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The perceived risk-benefit ratio for individuals with early active RA
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Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease in which the body's immune system attacks its own normal tissues. This abnormal autoimmune response can result in damage to many parts of the body, including the skin, joints, lungs, heart, brain, intestines, and kidneys. Kidney problems occur in 60-75 % of lupus patients. The development of lupus-related kidney disease (called lupus nephritis) is associated with an overall worse prognosis.
SLE is usually treated with drugs that try to block inflammation caused by the immune system. These treatments can create their own problems and they do not cure lupus. The drugs that are often used to treat lupus nephritis include prednisone (steroids), cyclophosphamide (Cytoxan), azathioprine (AZA or Imuran), and mycophenolate mofetil (MMF or Cellcept). The main purpose of this study is to evaluate the safety and tolerability of etanercept compared to placebo in combination with standard of care to treat individuals with active lupus nephritis.
Kidney problems associated with lupus nephritis range from asymptomatic protein in the urine to rapidly progressive glomerulonephritis, leading to end-stage renal disease. The goal of therapies is to control kidney manifestations in order to avoid kidney failure, the occurrence of other medical problems and death.
The treatment of lupus nephritis remains problematic. Despite the use of currently available therapies, patients experience disease relapse. Over time, patients develop significant morbidity from the disease as well as from medications used for treatment.
Etanercept, a TNF inhibitor, is proposed as a potential treatment for lupus nephritis. TNF increases the number of reactive B and T cells. TNF levels can be elevated in lupus. Etanercept is believed to work by blocking inflammation, and it is hoped that it will lessen the signs and symptoms of lupus-related kidney disease.
The purpose of this study is to evaluate the safety and tolerability of etanercept compared to placebo in combination with standard therapy to treat individuals with mild or moderately active lupus nephritis.
This study will last 1 year. Participants will be randomly assigned to receive either etanercept or placebo in addition to their regular medications. Participants will self-administer 50 mg etanercept or placebo injections once a week. They will continue receiving their usual treatment with corticosteroids and either MMF, Mycophenolic Acid, or AZA. Treatment with study medication will occur for 24 weeks.
There will be a screening visit followed by a randomization visit, where subjects will receive and learn how to administer the study drug. Subjects will come to the clinic for 9 study visits. A physical exam and blood and urine collection will occur at most study visits. Participants will also be asked to complete a questionnaire on their health at most study visits. Subjects will be contacted by phone 5 times during the 24-week period to assess for adverse events and worsening disease status.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Etanercept | Experimental | Participants in this group will self-administer 50 mg etanercept injections once a week for 24 weeks. They will continue receiving their usual treatment with corticosteroids and either mycophenolate mofetil (MMF), mycophenolic acid, or azathioprine (AZA). |
|
| Placebo | Placebo Comparator | Participants in this group will self-administer 50 mg placebo injections once a week for 24 weeks. They will continue receiving their usual treatment with corticosteroids and either mycophenolate mofetil (MMF), mycophenolic acid, or azathioprine (AZA). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Etanercept | Drug | 1.) Immune suppressant. 2.) Tumor necrosis factor (TNF) inhibitor. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Adverse Events (AEs)Grade 3 or Higher Experienced by Participant During Treatment Phase of Study | Number of adverse events (AEs) or serious adverse events (SAEs) Grade 3 or higher experienced by participant over the duration of the treatment period. [1] [1] This study graded the severity of AEs experienced by the study participant according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0. | 24 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participant Adverse Events (AEs) From Baseline to Early Study Withdrawal Visit | Number of participant AEs during the trial. This study graded the severity of AEs experienced by the study participant according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0. | 39 Weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Maria Dall'Era, MD | Division of Rheumatology, University of California, San Francisco | Study Chair |
| David Wofsy, MD | Department of Medicine, University of California, San Francisco | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35294 | United States | ||
| University of California at San Francisco |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15476222 | Background | Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum. 2004 Oct;50(10):3161-9. doi: 10.1002/art.20576. | |
| 16425572 | Background | De Rycke L, Baeten D, Kruithof E, Van den Bosch F, Veys EM, De Keyser F. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications. Lupus. 2005;14(12):931-7. doi: 10.1191/0961203305lu2240rr. |
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The participant signed an informed consent before study screening procedures commenced to assess eligibility criteria (lupus diagnosis with active nephritis, positive ANA, presence of dsDNA antibodies, and stable medication regimens of either mycophenolate mofetil (MMF, CellCept®, Myfortic®) or azathioprine at the screening visit.
Participant recruitment occurred at 6 sites. All sites were affiliated with a university and utilized a lupus clinic and outside referrals for recruitment. The first site (UCSF) was activated on 1 Feb 2008. The remaining 5 sites (Feinstein, Rochester, Colorado, Duke, and UAB) were activated over the next year.
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| ID | Title | Description |
|---|---|---|
| FG000 | Etanercept | Participants (or their caretaker) would administer 50 mg etanercept subcutaneous injections once weekly for 24 weeks. They would continue receiving their usual treatment with corticosteroids and either mycophenolate mofetil or azathioprine. |
| FG001 | Placebo | Participants (or their caretaker) would administer 50 mg placebo subcutaneous injections once weekly for 24 weeks. They would continue receiving their usual treatment with corticosteroids and either mycophenolate mofetil or azathioprine. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Etanercept | Participant self-administered 50 mg etanercept subcutaneous injections once weekly for 24 weeks. She continued receiving her usual treatment with corticosteroids and mycophenolate mofetil. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Adverse Events (AEs)Grade 3 or Higher Experienced by Participant During Treatment Phase of Study | Number of adverse events (AEs) or serious adverse events (SAEs) Grade 3 or higher experienced by participant over the duration of the treatment period. [1] [1] This study graded the severity of AEs experienced by the study participant according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0. | Posted | Number | Events | 24 Weeks |
|
|
Baseline to 39 weeks
This study graded the severity of adverse events experienced by the study participant according to criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Etanercept | Participant received self-administered 50 mg etanercept subcutaneous injections once weekly for 24 weeks while continuing to receive her usual lupus treatment of corticosteroids and mycophenolate mofetil. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
The study terminated early with 1 subject enrolled. Based on safety info from other trials, the protocol chairs decided possible risks to patients outweighed the potential benefits. Analysis of groups is not possible. Study objectives cannot be met.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Associate Director for Clinical Research | DAIT/NIAID | 301-594-7669 | DAITClinicalTrialsGov@niaid.nih.gov |
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| ID | Term |
|---|---|
| D008181 | Lupus Nephritis |
| ID | Term |
|---|---|
| D005921 | Glomerulonephritis |
| D009393 | Nephritis |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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| ID | Term |
|---|---|
| D000068800 | Etanercept |
| ID | Term |
|---|---|
| D007141 | Immunoglobulin Fc Fragments |
| D007128 | Immunoglobulin Fragments |
| D010446 | Peptide Fragments |
| D010455 | Peptides |
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| Lupus Treatment- Standard of Care | Drug | Individualized standard of care treatment for lupus with corticosteroids and with mycophenolate mofetil (MMF), mycophenolic acid, or azathioprine (AZA) |
|
| Placebo | Drug |
|
| Percent of Participants Who Achieved a Renal Response at Week 24 | Percent of study participants who achieved a renal response at 24 weeks.[1] [1]A renal response is defined as: 1) 50% reduction in proteinuria compared to baseline as measured by urinary protein: creatinine ratio; and 2) stable or improving renal function as defined by the Glomerular filtration rate (GFR) calculated based on the "Modification of Diet in Renal Disease" equation (Levy, AS, Coresh J, Galk E et al, National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med, 139(2): 137-47, 2003) | Week 24 |
| Time to Participant's Renal Response | Time to when participant achieved a renal response[1] [1]A renal response is defined as: 1) 50% reduction in proteinuria compared to baseline as measured by urinary protein: creatinine ratio; and 2) stable or improving renal function as defined by the Glomerular filtration rate (GFR) calculated based on the "Modification of Diet in Renal Disease" equation (Levy, AS, Coresh J, Galk E et al, National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med, 139(2): 137-47, 2003) | First 24 Weeks of Study Period |
| Participant Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) Score at Baseline and at Early Study Withdrawal Visit | Reported here is the baseline and week 39 Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) scores. The SLEDAI is a concise measure of lupus disease activity with excellent test-retest reliability and high responsiveness to clinically important changes in the disease. The total score is derived from ratings on 24 conditions plus the Physician's Global Assessment; 0 indicates inactive disease and the maximum theoretical score is 105, with higher scores representing increased disease activity. | Baseline, Week 39 (Early Study Withdrawal Visit) |
| Number of Participants With a C to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Mucocutaneous Score | Reported here is the number of participants with a change in their BILAG Mucocutaneous Score from C (at baseline) to B (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0). A maximum mucocutaneous score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system. | Baseline, Week 24 |
| Number of Participants With a B to D Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Musculoskeletal Score | Reported here is the number of participants with a change in their BILAG Musculoskeletal Score from B (at baseline) to D (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0).A maximum musculoskeletal score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system. | Baseline, Week 24 |
| Number of Participants With an A to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Renal Score | Reported here is the number of participants with a change in their BILAG Renal Score from A (at baseline) to B (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0).A maximum renal score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system | Baseline, Week 24 |
| Participant Medical Outcome Study Short-Form 36 (SF-36) Physical Component Score at Baseline and Week 24 | Reported here is the participant baseline and week 24 SF-36 Physical Component scores. The SF-36 measures 8 domains: physical functioning, role limitations due to physical health, body pain, social functioning, mental health, role limitations due to emotional problems, vitality, and general health perceptions[1]. The Physical Component scores of the SF-36 range from 0 to 100; 0 equals worst health state. Higher numbers reported here indicate more improvement in condition from baseline. [1]Ref: Ware JE, Sherbourne CD. The MOS36-item short-form health survey Med Care. 1992; 30:473-483. | Baseline, Week 24 |
| Participant Medical Outcome Study Short Form 36 (SF-36) Mental Component Score at Baseline and Week 24 | Reported here are the participant SF-36 Mental Component scores at baseline and week 24. The SF-36 measures 8 domains: physical functioning, role limitations due to physical health, bodily pain, social functioning, mental health, role limitations due to emotional problems, vitality, and general health perceptions.[1] The Mental Component score of the SF-36 ranges from 0 to 100; 0 equals worst health state. Higher numbers reported here indicate more improvement in condition from baseline. [1]Ref: Ware JE, Sherbourne CD. The MOS36-item short-form health survey. Med Care. 1992; 30:473-483 | Baseline, Week 24 |
| San Francisco |
| California |
| 94143 |
| United States |
| University of Colorado Health Sciences Center | Aurora | Colorado | 80045 | United States |
| Feinstein Institute for Medical Research NS-L1J Health System | Manhasset | New York | 11030 | United States |
| University of Rochester | Rochester | New York | 14642 | United States |
| Duke University Medical Center | Durham | North Carolina | 27709 | United States |
| 15801034 | Background | Mor A, Bingham CO 3rd, Barisoni L, Lydon E, Belmont HM. Proliferative lupus nephritis and leukocytoclastic vasculitis during treatment with etanercept. J Rheumatol. 2005 Apr;32(4):740-3. |
| 15370396 | Background | Scheinfeld N. A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat. 2004 Sep;15(5):280-94. doi: 10.1080/09546630410017275. |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | Participants |
|
| Day 0 GFR (mL/min per 1.73m^2) | Glomerular filtration rate (GFR) is calculated based on the "Modification of Diet in Renal Disease" equation (Levy, AS, Coresh J, Galk E et al, National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med, 139(2): 137-47, 2003) | Mean | Full Range | mL/min/1.73m^2 |
|
| Day 0 random urine protein | Mean | Full Range | mg/dL |
|
| SLEDAI total score | The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a concise measure of lupus disease activity with excellent test-retest reliability and high responsiveness to clinically important changes in the disease. The total score is derived from ratings on 24 conditions plus the Physician's Global Assessment; 0 indicates inactive disease and the maximum theoretical score is 105 with higher scores representing increased disease activity. | Mean | Full Range | Score |
|
|
|
| Secondary | Number of Participant Adverse Events (AEs) From Baseline to Early Study Withdrawal Visit | Number of participant AEs during the trial. This study graded the severity of AEs experienced by the study participant according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0. | Posted | Number | Events | 39 Weeks |
|
|
|
| Secondary | Percent of Participants Who Achieved a Renal Response at Week 24 | Percent of study participants who achieved a renal response at 24 weeks.[1] [1]A renal response is defined as: 1) 50% reduction in proteinuria compared to baseline as measured by urinary protein: creatinine ratio; and 2) stable or improving renal function as defined by the Glomerular filtration rate (GFR) calculated based on the "Modification of Diet in Renal Disease" equation (Levy, AS, Coresh J, Galk E et al, National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med, 139(2): 137-47, 2003) | Posted | Number | Percent of Participants | Week 24 |
|
|
|
| Secondary | Time to Participant's Renal Response | Time to when participant achieved a renal response[1] [1]A renal response is defined as: 1) 50% reduction in proteinuria compared to baseline as measured by urinary protein: creatinine ratio; and 2) stable or improving renal function as defined by the Glomerular filtration rate (GFR) calculated based on the "Modification of Diet in Renal Disease" equation (Levy, AS, Coresh J, Galk E et al, National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med, 139(2): 137-47, 2003) | Posted | Number | Weeks | First 24 Weeks of Study Period |
|
|
|
| Secondary | Participant Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) Score at Baseline and at Early Study Withdrawal Visit | Reported here is the baseline and week 39 Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) scores. The SLEDAI is a concise measure of lupus disease activity with excellent test-retest reliability and high responsiveness to clinically important changes in the disease. The total score is derived from ratings on 24 conditions plus the Physician's Global Assessment; 0 indicates inactive disease and the maximum theoretical score is 105, with higher scores representing increased disease activity. | Posted | Number | Points on a scale | Baseline, Week 39 (Early Study Withdrawal Visit) |
|
|
|
| Secondary | Number of Participants With a C to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Mucocutaneous Score | Reported here is the number of participants with a change in their BILAG Mucocutaneous Score from C (at baseline) to B (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0). A maximum mucocutaneous score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system. | Posted | Number | Participants | Baseline, Week 24 |
|
|
|
| Secondary | Number of Participants With a B to D Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Musculoskeletal Score | Reported here is the number of participants with a change in their BILAG Musculoskeletal Score from B (at baseline) to D (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0).A maximum musculoskeletal score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system. | Posted | Number | Participants | Baseline, Week 24 |
|
|
|
| Secondary | Number of Participants With an A to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Renal Score | Reported here is the number of participants with a change in their BILAG Renal Score from A (at baseline) to B (at week 24). A single alphabetic score (A through E) is used to denote disease severity. The BILAG score is a converted numerical score (A=9, B=3, C=1, D=0, E=0).A maximum renal score of 9 signifies higher disease activity and a score of 0 is indicative of inactive systematic lupus erythematosus (SLE) in the specified organ system | Posted | Number | Participants | Baseline, Week 24 |
|
|
|
| Secondary | Participant Medical Outcome Study Short-Form 36 (SF-36) Physical Component Score at Baseline and Week 24 | Reported here is the participant baseline and week 24 SF-36 Physical Component scores. The SF-36 measures 8 domains: physical functioning, role limitations due to physical health, body pain, social functioning, mental health, role limitations due to emotional problems, vitality, and general health perceptions[1]. The Physical Component scores of the SF-36 range from 0 to 100; 0 equals worst health state. Higher numbers reported here indicate more improvement in condition from baseline. [1]Ref: Ware JE, Sherbourne CD. The MOS36-item short-form health survey Med Care. 1992; 30:473-483. | Posted | Number | Score on a scale | Baseline, Week 24 |
|
|
|
| Secondary | Participant Medical Outcome Study Short Form 36 (SF-36) Mental Component Score at Baseline and Week 24 | Reported here are the participant SF-36 Mental Component scores at baseline and week 24. The SF-36 measures 8 domains: physical functioning, role limitations due to physical health, bodily pain, social functioning, mental health, role limitations due to emotional problems, vitality, and general health perceptions.[1] The Mental Component score of the SF-36 ranges from 0 to 100; 0 equals worst health state. Higher numbers reported here indicate more improvement in condition from baseline. [1]Ref: Ware JE, Sherbourne CD. The MOS36-item short-form health survey. Med Care. 1992; 30:473-483 | Posted | Number | Score on a scale | Baseline, Week 24 |
|
|
|
| 0 |
| 1 |
| 1 |
| 1 |
| Muscle Strain | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Otitis media | Infections and infestations | Systematic Assessment |
|
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| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D008180 | Lupus Erythematosus, Systemic |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D000602 |
| Amino Acids, Peptides, and Proteins |
| D007127 | Immunoglobulin Constant Regions |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D018124 | Receptors, Tumor Necrosis Factor |
| D018121 | Receptors, Cytokine |
| D011971 | Receptors, Immunologic |
| D011956 | Receptors, Cell Surface |
| D008565 | Membrane Proteins |