INDICATIONS

ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage... Read More, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated… Read More

SEAM-RA Study

Evaluation of etanercept and methotrexate in combination or as monotherapy in subjects with moderate to severe RA

Adverse Event Rates

During the double-blind period, rates for treatment-emergent adverse events, serious adverse events, and events leading to discontinuation were similar across all three treatment groups.1

No new safety signals were observed regarding the use of ENBREL or MTX1

Treatment-Emergent
Adverse Events1
MTX MonotherapyMono- therapy (n=100) ENBREL MonotherapyMono- therapy (n=99) ENBREL + MTX (n=53)
All treatment-emergent adverse events, n (%) 63 (63.0) 55 (55.6) 33 (62.3)
Serious adverse events 4 (4.0) 4 (4.0) 3 (5.7)
Adverse events leading to discontinuation of investigational product 3 (3.0) 2 (2.0) 0 (0.0)
Fatal adverse events 0 (0.0) 0 (0.0) 0 (0.0)
Treatment-Emergent Adverse Events Occurring in ≥5% of Patients, n (%)1,2 MTX MonotherapyMono- therapy (n=100) ENBREL MonotherapyMono- therapy (n=99) ENBREL + MTX (n=53)
Infections 28 (28.0) 31 (31.3) 14 (26.4)
Musculoskeletal and connective tissue disorder 33 (33.0) 19 (19.2) 11 (20.8)
Injury, poisoning, and procedural complications 10 (10.0) 9 (9.1) 3 (5.7)
Respiratory, thoracic, and mediastinal disorders 6 (6.0) 4 (4.0) 3 (5.7)
Gastrointestinal disorders 4 (4.0) 6 (6.1) 2 (3.8)
Nervous system disorders 5 (5.0) 4 (4.0) 2 (3.8)

Serious adverse events included:

  • MTX monotherapy: aortic pseudoaneurysm, arthritis reactive, pneumonia, respiratory syncytial virus infection, cholecystitis, hyponatremia, alcoholism, confusional state, chronic obstructive pulmonary disease, respiratory failure, and deep vein thrombosis2
  • ENBREL monotherapy: concussion, spinal fracture, rheumatoid arthritis, gastric ulcer hemorrhage, and pituitary tumor benign2
  • ENBREL + MTX: ankle fracture, osteoarthritis, and herpes zoster2
  • Study Design

    The SEAM-RA Study was a multicenter, randomized, withdrawal, double-blind controlled study that enrolled 371 patients with moderate to severe RA on ENBREL + MTX who had good disease control for 6 months before study entry. The study consisted of a 30-day screening period, a 24-week open-label run-in period, a
    48-week double-blind treatment period, and a 30-day safety follow-up period.1 Eligible patients (n=253) who were in SDAI remission (SDAI ≤3.3) were randomized to receive ENBREL + MTX combination therapy (n=51), ENBREL monotherapy (n=101), or MTX monotherapy (n=101).2

    Primary endpoint:1

    • Proportion of patients in SDAI remission (SDAI ≤3.3) at Week 48 without disease-worsening on ENBREL monotherapy compared with MTX monotherapy

    Select secondary endpoints:1

    • Proportion of patients in SDAI remission at Week 48 without disease-worsening on ENBREL + MTX compared with MTX monotherapy
    • Proportion of patients with disease-worsening and time to disease-worsening in ENBREL monotherapy, MTX monotherapy, and ENBREL + MTX combination therapy
    • Time to recapture SDAI remission after initiating ENBREL + MTX rescue therapy, the proportion of patients with disease-worsening who recaptured SDAI remission with rescue therapy, and their SDAI scores over time
    The SEAM-RA Study Design2

    *During the double-blind phase, patients with disease-worsening could receive rescue therapy with weekly ENBREL + MTX (ie, reestablished or continued combination therapy using the same doses received at study enrollment) in an attempt to recapture remission. Patients were considered to have disease-worsening if they had an increased SDAI score >3.3 and ≤11 on two consecutive visits at least 2 weeks apart, or SDAI >3.3 and ≤11 at any time on three or more separate visits, or SDAI >11 at any time.

Important Information About Risks

  • Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown3-5
  • NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)3
  • Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia3
  • Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants3
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported3
  • Tuberculosis (TB): Cases of reactivation TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment3

EOS, end of study; MTX, methotrexate; QW, every week; SEAM-RA, study of etanercept and methotrexate in combination or as monotherapy in subjects with rheumatoid arthritis; SDAI, simple disease activity index; TNF, tumor necrosis factor.

TEMPO Study

Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 disease-modifying antirheumatic drug (DMARD) other than MTX

Select Safety Results

Significant adverse events, medically important infections, and malignancy rates were similar across all 3 treatment arms6

Select Safety Results From the TEMPO Study Through Year 37*
MTX (n=228) ENBREL (n=223) ENBREL + MTX (n=231)
Treatment-emergent adverse events 201 (88.2%) 206 (92.4%) 210 (90.9%)
Discontinuation due to adverse events 52 (22.8%) 39 (17.5%) 35 (15.2%)
Serious adverse events 43 (18.9%) 51 (22.9%) 54 (23.4%)
Serious infections 19 (8.3%) 15 (6.7%) 17 (7.4%)
Malignancies 4 (1.8%) 6 (2.7%) 5 (2.2%)
Death 1 (0.5%) 2 (1%) 2 (1%)

*Including nonmelanoma skin cancers (MTX, ENBREL, ENBREL + MTX).

  • Study Design

    The TEMPO Study was a 3-year, multicenter, double-blind, randomized, controlled trial (RCT) of 682 patients in Europe, Australia, and Israel with moderate to severe RA (mean disease duration of 6.6 years) who had failed ≥1 DMARD other than MTX. Patients received either ENBREL 25 mg biweekly (BIW) + MTX (n=231), ENBREL 25 mg BIW + placebo (n=223), or placebo + MTX (n=228) over 3 years. Use of concomitant corticosteroids and/or NSAIDs was permitted.3,6,7

    • Primary endpoints: Numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks and change from baseline in mTSS at Year 16
    • Select secondary endpoints: ACR 20, ACR 50, ACR 70, CRP, HAQ score, and DAS 28 clinical remission6

Important Information About Risks

  • Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown3-5
  • NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)3
  • Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia3
  • Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants3
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported3
  • Tuberculosis (TB): Cases of reactivation TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment3

ACR, American College of Rheumatology; ACR 20/50/70, American College of Rheumatology (20/50/70) percent response; CRP, C-reactive protein; DAS 28, disease activity score in 28 joints; HAQ, Health Assessment Questionnaire; mTSS, modified total Sharp score; TEMPO, Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes.

ERA Study

Evaluation of ENBREL and MTX in early moderate to severe RA, including an analysis of MTX discontinuation

10 Years of Continuous Safety Data

  • The serious infections and malignancy rates in the LRA, COMET, TEMPO, and PsA studies were consistent with the rates shown here7-17
  • In patients receiving TNF-blocking agents, opportunistic infections, including TB, histoplasmosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, pneumocystosis, legionella, and listeriosis, have been reported3

Malignancy rates and serious infection rates were similar to MTX at Year 1 and consistent over 10 years10,11

Malignancy Rates Similar to MTX at Year 1 and
Consistent Over 10 Years (Events/Patient-Year)8,10,11,18*†‡§
Serious Infection Rates Similar to MTX at Year 1 and
Consistent Over 10 Years (Events/Patient-Year)8,10,11,19*†‡

*In the controlled portion, event rates were based on the definition of medically important infections (infections associated with hospitalization or intravenous antibiotics). For long-term therapy, serious infections were defined as all serious adverse events that were infectious.8

Observed on study or within 30 days after the last ENBREL dose. The population for each year reflects all adult patients at the time of analysis who received at least 1 dose of study drug.8

Includes all patients who received at least 1 dose of ENBREL in the randomized controlled trial (RCT) and/or the open-label extension (OLE).19

§Data are from clinical studies and include all Surveillance, Epidemiology, and End Results (SEER)-defined cancers (excluding nonmelanoma skin cancers, in situ carcinomas except bladder, and recurrent cancers), and comparisons are based on age and sex-matched cohorts.8

SIR = standardized incidence ratio, which is an estimate of the occurrence of the specified condition in the ENBREL population relative to what might be expected in a larger comparison population designated as normal or average, such as the general population.

Study Design

The Early RA (ERA) Study was a 1-year, multicenter, randomized, double-blind study of 632 patients with early moderately to severely active RA (≤3 years' duration) with mean disease duration of 11.2 months. In Year 1 of the study, patients were randomized to receive ENBREL 10 mg BIW (n=208), ENBREL 25 mg BIW (n=207), or MTX (up to 20 mg/week, n=217). At Year 2, patients continued in an open-label treatment period. At Year 3, patients switched to or continued ENBREL 25 mg BIW for an open-label extension (OLE) (n=468). MTX could be continued or started as necessary in the OLE at the investigator's discretion.3,8,10

  • All statistical analyses conducted during the OLE are considered descriptive and not confirmatory and therefore are not presented. Consider the following limitations when evaluating OLE results:
  • There is no concurrent control arm, limiting the estimate of treatment effect

    Data are based only on patients who continued taking ENBREL at each year. Reasons for discontinuation included lack of tolerability, lack of efficacy, and loss to follow-up. Response rates may represent an enriched proportion of patients with continued efficacy and tolerability

  • Additional Study Details
    • Primary endpoints: Numeric index of the ACR response (ACR-N) area under the curve (AUC) at Month 6 and change from baseline in mTSS at Year 118
    • Baseline patient demographics: Mean age was 50 years, 25% of patients were male, and mean disease duration was 11.2 months10,11
    The ERA Study3,8*

    *At the end of Year 2, patients switched to or continued on ENBREL 25 mg BIW.

Important Information About Risks

  • Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown3-5
  • NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)3
  • Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia3
  • Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants3
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported3
  • Tuberculosis (TB): Cases of reactivation TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment3

BIW, biweekly (twice a week); COMET, comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis; ERA, early rheumatoid arthritis; LRA, late rheumatoid arthritis; PsA, psoriatic arthritis.

Prescription Enbrel® (etanercept) is administered by injection.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before ENBREL use and periodically during therapy. Initiate treatment for latent infection prior to ENBREL use, 2) Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.

MALIGNANCIES

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.

In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.

Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.

Pediatric Patients

In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

NEUROLOGIC REACTIONS

Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

NEW ONSET OR WORSENING OF HEART FAILURE

Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.

HEMATOLOGIC REACTIONS

Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.

HEPATITIS B REACTIVATION

Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.

ALLERGIC REACTIONS

Allergic reactions associated with administration of ENBREL during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, discontinue administration of ENBREL and initiate appropriate therapy immediately.

IMMUNIZATIONS

Avoid concurrent administration of live vaccines with ENBREL. Patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.

AUTOIMMUNITY

Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if findings suggestive of lupus-like syndrome or autoimmune hepatitis develop and evaluate the patient.

NOT RECOMMENDED FOR GRANULOMATOSIS WITH POLYANGIITIS PATIENTS ON IMMUNOSUPPRESSANTS

The use of ENBREL in patients with granulomatosis with polyangiitis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.

INCREASED MORTALITY IN PATIENTS WITH MODERATE TO SEVERE ALCOHOLIC HEPATITIS

Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

ADVERSE REACTIONS

The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.

In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.

DRUG INTERACTIONS

The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Please see Prescribing Information and Medication Guide.

INDICATIONS

ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated in combination with methotrexate (MTX) or used alone.

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in adult patients with psoriatic arthritis. ENBREL can be used with or without MTX.

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

ENBREL is indicated for the treatment of active juvenile psoriatic arthritis in pediatric patients 2 years of age and older.

Prescription Enbrel® (etanercept) is administered by injection.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to

References:

  1. Curtis JR, Emery P, Karis E, et al. Etanercept or methotrexate withdrawal in rheumatoid arthritis patients in sustained remission. Arthritis Rheumatol. 2021;73(5):759-768.
  2. Data on file, Amgen; SEAM-RA CSR 20110186. April 23, 2020.
  3. Enbrel® (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation.
  4. HUMIRA (adalimumab) Prescribing Information. North Chicago, IL: AbbVie Inc.; 2021.
  5. REMICADE (infliximab) Prescribing Information. Horsham, PA: Janssen Biotech, Inc.; 2021.
  6. van er Heijde D, Klareskog L, Landewé R, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2007;56(12):3928-3939.
  7. Data on file, Amgen; TEMPO CSR 57599 3 yr Clinical. June 21, 2005.
  8. Weinblatt ME, Bathon JM, Kremer JM, et al. Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63(3):373-382.
  9. Data on file, Amgen; 1618 LRA Final. December 15, 2009.
  10. Data on file, Amgen; 1623 ERA 5 yr. October 20, 2003.
  11. Data on file, Amgen; 1623 ERA Final. December 15, 2009.
  12. Data on file, Amgen; 1630 PsA 2 yr. August 5, 2004.
  13. Data on file, Amgen; COMET 1 yr SIE Rates. April 9, 2009.
  14. Data on file, Amgen; COMET Biostats Safety Data Serious Infections. March 10, 2009.
  15. Data on file, Amgen; COMET CSR 69344 1 yr Clinical. September 18, 2007.
  16. Data on file, Amgen; COMET CSR 72719 2 yr Clinical. September 21, 2008.
  17. Data on file, Amgen; PRESERVE CSR Period 2. October 14, 2011.
  18. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586-1593.
  19. Genovese MC, Bathon JM, Fleischmann RM, et al. Long-term safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32:1232-1242.