Rheumatoid Arthritis:Emerging Treatments

March 2, 2006

Rheumatoid arthritis (RA) affects 1% ofadults during their most productiveyears and can result in significant disability.The goals of therapy are to reducepain, limit joint destruction, andpreserve function.

Rheumatoid arthritis (RA) affects 1% ofadults during their most productiveyears and can result in significant disability.The goals of therapy are to reducepain, limit joint destruction, andpreserve function.

In recent years, the armamentariumof agents that combat RA has greatlyexpanded. New biologic therapiesthat specifically target the immune responseare now available. Although disease-modifying antirheumatic drugs(DMARDs) such as methotrexate remainthe standard of care, these neweragents can be added to the regimenwhen monotherapy fails.

In this article, I offer generalguidelines for selecting the safest andmost effective regimens for your patientswith RA. I also describe how tomake best use of the newer therapies.

OVERVIEWEpidemiology.Women are affectedby RA about 3 times as often asmen. The presence of estrogen receptorson synovial cells and T cells suggestsan important hormonal relationship.Estrogens influence both T-cellsurvival and cytokine production.1This relationship between estrogenand immune disease may explain theincreased prevalence of RA in women.

RA appears to be geneticallylinked, with higher concordance inmonozygotic than dizygotic twins.2One genotype of HLA-DRB chains appearsto be a marker for RA.3 Approximately10% of patients with RA have anaffected first-degree relative.

Pathophysiology. RA is characterizedby synovial inflammation andprogressive erosion of cartilage andbone. The process begins with the activationof T cells, which results in proliferationof synovial cells, activation ofproinflammatory cells from the bonemarrow, and secretion of cytokines (includinginterleukin [IL]-1 and tumornecrosis factor α [TNF-α]) by macrophagesand fibroblast-like synovialcells.4 Many therapies for RA-includingcorticosteroids and TNF and IL-1antagonists-directly inhibit proinflammatorycytokine activities.

Disease progression. Symptomsof RA typically develop between thethird and sixth decades of life. Significantjoint abnormality and disabilityoccur within the first few years of disease.5,6 Eighty-three percent of patientswith RA experience joint-space narrowing,and 67% have joint erosions with-in the first 2 years (Figure).2 After 5years, joint erosions can be seen radiographicallyin 73% of patients.7 After 18years, all patients have joint-space narrowing,97% have joint erosions, and41% have malalignment.7

Economic impact. Patients withRA begin to incur significant costsearly in the course of illness. A study ofpatients with newly diagnosed activeRA that evaluated costs during the first6 months of illness showed that medicalcosts averaged $200 a month.8,9 Patientslost an average of 3.8 workdaysmonthly, at an indirect cost of $281.10Eighteen percent became work-disabledduring the first 6 months of illness.Work disability increased toabout 60% after 10 years of illness.10

 Table 1 –American College of Rheumatology classification criteria for acute rheumatoid arthritis*
Morning stiffness of joints lasting ≥ 1 h Soft tissue swelling or fluid at 3 or more joints Swelling or fluid in hand joints Simultaneous arthritic changes in symmetric joints Subcutaneous nodules Positive serum rheumatoid factor Joint erosions or decalcification on radiographs 

*A positive diagnosis requires 4 of the above criteria. Criteria 1 - 4 must be present for at least 6 weeks. Adapted from Arnett FC et al. Arthritis Rheum. 1988.

INITIAL EVALUATIONThe American College of Rheumatology(ACR) classification criteria (Table1) can help guide clinical diagnosis.11Laboratory testing is also useful in diagnosis,as well as in assessing prognosisand in monitoring the response to therapy.Rheumatoid factor-autoantibodiesfound in most patients with RA-mayalso be present in other rheumatologicconditions (eg, lupus erythematosus andSjgren syndrome) and infectious illnesses(eg, malaria and rubella). A highrheumatoid factor titer in patients withRA is associated with more aggressivedisease, greater joint destruction, andgreater functional disability.12,13 The Creactiveprotein (CRP) level and erythrocytesedimentation rate (ESR) are markersof the acute phase response. Elevationsin CRP level and ESR also correlatewith bone destruction.14

Evaluation includes an assessmentof comorbid illness and lifestylefactors that may aggravate RA (Algorithm).Frequently associated comorbidconditions that may be exacerbatedby either the pathophysiologicmechanisms that underlie RA or by itstreatment include infection, renal insufficiency,cardiovascular disease,chronic pulmonary disease, pepticulcer disease, and lymphoproliferativedisease.15,16 Psychological distress alsoincreases disability associated with RA;symptoms of anxiety, depression, andhopelessness need to be identified andtreated.17-19

Cigarette smoking is associatedwith an increased risk of RA. Longerduration of smoking is linked togreater risk, and heavier use is associatedwith more serious symptoms andbony erosions.20-22 Obesity is also a riskfactor, since adipose tissue releasesproinflammatory substances, includingIL-6, TNF-α, and CRP.23

 Table 2 –Key components of rheumatoid arthritis management
Periodic reassessment to monitor for active disease 

Patient education 

Medication 

Adapted from Goroll AH et al, eds. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 2000.

DISEASEMANAGEMENTTreatment involves a combinationof patient education, physical and occupationaltherapies, consultations with arheumatologist, and medical management(Table 2). Because the standardof care is moving from a more conservativeto a more aggressive approachthat involves early use of DMARDs, referralto a rheumatologist is recommendedat initial diagnosis. Followingthe initial rheumatology consultation,both the primary care provider andrheumatologist should be actively involvedin disease management. In general,consult a rheumatologist whenpatients present with persistent joint inflammation,require more intensivetherapy, or manifest one or more ofthe following indicators of poor prognosis:genotype HLA-DRB1 *04/04,high serum titer of rheumatoid factor,extra-articular manifestations, a largenumber of involved joints, age lessthan 30 years, female sex, or systemicsymptoms.24

Regularly monitor patients withevidence of active disease, such asjoint inflammation, stiffness, and fatigue.Patients require periodic measurementof serum inflammatorymarkers (eg, ESR or CRP) and radiographs.Functional assessments mayalso be performed with the ArthritisImpact Measurement Scales25 or theHealth Assessment Questionnaire.26The latter is a good predictor of longtermmortality.27 Patients in remission,as defined by the ACR criteria (Table3), may be seen every 6 months.28 Allpatients need to be followed indefinitelyfor disease flares, progression, andcomorbid illness.

Medications include both symptomaticanalgesics and DMARDs.Early, aggressive management of RAand consistent use of DMARDs mayresult in reduced long-term disability.29,30 NSAIDs and corticosteroidshave no effect on disability. Unfortunately,drug therapy does not reducethe higher mortality seen in patientswith RA.31

 Table 3 – American College of Rheumatology clinical definition of remission
Complete remission is defined as the absence of: Symptoms of active inflammatory joint pain Morning stiffness Fatigue Synovitis on joint examination Progression of radiographic damage on sequential radiographs Elevated ESR or CRP level 

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. Adapted from American College of Rheumatology. Arthritis Rheum. 1996.

PHARMACOTHERAPYThe goals of pharmacotherapyare to reduce joint destruction and inflammationand limit disease progressionsive initial treatment of all patientswith active RA is essential becausejoint destruction begins early in thecourse of the disease. Clinical andserologic activity has been linked toincreasing morbidity, loss of function,and mortality. Therefore, rapid controltranslates into better long-term outcomes,particularly in patients with alarge number of affected joints, earlyloss of function, and elevated inflammatorymarkers. Although combinationtherapy, new biologics, and mon-itoringcosts are more costly than traditionalmodalities, the higher costmust be weighed against the longtermexpense of poorly controlled RA,which often necessitates arthroplastyand hospitalization.32

Therapy is generally initiated withan NSAID and a DMARD. If patients failto respond, consider adding a secondDMARD or a low-dose oral glucocorticoid(10 mg or less of prednisone daily).When remission occurs, NSAIDs andglucocorticoids may be discontinued.DMARDs, however, are continued forthe long term. Treat RA flares with theaddition (or increased dosage) of oralglucocorticoids. Change to anotherDMARD may also be considered. RAflares that involve only a small numberof joints may also be treated with intraarticularglucocorticoids.

NSAIDs. Although effective forpain relief and reduction of inflammation,these agents do not prevent jointdestruction. They are used only as adjunctivetherapy for patients with activeRA. Long-term use of high doses ofNSAIDs may result in significantorgan toxicity. This risk is increasedwhen patients use combinations ofanalgesics.33 Commonly prescribedNSAIDs include aspirin, celecoxib, androfecoxib.

DMARDs. These agents reduceor prevent joint destruction and subsequentdisability.34 They include hydroxychloroquine,sulfasalazine, methotrexate,gold, and D-penicillamine. Allpatients with active RA, even thosewho have achieved adequate analgesicrelief from NSAIDs, are candidates forDMARD therapy.

Rheumatoid factor-negative patientswith mild disease may use hydroxychloroquineor sulfasalazine.35 Inpatients with severe RA, therapy is initiatedwith methotrexate. Patients who donot achieve an adequate response withmethotrexate may use a combination ofDMARDs or alternative DMARDs,such as gold, which are usually prescribedby a consulting rheumatologist.Periodic monitoring is recommendedfor most RA therapies (Table 4).

 Table 4 -Monitoring rheumatoid arthritis medications
Medication Adverse effectsLaboratory tests

NSAIDs GI distress, dizziness, bruising, bloody stoolsCBC count, liver functions, creatine

D-Penicillamine RashCBC count, platelets, urine for protein

Hydroxychloroquine Skin reaction, visual disturbance, GI distressPeriodic ophthalmologic examinations

Sulfasalazine Infection, bruising, bleeding, swelling, diarrheaCBC count

Methotrexate Elevated blood pressure, polyuria/polydipsia, swelling, shortness of breath, weight gain, visual disturbanceCBC count, platelets, liver functions, creatine, albumin

Gold Infection, bruising, bleeding, swelling, diarrheaCBC count, platelets, urine for protein

Glucocorticoids Elevated blood pressure, polyuria/polydipsia, swelling, shortness of breath, weight gain, visual disturbanceUrine for glucose

Leflunomide AlopeciaCBC count, liver functions

Etanercept InfectionUpdate vaccines before initiating therapy

Infliximab InfectionTB test before initiation of therapy

Anakinra Injection site reactionNeutrophil count

CBC, complete blood cell; TB, tuberculosis.

In the Early RA Study, patientsundergoing DMARD therapy were followedfor 5 years.35 Initially, 9% reportedmarked functional loss and 33% hadnormal functioning. During the studyperiod, 84% required the addition ofsecond-line DMARD therapy, 10% requireda wheelchair or home adjustment,17% underwent orthopedic surgery,and 8% had a major joint replacement.The study concluded that about16% of patients treated with conventionaldrug therapy function poorlyafter 5 years of treatment, 40% functionnormally, and the remaining patientsrange in function between marked disabilityand normal.

 Table 5 - A guide to disease activity in RA: American College of Rheumatology (ACR) criteria
Classification Extent of response

ACR 20 20%*

ACR 50 50%

ACR 70 70%

RA, rheumatoid arthritis. *An ACR 20 response is a reduction of at least 20% in the number of tender and swollen joints plus an improvement of at least 20% in 3 or more of these 5 criteria:

TARGETED NEWBIOLOGIC THERAPIESNew therapies are typically usedin conjunction with methotrexate forpatients who fail to achieve adequatebenefit from this agent alone or in patientswho have been inadequatelyhelped by or cannot tolerate otherDMARDs. The most effective newtreatments are a class of biologics thatinclude TNF-α antagonist therapies.36Response to treatment is rated usingACR criteria (Table 5). Overall, thesemedications are well tolerated. However,as with all immunosuppressive therapies,there is a theoretical increasedrisk of lymphoproliferative disease.

TNF-α antagonist therapy. Etanercept,one of 2 recently introduced agents,is a soluble receptor protein that binds tocirculating TNF-α. It is effective whetherused alone (25 mg SC twice weekly) orin combination with methotrexate.36,37According to the package labeling, morethan 60% of patients treated with etanerceptachieved an ACR 20 response, and40% achieved an ACR 50 response. Therespective rates among placebo recipientswere 23% and 5%.

Etanercept is well tolerated; localinjection-site reaction is the most commonside effect. In postmarketing reports,however, a small number of se-rious adverse events have been noted,including infections, sepsis, and death.The package insert carries a strongcaution on the use of etanercept in patientswith a history of recurring infectionsor with underlying conditionsthat may predispose to infection, suchas advanced or poorly controlled diabetes.Other adverse reactions includepyelonephritis and osteomyelitis.

Infliximab is a chimeric monoclonalantibody that binds circulatingTNF-α. In a study of patients whofailed to achieve an adequate responsewith methotrexate, the additionof infliximab (3 to 10 mg/kg IVevery 4 to 8 weeks) resulted in anACR 20 response in 50% of the treatedpatients (compared with 20% inthe placebo group), and an ACR 50response in 27% (vs 5% in the placebogroup).38 Some studies showed thatneutralizing antibodies develop in40% of patients using infliximabalone.39 Antibody production is reducedby combining infliximab withmethotrexate.40

The most common side effects ofinfliximab are GI distress and fatigue.However, as with etanercept, a smallnumber of serious infections havebeen reported; use caution in prescribingthis agent to patients who havechronic infection or a history of recurringinfections.40 Although the numberof cases of infection is small, tuberculosisand other opportunistic infectionshave been observed in patients takinginfliximab. Before beginning treatment,patients must be tested for tuberculosisif they are at significant riskfor exposure.

Pyrimidine synthesis inhibition.Pyrimidine is required for mitogeninducedproliferation of T cells, and inhibitionof pyrimidine synthesis is animportant step in RA. Leflunomide is areversible inhibitor of de novo pyrimidinesynthesis, with active metabolitesthat inhibit the rate-limiting step inpyrimidine synthesis and also inhibitIL-1 and TNF-α.41 Response to leflunomide,20 mg PO daily, is similar to thatachieved with methotrexate, 7.5 to15 mg weekly.

In one study, an ACR 20 responsewas seen in 52% of patients takingleflunomide, compared with 46% of patientstaking methotrexate and 26% ofpatients taking placebo.42 An ACR 50response was seen in 34% of theleflunomide group, compared with 23%of the methotrexate patients and 26%of the placebo group. Leflunomide isalso effective in combination withmethotrexate.43 Leflunomide may beassociated with elevated liver enzymelevels; regular monitoring is thus required,especially when this agent isused in combination with methotrexate.The most common side effects associatedwith leflunomide are diarrheaand alopecia, which occur in a minorityof patients.

IL-1 agonist therapy. The newlyapproved agent anakinra is an exogenousrecombinant human IL-1 receptorantagonist that augments diminishedlevels of naturally occurringIL-1Ra, as a counterbalance to thedetrimental effects of the diseaseheightenedactivity of IL-1 in bone resorption,erosion, and joint cartilagedestruction. Anakinra binds to IL-1receptors, thus preventing receptoractivation.

In one study, 43% of patientstreated with anakinra, 150 mg SC,had an ACR 20 response, comparedwith 27% of placebo-treated patients.44Anakinra-treated patients also experienceda 41% reduction in radiographicbone destruction over 24 weeks,compared with the placebo group.Anakinra is well tolerated; injectionsitereaction is the most common sideeffect.

The package labeling states thatanakinra is associated with an increasedincidence of serious infection.Treatment should be discontinued ifa serious infection develops. Assessmentsof neutrophil counts should bemade before treatment initiation,monthly for the first 3 months of treatment,and annually thereafter.

TNF-α and IL-1 function independentlyin the pathogenesis of RA.45However, the combination of anakinraand TNF receptor type I in rodents re-sults in synergistic inhibition of inflammation.46 These data suggest the needfor research in human clinical trials toevaluate the clinical effects of combinationtherapy. Because preliminarydata in humans treated with a combinationof anakinra and a TNF blockingagent indicate a high rate of serious infection,combination therapy is not recommendedat this time.

References:

REFERENCES:


1.

Cutolo M, Sulli A, Seriolo B, et al. Estrogens, theimmune response and autoimmunity. Clin ExpRheumatol. 1995;13:217-226.

2.

MacGregor AJ, Snieder H, Rigby AS, et al. Characterizingthe quantitative genetic contribution torheumatoid arthritis using data from twins. ArthritisRheum. 2000;43:30-37.

3.

Nepom GT, Nepom BS. Prediction of susceptibilityto rheumatoid arthritis by human leukocyte antigengenotyping. Rheum Dis Clin North Am. 1992;18:785-792.

4.

Feldmann M, Maini RN. The role of cytokines inthe pathogenesis of rheumatoid arthritis. Rheumatology(Oxford). 1999;38(suppl 2):3-7.

5.

Sherrer YS, Bloch DA, Mitchell DM, et al. Thedevelopment of disability in rheumatoid arthritis.Arthritis Rheum. 1986;29:494-500.

6.

Fuchs HA, Kaye JJ, Callahan LF, et al. Evidenceof significant radiographic damage in rheumatoidarthritis within the first 2 years of disease. J Rheumatol.1989;16:585-591.

7.

Pincus T, Fuchs HA, Callahan LF, et al. Earlyradiographic joint space narrowing and erosionand later malalignment in rheumatoid arthritis: alongitudinal analysis. J Rheumatol. 1998;25:636-640.

8.

Lanes SF, Lanza LL, Radensky PW, et al. Resourceutilization and cost of care for rheumatoidarthritis and osteoarthritis in a managed care setting:the importance of drug and surgery costs.Arthritis Rheum. 1997;40:1475-1481.

9.

Newhall-Perry K, Law NJ, Ramos B, et al, for theWestern Consortium of Practicing Rheumatologists.Direct and indirect costs associated with the onsetof seropositive rheumatoid arthritis. J Rheumatol.2000;27:1156-1163.

10.

Pincus T, Callahan LF. What is the naturalhistory of rheumatoid arthritis? Rheum Dis ClinNorth Am. 1993;19:123-151.

11.

Arnett FC, Edworthy SM, Bloch DA, et al. TheAmerican Rheumatism Association 1987 revisedcriteria for the classification of rheumatoid arthritis.Arthritis Rheum. 1988;31:315-324.

12.

van Zeben D, Hazes JM, Zwinderman AH, et al.Clinical significance of rheumatoid factors in earlyrheumatoid arthritis: results of a follow-up study.Ann Rheum Dis. 1992;51:1029-1035.

13.

van Leeuwen MA, Westra J, van Riel PL, et al.IgM, IgA, and IgG rheumatoid factors in earlyrheumatoid arthritis predictive of radiologicalprogression? Scand J Rheumatol. 1995;24:146-153.

14.

Amos RS, Constable TJ, Crockson RA, et al.Rheumatoid arthritis: relation of serum C-reactiveprotein and erythrocyte sedimentation rates to radiographicchanges. Br Med J. 1977;1:195-197.

15.

Baecklund E, Ekbom A, Sparen P, et al.Disease activity and risk of lymphoma in patientswith rheumatoid arthritis: nested case-control study.BMJ. 1998;317:180-181.

16.

Gabriel SE, Crowson CS, O’Fallon WM. Comorbidityin arthritis. J Rheumatol. 1999;26:2475-2479.

17.

Covic T, Adamson B, Hough M. The impactof passive coping on rheumatoid arthritis pain.Rheumatology (Oxford). 2000;39:1027-1030.

18.

Smarr KL, Parker JC, Kosciulek JF, et al. Implicationsof depression in rheumatoid arthritis: do subtypesreally matter? Arthritis Care Res. 2000;13:23-32.

19.

Strahl C, Kleinknecht RA, Dinnel DL. The roleof pain anxiety, coping, and pain self-efficacy inrheumatoid arthritis patient functioning. BehavRes Ther. 2000;38:863-873.

20.

Silman AJ, Newman J, MacGregor AJ. Cigarettesmoking increases the risk of rheumatoid arthritis:results from a nationwide study of disease-discordanttwins. Arthritis Rheum. 1996;39:732-735.

21.

Saag KG, Cerhan JR, Kolluri S, et al. Cigarettesmoking and rheumatoid arthritis severity. AnnRheum Dis. 1997;56:463-469.

22.

Karlson EW, Lee IM, Cook NR, et al. A retrospectivecohort study of cigarette smoking and riskof rheumatoid arthritis in female health professionals.Arthritis Rheum. 1999;42:910-917.

23.

Bastard JP, Jardel C, Bruckert E, et al. Elevatedlevels of interleukin 6 are reduced in serum and subcutaneousadipose tissue of obese women after weightloss. J Clin Endocrinol Metab. 2000;85:3338-3342.

24.

Goroll AH, May LA, Mulley AG Jr, eds. PrimaryCare Medicine: Office Evaluation and Management ofthe Adult Patient. Philadelphia: Lippincott Williams &Wilkins; 2000.

25.

Meenan RF, Gertman PM, Mason JH. Measuringhealth status in arthritis. Arthritis Rheum.1980;23:146-152.

26.

Fries JF, Spitz P, Kraines RG, et al. Measurementof patient outcome in arthritis. ArthritisRheum. 1980;23:137-145.

27.

Leigh JP, Fries JF. Mortality predictors among263 patients with rheumatoid arthritis. J Rheumatol.1991;18:1307-1312.

28.

American College of Rheumatology Ad HocCommittee on Clinical Guidelines. Guidelines forthe management of rheumatoid arthritis. ArthritisRheum. 1996;39:713-722.

29.

van der Heide A, Jacobs JW, Bijlsma JW, et al.The effectiveness of early treatment with “secondline”antirheumatic drugs: a randomized, controlledtrial. Ann Intern Med. 1996;124:699-707.

30.

Fries JF, Williams CA, Morfeld D, et al. Reductionin long-term disability in patients with rheumatoidarthritis by disease-modifying antirheumaticdrug-based treatment strategies. Arthritis Rheum.1996;39:616-622.

31.

Gabriel SE, Crowson CS, O’Fallon WM. Mortalityin rheumatoid arthritis: have we made an impactin 4 decades? J Rheumatol. 1999;26:2529-2533.

32.

March L, Lapsley H. What are the costs to societyand the potential benefits from the effectivemanagement of early rheumatoid arthritis? BaillieresBest Pract Res Clin Rheumatol. 2001;15:171-185.

33.

Bach PH, Berndt WO, Delzell E, et al. A safetyassessment of fixed combinations of acetaminophenand acetylsalicylic acid, coformulated with caffeine.Ren Fail. 1998;20:749-762.

34.

Emery P. Therapeutic approaches for earlyrheumatoid arthritis. How early? How aggressive?Br J Rheumatol. 1995;34(suppl 2):87-90.

35.

Young A, Dixey J, Cox N, et al. How does functionaldisability in early rheumatoid arthritis (RA)affect patients and their lives? Results of 5 years offollow-up in 732 patients from the Early RA Study(ERAS). Rheumatology (Oxford). 2000;39:603-611.

36.

Moreland LW, Baumgartner SW, Schiff MH, etal. Treatment of rheumatoid arthritis with a recombinanthuman tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337:141-147.

37.

Weinblatt ME, Kremer JM, Bankhurst AD, etal. A trial of etanercept, a recombinant tumor necrosisfactor receptor:Fc fusion protein, in patients withrheumatoid arthritis receiving methotrexate. N EnglJ Med. 1999;340:253-259.

38.

Maini R, St Clair EW, Breedveld F, et al, for theATTRACT Study Group. Infliximab (chimeric antitumournecrosis factor alpha monoclonal antibody)versus placebo in rheumatoid arthritis patients receivingconcomitant methotrexate: a randomisedphase III trial. Lancet. 1999;354:1932-1939.

39.

Elliott MJ, Maini RN, Feldmann M, et al. Repeatedtherapy with monoclonal antibody to tumornecrosis factor alpha (cA2) in patients with rheumatoidarthritis. Lancet. 1994;344:1125-1127.

40.

Gershon S, Wise R, Niu M, Siegel J. Postlicensurereports of infections during use of etanerceptand infliximab. Presented at: American College ofRheumatology National Scientific Meetings;Philadelphia; 2000.

41.

Breedveld FC, Dayer JM. Leflunomide: modeof action in the treatment of rheumatoid arthritis.Ann Rheum Dis. 2000;59:841-849.

42.

Strand V, Cohen S, Schiff M, et al, for theLeflunomide Rheumatoid Arthritis InvestigatorsGroup. Treatment of active rheumatoid arthritiswith leflunomide compared with placebo and methotrexate.Arch Intern Med. 1999;159:2542-2550.

43.

Weinblatt ME, Kremer JM, Coblyn JS, et al.Pharmacokinetics, safety, and efficacy of combinationtreatment with methotrexate and leflunomidein patients with active rheumatoid arthritis. ArthritisRheum. 1999;42:1322-1328.

44.

Bresnihan B, Alvaro-Gracia JM, Cobby M, et al.Treatment of rheumatoid arthritis with recombinanthuman interleukin-1 receptor antagonist. ArthritisRheum. 1998;41:2196-2204.

45.

van den Berg WB, Joosten LA, Kollias G, vanDe Loo FA. Role of tumour necrosis factor alpha inexperimental arthritis: separate activity of interleukin1 beta in chronicity and cartilage destruction.Ann Rheum Dis. 1999;58(suppl 1):I40-I48.

46.

Bendele AM, Chlipala ES, Scherrer J, et al.Combination benefit of treatment with the cytokineinhibitors interleukin-1 receptor antagonist andPEGylated soluble tumor necrosis factor receptortype I in animal models of rheumatoid arthritis.Arthritis Rheum. 2000;43:2648-2659.

47.

Bathon JM, Martin RW, Fleischmann RM, et al.A comparison of etanercept and methotrexate in patientswith early rheumatoid arthritis. N Engl J Med.2000;343:1586-1593.

FOR MORE INFORMATION:

  • Kremer JM. Rational use of new and existingdisease-modifying agents in rheumatoid arthritis.Ann Intern Med. 2001;134:695-706.

Updated information about RA may be obtainedon several Web sites: