Evaluation of etanercept and methotrexate in combination or as monotherapy in subjects with rheumatoid arthritis
Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 DMARD other than MTX
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. 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).1
Select secondary endpoints1:
EOS, end of study; MTX, methotrexate; QW, every week.
SDAI is a simple calculation and convenient tool for clinical practices to assess remission that’s in addition to DAS 28.* A patient’s SDAI is the sum of the following scores1,2:
*DAS 28 allows for up to 6 swollen joints, and a score of <2.6 meets the criteria for remission. SDAI allows for up to 2 swollen joints, and a score of ≤3.3 meets the criteria for remission. DAS 28 requires a value for ESR or CRP and a more complex calculation, for which a calculator may be necessary, while SDAI requires only simple addition of the component values. Lab testing is required.1,3
CRP, C-reactive protein; DAS 28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; SDAI, simple disease activity index.
|Mean age in years (SD)||55.9
|Mean disease duration in years (SD)||10.3
|% Rheumatoid factor positive||68.6||63.4||58.4|
|% Anti-CCP positive||68.6||66.3||65.3|
|Mean MTX dose mg/week (SD)||17.06
|Mean SDAI score (SD)||1.2
|Mean HAQ-DI (SE)||0.28
Anti-CCP, anti-cyclic citrullinated peptide; HAQ-DI, Health Assessment Questionnaire Disability Index.
ENBREL monotherapy helped significantly more patients maintain SDAI remission without disease-worsening compared with MTX monotherapy1
*Non-responder imputation. The primary analysis set included all randomized subjects. The analysis was conducted according to the original randomization assignment regardless of the actual treatment received during the study (as per intent-to-treat principle).
†ENBREL + MTX vs MTX monotherapy. The risk difference and its P value were estimated from the Chi-squared test with continuity correction.
‡ENBREL monotherapy vs MTX monotherapy. The risk difference and its P value were estimated from the Chi-squared test with continuity correction.
The time to disease-worsening was shorter for patients on MTX monotherapy compared to ENBREL monotherapy1
75% of patients on ENBREL monotherapy who received rescue therapy recaptured SDAI remission by the end of the study1
The COMET study was a 24-month, multicenter, randomized, double-blind, 2-period study of 542 patients with moderately to severely active RA (from ≥3 months‘ to ≤2 years‘ duration) with mean disease duration of 9 months and mean baseline disease activity score (DAS) 28 score of 6.5. 7 In Year 1 of the study, patients were randomized to receive once-weekly ENBREL 50 mg + weekly methotrexate (MTX), up to 20 mg/week (n=274); or MTX alone (n=268). 7 At Year 2, the original combination group either continued combination therapy (n=108) or received ENBREL monotherapy (n=108); the original MTX monotherapy group either received combination therapy (n=88) or continued MTX monotherapy (n=94). 7,8
|Mean age||51 years|
|Mean disease duration||9.0 months|
|Mean DAS 28||6.5|
|Mean tender joint count||25|
|Mean swollen joint count||17|
ENBREL + MTX delivers fast symptom improvement and helps stop radiographic progression
a ENBREL + MTX: n=265, MTX: n=262.
b ENBREL + MTX: n=265, MTX: n=263.
c ENBREL + MTX demonstrated a mean reduction of 27 mm on a visual pain scale of 100 mm at Week 2 compared to 8 mm for MTX alone.
d ENBREL + MTX: n=262, MTX: n=258.
CRP = C-reactive protein; LOCF = last observation carried forward.
a Patients were randomly assigned to 1 of 4 treatment groups (Group 1A, 1B, 2A, or 2B) at the beginning of the study. During Year 1 of the study, Groups 1A and 1B were combined in the ENBREL + MTX treatment arm, and Groups 2A and 2B were combined in the MTX treatment arm. Not all subjects randomized to Year 2 groups were present in the Year 2 efficacy population, due to withdrawals during Year 1. See Study Design for more information about the Year 1 and Year 2 study populations.8
The majority of ENBREL + MTX patients achieved a HAQ score consistent with the general population (HAQ ≤0.5)9,11*
* HAQ score of ≤0.5 is consistent with the score of the general population.11
† The data points shown at Year 1 represent results for combined study arms (Group 1A + Group 1B and Group 2A + Group 2B) reported at the end of Year 1 of treatment. For the study populations entering Year 2 of treatment, the percentages of patients who had achieved HAQ ≤0.5 at the Year 1 time point were 57%, 62%, 51%, and 43% in Groups 1A, 1B, 2A, and 2B respectively.11
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 7 years) who had failed ≥1 disease-modifying antirheumatic drug (DMARD) other than MTX.13-15 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.15-18
§ ENBREL + MTX vs MTX (P<0.0001); ENBREL vs MTX (P=0.0034); ENBREL + MTX vs ENBREL (P<0.0001).
**ENBREL + MTX vs MTX (P<0.01); ENBREL vs MTX (P<0.01); ENBREL + MTX vs ENBREL (P<0.01).
†† Major clinical response is achieving an ACR 70 response for a continuous 6-month period.
ITT = intent-to-treat.
‡‡ HAQ score of ≤0.5 is consistent with the score of the general population.24
a P<0.01 vs MTX; b P<0.05 vs MTX; c P<0.01 vs ENBREL.
§§ Per protocol, in order to read the Year 3 data (N=638), the Year 1 (N=648) and Year 2 data (N=622) were reread. Because of known variability in reading of the radiographic images in RA, all radiographs were reread and blinded to patient and time point by the 2 physicians who read the images for the Year 2 report. Thus, the Year 3 scoring of the radiographic images is considered a new reading of the Year 1 and Year 2 time points.
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.13,28,29 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 (n=468). MTX could be continued or started as necessary in the open-label extension (OLE) at the investigator's discretion.30-32
MODERATE TO SEVERE RHEUMATOID ARTHRITISLearn about RA safety results
Prescription Enbrel® (etanercept) is administered by injection.
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. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated 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. Empiric antifungal therapy should be considered 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. Patients should be closely monitored 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.
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.
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.
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.
CONGESTIVE 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.
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 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, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.
Live vaccines should not be administered to patients on ENBREL. Pediatric 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.
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 lupus-like syndrome or autoimmune hepatitis develops.
WEGENER'S GRANULOMATOSIS PATIENTS
The use of ENBREL in patients with Wegener’s granulomatosis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.
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.
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.
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.
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 (RA). ENBREL can be initiated in combination with methotrexate (MTX) or used alone.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). ENBREL can be used with or without MTX.
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 reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.