rheumatoid arthritis

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eMedicine Specialties > Rheumatology > Rheumatoid Arthritis

Howard R Smith, MD, Adjunct Professor of Medicine, Case Western Reserve University; Chief of Rheumatology, Director of The Herbert BellPain Management Center, Director of Research, Cleveland Clinic, Huron Hospital

Updated: Sep 22, 2010

Introduction

Background

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause thatprimarily affects the peripheral joints in a symmetric pattern. Constitutional symptoms, includingfatigue, malaise, and morning stiffness, are common. Extra-articular involvement of organs suchas the skin, heart, lungs, and eyes can be significant. RA causes joint destruction and thus oftenleads to considerable morbidity and mortality. With the recent addition of new and innovativetherapies, the treatment of RA is rapidly advancing.

For supplementary information, see Medscape’s Rheumatoid Arthritis Resource Center.

Pathophysiology

RA has no known cause. Although an infectious etiology has been speculated (eg, Mycoplasmaorganisms, Epstein-Barr virus, parvovirus, rubella), no organism has been proven responsible. RAis associated with numerous autoimmune responses, but whether autoimmunity is a secondary orprimary event is still unknown.

RA has a significant genetic component, and the shared epitope of the HLA-DR4/DR1 cluster ispresent in up to 90% of patients with RA, although it is also present in more than 40% of controls.Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic processthat progresses to uncontrolled inflammation and consequent cartilage and bone destruction.Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellularroles in the pathophysiology of RA, while B lymphocytes produce autoantibodies (ie, rheumatoidfactors [RFs]). Abnormal production of numerous cytokines, chemokines, and other inflammatorymediators (eg, tumor necrosis factor alpha [TNF-alpha], interleukin (IL)–1, IL-6, transforminggrowth factor beta, IL-8, fibroblast growth factor, platelet-derived growth factor) has beendemonstrated in patients with RA. Ultimately, inflammation and exuberant proliferation of synovium(ie, pannus) leads to destruction of various tissues, including cartilage, bone, tendons, ligaments,and blood vessels. Although the articular structures are the primary sites involved by RA, othertissues are also affected.

Frequency

International

Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and theprevalence rate is approximately 1%. RA affects all populations, although the disease is muchmore prevalent in some groups (eg, 5-6% in some Native American groups) and much lessprevalent in others (eg, black persons from the Caribbean region). First-degree relatives ofindividuals with RA are at an increased risk (2- to 3-fold) of the disease. Disease concordance inmonozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important

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role. Because the worldwide frequency of RA is relatively constant, a ubiquitous infectious agenthas been postulated to play an etiologic role.

Mortality/Morbidity

RA does not usually follow a benign course. It is associated with significant morbidity, disability,and mortality.

Daily living activities are impaired in most individuals with RA. Spontaneous clinical remissionis uncommon (approximately 5-10%). After 5 years of disease, approximately 33% of patientsare unable to work; after 10 years, approximately half have substantial functional disability.Poor prognostic factors include persistent synovitis, early erosive disease, extra-articularfindings (including subcutaneous rheumatoid nodules), positive serum RF findings, familyhistory of RA, male sex, and advanced age.

Life expectancy in patients with RA is shortened by 5-10 years, although the mortality ratemay be lower in those who respond to therapy. Increased mortality rates are associated withpoor functional status, age, male sex, socioeconomic factors (eg, level of education), positiveRF findings, extra-articular disease, elevated acute-phase response (erythrocytesedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity (eg, moreinvolved joints). Factors that increase the mortality risk include infections, cardiovasculardisease, renal disease, GI bleeding, and lymphoproliferative disorders; these events may bedirectly due to the disease and its complications (eg, vasculitis, amyloidosis) or to therapy-induced adverse effects.

A meta-analysis by Meune et al (2009) suggests that, despite data suggesting that thecourse of RA may have become milder over the past decades, the risk of cardiovasculardeath in patients with RA continues to be 60% higher than in the general population. Instudies including 91,916 patients with RA, the overall pooled standardized mortality ratio(SMR) was 1.6 (95% confidence interval, 1.5-1.8; I(2) = 93%; P (het) <0.0001).Meta-regression analyses revealed neither any trend in SMR over time (P = 0.784) nor anyrelation with disease duration at the time of inclusion (P = 0.513). Meune et al conclude thatreducing cardiovascular mortality should remain a major issue in RA management.[1 ]

Race

RA affects all ethnic groups, although the disease is much more prevalent in some groups (eg,5-6% in some Native American groups) and much less prevalent in others (eg, black persons fromthe Caribbean region).

Sex

RA is 2-3 times more common in females than in males.

Age

The frequency of RA increases with age and peaks in persons aged 35-50 years. Nevertheless,the disease is observed in both elderly persons and children.

Juvenile inflammatory arthritis (JIA) is classified as polyarticular (multiple joints),pauciarticular (<5 joints), or systemic. Systemic JIA is often associated with fever, rash, andorgan involvement; it is also called Still disease.

Polyarticular RF-positive arthritis in children generally follows a clinical course that is similar


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to adult RA.

For additional information on juvenile rheumatoid arthritis, see the article JuvenileRheumatoid Arthritis in eMedicine’s Pediatrics: General Medicine volume.

Clinical

History

The American College of Rheumatology developed the following criteria for the classification ofrheumatoid arthritis (RA).

Morning stiffness: This occurs in and around the joints and lasts at least 1 hour beforemaximal improvement.

1.

Arthritis of 3 or more joint areas: At least 3 joint areas simultaneously have soft-tissueswelling or fluid (not bony overgrowth) observed by a physician. The 14 possible areasinclude the right and left proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist,elbow, knee, ankle, and metatarsophalangeal (MTP) joints.

2.

Arthritis of hand joints: At least one area in a wrist, MCP, or PIP joint is swollen.3.Symmetric arthritis (simultaneous involvement of the same joint areas on both sides of thebody): Bilateral involvement of PIPs, MCPs, and MTPs is acceptable without absolutesymmetry.

4.

Rheumatoid nodules: Subcutaneous nodules are present over bony prominences orextensor surfaces or in juxta-articular regions.

5.

Serum RF: Abnormal amounts of serum RF are demonstrated by any method for which theresult has been positive in fewer than 5% of healthy control subjects.

6.

Radiographic changes typical of RA on posteroanterior hand and wrist radiographs, whichmust include erosions or unequivocal bony decalcification localized in or most markedadjacent to the involved joints: Osteoarthritic changes alone do not qualify.

7.

The presence of 4 criteria supports the diagnosis of RA. Criteria 1-4 must be present for at least 6weeks, and a physician must observe criteria 2-5. These criteria are intended as a guideline forclassification of patients, often for research purposes. They do not absolutely confirm or exclude adiagnosis of RA in a particular patient, especially in those with early arthritis.

Patients with RA often present with constitutional symptoms, including malaise, fever, fatigue,weight loss, and myalgias. They may report difficulty performing activities of daily living (eg,dressing, standing, walking, personal hygiene, using their hands).

Most patients with RA have an insidious onset. It may begin with systemic features, such as fever,malaise, arthralgias, and weakness, before the appearance of overt joint inflammation andswelling. A small percentage of patients with RA (approximately 10%) have an abrupt onset withthe acute development of synovitis and extra-articular manifestations. Spontaneous remission isuncommon, especially after the first 3-6 months.

Physical

Joint involvement is the characteristic feature of RA. In general, the small joints of the hands andfeet are affected in a relatively symmetric distribution. The most commonly affected joints, indecreasing frequency, include the MCP, wrist, PIP, knee, MTP, shoulder, ankle, cervical spine,hip, elbow, and temporomandibular joints. Joints show inflammation with swelling, tenderness,warmth, and decreased range of motion. Atrophy of the interosseous muscles of the hands is atypical early finding. Joint and tendon destruction may lead to deformities such as ulnar deviation,boutonnière and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis.


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Other commonly observed musculoskeletal manifestations include tenosynovitis and associatedtendon rupture due to tendon and ligament involvement, most commonly involving the fourth andfifth digital extensor tendons at the wrist; periarticular osteoporosis due to localized inflammation;generalized osteoporosis due to systemic chronic inflammation, immobilization-related changes, orcorticosteroid therapy; and carpal tunnel syndrome. Most patients with RA have muscle atrophyfrom disuse, which is often secondary to joint inflammation.

Effect of RA on organs and organ systemsCutaneous: Subcutaneous nodules (rheumatoid nodules) develop in many patientswith RA whose RF value is abnormal, often over pressure points (eg, olecranon).Vasculitic lesions of the skin may manifest as palpable purpura or skin ulceration.

Cardiac: Cardiovascular morbidity and mortality are increased in patients with RA.Nontraditional risk factors appear to play an important role. Myocardial infarction,myocardial dysfunction, and asymptomatic pericardial effusions are common;symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronaryvasculitis, valvular disease, and conduction defects are occasionally observed.

Pulmonary: RA involvement of the lungs may take several forms, including pleuraleffusions, interstitial fibrosis, nodules (Caplan syndrome), and bronchiolitis obliterans-organizing pneumonia. Methotrexate (MTX) therapy can induce interstitial fibrosis thatmay be difficult to distinguish from that which naturally occurs in patients with RA.

GI: Intestinal involvement, as with kidney involvement, is often secondary to associatedprocesses such as medication effects, inflammation, and other diseases. The liver isoften affected in patients with Felty syndrome (ie, RA, splenomegaly, and neutropenia).

Renal: The kidneys are usually unaffected by RA directly. Secondary involvement iscommon, including that due to medications (eg, nonsteroidal anti-inflammatory drugs[NSAIDs], gold, cyclosporin), inflammation (eg, amyloidosis), and associated diseases(eg, Sjögren syndrome with renal tubular abnormalities).

Vascular: Vasculitic lesions can occur in any organ but are most commonly found in theskin. Lesions may present as palpable purpura, skin ulcers, or digital infarcts.

Hematologic: Most active patients have an anemia of chronic disease. Severalhematologic parameters parallel disease activity, including normochromic-normocyticanemia, thrombocytosis, and eosinophilia, although the latter is uncommon.Leukopenia is a finding in patients with Felty syndrome.

Neurologic: Nerve entrapment is common, such as with the median nerve in carpaltunnel syndrome. Vasculitic lesions, mononeuritis multiplex, and cervical myelopathymay cause serious neurologic consequences.

Ocular: Keratoconjunctivitis sicca is common in individuals with RA and is often theinitial manifestation of secondary Sjögren syndrome. The eye may also haveepiscleritis, uveitis, and nodular scleritis that may lead to scleromalacia.

The American College of Rheumatology has developed criteria to aid in determining theprogression, remission, and functional status of patients with RA.

Progression of RA (clinical and radiologic staging)Stage 1 (early RA)

No destructive changes observed upon roentgenographic examinationRadiographic evidence of osteoporosis possible

Stage II (moderate progression)Radiographic evidence of periarticular osteoporosis, with or without slight


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subchondral bone destructionSlight cartilage destruction possibleJoint mobility possibly limited; no joint deformities observedAdjacent muscle atrophyExtra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible

Stage III (severe progression)Radiographic evidence of cartilage and bone destruction in addition toperiarticular osteoporosisJoint deformity (eg, subluxation, ulnar deviation, hyperextension) without fibrousor bony ankylosisExtensive muscle atrophyExtra-articular soft-tissue lesions (eg, nodules, tenosynovitis) possible

Stage IV (terminal progression)Fibrous or bony ankylosisCriteria of stage III

Remission of RA (≥5 of conditions below for at least 2 consecutive months)Duration of morning stiffness not exceeding 15 minutes

No fatigue

No joint pain

No joint tenderness or pain with motion

No soft-tissue swelling in joints or tendon sheaths

ESR of less than 30 mm/h in a female or less than 20 mm/h in a male

Functional status of patients with RAClass I - Completely able to perform usual activities of daily living

Class II - Able to perform usual self-care and vocational activities but limited inavocational activities

Class III - Able to perform usual self-care activities but limited in vocational andavocational activities

Class IV - Limited in ability to perform usual self-care, vocational, and avocationalactivities

Causes

The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectiousfactors may play significant roles. Socioeconomic, psychological, and lifestyle factors mayinfluence disease outcome.

GeneticApproximately 60% of US patients with RA carry a shared epitope of the HLA-DR4cluster, which constitutes one of the peptide-binding sites of certain HLA-DR moleculesassociated with RA (eg, HLA-DR beta *0401, 0404, or 0405); in addition, HLA-DR1(HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly incertain southern European areas.

Other HLA-DR4 molecules (eg, HLA-DR beta *0402) do not share the same epitopeand do not confer risk. Genes other than those of the major histocompatibility complexare also involved, and results from sequencing genes of RA families suggest the


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presence of several susceptibility genes and several resistance genes.

EnvironmentalFor many decades, numerous infectious agents have been suggested to induce RA.Among these are Mycoplasma organisms, Epstein-Barr and rubella viruses, andothers.

This supposition is further supported indirectly by the following:Occasional reports of flulike disorders preceding the start of arthritisThe inducibility of arthritis in experimental animals with different bacteria orbacterial products (eg, streptococcal cell walls)The presence of bacterial products including bacterial RNA in patients' jointsThe activity of several agents that have antimicrobial effects as disease-modifyingdrugs (eg, gold salts, antimalarials, minocycline)

HormonalSex hormones may play a role, as evidenced by the disproportionate number offemales with RA, its amelioration during pregnancy, its recurrence in the earlypostpartum period, and its reduced incidence in women using oral contraceptives.

Hyperprolactinemia may be a risk factor for RA.

ImmunologicAll of the major immunologic elements play fundamental roles in the initiation,propagation, and maintenance of the autoimmune process of RA. The exactorchestration of the cellular and cytokine events that lead to pathologic consequences,such as synovial proliferation and subsequent joint destruction, is complex. It involvesT and B lymphocytes, antigen-presenting cells (eg, B cells, macrophages, dendriticcells), and numerous cytokines. Aberrant production and regulation of bothpro-inflammatory and anti-inflammatory cytokines and cytokine pathways are found inRA.

T cells are assumed to play a pivotal role in the initiation of RA, and the key player inthis respect is assumed to be the Th1 CD4 cells. (T helper 1 cells produce IL-2 andinterferon gamma.)

These cells may subsequently activate macrophages and other cell populations,including synovial fibroblasts. Macrophages and synovial fibroblasts are the mainproducers of the proinflammatory cytokines TNF-alpha and IL-1.

B cells are important in the pathologic process and may serve as antigen-presentingcells. B cells also produce numerous autoantibodies (eg, RF, to citrullinated proteins)and secrete cytokines. Elimination of populations of B cells with monoclonal antibodies(eg, rituximab) offers another effective therapeutic option. While rituximab may be usedas a sole agent, it is often used in combination with MTX. Rituximab has been shown tobe effective in reducing the signs and symptoms in adult patients with moderately toseverely active RA who have had an inadequate response to one or moreTNF-antagonist therapies.[2,3,4 ]

Experimental models suggest that synovial macrophages and fibroblasts may becomeautonomous and thus lose responsiveness to T-cell activities in the course of thedisease.

The hyperactive and hyperplastic synovial membrane is ultimately transformed intopannus tissue and invades cartilage and bone, the latter being degraded by activatedosteoclasts.

The major difference between RA and other forms of inflammatory arthritis, such as


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psoriatic arthritis, does not lie in their cytokine patterns but rather in the highlydestructive potential of the RA synovial membrane and in the local and systemicautoimmunity. Whether these two events are linked is unclear; however, theautoimmune response conceivably leads to the formation of immune complexes thatactivate the inflammatory process to a much higher degree than normal. This theory issupported by the much worse prognosis of RA among patients with positive RF results.

In patients with RA, autoantibodies are directed not only against immunoglobulin G(IgG), ie, RFs, but also against various other antigens, such as nuclear antigens (RA33, EBNA), citrullinated proteins (anti-CCP antibodies), collagen, and glucose-6-phosphate isomerase.

Differential Diagnoses

Amyloidosis, Overview Myelodysplastic Syndrome

Calcium Pyrophosphate Deposition Disease Osteoarthritis

Cryoglobulinemia Paraneoplastic Syndromes

Fibromyalgia Polychondritis

Hepatitis B Polymyalgia Rheumatica

Hypothyroidism Psoriatic Arthritis

Inflammatory Bowel Disease Sarcoidosis

Lyme Disease Sjogren Syndrome

Mediterranean Fever, Familial Systemic Lupus Erythematosus

Multicentric Reticulohistiocytosis Whipple Disease

Other Problems to Be Considered

Infectious arthritis - Bacteria (eg, Lyme disease), fungi, mycobacteria, viruses (eg, hepatitisB, rubella, parvovirus, human T-cell leukemia virus 1)

Autoimmune connective tissue diseases (eg, systemic lupus erythematosus, progressivesystemic sclerosis, mixed connective tissue disease, Sjögren syndrome, vasculitis,cryoglobulinemias)

Other rheumatic diseases (eg, polyarticular gout, seronegative spondyloarthropathy [eg,ankylosing spondylitis, reactive arthritis])

Subacute bacterial endocarditis

Hemoglobinopathies

Angioimmunoblastic lymphadenopathy

Workup

Laboratory Studies

No pathognomonic test is available to help confirm the diagnosis of rheumatoid arthritis (RA);instead, the diagnosis is made using clinical, laboratory, and imaging features.

Markers of inflammation, such as ESR and CRP, are associated with disease activity;


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additionally, the CRP value over time correlates with radiographic progression.

Hematologic parameters include a CBC count and synovial fluid analysis.Complete blood cell count

Anemia of chronic disease is common and correlates with disease activity; itimproves with successful therapy.Hypochromic anemia suggests blood loss, commonly from the GI tract(associated with NSAIDs).Anemia may also be related to disease-modifying antirheumatic drug (DMARD)therapy.Thrombocytosis is common and is also associated with disease activity.Thrombocytopenia may be a rare adverse event of therapy and may occur inpatients with Felty syndrome.Leukocytosis may occur but is usually mild.Leukopenia may be a consequence of therapy or a component of Feltysyndrome, which may then respond to DMARD therapy.

Synovial fluid analysisInflammatory synovial fluid (WBC count >2000/µL) is present with WBC countsgenerally from 5,000-50,000/µL.Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (incontrast with mononuclear cell predominance in the synovium).Because of a transport defect, the glucose levels of pleural, pericardial, andsynovial fluids in patients with RA are often low compared to serum glucoselevels.

Immunologic parameters include autoantibodies (eg RF, anti-RA33, anti-CCP, antinuclearantibodies).

Rheumatoid factorRF is present in approximately 60-80% of patients with RA over the course of theirdisease but is present in fewer than 40% of patients with early RA.RF values fluctuate somewhat with disease activity, although high-titered RFgenerally remains present even in patients with drug-induced remissions.

Antinuclear antibodies: These are present in approximately 40% of patients with RA,but test results for antibodies to most nuclear antigen subsets are negative.

Newer antibodies (eg, anti-RA33, anti-CCP): Recent studies of anti-CCP antibodiessuggest a sensitivity and specificity equal to or better than those of RF, with anincreased frequency of positive results in early RA. The presence of both anti-CCPantibodies and RF is highly specific for RA. Additionally, anti-CCP antibodies, as doRF, indicate a worse prognosis.

Imaging Studies

Radiography: Note that erosions may be present in the feet, even in the absence of pain andin the absence of erosions in the hands.

Extremities - Hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine

Others when indicated

MRI: This modality is used primarily in patients with abnormalities of the cervical spine; earlyrecognition of erosions based on MRI images has been sufficiently validated.

Ultrasonography: This allows recognition of effusions in joints that are not easily accessible


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(eg, hip joints, shoulder joints in obese patients) and cysts (Baker cysts). High-resolutionsonograms may allow visualization of tendon sheaths, changes and degree ofvascularization of the synovial membrane, and even erosions; however, this needs furthervalidation. Ultrasonography may be used as an office-based procedure.

Bone scanning: Findings may help to distinguish inflammatory from noninflammatorychanges in patients with minimal swelling.

Densitometry: Findings are useful for helping diagnose changes in bone mineral densityindicative of osteoporosis.

Other Tests

HLA-DR4 (shared epitope) may constitute a helpful marker in early undifferentiated arthritis.

Procedures

Joint aspiration, diagnostic arthroscopy (histology), and biopsies (eg, skin, nerve, fat, rectum,kidney) may be considered if vasculitis or amyloidosis is suggested.

Histologic Findings

The lymphoplasmacytic infiltration of the synovium with neovascularization seen in RA is similar tothat seen in other conditions characterized by inflammatory synovitis. Early rheumatoid nodulesare characterized by small-vessel vasculitis and later by granulomatous inflammation.

Treatment

Medical Care

The optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach ofpharmacologic and nonpharmacologic therapies.

NonpharmacologicEducation is important in helping patients to understand their disease and to learn howto cope with its consequences.

Physiotherapy and physical therapy are initiated to help improve and sustain range ofmotion, to increase muscle strength, and to reduce pain.

Occupational therapy is initiated (1) to help patients to use joints and tendonsefficiently without stressing these structures, (2) to help decrease tension on the jointswith specially designed splints, and (3) to cope with daily life through adaptations tothe patients' environment and the use of different aids.

Orthopedic measures include reconstructive and replacement-type surgical measures.

PharmacologicThe American College of Rheumatology is developing RA recommendations andalgorithms for the use of nonbiological and biological DMARDs for patients with RA.

DMARDs represent the most important measure in the successful treatment of RA.DMARDs can retard or prevent disease progression and, thus, joint destruction andsubsequent loss of function.

Successful DMARD therapy may eliminate the need for other anti-inflammatory or


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analgesic medications.

Until the full action of DMARDs takes effect, anti-inflammatory or analgesic medicationsmay be required as bridging therapy to reduce pain and swelling.

DMARDs can be classified into xenobiotic and biological agents.

Xenobiotic agents include the following:The xenobiotic DMARDs, ie, gold salts (eg, aurothiomalate, auranofin, others),D-penicillamine, chloroquine and hydroxychloroquine, sulfasalazine (SSZ),methotrexate (MTX), azathioprine, and cyclosporin A, have been widely used totreat RA; some have been used for decades.MTX and SSZ are the most active compounds in terms of frequency of remissionsand time to onset of action and provide the best risk-benefit ratios. MTX alone orin combination with other agents has become the standard of care for moderate-to-severe RA.Minocycline may act as a DMARD through its action as a matrix metalloproteinaseinhibitor.Leflunomide is the most recent addition to the xenobiotics and has an activity thatis similar to that of SSZ and MTX.SSZ is dosed up to 2-4 g/d, while MTX is administered up to 25 mg once a week(PO, IV, IM, or SC). Both SSZ and MTX are started at lower dosages and areincreased to full dosages within approximately 4-6 weeks. Monitoring of CBCcounts and liver enzymes is important because of the drugs' hematologic andhepatic toxicities. Approximately 1% of patients develop agranulocytosis to SSZ orpneumonitis to MTX. Leflunomide is usually initiated with a loading dose of 100mg/d for 3 days and is then continued at 20 mg/d. CBC counts and liver enzymesalso must be monitored. Most of these drugs have been shown to improve signsand symptoms (as well as quality of life) and to significantly retard radiographicprogression of RA.Visser et al (2009) conducted a systematic review to assess the evidence for theoptimal treatment of RA with MTX. The study sought to establish the optimaldosage and route of administration of MTX. In the review of 1748 articlesidentified in the literature, 38 met inclusion criteria. The analysis concluded thatan initial MTX dose of 15 mg/week orally with escalation of 5 mg/month to achievetarget doses of 25-30 mg/week or maximum tolerable doses was the optimal,evidence-based dosing strategy. Starting at higher initial doses or too rapid ofescalation is limited by toxicity. Conversion from oral to subcutaneousadministration of MTX is suggested for patients who have an inadequateresponse to oral therapy.[5 ]

Combination therapy appears to be helpful in patients whose RA insufficiently orcompletely fails to respond to monotherapy with a DMARD. Several compoundshave been successfully combined without unexpected added risks; these usuallyinclude MTX as one of the drugs, ie, MTX plus SSZ plus an antimalarial, MTXplus leflunomide, or MTX plus biologics. In general, the same precautions areneeded as with the single compounds, although liver and bone marrow toxicitymay be increased if compounds affecting these organs are combined.The most important and most common adverse events relate to liver and bonemarrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds,D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts,D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds,SSZ), autoimmunity (D-penicillamine, SSZ, minocycline), and infections(azathioprine, cyclosporine A). Antimalarials may cause ocular toxicity. Wolfe andMarmor studied nearly 4,000 patients with RA or SLE who had used theantimalarial hydroxychloroquine and concluded that the risk of


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hydroxychloroquine toxicity was relatively low but increased (>1%) after 7 years oftherapy.[6 ]Nevertheless, these drugs, when used with appropriate clinical andlaboratory control monitoring, are usually well tolerated. Adverse events typicallybecome rarer after the first 2-3 months. Most adverse events are reversible withdrug cessation or with dose reduction.In clinical trials, 30-70% of patients using DMARDs, either alone or in combinationtherapy, achieve partial responses according to the American College ofRheumatology's disease activity score. Currently, predicting which patients willnot respond is not possible. In clinical practice, attempting to reduce diseaseactivity as much as possible by (1) increasing the dose of medication (eg, MTX),(2) switching to other DMARDs in those who do not respond or in those withresponses regarded as insufficient, or (3) initiating combination therapy isimportant. Because patients may require 2-3 months to achieve a full response toDMARDs, decisions regarding changes in medication are often delayed until thattime.

Biological agents include the following:The recognition of TNF-alpha and IL-1 as central proinflammatory cytokines hasled to the development of agents that block these cytokines or their effects. TheTNF blockers include etanercept, infliximab, and adalimumab. Etanercept, abivalent p 75–TNF receptor linked to the Fc portion of human IgG, is administeredat 25 mg SC twice weekly or 50 mg SC weekly, with or without concomitant MTX.Infliximab, a chimeric monoclonal antibody against TNF-alpha, is administered atdoses of 3 mg/kg IV at weeks 0, 2, and 6 and then every 4-8 weeks, usually withMTX. Adalimumab, a recombinant human IgG1 monoclonal antibody specific forhuman TNF monoclonal antibody, is administered 40 mg SC every 2 weeks.These agents are expensive. Consensus statements do not recommend their useuntil at least one xenobiotic DMARD, usually MTX, has been administered withoutsufficient success. In clinical trials, up to 70% of patients achieve significantresponses, but remissions are not usually observed.[7 ]

These agents bind TNF and thus prevent its interaction with its receptors;infliximab binds to cells that express membrane TNF, while etanercept bindslymphotoxin (formerly termed TNF-beta) in addition to soluble TNF-alpha. Failureto respond to one TNF blocker does not preclude response to another. As withxenobiotics, the decision to continue or stop biological agents can often be madewithin 3 months after initiation of therapy.Adverse effects associated with the biological agents include the generation ofantibodies against these compounds, emergence of antinuclear antibodies,occasional drug-induced lupuslike syndromes, and infections (includingtuberculosis). Rarely, demyelinating disorders and bone marrow suppression mayoccur. Acute and chronic infections, demyelinating disorders, and recentmalignancies are contraindications for TNF blockers. Thoroughly searching forlatent tuberculosis using chest radiography and/or purified protein derivative(PPD) testing is recommended before these agents are started.Another biological agent is anakinra (IL-1 receptor antagonist [IL-1ra]). IL-1raoccupies the IL-1 receptor without triggering it and prevents receptor binding ofIL-1. It is given at a dose of 100 mg/d SC. In clinical trials, a significant responsewas observed in approximately 40% of patients with RA.Abatacept is a selective costimulation modulator that inhibits T-cell activation bybinding to CD80 and CD86, thereby blocking their interaction with CD28. CD28interaction provides a signal needed for full T-cell activation that is implicated inRA pathogenesis. It is dosed according to body weight (vida infra); after initialinfusion, repeat on week 2 and week 4, then every 4 weeks following.


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Fleischmann et al examined safety and efficacy of certolizumab monotherapy in220 patients RA in whom DMARD therapy had failed. Patients were randomized1:1 to receive certolizumab 400 mg or placebo every 4 weeks for 24 weeks. At 24weeks, 45.5% of the certolizumab group achieved a 20% improvement accordingto the American College of Rheumatology criteria (ACR20), whereas 9.3% of theplacebo group achieved ACR20 (P <0.001). Statistically significant differencesbetween certolizumab and placebo were observed as early as week 1 throughweek 24 (P <0.001).[8 ]

Smolen et al evaluated the effect of certolizumab plus MTX versus placebo plusMTX in patients with RA. The primary endpoint was ACR20 response at week 24.Patients (n=619) were randomized to receive certolizumab 400 mg at weeks 0, 2,and 4 followed by 200 mg or 400 mg plus MTX every 2 weeks, or placebo plusMTX every 2 weeks. Significantly more patients who received certolizumab 200mg or 400 mg achieved ACR20 compared with those who received placebo (P<0.001), with rates of 57.3%, 57.6%, and 8.7%, respectively. Radiographicprogression was significantly inhibited with certolizumab 200 mg (0.2), 400 mg(-0.4) compared with placebo (1.2). When compared with placebo plus MTX,certolizumab plus MTX significantly relieved signs and symptoms, improvedphysical function, and inhibited radiographic progression in patients with RA.[9 ]

In addition to improving signs and symptoms and quality of life, all biologicagents significantly retard radiographic progression of joint erosions.Golimumab, a new human anti–TNF-alpha monoclonal antibody, inhibitsTNF-alpha bioactivity, thereby modulating immune activity in patients with RA.Emery et al (2009) conducted a 52-week, randomized, double-blind, placebo-control study, followed by an open-label extension through 5 years to assess thesafety and efficacy of golimumab in MTX-naive patients with RA. Patients (n=637)were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plusplacebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mgplus MTX (group 4). Intent-to-treat analysis showed no significant differences inthe primary endpoint between group 1 and groups 3 and 4 combined, indicatingefficacy of golimumab in RA. The incidence of serious adverse events was similaramong all treatment groups.[10 ]

Treatment with rituximab may deplete CD20+ B cells, and Bingham et alinvestigated whether this may affect patients' response to immunization. In acontrolled trial in 103 patients, responses to pneumococcal polysaccharidevaccine were lesser in patients with RA receiving rituximab and methotrexate thanin those receiving methotrexate alone (57% vs 82%, respectively, showed a 2-foldrise in titer in response to ≥1 serotype). Decreased response to keyhole limpethemocyanin (KLH) (neoantigen) was also seen in the rituximab-treated patients(47% vs 93%). However, the ability to maintain a positive delayed-typehypersensitivity to a Candida albicans skin test was comparable in both groups,as was response to tetanus toxoid. They concluded that, to maximizeimmunization responses, polysaccharide and primary immunizations should beadministered before starting rituximab treatment.[11 ]

GlucocorticoidsGlucocorticoids are potent anti-inflammatory drugs and are commonly used inpatients with RA to bridge the time until DMARDs are effective.Doses of up to 10 mg of prednisone per day are typically used, but some patientsmay require higher doses.Timely dose reductions and cessation are important because of the adverseeffects associated with long-term steroid use.

Nonsteroidal anti-inflammatory drugs


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NSAIDs interfere with prostaglandin synthesis through inhibition of the enzymecyclooxygenase (COX), thus reducing swelling and pain. However, they do notretard joint destruction and, therefore, when used alone, are not sufficient to treatRA. Similar to glucocorticoids, they can be reduced in dose or discontinued withsuccessful DMARD therapy.Several dozen NSAIDs are available and can be classified into different groups ofcompounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen,piroxicam, and diclofenac.In the early 1990s, 2 isoforms of COX were discovered, ie, COX-1 and COX-2.Traditional NSAIDs inhibit both COX-1 and COX-2.The coxibs (COX-2 inhibitors), a new group of compounds, have recently beendeveloped. These compounds have a significant preference for COX-2 overCOX-1. COX-1 has a protective role, particularly in the stomach, while COX-2 isstrongly up-regulated during inflammation.Coxibs, with their selectivity for COX-2, have been shown to be clinicallyefficacious and are accompanied by significantly reduced GI toxicity, the majoradverse event related to the use of nonselective COX inhibitors (ie, NSAIDs).Other adverse effects, such as water retention, hypertension, and abnormaltransaminase levels, are observed with both nonselective and COX-2–selectivedrugs. Whether and to what degree nonaspirin NSAIDs, coxibs, or both havecardiovascular toxicity has not been definitively settled.COX-2 inhibitors and traditional NSAIDs plus a proton-pump inhibitor have similarupper GI toxicity. A study by Chan et al (2010) compared the risk of clinicaloutcomes across the entire GI tract between the 2 drug regimens. A lowerincidence of GI toxicity with COX-2 inhibitors was observed and a significantlygreater number of patients in the NSAID/proton-pump inhibitor group withdrewearly because of GI adverse events compared with the COX-2 inhibitor group (P=0.0006).[12 ]

AnalgesicsAcetaminophen/paracetamol, tramadol, codeine, opiates, and various otheranalgesic medications can also be used to reduce pain.These agents do not affect swelling or joint destruction.

Experimental therapiesDespite significant advances over the past decades, RA continues to be anincurable disease. The disease remains active in many patients whose conditionspartially or completely fail to respond to DMARDs. Therefore, a vigorous search isunderway for new therapeutic agents.Although not truly experimental because it has been approved for use in RA, animmunoadsorbent column (Prosorba) is used on occasion to treat patients withresistant RA. Weekly exchanges are given for 12 weeks.New TNF blockers are in clinical trials and include certolizumab, a Fab pegylatedfragment of a humanized monoclonal antibody.Several new CD20 B-cell–targeted biologic agents are under investigation,including atacicept, AMG 623, B3-FCc, Br3-Fc, belimumab, epratuzumab,ofatumumab, ocrelizumab, and TRU-015.Biologics capable of blocking IL-6 (tocilizumab) or interfering with T-cell/non–T-cell interactions look to be very promising.Xenobiotics directed at molecules involved in transduction of TNF, those involvedwith the receptor for the lymphotoxin-b receptor, or IL-1–mediated signals (eg,AMG 108, an IL-1ra) could prove helpful.Inhibition of matrix metalloproteinases, although initially unsuccessful, couldprove to be efficacious, as could agents that inhibit activation of osteoclasts.


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Apheresis procedures are being investigated.High-dose immunosuppression combined with autologous stem celltransplantation has been used in study protocols for patients whose conditionsare resistant to other therapies.

Early therapyMany studies have revealed that early treatment of RA (ie, within months of onset)with DMARDs can not only more efficiently retard disease progression than latertreatment, but may also induce more remissions. Thus, early therapy withDMARDs has become the standard of care.Importantly, note that patients with early forms of arthritis should be evaluated by,and if necessary, referred to physicians who are experienced in the diagnosis andtreatment of RA.In a study by van Vollenhoven et al, patients with early RA were administeredMTX (up to 20 mg/wk). Study participants not achieving low disease activity after3-4 months were randomized to receive either sulfasalazine andhydroxychloroquine or infliximab in addition to MTX. Of 487 patients who wereinitially enrolled, 258 had not achieved low disease activity with MTX and werethen randomized to receive additional treatment (in addition to MTX) withsulfasalazine and hydroxychloroquine (n=130) or infliximab (n=128). In thesulfasalazine and hydroxychloroquine group, 32 of 130 (25%) achieved theprimary outcome defined as a good response according to the European LeagueAgainst Rheumatism (EULAR). In the infliximab group, 50 of 128 (39%) attainedthe primary outcome. The authors concluded that, in early RA that fails MTXtreatment, the addition of a tumor necrosis factor antagonist is superior toaddition of conventional DMARDs.[13 ]

Secchiero et al sought to determine the relationship between therapeuticresponse to DMARDs and serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin in patients with early RA.[14 ]TRAILand osteoprotegerin serum concentrations were measured at baseline and at 1year. Patients who had a clinical response (as measured by the 28-joint countDisease Activity Score) were noted to have significantly higher baselineconcentrations of TRAIL after 1 year of therapy compared with patients who didnot have a clinical response to DMARDs. The authors suggest that TRAILconcentrations may be an important factor in therapeutic response to DMARD inpatients with early RA.

Surgical Care

Cervical spine involvement usually affects C1-C2 and may potentially cause serious neurologicconsequences. Patients who are to undergo intubation or procedures that may involvemanipulation of the neck should undergo careful evaluation of the cervical spine.

Patients with RA often need multiple operations over time (eg, synovectomy, tendon corrections,joint replacements).

Consultations

Orthopedists

Physical and rehabilitative medicine specialists

Medication


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Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach ofpharmacologic and nonpharmacologic therapies.

Disease-modifying antirheumatic drugs

Xenobiotics include gold salts (eg, aurothiomalate, auranofin, others), D-penicillamine,chloroquine and hydroxychloroquine, SSZ, MTX, azathioprine, and cyclosporin A and have beenwidely used to treat RA.

Leflunomide (Arava)

First new DMARD approved in more than 10 years. Blocks autoimmune antibodies and reducesinflammation. Inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidinesynthesis pathway. Studies indicate that it reduces symptoms, possibly better than MTX, and mayeven slow progression of RA. Use with caution in renal insufficiency

Dosing

Adult

Initial: 100 mg/d PO for 3 dMaintenance dose: 10-20 mg/d PO

Pediatric

Not established

Interactions

Cholestyramine and charcoal reduce effects; concomitant rifampin increases toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Serious adverse reactions include hepatotoxicity and immunosuppression; other reactions includenausea, diarrhea, abdominal pain, rash, bronchitis, headache, hypertension, dizziness, andalopecia; caution if impaired liver or renal function or if immunodeficient; leflunomide is a prodrugand active metabolite has a very long plasma half-life (approximately 15 d); with serious toxicity,can be cleared more quickly using cholestyramine 8 mg tid

Methotrexate (Rheumatrex, Folex PFS)

Unknown mechanism of action in treatment of inflammatory reactions, although it is a knowninhibitor of dihydrofolate reductase and causes extracellular release of adenosine, a knowninhibitor of immune and inflammatory pathways. Ameliorates symptoms of inflammation (eg, pain,swelling, stiffness). Gradually adjust dose to attain satisfactory response.

Dosing


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Adult

7.5-25 mg PO/IV/IM/SC qwk

Pediatric

Not established

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoallowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or itsderivatives contained in some vitamins may decrease response; probenecid, NSAIDs, salicylates,procarbazine, and sulfonamides, including TMP-SMZ, can increase plasma levels; may decreasephenytoin plasma levels; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic inflammation or insufficiency; documentedimmunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia,leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor CBC counts monthly and liver and renal function every 1-3 mo during therapy (monitormore frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg,renal insufficiency, dehydration); has toxic effects on hematologic, GI, and pulmonary systems;discontinue if significant drop in blood counts occurs; fatal reactions reported when administeredconcurrently with NSAIDs or in setting of significantly impaired renal function; folic acidsupplementation (1 mg/d) may decrease adverse GI effects

Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

Acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.

Dosing

Adult

Initial: 1 g PO tid/qidMaintenance: 2 g/d PO in divided doses

Pediatric

<2 years: Not established>2 years: 40-60 mg/kg/d PO in 3-6 divided doses, followed by maintenance dose of 20-30 mg/kg/ddivided qid

Interactions

Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of oralanticoagulants, oral hypoglycemic agents, and MTX

Contraindications


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Documented hypersensitivity to sulfa drugs or any component; GI or GU obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction;adverse effects include anorexia, nausea/vomiting, diarrhea (enteric-coated tabs may reduceadverse GI effects), photosensitivity, headache, dizziness, urticaria/pruritus, hemolytic anemia,interstitial nephritis, acute nephropathy, hematuria, cirrhosis, jaundice, and hepatic necrosis (rare)

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils, inhibits locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate (200 mg) is equivalent to155-mg hydroxychloroquine base and 250-mg chloroquine phosphate.

Dosing

Adult

400-600 mg PO qd with food or milk

Pediatric

Not established

Interactions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to4-aminoquinolones

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may useif benefits outweigh risk to fetus

Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended forlong-term use in children; visual symptoms or muscular weakness may occur; perform periodic(q6mo) ophthalmologic examinations; test periodically for muscle weakness

Biologicals

Various biologic agents are used to rheumatic actions on joints and may include TNF–alphainhibition and targeted monoclonal antibodies.

Data accumulated from 3 Swedish registries analyzed the cancer risk in 6,366 patients with RAtaking TNF blockers. Data were compared with 61,160 patients with RA who were biologics-naive,5,989 patients starting methotrexate, 1,838 patients starting DMARD combination therapy, and the


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general Swedish population. Results showed that, among patients taking TNF blockers (25,693person-years of follow-up in 6,366 patients over 6 y), 240 developed first-time cancer, yielding arelative risk (RR) of 1.00 (confidence interval, 95%; 0.86-1.15) compared with the biologics-naivecohort. Similar RRs were shown with the other cohorts. The authors did not observe an increasedrisk for cancer with TNF blockers in this study.[15 ]

A meta-analysis conducted by Wiens et al (2010) evaluated the efficacy of adalimumab (n=1524),etanercept (n=1029), infliximab (n=1116), and placebo (n=2834) for the treatment of rheumatoidarthritis. American College of Rheumatology improvement criteria were used to assess efficacy.Etanercept and adalimumab demonstrated higher efficacy with short-term treatment (ie, 12-30 wk),whereas adalimumab was most effective for long-term therapy (ie, 1-3 y).[16 ]

Tsuzaka et al found that the baseline ADAMTS5 (a disintegrin and metalloproteinase withthrombospondin motifs 5) mRNA level may be used as a biomarker for prediction of the responseto infliximab in patients with rheumatoid arthritis. ADAMTS5 is said to play a significant role incartilage deterioration. Low baseline ADAMST5 levels were significantly lower in the goodresponder group compared with those in the nonresponder and moderate responder groups.[17 ]

According to a study by Caporali et al, anti-TNF-alpha therapy is safe and hepatitis B reactivationdid not occur in carriers of antibodies to hepatitis B core antigen (anti-HBc) who were affected bychronic inflammatory arthropathies.[18 ]

Rituximab (Rituxan)

Chimeric IgG1-kappa monoclonal antibody directed against the CD20 antigen found on thesurface of normal and malignant B lymphocytes. The Fab domain of rituximab binds to CD20antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-celllysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab in combination withmethotrexate is indicated to reduce signs and symptoms in adult patients with moderately toseverely active RA who have had an inadequate response to one or more TNF antagonisttherapies.

Dosing

Adult

Give two 1-g IV infusions 2 wk apartGlucocorticoids administered as methylprednisolone 100 mg IV or equivalent 30 min prior to eachinfusion are recommended to reduce incidence and severity of infusion reactions

Pediatric

Not established

Interactions

No formal drug interaction studies performed with rituximab; renal toxicity reported with drug incombination with cisplatin in clinical trials (in clinical trials involving patients with RA, concomitantadministration of methotrexate or cyclophosphamide did not alter pharmacokinetics of rituximab)

Contraindications

Documented hypersensitivity or IgE-mediated hypersensitivity to murine proteins or anycomponent of product


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Precautions

Pregnancy


Precautions

Safety and efficacy of re-treatment not established in controlled trials; not recommended inpatients with RA and no prior inadequate response to one or more TNF antagonists; has causedsevere infusion reactions (in some cases, reactions were fatal); hepatitis B virus (HBV) reactivationwith fulminant hepatitis, hepatic failure, and death has been reported in some patients withhematologic malignancies treated with rituximab; hypersensitivity reactions (non–IgE-mediatedreactions reported); mucocutaneous reactions, some with fatal outcome, have been reported inpatients treated with rituximab; vaccination with live-virus vaccines not recommended

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its bindingto TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production ininflamed areas. Used with MTX in patients who have inadequate response to MTX monotherapy.

Dosing

Adult

3 mg/kg IV at weeks 0, 2, and 6; then q4-8wk, usually with MTX; some patients require higherdoses (4-5 mg/kg)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; active infection; demyelinating disorders or multiple sclerosis;tuberculosis

Precautions

Pregnancy


Precautions

TNF-alpha modulates cellular immune responses; anti–TNF therapies, such as infliximab, mayadversely affect normal immune responses and allow development of superinfections; mayincrease risk of reactivation of TB in patients with certain granulomatous infections; PPD-positivepatients require TB prophylaxis; may cause anti-DNA antibodies and drug-induced lupus; cautionin congestive heart failure

Etanercept (Enbrel)


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Amaya

Highlight

Amaya

Highlight

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surfacereceptors, which, in turn, decreases inflammatory and immune responses.

Dosing

Adult

25 mg SC twice weekly or 50 mg SC once weekly with or without concomitant administration ofMTX

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; active infection; sepsis; concurrent live vaccination; demyelinatingdisorders or multiple sclerosis; tuberculosis

Precautions

Pregnancy


Precautions

Caution in impaired renal function and asthma; discontinue administration if serious infectiondevelops; adverse effects may include injection-site pain, localized erythema, rash, URIsymptomology, GI upset, nausea, vomiting, rhinitis, cough, and drug-induced lupus; caution incongestive heart failure

Adalimumab (Humira)

Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduceinflammation and inhibit progression of structural damage in moderate-to-severe rheumatoidarthritis. Reserved for those who experience inadequate response to one or more DMARDs. It canbe used alone or in combination with MTX or other DMARDs. Binds specifically to TNF-alpha andblocks interaction with p55 and p75 cell-surface TNF receptors.

Dosing

Adult

40 mg SC q2wk; may increase to 40 mg SC qwk in some patients not taking concomitant MTX

Pediatric

Not established

Interactions

May interfere with immune response to live virus vaccine (MMR) and reduce efficacy; MTXdecreases clearance (available data do not support adjusting dose of either HUMIRA or MTX)

Contraindications

Documented hypersensitivity; active infection; demyelinating disorders or multiple sclerosis;


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tuberculosis

Precautions

Pregnancy


Precautions

Causes immunosuppression; may reactivate tuberculosis infection; increases risk for lymphomadevelopment; associated with CNS demyelination (rare); discontinue if serious infection develops;autoantibody development may occur, causing lupuslike syndrome; caution in congestive heartfailure

Golimumab (Simponi)

TNF-alpha inhibitor. Decreases inflammation caused by overproduction of TNF associated withchronic inflammatory diseases. Indicated for moderate-to-severe RA, active psoriatic arthritis, andactive ankylosing spondylitis. Available as 50-mg/mL, single-dose Simponi SmartJect(Autoinjector) or a prefilled syringe.

Dosing

Adult

50 mg SC monthly in conjunction with methotrexate

Pediatric

<18 years: Not established

Interactions

Higher incidence of serious infections may occur when coadministered with abatacept, anakinra,or rituximab (do not administer concurrently); may decrease humoral response to live-virusvaccines (eg, MMR)

Contraindications

Documented hypersensitivity; active infections

Precautions

Pregnancy


Precautions

Similar to other TNF-alpha inhibitors, may cause reactivation of tuberculosis or hepatitis B; testpatients for latent tuberculosis before initiating treatment; serious infections (eg, bacterial sepsis,severe invasive fungal infections, opportunistic infections) may occur; do not initiate if infectionexists, and discontinue if serious infection or sepsis develops; lymphoma incidence increased overgeneral population; may exacerbate existing demyelinating disease or cause new onset ofdemyelinating disease; may worsen heart failure or may cause new onset of heart failure; commonadverse effects include upper respiratory tract infection, sore throat, and nasal congestion

Nonsteroidal anti-inflammatory drugs

These agents interfere with prostaglandin synthesis through inhibition of the COX enzyme, thus


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reducing swelling and pain. However, they do not retard joint destruction and alone are notsufficient to treat RA. As with glucocorticoids, dose can be reduced or drug discontinued withsuccessful DMARD therapy.

Coxibs and NSAIDs have been given a "black box" warning by the US Food and DrugAdministration regarding their potential for increased serious cardiovascular thrombotic events.NSAIDs may increase the risk of serious cardiovascular thrombotic events, MI, and stroke, whichcan be fatal. NSAIDs also increase the risk of serious adverse GI effects, including stomach orintestinal bleeding, ulceration, and perforation, which can be fatal. Elderly patients are at greaterrisk for serious GI events.

Several dozen NSAIDs are available, which can be classified into different groups of compounds.Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.

Selective COX-2 inhibitors may be considered for patients at risk for GI bleeding. Combinationproducts that include an NSAID and a proton pump inhibitor are also an option.

Ibuprofen (Motrin, Advil)

Indicated for patients with mild to moderate pain. Inhibits inflammatory reactions and pain bydecreasing prostaglandin synthesis.

Dosing

Adult

200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d

Pediatric

<6 years: Not established6 months to 12 years: 4-10 mg/kg/dose PO tid/qid>12 years: Administer as in adults

Interactions

Administration with aspirin increases risk of inducing serious NSAID-related adverse effects;probenecid may increase concentrations and, possibly, toxicity; may decrease effect ofhydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide andthiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs ofbleeding); may increase risk of MTX toxicity; phenytoin levels may be increased whenadministered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renalinsufficiency, or high risk of bleeding

Precautions

Pregnancy



Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function;


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caution in coagulation abnormalities or during anticoagulant therapy

Celecoxib (Celebrex)

Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain andinflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeuticconcentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. Seek lowestdose for each patient.

Dosing

Adult

Up to 200 mg/d bid PO

Pediatric

Not established

Interactions

Coadministration with fluconazole may cause increase in celecoxib plasma concentrationsbecause of inhibition of celecoxib metabolism; coadministration with rifampin may decreasecelecoxib plasma concentrations

Contraindications


Precautions

Pregnancy


Precautions

May cause fluid retention and peripheral edema; caution in compromised cardiac function,hypertension, and conditions predisposing to fluid retention; caution in severe heart failure andhyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signsof infection; caution in the presence of existing controlled infections; evaluate therapy whensymptoms or lab results suggest liver dysfunction

Ketoprofen (Orudis, Oruvail)

For relief of mild to moderate pain and inflammation. Small dosages are initially indicated in smalland elderly patients and in those with renal or liver disease. Doses of more than 75 mg do notincrease therapeutic effects. Administer high doses with caution and closely observe patient forresponse.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 300 mg/d

Pediatric

<3 months: Not established3 months to 12 years: 0.1-1 mg/kg PO q6-8h


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>12 years: Administer as in adults

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect ofhydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide andthiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs ofbleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased whenadministered concurrently

Contraindications


Precautions

Pregnancy



Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function;caution in coagulation abnormalities or during anticoagulant therapy

Naproxen (Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activityof cyclo-oxygenase, which is responsible for prostaglandin synthesis.NSAIDs decrease intraglomerular pressure and decrease proteinuria.

Dosing

Adult

250-500 mg PO bid; may increase to 1.5 g/d for limited periods

Pediatric

<2 years: Not established>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d

Interactions


Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renalinsufficiency

Precautions


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Pregnancy



Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillarynecrosis may occur; patients with preexisting renal disease or compromised renal perfusion riskacute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal duringtherapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluationand may require discontinuation of drug

Esomeprazole and naproxen (Vimovo)

Naproxen component is indicated for relief of signs and symptoms of osteoarthritis, rheumatoidarthritis, and ankylosing spondylitis. Naproxen is an NSAID that inhibits inflammatory reactionsand pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandinsynthesis.Esomeprazole component is indicated to decrease risk of gastric ulcers in patients at risk ofdeveloping NSAID-associated gastric ulcers. Esomeprazole is the S-isomer of omeprazole, aproton pump inhibitor. Inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system atsecretory surface of gastric parietal cells.

Dosing

Adult

1 tab PO bid at least 30 min acDelayed-release tab; swallow whole and do not chew, crush, dissolve, or splitAvailable in 2 dosage strengths: Esomeprazole 20 mg and naproxen 375 mg per tab oresomeprazole 20 mg and naproxen 500 mg per tab

Pediatric

<18 years: Not established

Interactions

Concomitant use of NSAIDs may reduce antihypertensive effect of ACE inhibitors, diuretics, andbeta-blockers; NSAIDs increase lithium plasma levels; concomitant use with methotrexate mayincrease methotrexate toxicity; concomitant use with warfarin may result in increased risk ofbleeding complications (monitor INR and prothrombin time); esomeprazole inhibits gastric acidsecretion and may interfere with absorption of drugs for which gastric pH is an importantdeterminant of bioavailability (eg, ketoconazole, iron salts, digoxin, atazanavir, nelfinavir);esomeprazole inhibits CYP2C19 and therefore may alter serum levels/activity of CYP2C19substrates; esomeprazole is extensively metabolized by CYP2C19 and CYP3A4

Contraindications

Documented hypersensitivity; NSAIDs are contraindicated for perioperative pain in the setting ofcoronary artery bypass graft surgery (increased risk of MI and stroke); NSAIDs are contraindicatedduring late pregnancy (risk of premature closure of ductus arteriosus)

Precautions

Pregnancy


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Precautions

May cause anaphylactoid reaction; not recommended with severe hepatic impairment or moderate-to-severe renal impairment; common adverse effects (>5%) include erosive gastritis, dyspepsia,gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nauseaNSAIDs carry black box warning regarding GI hemorrhage and serious thrombotic sequelae

Piroxicam (Feldene)

Decreases activity of cyclo-oxygenase, which in turn inhibits prostaglandin synthesis. Theseeffects decrease formation of inflammatory mediators.

Dosing

Adult

10-20 mg/d PO qd

Pediatric

0.2-0.3 mg/kg/d PO qd; not to exceed 15 mg/d

Interactions


Contraindications

Documented hypersensitivity; active GI bleeding

Precautions

Pregnancy



Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillarynecrosis may occur; increases risk of acute renal failure in patients with preexisting renal diseaseor compromised renal perfusion; reversible leukopenia may occur (discontinue if there is persistentleukopenia, granulocytopenia, or thrombocytopenia)

Diclofenac (Voltaren)

Designated chemically as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt,with an empirical formula of C14 H10 Cl2 NO2 NA. One of a series of phenylacetic acids that has


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demonstrated anti-inflammatory and analgesic properties in pharmacological studies. Believed toinhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Cancause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment.Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronideconjugation. Delayed-release, enteric-coated form is diclofenac sodium, and immediate-releaseform is diclofenac potassium. Has relatively low risk for bleeding GI ulcers.

Dosing

Adult

25 mg PO bid/tidIf well tolerated, increase by 25 or 50 mg at weekly intervals until satisfactory response is obtainedor total daily dose of 150-200 mg PO is reachedHigher doses generally do not increase effectiveness

Pediatric

<12 years: Not established>12 years: Administer as in adults

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect ofhydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide andthiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs ofbleeding) may increase risk of methotrexate toxicity; phenytoin levels may be increased whenadministered concurrently

Contraindications

Documented hypersensitivity; do not administer into CNS or give to patients with peptic ulcerdisease, recent GI bleeding or perforation, renal insufficiency, and those at high risk of bleeding

Precautions

Pregnancy



Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillarynecrosis may occur; increases risk of acute renal failure in patients with preexisting renal diseaseor compromised renal perfusion; low white blood cell counts occur rarely, and usually return tonormal in ongoing therapy; discontinuation of therapy may be necessary if there is persistentleukopenia, granulocytopenia, or thrombocytopenia

Analgesics

Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medicationscan be used to reduce pain. These agents do not affect swelling or joint destruction.

Acetaminophen (Tylenol, Feverall, Tempra)

Used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, with upper


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GI disease, or who are taking oral anticoagulants.

Dosing

Adult

325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

Interactions

Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine,hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy


Precautions

Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe orrecurrent pain or high or continued fever may indicate serious illness; contained in many OTCproducts, and combined use with these products may result in cumulative doses exceedingrecommended maximum dose

Tramadol (Ultram)

Inhibits ascending pain pathways, altering perception of and response to pain. Also inhibitsreuptake of norepinephrine and serotonin.

Dosing

Adult

50-100 mg PO q4-6h; not to exceed 400 mg/d

Pediatric

Not established

Interactions

Decreases carbamazepine effects significantly; cimetidine increases toxicity, risk of serotoninsyndrome with coadministration of antidepressants

Contraindications

Documented hypersensitivity; opioid-dependency; concurrent use of MAOIs or within 14 d; use ofSSRIs, TCAs, or opioids or acute alcohol intoxication; history of seizures (it may lower seizurethreshold)

Precautions


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Pregnancy


Precautions

Can cause dizziness, nausea, constipation, sweating, or pruritus; additive sedation with alcoholand TCAs; abrupt discontinuation can precipitate opioid withdrawal symptoms; adjust dose in liverdisease, myxedema, hypothyroidism, or hypoadrenalism; pregnancy and breastfeeding; seizure;development of tolerance or dependency with extended use

Immunomodulators

These agents interfere with cytokine actions responsible for inflammation.

Anakinra (Kineret)

Competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). IL-1 is found in excessin patients with RA and is produced in response to inflammatory stimuli. By blocking IL-1 binding,inflammation and pain associated with RA are inhibited. Indicated for RA in patients in whom oneor more DMARDs have failed. Should be administered at approximately the same time every day.

Dosing

Adult

100 mg/d SC

Pediatric

Not established

Interactions

None reported; higher rate of serious infections and neutropenia possible when coadministeredwith TNF blocking agents (eg, etanercept, infliximab); may decrease response to live virusvaccines

Contraindications

Documented hypersensitivity to product or Escherichia coli –derived products; active infections

Precautions

Pregnancy


Precautions

Serious infections may occur (discontinue treatment if serious infection develops); neutropeniamay occur (especially if administered concomitantly with TNF blocking agents); most commonadverse effect is local reaction at site of injection; caution in breastfeeding

Abatacept (Orencia)

Selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86,thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cellactivation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA,


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slowing progression of structural damage, and improving physical function in adults withmoderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNFantagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, becauseof increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use withanakinra (insufficient experience).

Dosing

Adult

Dose according to body weight; after initial administration, repeat at 2 and 4 wk after first infusion,then q4wk; infuse over 30 min<60 kg: 500 mg IV60-100 kg: 750 mg IV>100 kg: 1 g IV

Pediatric

Not established

Interactions

In clinical trials, coadministration with TNF antagonists resulted in increased risk of seriousinfections; do not administer concurrently with live virus vaccines (eg, MMR) or within 3 mo ofdiscontinuation

Contraindications


Precautions

Pregnancy


Precautions

Discontinue if serious infection occurs; patients with COPD developed adverse effects morefrequently, including COPD exacerbations, cough, rhonchi, and dyspnea; serious adversereactions include serious infections (3% vs 1.9% placebo); malignancy frequency was similar tothat of placebo (1.3% vs 1.1% placebo), with the exception of lung cancer (0.2% vs 0% placebo);common adverse effects include headache, upper respiratory tract infection, nasopharyngitis, andnausea

Tocilizumab (Actemra)

Interleukin 6 (IL-6) receptor inhibitor. IL-6 inhibition results in a decreased C-reactive protein levelto within reference range, decreased values in other pharmacodynamic parameters (eg,rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and increased hemoglobin value.Indicated for moderate-to-severe active RA in adults who have had an inadequate response to 1 ormore TNF-antagonist therapies. May be used alone or in combination with methotrexate or otherdisease-modifying antirheumatic drugs.

Dosing

Adult

4 mg/kg IV q4wk initially; may increase to 8 mg/kg q4wk based on clinical response; not to exceed


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800 mg/dose q4wk; administer IV infusion over 1 h (do not administer as bolus or push)

Pediatric

Not established

Interactions

Not studied with TNF antagonists; do not give live vaccines concurrently; inhibition of IL-6signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levelsthan those prior to therapy, leading to increased metabolism of drugs that are CYP450 substrates;affects multiple CYP450 enzymes, and resultant enzyme restoration may increase metabolism anddecrease effectiveness of certain drugs (eg, oral contraceptives, lovastatin, simvastatin,atorvastatin, warfarin, cyclosporine, theophylline, omeprazole); effect may last for several weeksafter stopping therapy

Contraindications


Precautions

Pregnancy


Precautions

Boxed warningSerious infections can occur; if serious infection develops, discontinue until infection is controlled;monitor for tuberculosis before and throughout therapy

PrecautionsAnaphylaxis or serious hypersensitivity has been reported; common adverse effects (ie, >5%)include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increasedALT level; do not use in the presence of any active infection (including localized); caution in GIperforation; monitor neutrophil, platelet, lipid, and liver function test valuesRecommended not to initiate if absolute neutrophil count <2000/mm3, platelet count<100,000/mm3, or AST/ALT value >1.5 times the upper limit of normal

Glucocorticoids

These agents are potent anti-inflammatory drugs commonly used in patients with RA to bridge thetime until DMARDs are effective. Doses of up to 10 mg/d of prednisone are typically used, butsome patients may require higher doses. Adverse events associated with long-term steroid usemake dose reductions and cessation important in due course.

Prednisone (Deltasone, Meticorten, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation byreversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomalmembranes and also suppresses lymphocytes and antibody production.

Dosing

Adult

10-60 mg/d PO or divided bid/qid; generally, maintenance dose should be <10 mg/d; alternatively,


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may be given IM, IV, or intra-articularly

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may causedigitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increasemetabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemiawith coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connectivetissue infections, and fungal or tubercular skin infections; GI ulceration

Precautions

Pregnancy


Precautions

Hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia,osteoporosis, euphoria, psychosis, growth suppression, and infections may occur withglucocorticoid use; abrupt discontinuation may cause adrenal crisis

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversingincreased capillary permeability.

Dosing

Adult

100 mg IV or equivalent

Pediatric

Not established

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogensmay increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decreaselevels of methylprednisolone (adjust dose); monitor patients for hypokalemia when administeredconcurrently with diuretics; grapefruit juice increases prednisolone concentrations;methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasmalevels of each drug

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy


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Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria,psychosis, growth suppression, myopathy, and infections are possible complications ofglucocorticoid use;Depo-Medrol contains benzyl alcohol, which is potentially toxic when administered locally to neuraltissue; administration of Depo-Medrol by other than indicated routes, including the epidural route,has been associated with reports of serious medical events such as arachnoiditis, meningitis,paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, seizures, visualimpairment (eg, blindness, ocular, and periocular inflammation), and residue or slough at injectionsite

Follow-up

Deterrence/Prevention

Rheumatoid arthritis (RA) is a progressive inflammatory disease.The current approach to management of RA emphasizes aggressive control ofinflammation to prevent long-term damage using early DMARD therapy, including theuse of single or combination DMARDs.

Early use of DMARDs had traditionally been avoided until patients show signs of jointdamage; however, this strategy has proved ineffective over several years. Patientsexperience poor long-term outcomes, including severe functional declines, radiographicprogression of disease, work disability, and premature mortality.

Two issues appear to be sources of confusion regarding long-term outcomes of treatment.First, a small percentage of patients who meet diagnostic criteria for RA have aself-limited process with spontaneous remission. Thus, in the absence of signs ofprogression, some patients are diagnosed with, and subsequently treated for, otherconditions.

Second, measures of inflammatory activity, such as joint swelling or ESRs, are oftenused to assess inflammatory activity. However, these indices are less-useful endpointsfor evaluation than severe long-term outcomes, such as work disability or jointdeformity and radiographic changes (the latter two are irreversible). During a period inwhich inflammatory markers may be stable or even improved, radiographic progressionand functional decline can occur.

The older traditional DMARDs, injectable gold salts and penicillamine, rarely inducesustained remission and are usually discontinued within 2 years. Because better agents areavailable, they are rarely used.

DMARDs, such as MTX and SSZ, have greater long-term effectiveness but still rarely inducetrue remission.

Optimal control may require combination therapy. Recent studies have shown that MTXcombined with other DMARDs is more effective and has acceptable toxicity compared withmonotherapy. Although the combination is not commonly used, cyclosporine with MTXresults in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, andhydroxychloroquine may provide substantially greater clinical improvement than MTX aloneor SSZ plus hydroxychloroquine.[19 ]In combination with infliximab, MTX provides a superiorresponse to monotherapy.[20 ]In combination with etanercept, MTX provides a higher rate of


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meaningful clinical response. Toxicities of these drug combinations are rarely moresignificant than those occurring with any of the individual agents used alone.

The goal of contemporary management of RA should be complete remission or no evidenceof disease activity.

Achieving this goal likely requires ongoing drug therapy, probably using a combinationof MTX with some other DMARD, although some patients may still respondsatisfactorily to monotherapy.

More long-term studies are needed to evaluate potential important adverse effectsassociated with combination therapy before definite recommendations can be made.

Complications

RA itself is not fatal, but complications of the disease may shorten survival by years in someindividuals. In general, RA is progressive and cannot be cured; in some, the diseasegradually becomes less aggressive and symptoms may even improve. However, if bone andligament destruction and any deformities have occurred, the effects are permanent.

Joint disability and pain with daily life are common. Affected joints can become deformed,and the performance of even ordinary tasks may be very difficult or impossible. According toone survey, 70% of patients with RA believe the disease prevents them from living a fullyproductive life. In 2000, a study in England found that approximately one third of individualsstop working within 5 years of the onset of disease.

RA is a systemic disease that can affect other parts of the body in addition to joints. Theseeffects include the following:

Peripheral neuropathy: This condition affects nerves, most often those in the handsand feet. It can result in tingling, numbness, or burning.

Anemia

Scleritis: This is an inflammation of the blood vessels in the eye that can result incorneal damage, scleromalacia, and, in severe cases of nodular scleritis, perforation.

Infections: Patients with RA have a higher risk for infections. The immunosuppressivedrugs required for treatment further increase that risk.

GI problems: Although patients with RA may experience stomach and intestinaldistress, lower rates of stomach and colorectal cancers have been reported amongpatients with RA.

Osteoporosis: Osteoporosis is more common than average in postmenopausal womenwith RA. The hip is particularly affected. The risk for osteoporosis also appears to behigher than average in men with RA who are older than 60 years.

Lung disease: One small study found a very high prevalence of lung disease(pulmonary inflammation and fibrosis) in patients newly diagnosed with RA. However,the association between a history of smoking and a higher risk for RA may at leastpartially account for this finding. Cigarette smoking, in any case, may increase theseverity of the disease.

Heart disease: RA can affect the blood vessels and independently increases the risk forcoronary ischemic heart disease.

Sjögren syndrome: Keratoconjunctivitis sicca is a common complication of RA. Oralsicca and salivary gland enlargement are less common.

Felty syndrome: This condition is characterized by the combination of splenomegaly,


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leukopenia (neutropenia), and recurrent bacterial infections. Felty syndrome sometimesresponds to DMARD therapy.

Lymphoma and other cancers: Alterations in the immune system associated with RAmay play a role in the higher risk for lymphoma observed in patients with RA.Aggressive treatments for RA that suppress the immune system may help prevent thiscancer, but more research is needed to evaluate this possibility. Other cancers thatmay occur with increased frequency in patients with RA include prostate and lungcancers.

Macrophage activation syndrome: This is a life-threatening complication of RA andrequires immediate treatment with high-dose steroids and cyclosporin A. Patients withRA should be aware of symptoms, which include persistent fever, weakness,drowsiness, and lethargy.

Prognosis

The clinical course of RA is generally one of exacerbations and remissions. Approximately40% of patients with RA become disabled after 10 years, but outcomes are highly variable.[21

]Some patients experience a relatively self-limited disease, and others have a chronicprogressive illness.

Improvements in the detection of early joint injury have provided a previously unappreciatedview of the ubiquity and importance of early joint damage. Nonetheless, predicting thecourse of an individual case of RA at the outset remains difficult, although theHLA-DRB1*04/04 genotype, a high serum titer of autoantibodies (eg RF, anti-CCP), extra-articular manifestations, a large number of involved joints, age younger than 30 years,female sex, and systemic symptoms all correlate with an unfavorable prognosis in terms ofjoint damage and disability. Insidious onset is also an unfavorable sign.

The absence of RF does not necessarily portend a good prognosis. Outcome iscompromised when diagnosis and treatment are delayed. Other laboratory markers of a poorprognosis include early radiologic evidence of bony injury, persistent anemia of chronicdisease, elevated levels of the C1q component of complement, and the presence ofanti-CCP antibodies.

RA that remains persistently active for more than one year is likely to lead to joint deformitiesand disability. Periods of activity lasting only weeks or a few months followed byspontaneous remission portend a better prognosis.

The overall mortality rate in patients with RA is reportedly 2.5 times that of the generalpopulation. In those with severe articular and extra-articular disease, the mortality rateapproaches that of patients with 3-vessel coronary disease or stage IV Hodgkin disease.Much of the excess mortality derives from infection, vasculitis, and poor nutrition. With theexception of lymphoma, mortality from cancer is unchanged.

Most data on disability rates derive from specialty units caring for referred patients withsevere disease. Little information is available on patients cared for in primary care communitysettings. Estimates suggest that more than half of these patients remain fully employed,even after 10-15 years of disease, with a third having only intermittent low-grade disease andanother third experiencing spontaneous remission.

A study of prognosis in patients with RA by Balsa et al (2010) found a decreased risk ofsevere disability in homozygous and heterozygous carriers of the 33T allele in the IL-4 gene;the model also included absence of anti-CCP antibodies and the single-nucleotide


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polymorphism rs2476601 on the PTPN22 gene. In contrast, homozygous and heterozygouscarriers of the 1858T allele on the PTPN22 gene had a decreased probability of remission.[22

]

Patient Education

Patient education and counseling are well worth the time invested because they help to reducepain, disability, and frequency of physician visits. They represent the most cost-effectiveintervention for RA.

Informing the patient of the diagnosisWith a potentially disabling disease such as RA, the act of informing the patient of thediagnosis takes on major importance. The goal is to satisfy the patient's informationalneeds regarding the diagnosis, prognosis, and treatment in appropriate detail. Carefulquestioning and empathic listening are required to understand the patient'sperspective, requests, and fears.

Telling patients more than they are intellectually or psychologically prepared to handle(a common practice) risks making the experience so intense as to trigger withdrawal.Conversely, failing to address issues of importance to the patient compromises thedevelopment of trust. The patient needs to know that the primary physicianunderstands the situation and is available for support, advice, and therapy as the needarises. Encouraging the patient to ask questions helps to communicate interest andcaring.

Discussing prognosis and treatmentPatients and families do best when they know what to expect and can view the illnessrealistically. Uncertainty greatly contributes to the disease of RA. Many patients fearcrippling consequences and dependency.

The most common disease manifestations should be described. Without building falsehopes, the physician can point out that spontaneous remissions can occur and thatmore than two thirds of patients live independently without major disability. In addition,emphasize that much can be done to minimize discomfort and to preserve function. Areview of available therapies and their efficacy helps to overcome feelings ofdepression stemming from an erroneous expectation of inevitable disability.

Even in patients with severe disease, guarded optimism is now appropriate, given thehost of effective and well-tolerated disease-modifying treatments that are emerging.

Abandonment is a major fear. Patients are relieved to know that they will be closelyobserved by the primary physician and health care team, working in conjunction with aconsulting rheumatologist and physical/occupational therapist, all of whom arecommitted to maximizing the patient's comfort and independence and to preservingjoint function.

Dealing with misconceptionsSeveral common misconceptions deserve attention. A substantial proportion of patientsand their families feel that they have done something to cause the illness. Explainingthat no known controllable precipitants exist helps to eliminate much unnecessary guiltand self-recrimination.

Dealing in an informative, evidence-based fashion with a patient who expresses interestin alternative and complementary forms of therapy can help limit expenditures onineffective treatments.


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Another misconception is that a medication must be expensive to be helpful. GenericNSAIDs, low-dose prednisone,[23 ]and the first-line disease-modifying agents are quiteinexpensive, yet remarkably effective for relieving symptoms, a point that bearsemphasizing. The sense that one must be treated with the latest TNF inactivator canbe addressed by a careful review of the overall treatment program and the proper roleof such agents in the patient's plan of care.

The active participation of the patient and family in the design and implementation ofthe therapeutic program helps to boost morale and to ensure compliance, as doesexplaining the rationale for the therapies used.

Preserving a sense of self-worthA major goal is to preserve the patient's sense of worth and independence. However,when fatigue, morning stiffness, or specific joint disease interferes with a patient'scapacity to carry out the usual responsibilities at work and at home, counseling will benecessary to recommend modification of work responsibilities and perhaps retraining.Recognition and treatment of concomitant depression is important.

With the use of occupational therapy, the treatment effort is geared to helping thepatient maintain a meaningful work role within the limitations of the illness.

The family plays an important part in striking the proper balance between dependenceand independence. Household members should avoid overprotecting the patient (eg,refraining from intercourse out of fear of hurting the patient) and should work to sustainthe patient's pride and ability to contribute to the family. Allowing the patient with RA tostruggle with a task is sometimes constructive.

In a systematic literature review and meta-analysis, Baillet et al determined thatcardiorespiratory aerobic exercise is safe for people with stable rheumatoid arthritis andmay actually improve muscle strength.[24 ]

Supporting the patient with debilitating diseasePersons with long-standing severe disease who have already sustained muchirreversible joint destruction benefit from an emphasis on comfort measures, supportivecounseling, and attention to minimizing further debility. Such patients need help ingrieving for their disfigurement and loss of function.

An accepting, unhurried, empathic manner allows the patient to express feelings. Theseemingly insignificant act of touching does much to restore a sense ofself-acceptance. Attending to pain with increased social support, medication, and arefocusing of attention to function are useful. A trusting and strong patient-doctorrelationship can do much to sustain a patient through times of discomfort anddisability.

For excellent patient education resources, visit eMedicine's Arthritis Center and MuscleDisorders Center. Also, see eMedicine's patient education articles Rheumatoid Arthritis,Juvenile Rheumatoid Arthritis, Understanding Rheumatoid Arthritis Medications, ChronicFatigue Syndrome, and Chronic Pain.

Miscellaneous

Medicolegal Pitfalls

Failure to properly monitor patients for adverse effects of DMARD therapy

Failure to control overuse of corticosteroids, with resultant toxicity


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[Best Evidence] Bingham CO 3rd, Looney RJ, Deodhar A, et al. Immunization responses inrheumatoid arthritis patients treated with rituximab: results from a controlled clinicaltrial. Arthritis Rheum. Jan 2010;62(1):64-74. [Medline].

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[Best Evidence] Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, GoldsteinJL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis andrheumatoid arthritis (CONDOR): a randomised trial. Lancet. Jul17 2010;376(9736):173-9. [Medline].

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compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patientswith early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. Aug8 2009;374(9688):459-66. [Medline].

Secchiero P, Corallini F, Castellino G, et al. Baseline serum concentrations of TRAIL in earlyrheumatoid arthritis: relationship with response to disease-modifying antirheumatic drugs. JRheumatol. Jul 2010;37(7):1461-6. [Medline].

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[Best Evidence] Askling J, van Vollenhoven RF, Granath F, et al. Cancer risk in patients withrheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the riskchange with the time since start of treatment?. ArthritisRheum. Nov 2009;60(11):3180-9. [Medline].

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Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C. Safety oftumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surfaceantigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases. ArthritisCare Res (Hoboken). Jun 2010;62(6):749-54. [Medline].

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Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in thetreatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritiswith Concomitant Therapy Study Group. N Engl J Med. Nov30 2000;343(22):1594-602. [Medline].

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[Best Evidence] Balsa A, Del Amo J, Blanco F, et al. Prediction of functional impairment andremission in rheumatoid arthritis patients by biochemical variables and geneticpolymorphisms. Rheumatology (Oxford). Mar 2010;49(3):458-66. [Medline].

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Baillet A, Zeboulon N, Gossec L, Combescure C, Bodin LA, Juvin R. Efficacy ofcardiorespiratory aerobic exercise in rheumatoid arthritis: meta-analysis of randomizedcontrolled trials. Arthritis Care Res (Hoboken). Jul 2010;62(7):984-92. [Medline].

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[Guideline] American College of Rheumatology Ad Hoc Committee on ClinicalGuidelines. Guidelines for the management of rheumatoid arthritis. American College ofRheumatology Ad Hoc Committee on Clinical Guidelines. ArthritisRheum. May 1996;39(5):713-22. [Medline].

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Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987revised criteria for the classification of rheumatoid arthritis. ArthritisRheum. Mar 1988;31(3):315-24. [Medline].

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Keywords

rheumatoid arthritis, RA, systemic inflammatory disease, rheumatoid factor, RF, cyclooxygenase,COX-1, COX-2, nonsteroidal anti-inflammatory drugs, NSAIDs, disease-modifying antirheumaticdrugs, disease-modifying anti-rheumatic drugs, DMARDs, joint destruction, uncontrolledinflammation, cartilage destruction, bone destruction, morning stiffness, rheumatoid nodules

Contributor Information and Disclosures

Author

Howard R Smith, MD, Adjunct Professor of Medicine, Case Western Reserve University; Chief ofRheumatology, Director of The Herbert Bell Pain Management Center, Director of Research,Cleveland Clinic, Huron HospitalHoward R Smith, MD is a member of the following medical societies: American College ofRheumatology and Ohio State Medical AssociationDisclosure: Pfizer Honoraria Speaking and teaching; Roche Consulting fee Consulting

Medical Editor

Kristine M Lohr, MD, MS, Professor, Department of Internal Medicine, Center for theAdvancement of Women's Health and Division of Rheumatology, Director, Rheumatology TrainingProgram, University of Kentucky College of MedicineKristine M Lohr, MD, MS is a member of the following medical societies: American College ofPhysicians, American College of Rheumatology, and American Medical Women's AssociationDisclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicineDisclosure: eMedicine Salary Employment

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Departmentof Medicine, Temple University School of MedicineElliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanCollege of Physicians, and American College of RheumatologyDisclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education,Associate Professor of Medicine, University of Miami Miller School of MedicineAlex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha,American College of Physicians-American Society of Internal Medicine, and Society of GeneralInternal MedicineDisclosure: Nothing to disclose.

Chief Editor


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Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; ChairmanEmeritus, Department of Internal Medicine, Western Pennsylvania HospitalHerbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha,American College of Physicians, American College of Rheumatology, American MedicalAssociation, and Phi Beta KappaDisclosure: ACP PEER Honoraria Independent contractor; Stock ownership in multiplePharmaceutical companies Ownership interest Other

Further Reading

Additional resources on rheumatoid arthritis are available at Medscape's Rheumatoid Arthritis Resource Center.

Clinical trials

RESTART C0168Z05 Rheumatoid Arthritis Study

A Study to Evaluate the RNA Signature of Rheumatoid Arthritis From Synovium and Whole Blood

Evaluation of EULAR-RAID Score in Rheumatoid Arthritis Patients (Rainbow)

PPAR-Gamma Agonists, Rheumatoid Arthritis and Cardiovascular Disease (RA PPAR)

Rheumatoid Arthritis (RA) Moderate to Low Disease Activity Study (CERTAIN)

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