kg/d ay may be used as a ' therapeut ic brid ge' (see sectio ns 2.2 and 10). Data on the phar macokinetics of methotrexate in children are limited, most of what is known being generated by animal or ad ult hu man research. Methotre xate is effective ly absorbed at a variable rate after oral ad ministration, with peak seru m concentratio ns achieved 2 hours after oral ingestion . Its volume of distributi on is 0.25 L/kg and the half-life is 6 hour s. The dr ug is 50% protein bound and transported 10 the liver where it is partially converted to 7-hydroxy -methot rexate before being 30 to 80% elim ina ted by active tubular secretion (Furst & Kremer 1988). Recent stud ies have sho wn that biliary eliminat ion is also significant and that enterohepatic circulation of up to 3C1Jl.J may occur [N uem berg et aJ. 1990). Meth otrexate is actively transported into cells, where glutamate residues are added. This mechani sm increases the inhibito ry action on dih ydrofolic red uctase, and also prevents metho trexate 'escap ing' from the cell. Polyglutam ation is felt to play an important role in intracelullar conservat ion, liver toxicity and absorption failure (Krem er et al. 1986). Very low intracellular concentrat ions are requi red to be effective and such concentrations are read ily achieved wit h weekly ora l doses (ta ble I). Meth otrexate interaction with other dr ugs has been of some concern . Meth otrexate half-life may be prolonged by several NSAIDs, alth ou gh this

Drugs 43 (6) 1992

find ing was not confirmed in a study using ibuprofen and llurbiprofen (Skeith et al. 1990) and its clinical significance is uncertain . Methotrexate is well tolerated by children . Althou gh up to 47% of patien ts may have some toxicity, most symptoms are of mi nimal significance. Reactions commonly seen include stoma titis. upper gastroi ntestina l upset. d iarrhoea, abdominal pain and liver enzyme elevation. Such reactions are usually self-limi ting (Rose et at 1990a) and may also relate to folic acid depletio n (Morgan et al. 1990). Bone marrow suppression has been reported but is rare and idiosyncratic; however, megaloblastic changes are more commo n and relate to folic acid depletion. Very un usual reactions including hair loss, gynaccomasria. transient azoosperm ia, impotence and CNS disturbance have rarely been repo rted in children. The adverse reaction which has received the greatest attention is chronic liver fibrosis. Several stud ies in ad ults with rheumatoid arthritis have shown contrad ictory results, and in children liver fibrosis has not been observed (Aponte & Petrelli 1988; Bjorkm an et al. 1988; Kremer & Kaye 1989; Kremer et al. 1989; Rau et al. 1989). Seven JR A pat ient s biop sed after an average cu mulative dose of 1709mg had normal liver histology (Gr aham et al. 1990). However, a recent report showed severe liver fibrosis in a girl with methotrexate-treated J RA (Keirn et al. 1990). Methotrexate-indu ced interstitial pneu moni tis is a severe toxic reaction seen mainly at doses used in cancer chemotherapy but that has also been reported in patients with rheum atoid arth ritis. Its occurrence is unp redictab le, presumab ly idiosvncratic, and thus far not reported in children. Chro nic pulmona ry disease has been stud ied in adults by serial pulmo nary function tests and in a cross-sectional study in childre n (Crook et al. 1989; Rose et al. I990b). In both groups no abnormalities were seen. Meth otrexate is potentia lly teratogenic and sho uld be disco ntin ued if pregnancy occurs. Long term studies o n fert ility of JR A patients receiving meth otre xate are still not available. To monitor methotrexate adm inistratio n a peri-

Management of Juveni le Rheumatoid Arthritis

pheral blood count, mean cell volume, liver and renal function tests, and urine analysis should be performed to obtain a baseline. Then complete blood count (with mean cell volume) and transami nase level assessment are recommended weekly for 3 weeks, biweekly for 2 weeks and then monthly. In abou t 40% of pat ients some liver enzyme abnormality develops after between 6 and 9 months of therapy. In such cases methotrexate may be withheld for several doses with weekly liver enzyme monitoring. If liver enzymes normalise, the drug may be restarted at the same dosage; if the cycle reappears after rcchallenge at the same dose, the drug should be stopped and restarted after several weeks at a reduced dose. Mild gastrointestinal upset and a single episode of liver enzyme elevation are the most commonly observed adverse reactio ns. Some authors recommend liver histology after 2 years of exposure.

4, Gold Salts The mechanism of action of gold salts remains unk nown despite mult iple in vitro studies. Recent reports of in vitro models have shown inhibition of macrophage differentiation (Littman et al. 1990) and decreased HLA-DR expression after interferon-v stimulation (Kawakami et al. 1990). It seems likely that gold exerts its antirheumatic a nd a nti-inflammatory effects at multip le sites in the imm une system. 4.1 Sodium Aurot hiomalate Sodium aurothio malate has long been an excellent optio n for the treatm ent of progressive or severe polyarticular JRA. A study on int ra muscular gold efficacy by Brewer et al. (1980) includi ng 51 JR A pat ients showed a rate of global improvement of jo int disease severity of 63% and improved jo int counts (i.e. number of swollen joints) in 49%. A 50% rate of efficacy ca n be reasonably assumed (Fink 1990) particularly in the polyarticular forms of the disease. Sodium aurothiomalate is given by weekly deep intramuscu lar injection. An initial test dose of 0.25

857

mg/kg should be given and increased weekly by 25% until the target dose of I mg/kg,lweek is reached. Once a cumu lative dose of 500 to lOOOmg has been delivered the patient should be reassessed clinically, and the drug discontinued if there is no improvement. Beneficial effects are seen after 6 to 12 weeks, but the optimal response generally takes 3 to 12 months. If a good clinical effect occurs, the frequency of injections may be gradually decreased to a single monthly dose of I mg,lkg (table I). Dosage is adj usted as the patient grows and gains weight, and the frequency of injection can be increased ifthe patient's disease flares. Most patients are treated with monthl y gold for several years after the disease has gone into remission, at which point the drug may be discontinued and only restarted if a flare occurs. Concomitant NSAIDs can often be discontinued. Many side effects have been related to injectable gold. The most important are skin rash, oral ulcers, renal toxicity and bone marrow toxicity. The rash is usually mildly red, maculopapular, itchy and scaly and subsides after drug discontinuation. Other skin rashes, including urticaria, bullous rashes a nd severe exfoliative dermat itis, have been described (Fink 1990). Gold-induced renal disease is a membranous glomerulonephritis usually presenting with proteinuri a which may be severe. Again, drug discontinuation is usually effective altho ugh corticosteroids may be useful. Mild cases of proteinuria and haemat uria are most common. In these cases the injections can be restarted at a lower dose after a I-mont h discontinuat ion. Thrombocytopenia is the most common bone marrow-related toxicity, followed by leucopenia. The overall rate for gold therapy discontinuation in children is 25% (Fink 1990). To monitor toxicity, a urinalysis, blood count and platelet count should be performed before each injection. Toxicity may occur late in the course (after I year of treatment ), thus laboratory tests for toxicity should continue as long as the patient is being treated. To ensure compliance and effective monitoring it is often preferable to see the patien t weekly and inject patients in the clinic or office.

Drugs 41 (6) 1991

858

Injecta ble gold is an excellent therapeut ic option whic h ca n be used ea rly in patients with severe o r aggressive d isease. It is not generally effeclive 10 treat the feve r and systemic feat ures of systemic JR A, although it may lead to improvement of joint involvement. In recent years. use of methotrexate is displacing sodium aurothiomalate because the latter may ha ve a long (,). to e-momh ) delay before therapeutic effect is obtained and it requires weekly injectio ns which some child ren do not tolerate well. Nevertheless. in ma ny child ren it remai ns an excellent first line renuuiu-ve agent and, if an effective respo nse is ob tained. a simple regimen of monthly injections may suffice to maintain long term therapeutic response. Pat ients with long term or aggressive polyarticular disease or paucianicular patien ts with extended/se vere joi nt involvement are good ca ndidates. We are more inclined to use metho trexate for polyarticular JRA. but ma ny rheumetologl srs will indicate injectab le gold in such cases. 4.2 Aura nofin Oral gold therap y has been clinica lly evaluated in ad ult rheumatoid arthritis since 1976 and showed significant efficacy co mpared to placebo in multiple co ntrolled studies (Ward et al. 1983: Wenger et al. 1983). Between 1983 and 1986 the first evaluations in children were published. again with favourable results (Brewer et al. 1983: Giannini et a l. 1983). However. in a 6-mon th double-blind multicentre inter national study involving 23 1 J RA patients. aura nofin was only mode stly better than placebo (Giannini et at 1990) showing 66% impro vement versus 56% improv ement in the placebo group. Auran ofin is a reasonably safe dru g. The most common adverse .reactio n is diarrh oea. In the stud y by G iannini et at (1990) 16 episodes of diarrh oea. 2 of abdominal pain and 7 dermatological symptom s (pruritus. xerode rma . bruising and rash) were seen among the 11 9 treated patien ts. Toxicity is monitored by obta ining peripheral blood counts and a urine analysis once for 2 weeks and then monthly. If gastrointestinal to xicity is observed

' weekend breaks' or missing a daily dose may lim it toxicity. Auran ofin is a n alterna tive to sodium aurothiomalate in selected patient s with progressive or sustained di sease. Young child ren may tolerate th is better than a weekly injectable regimen: however. the therapeu tic benefit of this fonn may be less.

s. Sulfasalatitl ~ Sulfasalazine [salazosulpha pyridi ne) has been used to treat inflammatory bowel disease for years. In the early 19805 several trials of sulfasalazine in adult rheumatoid arthritis were performed with promising results. One of the first reports of its use in J RA was published in 1986 as a pilot study involving 18 patien ts (Ozdoga n et al. 1986). It became clear that sulfasalazine may reduce disease activity in JR A but toxicity emerged as a significa nt limiting factor. A recent report of its use in 18 JR A patien ts who had failed conve ntio nal therapy demonstrated improvem ent in 50% of the cases within a 3-mo nth period (Jacobs 1990). The drug had to be discon tinued in 20% of the child ren because of side effects. The main area s of sulfasalazinc toxicit y are the skin. bone marrow and gastrointestinal tract. Questioning abo ut gastrointestinal tract irritation (as with NSAIDs) and month ly blood cell counts are generally sufficient to detect to xicity. The most common side effects a re allergic reactions involving the skin. and include maculopap ular. urticarial and mult iforme rashes. Serum sickness has been repo rted (Jacobs 1990) and may be a major limiting factor. Sulfasalazine is potentially useful in treating J RA when a rapidl y effective disease modifying agent is desired. It may be especially useful for pat ients with spondyloa rthri tic features or in those with arthritis related to inflammatory bowel disease. psoriasis or ju ven ile a nkylosing spo ndylitis.

6.

H}'dro;rychloroqu;t1~

Man y mechanisms of action of hydroxychlc requine have been pro posed, including DNA and RNA synthesis inhibition, lysosomal stabilisation.

Management of Juvenile Rheumatoid Arthritis

and interference with prostaglandin synthesis (van Kerckhove et at 1988). The use of hydroxychloroquine is popular am ong rheumatclog ists treating ad ult rheumatoid arthritis, but is used less commo nly to treat JRA . This may in part be due to the results ofthe doubleblind multicentre placebo-controlled study conducted by the PRCSG which suggested that hyd roxychloroquine is little better than placebo in treating JRA (Brewer et al. 1986). In thi s study, the placebo group (receiving onl y fixed doses of NSAIDs) had 47% improvement by global physician assessment while the hydroxychloroqumc group had 50% impro vement after 6 months. Despite having a delayed onset of action of 3 to 6 months (Cassidy & Petty 1990), 88% ofthe patients who event ually responded to the drug did so before 6 months. In the stud y by Brewer et al. (1986) invol ving 162 child ren with JRA, 5 of the II dropouts in the hydroxychloroquin e group were related to lack of efficacy, and 3 were due to toxicity. Hydroxychlorequine is used instead of chloroquine because of its safety profile. Its current use is mostly for cutan eous rashes associated with lupus and dermatom yositis, and for moderately severe polyarticular arth ritis in lupus and JRA. A baseline and then biannual retinal examination is the most important monit oring measure d uring treatm ent. Colour blindn ess and macular retini tis are the warning signs of hydroxychloroquine toxicity, while corneal depo sits are a severe indicator of toxicity. Hydroxychloroquine tends to accumulate in pigmented tissue including the pigmentary layer in the retina and the skin melanocytes. Thu s, the hair and skin can be monitored for dep igmentation. The drug should not be used in children under 8 years of age due to difficulties in colour vision evaluation, and therap y should not be continued for prolonged periods (;1:. 2 to 3 years).

7. Penicillamine When first introduced there was much enthusiasm about the potential value of penicillamin e as an alternati ve to gold in patient s who had not

859

shown a satisfactory response to the latter. Its use declined significantly after results of the PRCSG stud y showed little improvement over placebo in a large double-blind controlled study (Brewer er al. 1986). Penicillamin e may, however, be useful in managing skin complications of scleroderma and thus is often considered for use in arthritis asso-ciated with that condition, although its effectiveness has not been fully established. Penicillamine affects the immun e system via poorl y defined mechanisms. It has multipl e biochemical effects which include inhibition of disulphide bond forma tion , prevention of post-tran slational steps in collagen synthesis, and metal chelation, It is not established which, ifany, of these is important in its mechanism of action in rheumatic diseases. Adverse reaction s to penicillamine include bone marrow suppression, rashes, and aut oimmune reactions (systemic lupus erythematosus-like synd rome, myositis, myasthenia, memb ranous glo-merulonephritis and Good pasture's syndrome). Urine analysis and blood counts should be monitored every 3 to 4 weeks (weekly for the first month), creatine phosphokinase twice a year and, if antinucl ear ant ibod y-negative, antinucl ear antibody annually. Allergy to the drug is fairly common and some patients who show allergy to penicillamine are also allergic to gold and penicillin. A recent study involving 718 rheumat oid arthritis patients treated with penicillamin e showed a clustering of HLA-DR-2 amon g those who developed penicillamin e-mediated myositis (Taneja et al. 1990).

8. Immunosuppressants Azathioprine has been shown to be better than placebo in contro lling disease activity (Kvien et at 1986). However, due to its compa ratively weak activit y it is not commo nly used to treat JRA. Nevertheless, it is a relatively safe drug which may be used in selected cases. Monthl y bone marrow and liver function monit oring with peripheral blood count are required during treatm ent. Chlora mbucil is being used in occasional

Drugs 43 (6) /992

860

patients who fail alternative ther apies such as gold and methotrexate (both oral and int ramuscular ). With severe or aggressive d isease (e.g. uncont rollab le uveitis) it may be prescribed early. Cyclophos pha mide is not co m monly used to treat the synovi tis ofJRA . Cyc1osporin is being used with enthusiasm in Europe and several studies have sho wn efficacy in ad ult rheuma toid art hritis , but ex perience in children is limited. It s pos tulated

mechanism is through inhibition of interleukin-j tra nscription, and as an immunosupressor it is close to ideal due to the lack of genera lised bo ne marrow supress ion (Kahan 1989). H owever , rena l toxici ty

is a limiting factor.

9. GammaglobuUn and Monoclonal Antibodies Th e initial eve nt of the im m une cascade is the ant igen presenta tio n . Th e presen tin g cell (e.g. a macrophage or a den dri tic cell) express ing class I or II HL A surface prot ein s with the processe d a ntigen 'se lects' lymp hocytes with CD8 or CD4 on the ce ll surface to interact with it. Thi s proce ss seems abnormal in JRA and in other autoi mmune d iseases. Failure of self-tolerance , mo lec ular mim icry wit h infective agen ts, and other models have been proposed to ex plai n such an ab no rmal activat ion . A co m plex network of intercellula r signals medi at ed by Iymphok ines and their recep tors is trig. gered with several results: activation of effector cells (m ainl y activ ated synovial fibroblasts) ; and actio vat ion of met abolic path ways, includi ng prostagland in secret ion, oxygen free radical liberati on and lysosom al enzyme (e.g. collagenase) secretion. Fro m the prostaglandin inhibitor as pirin (sectio n 1.1) to the in terleukin-2 synthesis inhibitor cyclosporin (section 8) we have moved ' pro ximally' in inhi bition of the chain of infla m matory events. Curre nt work suggests that imm unog lubulin may be effective in inhibiting the initiation of the chai n. In a recent pilot stu dy gam maglo bu lin therapy was used successfully to tr eat systemic onset JRA (Lang et al. 199 1). O ngoing rnul ticen tre controlled studies are being design ed to assess its efficacy in systemic a nd polyarticu lar JRA.

Gammaglobuli n is an expensive tool that may pro ve effect ive in hel ping to control seve re JRA which has failed to respond to alternative therapies. Monoclonal antibodies against C D4 as well as smaller bloc king mo lecules are also under investigatio n. Ot her targets for monoclonal antibodi es include HL A. D R, the interleukin-l and -2 recept ors, and CD5 . Specific targeted mod ulat ion of the im m une system is the goa l of current immu no-p harmacclogical resea rch.

10. Further Clinical Considerations Morning Stiffness: Child ren sho uld be q uestio ned regarding morning lim ping or morn ing co m plaints as an indi cator of di sease activity and respo nse to therapy. Besides physical measures such as an electric blanket or warm bath , night-t ime indo methacin or naproxen ma y be helpfu l 10 relieve ea rly morning stiffness. If the patient is on chronic cort icostero ids an earlier morn ing dose (e.g. at 6a m) may be useful. Uveitis: Unresponsive uveiti s may occasionally need to be treated 'systemically' with cort icosteroids or immunos uppresive agents such as chloram bucil. Recent evide nce suggests that NSAIDs are also helpful in controlling inflammatory eye d isease in JRA . When to Stop Treatment: There is no uniform agree me nt among rheu matologists regard ing when to cease treatment. Some rheumatologists con tin ue treat ment for all pat ients with an y indi cation of persistent d isease acti vity. Others might choose not to treat so me patients with low disea se activity and no attendant morbidi ty (e.g. an ado lescent with mo noarticular JRA whose ra nge of motion a nd extremity growth are normal, an d who has per sistent mild joint swelling without erosi ons). A decision to stop treatmen t despite mi ld ongoing di sease may be justified if the patient or family have stro ng feelings aga inst taki ng a medi cation , or if the NSAID is not having any perceptible effect. Active polyarticular and systemic forms of J RA are usu ally undergoin g consta nt treatmen t un til the di sease enters a susta ined period of remi ssion where there is

Mana gem ent of Juven ile Rheu matoid Arthritis

no clinical or laboratory evidence of active di sease. Medication can then be safely tapered. Compliance: Ad ult studies show that compllance with N$AIDs in rheumatoid art hritis is close to 50%. Questioning abo ut compliance is very important. Sometimes changing the daily sched ule (no 'school pills' ), the preparation (eliminat ing gastrointestinal upset or improving palatabil ity), or reinforcing the importance of the treatm ent are sufficient. Concomitant Treatment with Two NSAIDs: Simultaneo us use of 2 di fferent NSAIDs may lead to an increased risk of NSAID toxicity. However, such therapy may provide add itional clinical response. As alread y noted a night-time dose of indomethacin or naproxen may help to prevent morn ing stiffness. Indomethacin added to a therapeutic dose of tolmetin or a salicylate may lead to significant improvement of the fever and joint symptoms in systemic J RA. Perioperative Treatment: NSAIDs may be stopped 3 to 4 days prior to surgery if the operation is expected to be associated with significant bleeding. Bleeding time sho uld be checked before surgery to be certain that the antiplatelet effect of the NSAID has di ssipated. A short course of steroids can be used to control disease activ ity. Pat ients receiving chronic corticosteroid therapy (> 15 mg/ day for I week or 7.5 to ISmg for I month) should receive 30 mg/m 2 of intramu scula r hydrocortisone every 6 hours in the 24 hours immediately before surgery and intravenous hourly during the proced ure. Another dose sho uld be given I hour later in the recovery room. If the oral ro ute is contraindicated the patient sho uld receive the regular equivalent of parenteral prednisolone to prevent disease flaring. Methotrexate may be cont inued. Im m unosu ppressa nt-ind uced bon e ma rrow depression should be closely monitored postoperatively. Haemorr hagic diat hesis due to platelet inhibition is rarely a clinical problem. Therapeutic 'Bridge': Patients with severe JR A may not be able to wait for the beginn ing of the effect of a selected disease modifying agent. Intravenous methylpred nisolone pulses and oral prednisone are the most commonly used measures for

86 1

this period of time. In monoarticular disease an intra-articular injection with triamcinolone may be used.

11. Conclusions The recognitio n of JRA as a potentially disabling di sease and the acceptable safety profile of some of the disease mod ifying d rugs have led to more aggressive therapeutic intervent ion by rheumatologists. Although NSAIDs continue to be the first line of treatment , disease mod ifiers like methot rexate and sulfasalazine ha ve gained extensive popularity in recent years. Well defined lines of research are presently addressing the following areas: (a) development of a corticosteroid with less cushingoid side effects (possibly deflazacort); (b) development of a sulphonamide with fewer autoimmune side effects tha n sulfasalazine; (c) developmen t of a kidneyspari ng cyclosporin-Iike dr ug; and (d) protocols for com bination therapy with disease modifying agents (e.g. methot rexate plus hydro xychloroquin e). Some encouraging results ha ve been obtained with monoclona l antibodies directed against surface antigens expressed by different subsets of T cells, B cells and macrop hages in ad ults. The aim is to induce lysis limited to pathogenic cells. Uncontrolled studies have been done with anti-CD4 thera py in rheu matoid arthritis with init ial good results (Reiter ct al. 1991). Although biological therap y may be the most promising current line of research, it remains to be seen whether an y of these agents will becom e major therapeutic avenues in the future.

References Abramson S8. Weissman G . The mecha ni~m of act ion of non_ ste roidal ant inflammatory drugs. Arth ritis and Rheumatism 32: 1-8. 1989 Alarcon G. Schro henlohe r RE, Bartolucci AA. Ward J R, et a1. Supression of rheumatoid Factor production by methotrexate in patients wit h rheumatoid art hritis. Arthritis and Rheumatism 33: J J56-116 1, J990 Ansell BM. J uvenile chronic arthritis. Scandinav ian Joum al of Rheu malOlogy 66 (Supp1.): 47-50. 1987 Apon te J. Petrelli M. Histopathologic find ings in the liver of rheumatoid arthri tis pat;ent~ treated wilh long_term bolus metho trexa te. Arthri tis and Rheumat ism 31: 1457_J462. 1988

862

Bj ork man DJ. Ham mond EH . Lee RO . Clegg 00. Tol man KG . Hepat ic ultra struc ture after melholrl:~ale therap y for rheu-

matoid art hrit is. Arthritis and Rheu mal im ) 1: 1465-141 I. 1988 EJ. G iann ini EH, Barkley E. Gol d the rapy in Ihe management of juvenile rhe uma toid art hritis. Arth ritis an d Rheu ma tism 23: 404-4 11,1 980 Brewer EJ. Gian nini EH. Person DA. Early expe riences with aUTanofin in j uvenile rheu matoid arthritis. American Journal of Medicin e 75: 152-156. 198 3 Brewer EJ. Gianni ni EH. Kuzmina N. Alekscev L. Penicillamine and hydrox ychloroqu ine in the trea lmen t of severe juven ile rheumatoid art hrit is. New England Jou rnal of Med icine 3 14: 1269-76. 1986 Cassidy JT. Petty RE. Basic concepts of drug lherapy. In Cassidy JT & Pelly RE (Eds) TU lbook of pediatr ic rhe uma tology. 2nd ed .. Churchill Livingstone. 1990 Croo k AD. Furst DE. Helmers RA. Da yton CS. Floe rchingcr C. et al. Methotrexate does not-alter pulmonary function in patients with rheu mato id art hrit is Arth ri tis and Rheum atism 32: S6O. 1989 Da nao T. Ste inbru nner J. Medendorp S. Macken zie AH. Segal AM. Methot rexa te in ju ~eni le rheumatoid art hri tis, Arth ritis and Rheumatism 32: S28. 1989 Fink CWo Med ical treatmen t of ju ~e nile arth ritis. Cl inical Or' thoped ics and Related Research 259: 60-69. 1990 Fries J F. Miller S R. Spitz PW. Willia ms CA. Hube rt HB. et al. T oward s an epidem iology of gastropathy assoc iated wit h nonster oida l anti inflamma tory drug use, Gastroenterology 96 (Supp1.): 647-655. 1989 Fries J F. Singh G . Lenert L. Furst DE. Aspir in. hvdros yclorcQuine. and hepa tic enzyme abnorma lities with methotreU le in rheum ato id arth rit is. Arthritis an d Rheumat ism 33: 16111619. 1990 Furst DE. Kremer JM . Met hotrexat e in rheumat oid art hritis. Art hritis and Rheumat ism 3 1: 305-3 14. 1988 Gian nini EH. Brewer EJ. Methotrexate in the tre atme nt of recalcitra nt JRA . Result s of lhe double_blind . placebo (Pl con trolled. rando mized trial. Abstract. Art hritis an d Rheu mat ism 32: S82. 1989 G iann ini EH. Brewer EJ. Kuzmina N. Shai kov A. Wallin B.et al. Auranolin in the tre atm ent of j u ~eni le rheumat oid art hritis. Art hrit is and Rheum ati sm 33: 466-476. 1990 G iann ini EH. Brewer EJ. Person DA. Auranofin in the treat men t of juven ile rheumat oid anhritis. Journal of Pediat rics 102: 13S14 1. J98 3 G raham LD. Riv as-Cnaccn RF, Myones BL. Lack of he patetoxicity with chronic adm inistrat ion of methotr exate in ju ~enile rheu matoid arthritis, Arthritis an d Rheu matism 33: SI 44. 1990 G ub ncr R. August S. Gi nsberg V. Thera peutic su ppression of tisSue reaclivi ty. Effects of am ino pteri n in rheumat oid arthritis and psoriasis. American Journal of Medical Science 221: 176Ig4. 1951 Hine RJ. Everso n MP. Hardi n J M. Morgan SA. Alarcon GS. et at. Methotr exate therapy in rheumatoid arthritis patie nts dimin ishes lectin- indu ced mono nu clear cell pro liferat ion. Rheumatology Internat ional 10: 165-169. 1990 Hu S. Mitcho YI... Or onsky AL, Kerwar SS. St ud ies on the effect of met hotreute on macroph age function. Journa l of Rheumato logy 15: 206-209. 1988 Jacobs J. Sul phasalazine in the lreat ment of childhood arth ritis. A prelim inary repo rt. Pediatri c Research 27: "7 A. 1990 Kah an BD. Cyclosporin. New England Journal of Med icine 32 1: 112 5-1738. 1989 Kawakami A. Eguchi K. Migita K. Hid etc N. Orsubc T. er al. Inhibitory effects of gold sodium thiomalate on the prolifcration an d interferon-indu ced H LA-D R ex pression in human endotehat cells. Journa l of Rheumato logy 17: 430-4 35. 1990 Keirn D. Ragsda le C. Heilderberger K. Sullivan D, Hcpatic IiB~wer

Drugs 43 (6) 1992

brosis wit h the use of methotrecate for juve nile rheum atoid arth ritis. Journal of Rheumatology' 7: 846-848. 1990 Kremer J M. Oanvan J. Streck fuss A. Kamen B. Methotrexat e metabolism. Analysis in blood a nd liver of rheumatoid arthrit is patients, Association with hepatic folate deficiency an d format ion of polyglutamates. Arthri tis and Rheumatism 29: 832-835. 1986 Kremer JM. Kaye G. Electron microscopic anal)'sis of sequenlial liver biopsy samples from palient s with rheumatoid art hritis. Arthritis an d Rheu matism 32: 1202-12 13. 1989 Krem er J M. l.u RG. Tolma n KG . Liver histology in rheumatoid arth ritis patient s receivi ng long-term methotrexate therapy. Arthritis an d Rheu matism 32: 12 1- 127. 1989 Kvien T K. Hoveraat HM. Stands tad B. Azathio prine versus placebo in patients with ju venile rheumat oid arthrit is. Journa l of Rheu matology 13: 1I8· J23. 1986 Lang BA. Laxer RM, Murphy G. Silverman ED. Roifman C M. Tre atment of derm ato myositis with intrave nous gammaglobulin. American Journal of Medicine 91: 169-172. 199 1 Lill man BH. Carlson PL. Loose LD. Sanders KM. Effects of gold sodiu m thiomalate and tcr uda p sodium (C P6,2482-2) on a model of macro phage difcrenl iation USin8 HL..(,() cells. Arthritis and Rheum atism 33: 29·36. 1990 Madagan. T he treatmen t of acute rheu matism with salicin. Lancet I: 342-343. 1876 Morgan SL, Baggoll JE , Altz·Smi th M, Folate status of rhcumatoid art hritis patients rcre ivinglo ng·term. low do se met h", trexate therapy. Arthri tis and Rheumat ism 30: 1348-1356. 1987 Morga n S L. Baggot JE. Vaughin WHo Young PK. Austi n I V. et al. Th e effect of folic acid supplementation on the toxicity of low-dose methotr eu te in pat ients with rheumatoid arth ritis. Art hrit is and Rheu mat ism 33: 9- 18. 1990 Neshcr G . Moo re T. The in " jITO effects of methOieUte on peri. pheral blood monon uclear cells. Arthri tis and Rheumatism 33: 954_959. 1990 Nordstrom DM . West SG. Andersen PA. Sharp Puhe met h", trexaie therapy in rheumatoid art hritis. A co ntrolle d pros pect ive roen tgenographic st udy. Annals of Internal Med icine 107: 797-80 1. 1987 Nuernberg B. Koehnke R. Solsky M. Hoffman J . Furst D. Biliary eli mi nat ion of low-cose methotr exate in humans. Art hritisand Rheumat ism 33: 898-902. 1990 Olse n NJ. Calla han LF. Pincus T. Immunologic stud ies of rheumatoid an hrius patien ts treated with met hotrexa te. Art hritis and Rheu malism 30: 481-488. 1987 Olse n NJ . Murra y LM. Annproliferanve effects of merboerexare on peripheral blood mon onuclear cells. Arthritis and Rheu matism 32: 378-385. 1989 Ozdogan H, T urunc M. Deringol B. Yurdak ul S. Yacizi H. Sulphasajazm e in the treat men t of juvenile rheumatoid art hrilis. A prelim inary open trial. Journal of Rheumatology 13: 12412.5. 1986 Rau R. Karger T. Herbo rn G, Frenzel H_ Liver biop sy findings in patients with rheum atoid art hri tis undergoing long-te rm trea tment with methotrexa te. Journal of Rheuma tology 16: 489. 493. 1989 Reiter C. Kakavand B. Rieber EP. Schauee jorchner M. Riethmuller G . et al. T reatment of rheumatoi d arthritis with monoc lonal C04 an tibody M·Tl 5 1. Arthritis and Rheu matis m 34: 525-536. 1991 Rose CD. Eichen field AH. Gol dsmi th DP. Athreya BH. Safety and efmcaey of methotre xate the rapy in j uvenile rheuma toid art hri tis. Abstract. Arthr itis an d Rheumatism 32: S28. 1989 Rose C D. Pad man R. Wesdock KA. Singsen BH. Methotrexate safety in j uvenile rheumatoid arthritis URAl. Arthri tis and Rheumati sm 33: S95. 1990b Rose CD. Singsen BH. Eiehen fleld AH. Goldsm ith DP. Athreya BH. Sa fety and efficacy of met hotre xate thera py in juv enile rheum atoi d arthritis Jou rnal of Pediatrics 11 7: 653-659. 1990a

n.

Management of Juvenile Rheum ato id Arthritis

Rosenberg AM, Advanced drug therapy for j uvenile rheumatoid art hrit is. Jo urnal of Pediat rics 114: 171_178. 1989 & haller JG . Juvenile Rheumatoid Arthritis. & ries I. Arthritis and Rheumat ism 10 (SuppL 1): 165-170. 1917 Segal R. Cas pi D. Tishler M. Vigler J. Yaron M. Short rerrn effects of low dose methotrexate on the acute phase reaction in patients with rheumatoid arthritis, Journa l of Rheumatology 16: 9 14917. 1989 Segal R. Mozes E. Yaron M. Tartakovsky B. The effects of melhotrexatc on the produ Ction and ad ivity of interleukin-l. Arthritis and Rheumatism 31; 370-377. 1989 Segal R. Varon M. Tartako vsky B. Rescue of inlerleukin-I activity by leuco vorin following inhibition by met hotrexate in a murine in vnro system. Arthritis and Rheumatism 33: 1745-174g. 1990 Skeith KJ. Russell AS. Fakkreddi n J. Cootes J. Friedman H. Lack of significant interac lion belween low dose methotrexate and ibuprofen or nurbi profen in patients with art hritis. Journal of Rheumat ology 17; 1008-1011. 1990 Sparling M. Matteson P. Wood B. fe lly R. Radiogr aphic follow up of joints injected with triam cinolone hexacctonide for the managem ent of childhood art hritis. Arthri tis and Rheumatism 33: 811-826. t990 Sperling RI. Coblyn JS. Larkin J K. senrncaso AI. Austen FK. et at. Inhibition of leukotriene B4 synthesis in neutro phils from palients ",ith rheumato id arthritis by a single oral dose of m ethotre ~ ate. Arthritis and Rheumatism 33: 1149-1155. 1990 Stewart KA. Mackenzie AH. Clough JD . Wilke WS. Folale supplementat ion in merhot rexate-rreared rheumaloid arthritis patients. Semina rs in Arthritis and Rheumatism 10: ]. 7. 199 1. Suarez SM. Cohen PRoDelco V. Bullous photosensitivity to napro~e n: ·pseudoporphyria'. Arthritis and Rheu matis m 33: 903908. 1990 Taneja V. Mehra N. Singh YN. Kumar A. Malaviya A. et al. HLA-D region genes and susceptib ility to d-penicillarmne in· duced myositis. CorreSlX'ndence. Arthr itis and Rheumatism 33: 1445-1446. 1990 Truckenbrodt H. Hafner R. Meth otrexate t hera py in ju venile

863

rheum atoid arthri tis, Arthritis and Rheumatism 29: 80 1·807. 1986 T ugwell P. Bennet K. Ge m M. Methotrexate in rheuma toid arthritis. Indications. oontra indications. efficacyand safet y. Annals of Internal Medicine 107: 358-366. 1987 van Kerckhove C. G iann ini EH. Lovell DJ. Temporal patter ns of respon se to d-penieillamine. hyd ro~ychloroq ui ne and placebo in j uvenile rheumatoid arthritis. Arthritis and Rheumatism 31: 1251-1257. 1988 Wallace CA, BIeyer WA. Sherry DD. Salmonson KL. Wedgwood RJ . Toxicity and seru m levels of me t h otre ~a te in children with juvenile rheuma toid arth ritis. Arthritis and Rheumatism 32: 617-681. 1989 Ward JR . Williams HJ . Egger MG. Reading JC, Boyce E. et at. Compa rison of auranofin. gold sodium th iomalate and placebo in the treatm ent of rheumatoid arthritis: a conlrolled clinical trial. Arthritis and Rheumat ism 16: 1303-1315. 1983 w einblan ME. Coblyn JS. Fox DA. Frase PA. Holdsworth DE, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. New England Jo urnal of Medicine 3 12: 818-822. 1985 Weinblall ME. Fraser P. Elevat ed mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis and Rheumat ism 32: 1592.1596. 1989 Wenger ME. Alexander S. Bland J H. Blechman WJ . Auranofin vs placebo in the treatment of rheumat oid arthritis. American Jo urnal of Medicine 75 (Suppl.): 113-127. 1983 While C. Reversal of methotrexate binding to dihydro folate reductase by dihydrofolate. Jou rnal of Biological Chemistry 254: 10 889-10895. 1979 Willia ms Hj . Willkens RF. Samuelson CO. Alarcon GS. G uttad· uria M. Comparison of low-dose oral pulse methotrexate and placebo in the treat ment of rheumatoid arthritis. Arthritis and Rheumatism 28: 72 1. 730.1 985 Wilske KR. Healey LA. Remodeling the pyramid. A concept whose time has come. Journal of Rheuma tology 16: 565-567. 1989 CorreslX'ndence and reprinlS: Dr Carlos D. Rose. Division of Rheumatology. Alfred l. du Pont lnstitute . 1600 Rockland Rood. Wilmington, DE 19899. USA.