Rheumatoid Arthritis:Emerging Treatments

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

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

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

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).

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.

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.

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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:

• www.hopkins-arthritis.som.jhmi.eduExcellent information about RA diagnosis,pathophysiology, and treatment options.

• www.rheumatology.orgAmerican College of Rheumatology Web site,which includes a search feature to find a localrheumatologist.
• http://my.webmd.com/condition_center/rhaWebMD provides good general information about RA.
• http://www.nih.gov/niams/healthinfo/juvarthr.htmComprehensive information on juvenile RA.