Etanercept

Number: 0315

Table Of Contents

Policy

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with one of the following:

   1. Rheumatoid arthritis, articular juvenile idiopathic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, reactive arthritis, and Behcet’s disease: rheumatologist;
   2. Psoriatic arthritis and hidradenitis suppurativa: rheumatologist or dermatologist;
   3. Plaque psoriasis: dermatologist;
   4. Graft versus host disease: oncologist or hematologist;
   5. Immune checkpoint inhibitor-related inflammatory arthritis: oncologist, hematologist, or rheumatologist
   6. Immune checkpoint inhibitor-related toxicity: oncologist, hematologist, or dermatologist.

2. Criteria for Initial Approval

   Aetna considers Enbrel (etanercept) medically necessary for the following indications, where the member has a documented negative tuberculosis (TB) test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnote1* within 6 months of initiating therapy for persons who are naive to biologic drugs or targeted synthetic drugs associated with increased risk of TB:

   1. Rheumatoid arthritis (RA)

   1. For adults members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Xeljanz) indicated for moderately to severely active RA; or
   2. For adult members for treatment of moderately to severely active RA when all of the following criteria are met:
      

      1. Member meets either of the following criteria:

         1. Member has been tested for either of the following biomarkers and the test was positive:

            1. Rheumatoid factor (RF); or
            2. Anti-cyclic citrullinated peptide (anti-CCP); or

         2. Member has been tested for all of the following biomarkers:

            1. RF; and
            2. Anti-CCP; and
            3. C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR); and

      2. Member meets either of the following criteria:

         1. Member has had an inadequate response to at least a 3-month trial of methotrexate despite adequate dosing (i.e., titrated to at least 15 mg/week); or
         2. Member has an intolerance or contraindication to methotrexate (see Appendix A);

   2. Articular juvenile idiopathic arthritis (JIA)

      1. For members 2 years of age or older who have previously received a biologic or targeted synthetic drug (e.g., Xeljanz) indicated for moderately to severely active articular juvenile idiopathic arthritis; or
      2. For members 2 years of age or older for treatment of moderately to severely active articular JIA when any of the following criteria is met:
         
         
         1. Member has had an inadequate response to methotrexate or another conventional synthetic drug (e.g., leflunomide, sulfasalazine, hydroxychloroquine) administered at an adequate dose and duration; or
         2. Member has had an inadequate response to a trial of scheduled non-steroidal anti-inflammatory drugs (NSAIDs) and/or intra-articular glucocorticoids (e.g., triamcinolone hexacetonide) and one of the following risk factors for poor outcome:
            
            
            1. Involvement of ankle, wrist, hip, sacroiliac joint, and/or temporomandibular joint (TMJ); or
            2. Presence of erosive disease or enthesitis; or
            3. Delay in diagnosis; or
            4. Elevated levels of inflammation markers; or
            5. Symmetric disease; or

         3. Member has risk factors for disease severity and potentially a more refractory disease course (see Appendix B) and member also meets one of the following:

            1. High-risk joints are involved (e.g., cervical spine, wrist, or hip); or
            2. High disease activity; or
            3. Is judged to be at high risk for disabling joint disease;

   3. Psoriatic arthritis (PsA)

      1. For members 2 years of age or older who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Otezla) indicated for active psoriatic arthritis; or
      2. For members 2 years of age or older for treatment of active psoriatic arthritis when either of the following criteria is met:
         
         

         1. Member has mild to moderate disease and meets one of the following criteria:

            1. Member had an inadequate response to methotrexate, leflunomide, or another conventional synthetic drug (e.g., sulfasalazine) administered at an adequate dose and duration; or
            2. Member has an intolerance or contraindication to methotrexate or leflunomide (see Appendix A), or another conventional synthetic drug (e.g., sulfasalazine); or
            3. Member has enthesitis or predominantly axial disease; or

         2. Member has severe disease;

   4. Ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA)

      1. For adult members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Xeljanz) indicated for active ankylosing spondylitis or active axial spondyloarthritis; or
      2. For adult members for treatment of active ankylosing spondylitis or active axial spondyloarthritis when any of the following criteria is met:
         
         
         1. Member has had an inadequate response to at least two non-steroidal anti-inflammatory drugs (NSAIDs); or
         2. Member has an intolerance or contraindication to two or more NSAIDs;

   5. Plaque psoriasis (PsO)

      1. For members 4 years of age or older who have previously received a biologic or targeted synthetic drug (e.g., Sotyktu, Otezla) indicated for the treatment of moderate to severe plaque psoriasis; or
      2. For members 4 years of age or older for treatment of moderate to severe plaque psoriasis when any of the following criteria is met:
         
         
         1. Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; or
         2. At least 10% of body surface area (BSA) is affected; or
         3. At least 3% of body surface area (BSA) is affected and the member meets either of the following criteria:
            
            
            1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine, or acitretin; or
            2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine, and acitretin (see Appendix A);

   6. Reactive arthritis

      1. For members who have previously received a biologic indicated for reactive arthritis; or
      2. For treatment of reactive arthritis when either of the following criteria is met:
         
         
         1. Member has had an inadequate response to methotrexate or sulfasalazine; or 
         2. Member has an intolerance or contraindication to methotrexate (see Appendix A) and sulfasalazine (e.g. porphyria, intestinal or urinary obstruction);

   7. Hidradenitis suppurativa

      1. For members who have previously received a biologic indicated for the treatment of severe, refractory hidradenitis suppurativa; or
      2. For treatment of severe, refractory hidradenitis suppurativa when either of the following is met:
         
         
         1. Member has had an inadequate response to an oral antibiotic used for the treatment of hidradenitis suppurative (e.g., clindamycin, metronidazole, moxifloxacin, rifampin, tetracyclines) for at least 90 days; or
         2. Member has an intolerance or contraindication to oral antibiotics used for the treatment of hidradenitis suppurative;

   8. Graft versus host disease

      For treatment of graft versus host disease when either of the following criteria is met:

      1. Member has had an inadequate response to systemic corticosteroids; or
      2. Member has an intolerance or contraindication to corticosteroids;

   9. Behcet’s disease

      1. For members who have previously received apremilast (Otelzla) or a biologic indicated for the treatment of Behcet’s disease; or
      2. For the treatment of Behçet’s disease when the member has had an inadequate response to at least one non-biologic medication for Behçet’s disease (e.g., azathioprine, colchicine, cyclosporine, systemic corticosteroids);

   10. Immune checkpoint inhibitor-related toxicity

       1. For treatment of immune checkpoint inhibitor-related toxicity when the member has Stevens-Johnson syndrome or toxic epidermal necrolysis; or
       2. For treatment of immune checkpoint inhibitor-related toxicity when the member has severe immunotherapy-related inflammatory arthritis and meets either of the following:
          
          
          1. Member has had an inadequate response to corticosteroids or a conventional synthetic drug (e.g., methotrexate, sulfasalazine, leflunomide, hydroxychloroquine); or
          2. Member has an intolerance or contraindication to corticosteroids and a conventional synthetic drug (e.g., methotrexate, sulfasalazine, leflunomide, hydroxychloroquine).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

3. Continuation of Therapy

   Aetna considers continuation of etanercept therapy medically necessary for the following indications: 

   1. Rheumatoid arthritis (RA)

      For all adult members (including new members) who are using the requested medication for moderately to severely active RA and who achieve or maintain a positive clinical response as evidenced by disease activity improvement of at least 20% from baseline in tender joint count, swollen joint count, pain, or disability;

   2. Articular juvenile idiopathic arthritis (JIA)

      For all members 2 years of age or older (including new members) who are using the requested medication for moderately to severely active articular JIA and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:

      1. Number of joints with active arthritis (e.g., swelling, pain, limitation of motion); or
      2. Number of joints with limitation of movement; or
      3. Functional ability;

   3. Psoriatic arthritis (PsA)

      For all members 2 years of age or older (including new members) who are using the requested medication for psoriatic arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:

      1. Number of swollen joints; or
      2. Number of tender joints; or
      3. Dactylitis; or
      4. Enthesitis; or
      5. Axial disease; or
      6. Skin and/or nail involvement;

   4. Ankylosing spondylitis (AS) and axial spondylarthritis (axSpA)

      For all adult members (including new members) who are using the requested medication for ankylosing spondylitis or non-radiographic axial spondyloarthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:

      1. Functional status; or
      2. Total spinal pain; or
      3. Inflammation (e.g., morning stiffness);

   5. Plaque psoriasis (PsO)

      For all members 4 years of age or older (including new members) who are using the requested medication for moderate to severe plaque psoriasis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when either of the following is met:

      1. Reduction in body surface area (BSA) affected from baseline; or
      2. Improvement in signs and symptoms from baseline (e.g., itching, redness, flaking, scaling, burning, cracking, pain);

   6. Reactive arthritis

      For all members (including new members) who are using the requested medication for reactive arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition (e.g., tender joint count, swollen joint count, or pain);

   7. Hidradenitis suppurativa

      For all members (including new members) who are using the requested medication for severe, refractory hidradenitis suppurativa and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when any of the following is met:

      1. Reduction in abscess and inflammatory nodule count from baseline; or
      2. Reduced formation of new sinus tracts and scarring; or
      3. Decrease in frequency of inflammatory lesions from baseline; or
      4. Reduction in pain from baseline; or
      5. Reduction in suppuration from baseline; or
      6. Improvement in frequency of relapses from baseline; or
      7. Improvement in quality of life from baseline; or
      8. Improvement on a disease severity assessment tool from baseline;

   8. Immune checkpoint inhibitor-related inflammatory arthritis

      For all members (including new members) who are using the requested medication for immunotherapy-related inflammatory arthritis and who achieve or maintain a positive clinical response with the requested medication as evidenced by low disease activity or improvement in signs and symptoms of the condition;

   9. Graft versus host disease and immune checkpoint inhibitor-related toxicity

      For all members (including new members) requesting authorization for continuation of therapy must meet all initial selection criteria;

   10. All other indications

       For all members (including new members) who are using the requested medication for an indication outlined in Section II and who achieve or maintain a positive clinical response with the requested medication as evidenced by low disease activity or improvement in signs and symptoms of the condition.

   Footnote1* If the screening test for TB is positive, there must be further testing to confirm there is no active disease. Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication.

4. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0341 - Infliximab
   3. CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions
   4. CPB 0655 - Adalimumab (Humira)
   5. CPB 0720 - Abatacept (Orencia)
   6. CPB 0761 - Certolizumab Pegol (Cimzia)
   7. CPB 0790 - Golimumab (Simponi and Simponi Aria)
   8. CPB 0905 - Secukinumab (Cosentyx)
   9. CPB 0912 - Ustekinumab (Stelara)

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Dose optimization with 50 mg product formulations should be used when possible. Exceptions for higher quantities of 25 mg vials will be allowed when the member has a latex allergy or is following FDA-approved weight-based dosing. Below includes dosing recommendations as per the FDA-approved prescribing information. 

Etanercept is available as Enbrel for:

• Injection: 25 mg/0.5 mL and 50 mg/mL solution in a single-dose prefilled syringe
• Injection: 50 mg/mL solution in single-dose prefilled SureClick® Autoinjector
• Injection: 25 mg/0.5 mL solution in a single-dose vial
• Injection: 25 mg lyophilized powder in a multiple-dose vial for reconstitution
• Injection: 50 mg/mL solution in Enbrel Mini® single-dose prefilled cartridge for use with the AutoTouch® reusable autoinjector only.

Enbrel is intended for use under the guidance and supervision of a physician. Persons may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Persons should not self-administer until they receive proper training in how to prepare and administer the correct dose.

Enbrel is administered by subcutaneous injection for the following FDA-approved indications:

• Adults with Rheumatoid Arthritis (RA), Ankylosing Spondylitis, or Psoriatic Arthritis (PsA): 50 mg once weekly with or without methotrexate (MTX)
• Adults with Plaque Psoriasis (PsO):
  
  
  • Starting dose: 50 mg twice weekly for 3 months
  • Maintenance dose: 50 mg once weekly
    
    

• Pediatrics 4 years of age or older with Plaque Psoriasis (PsO), or 2 years or older with Polyarticular Juvenile Idiopathic Arthritis (pJIA) or Juvenile Psoriatic ARthritis (JPsA): 

  • Weight of 63 kg (138 pounds) or more: 50 mg weekly
  • Weight less than 63 kg (138 pounds): 0.8 mg/kg weekly with a maximum of 50 mg per week.

Source: Immunex Corporation (Amgen), 2023

Experimental and Investigational

1. Aetna considers concomitant use of etanercept with any other biologic drug (e.g., abatacept, adalimumab, anakinra, infliximab, rilonacept, tocilizumab) or targeted synthetic drug (e.g. tofacitinib) experimental and investigational for the same indication because the effectiveness of this approach has not been established.

2. Aetna considers etanercept experimental and investigational for all other indications, including any of the following, because its effectiveness for these indications has not been established (not an all-inclusive list):

   • Alzheimer disease dementia
   • Asthma
   • Back pain (including discogenic low back pain, radicular pain caused by lumbar spinal stenosis/lumbosacral radiculopathy/sciatica)
   • Bronchiolitis obliterans
   • Chronic heart failure
   • Churg-Strauss syndrome
   • Dyshidrotic eczema
   • Erythema nodosum leprosum
   • Familial Mediterranean fever
   • Granuloma annulare
   • Hand osteoarthritis
   • Idiopathic pulmonary fibrosis
   • Inclusion-body myositis
   • Inflammatory bowel disease (e.g., Crohn's disease) arthritis
   • Kawasaki disease
   • Keloid
   • Knee osteoarthritis
   • Langerhans cell histiocytosis
   • Lumbar disc herniation
   • Lupus erythematosus
   • Neck pain
   • Neurocysticercosis
   • SAPHO syndrome
   • Sarcoidosis
   • Sjogren's syndrome
   • Stroke
   • Transplantation-related lung injury after hematopoietic stem cell transplantation
   • Traumatic brain injury
   • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as Hibernian fever
   • Uveitis
   • Wegener's granulomatosis. 

3. Aetna considers the use of CD11c expression and DNA methylation as biomarkers of etanercept response experimental and investigational because the effectiveness of these approaches has not been established.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Moderately to severely active rheumatoid arthritis (RA)
• Moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) in patients aged 2 years and older
• Active psoriatic arthritis (PsA)
• Active ankylosing spondylitis (AS)
• Chronic moderate to severe plaque psoriasis (PsO) in patients aged 4 years or older who are candidates for systemic therapy or phototherapy
• Juvenile psoriatic arthritis in patients aged 2 years and older (JPsA)

Compendial Uses

• Non-radiographic axial spondyloarthritis
• Oligoarticular juvenile idiopathic arthritis
• Reactive arthritis
• Hidradenitis suppurativa, severe, refractory
• Behcet’s disease
• Graft versus host disease
• Immune checkpoint inhibitor-related toxicity

Etanercept is available as Enbrel (Immunex Corporation), a tumor necrosis factor (TNF) blocker. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor linked to the Fc portion of human IgG1. Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface (TNF) receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. TNF is present in the synovium and stimulates synoviocyte proliferation and production of inflammatory mediators, which leads to recruitment of inflammatory mediators, neoangiogenesis, and joint destruction. Elevated levels of TNF are found in involved tissues and fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Enbrel includes black-box warnings about the risk of serious infections, such as, increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. Enbrel should be discontinued if a patient develops a serious infection or sepsis during treatment.Perform test for latent TB; if positive, start treatment for TB prior to starting Enbrel. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. The black-box warning also includes risk of malignancies. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel (Immunex, 2022). 

Most common adverse reactions (incidence greater than 5%) include infections and injection site reactions. Drug interactions with Enbrel use include live vaccines, which should not be given with Enbrel. Combination use with anakinra increases the risk of serious infection. Combination use with abatacept increases risk of serious adverse events, including infections. Combination use with cyclophosphamide is not recommended (Immunex, 2022). 

Labeled warnings and precautions for Enbrel use include the following:

• Do not start Enbrel during an active infection. If an infection develops, monitor carefully and stop Enbrel if infection becomes serious.
• Consider empiric anti-fungal therapy for patients at risk for invasive fungal infections who develop a severe systemic illness on Enbrel (those who reside or travel to regions where mycoses are endemic).
• Demyelinating disease, exacerbation or new onset, may occur.
• Cases of lymphoma have been observed in patients receiving TNF-blocking agents.
• Congestive heart failure, worsening or new onset, may occur. 
• Advise patients to seek immediate medical attention if symptoms of pancytopenia or aplastic anemia develop, and consider stopping Enbrel. 
• Monitor patients previously infected with hepatitis B virus for reactivation during and several months after therapy. If reactivation occurs, consider stopping Enbrel and beginning anti-viral therapy. 
• Anaphylaxis or serious allergic reactions may occur. 
• Stop Enbrel if lupus-like syndrome or autoimmune hepatitis develops.

Alzheimer Disease Dementia

In a double-blind, phase II clinical trial, Butchart et al (2015) examined if etanercept is well-tolerated and obtained preliminary data on its safety in Alzheimer disease (AD) dementia.  Patients with mild-to-moderate AD dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once-weekly or identical placebo over a 24-week period.  Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period.  A total of 41 subjects (mean age of 72.4 years; 61 % men) were randomized to etanercept (n = 20) or placebo (n = 21).  Etanercept was well-tolerated; 90 % of subjects (18/20) completed the study compared with 71 % (15/21) in the placebo group.  Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns.  While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function.  The authors concluded that the findings of this study showed that subcutaneous etanercept (50 mg/week) was well-tolerated in this small group of patients with AD dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients.

Antidrug Antibodies and Response to Biologic Disease–Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Bitoun and colleagues (2023) state that findings from a prospective cohort study of 230 patients with rheumatoid arthritis (RA) suggests that antidrug antibodies are associated with a diminished response to biologic disease–modifying antirheumatic drugs (bDMARDs). The authors analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of adult patients with RA who were initiated on a new bDMARD (adalimumab, infliximab (grouped as anti–tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician). Patients were recruited between March 2014 to June 2016, with study completion in 2018 and data analysis completed June 2022. "The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery [MSD]) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay." "Patients who withdrew from the study before month 12 were considered to be nonresponders at month 12 in the logistic regression models except if they had 2 previous responding visits before dropout and their withdrawal was not due to adverse effects or treatment failure, in which case they were imputed as responders at month 12. Patients who changed their drugs were considered as nonresponders. Univariate and multivariable models were performed on complete cases." The authors found that at month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50% with rituximab, and 20% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (P < .001). A similar association was found for tocilizumab alone (P = .03). In the multivariable analysis, antidrug antibodies, body mass index (BMI), and rheumatoid factor (RF) were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody–negative vs antidrug antibody–positive status (mean difference, −9.6 [95% CI, −12.4 to −6.9] mg/L; P < .001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05). The authors concluded that of patients with RA, response to biologic drugs was inversely associated with antidrug antibody positivity, and that monitoring of antidrug antibodies could be considered in the management of patients with RA, specifically nonresponders.

Bitoun et al acknowledged the following limitations to their prospective cohort study:

• The study demonstrated an association when all biologic drugs were analyzed together; however, the study was not powered to demonstrate an association for each drug class;
• There was a substantial proportion of patients in the unclassified category, as those pateints were defined as strictly missing 1 or more antidrug antibody measurements for the analysis of response at month 12;
• The antidrug antibodies were not the only factors that were independently inversely associated with response to treatment in the generalized estimating equation (GEE) analysis;
• The MSD technique is not widely available to clinicians; however, the authors state the percentage of immunized patients in this study is within the same range observed in other studies using the available "classical sandwich ELISA technique"; and
• Secondary end points were not corrected for multiple tests and should be considered exploratory.

Axial Spondyloarthritis

Song et al (2011) evaluated the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years.  Patients were randomly assigned to etanercept (n = 40) or sulfasalazine (n = 36) treatment over 48 weeks.  All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine.  MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by 2 radiologists, blinded for treatment arm and MRI time point.  In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p = 0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48.  A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p = 0.01).  The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p = 0.04 for difference).  A total of 50 % of patients reached clinical remission in the etanercept group versus 19 % in the sulfasalazine group at week 48.  The authors concluded that in patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients.  This effect correlated with a good clinical response in the etanercept group.

CD11c Expression as a Biomarker of Response to Etanercept

Smith et al (2015) examined the predictive value of a previously reported association between CD11c expression and response to the TNF inhibitor (TNFi) biologics, adalimumab and etanercept.  Real-time quantitative polymerase chain reaction (qPCR) was performed using whole blood RNA samples obtained from 75 RA patients about to commence treatment with a TNFi biologic drug, whose response status was determined at 3-month follow-up using the EULAR classification criteria.  Relative quantification of CD11c using the comparative CT method outputted differential expression between good-responders and non-responders as a fold-change.  Relative expression of CD11c in patients receiving TNFi biologics yielded a decrease of 1.025-fold in good-responders as compared to non-responders (p = 0.36).  Upon stratification of patients dependent upon the specific drug administered, adalimumab or etanercept, similar findings to the full cohort were observed, decreases of 1.015 (p = 0.33) and 1.032-fold (p = 0.13) in good-responders compared to non-responders, respectively.  The authors concluded that the findings of this study showed that CD11c expression did not correlate with response to TNFi biologics when tested for within pre-treatment whole blood samples of RA patients.

Chronic Pain

In an uncontrolled, open-label study, Tobinick (2003) presented the case histories of 2 patients (1 woman and 1 man) presenting with a history of chronic neck pain refractory to various treatments.  Both patients were treated with etanercept 25 mg by subcutaneous (s.c.) injection to the cervical region (case 1) or the posterior neck overlying the spine (case 2).  Both patients experienced almost complete pain relief as assessed subjectively.  In case 1, the Oswestry Disability Index (ODI) score decreased from 58 before treatment to 6 one day following treatment.  In addition, 1 day after treatment the patient reported a subjective assessment of 98 % pain improvement, 100 % sensory improvement, and 100 % weakness improvement.  She has remained asymptomatic for more than 1 year.  In case 2, the Oswestry score decreased from 44 before treatment to 4 two months after treatment.  The patient reported 100 % pain relief and 90 % sensory improvement 1 day after treatment.  At 8-month follow-up, pain improvement continued to be 100 % and sensory improvements was 75 %.  The authors concluded that etanercept, delivered by targeted s.c. injection, may be of benefit for selected patients with resistant pain associated with cervical disc disease.  They stated that further study of this new treatment modality is warranted.

Tobinick and Britschgi-Davoodifar (2003) examined the potential of etanercept, delivered by peri-spinal administration, for the treatment of pain associated with intervertebral disc disease.  Charts from 20 selected patients treated by peri-spinal delivery of etanercept 25 mg for severe, chronic, treatment-resistant discogenic pain were reviewed.  Therapeutic benefit was assessed clinically and was documented by changes in a validated pain instrument, the ODI.  Patients were treated off-label with etanercept; 5 detailed case reports were presented, including 3 additional patients.  Rapid, substantial and sustained clinical pain reduction was documented in this selected group of patients.  The cohort of 20 patients had a mean age of 56.5 and mean duration of pain of 116 months.  Nine of the patients had undergone previous spinal surgery; 17 had received an epidural steroid injection or injections (mean 3.2).  This group of patients received a mean of 1.8 doses (range of 1 to 5, median 1.0) of etanercept during the observation period.  The mean length of follow-up was 230 days.  Clinical improvement was confirmed by a decrease in the calculated ODI from a mean of 54.85 +/- 12.5 at baseline, improving to 17.2 +/- 15.3 (p < 0.003) at 24 days and ending at 9.8 +/- 13 (p < 0.003) at 230 days.  The authors concluded that etanercept delivered by peri-spinal administration may offer clinical benefit for patients with chronic, treatment-resistant discogenic pain.  They stated that further study of this new treatment modality is needed.

Tobinick and Davoodifar (2004) presented the clinical results obtained utilizing peri-spinal etanercept off-label for treatment-refractory back and neck pain in a clinical practice setting.  The medical charts of all patients who were treated with etanercept for back or neck pain at a single private medical clinic in 2003 were reviewed retrospectively.  Patients were treated if they had disc-related pain which was chronic, treatment-refractory, present every day for at least 8 hrs, and of moderate or severe intensity.  Patients with active infection, demyelinating disease, uncontrolled diabetes, lymphoma or immunosuppression were excluded from treatment with etanercept.  Etanercept 25 mg was administered by s.c. injection directly overlying the spine.  Visual analog scales (VAS, 0 to 10 cm) for intensity of pain, sensory disturbance, and weakness prior to and 20 mins, 1 day, 1 week, 2 weeks, and 1 month after treatment were completed.  Inclusion criteria for analysis required baseline and treatment VAS data.  Before and after treatment VAS comparisons for intensity of pain, sensory disturbance, and weakness.  A total of 143 charts out of 204 met the inclusion VAS criteria.  The 143 patients had a mean age of 55.8 +/- 14, duration of pain of 9.8 +/- 11 years, and an initial ODI of 42.8 +/- 18, with 83 % having back pain, 61 % sciatica, and 33 % neck pain; 30 % had previous spinal surgery, and 69 % had previously received epidural steroid injections (mean of 3.0 +/- 3).  Patients received a mean of 2.3 +/- 0.7 doses of peri-spinal etanercept separated by a mean interval of 13.6 +/- 16.3 days.  The mean VAS intensity of pain, sensory disturbance, and weakness were significantly reduced after peri-spinal etanercept at 20 mins, 1 day, 1 week, 2 weeks, and 1 month with a p < 0.0001 at each time interval for the first dose in this patient population.  The authors concluded that peri-spinal etanercept is a new treatment modality that can lead to significant clinical improvement in selected patients with chronic, treatment-refractory disc-related pain.  Generalizability of the present study results was limited by the open-label, uncontrolled methodology employed.  Based on this and other accumulating recent studies, etanercept may be useful for both acute and chronic disc-related pain.  The authors stated that further study of this new treatment modality utilizing double-blind placebo-controlled methodology is indicated.

Discogenic Low Back Pain

In a prospective, randomized clinical trial, Sainoh et al (2016) examined the analgesic effect of intradiscal administration of etanercept in patients with discogenic low back pain (LBP).  A total of 77 patients diagnosed with discogenic LBP were included in this study.  Patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 ml] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 ml]) groups.  Patients received a single intradiscal injection.  Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded.  The ODI scores at baseline and at 4 and 8 weeks after injection were evaluated.  Post-injection complications were recorded and evaluated.  In the etanercept group, the NRS scores were significantly lower than in the control group at every time-point after the injection for 8 weeks (p < 0.05).  Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (p < 0.05).  However, the ODI scores were not significantly different at 8 weeks; complications were not observed.  The authors concluded that single intradiscal administration of etanercept can alleviate intractable discogenic LBP for up to 8 weeks.  They stated that TNF-alpha may be involved in discogenic pain pathogenesis; this procedure is a novel potential treatment and longer-term effectiveness trials are needed.

Discoid Lupus Erythematosus

In a Cochrane review, Jessop et al (2009) evaluated the effects of drugs for discoid lupus erythematosus.  In June 2009, these investigators updated their searches of the Cochrane Skin Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2009), MEDLINE, EMBASE, LILACS, and online ongoing trials registers.  The reference lists of relevant reviews were searched.  Index Medicus (1956 to 1966) was hand-searched and authors were approached for information about unpublished trials.  These researchers included all randomized trials of drugs to treat people with discoid lupus erythematosus.  Drugs included in the search were azathioprine, chloroquine, clofazimine, corticosteroids, (oral and topical), dapsone, gold, interferon alpha-2a, methotrexate, phenytoin, retinoids, sulphasalazine, thalidomide, topical calcineurin blockers (pimecrolimus and tacrolimus), and biological agents (etanercept, efalizimab, infliximab, and rituximab).  Two reviewers independently examined each retrieved study for eligibility.  Two trials involving 136 participants were included.  No new trials were included in this update.  In a cross-over study of 12 weeks duration, fluocinonide 0.05 % cream (a potent topical corticosteroid), appeared to be better than hydrocortisone 1 % cream (a mild corticosteroid) when the first arm of the trial involving 78 participants was analyzed at 6 weeks.  Clearing or excellent improvement was seen in 27 % of people using fluocinonide and in 10 % of those using hydrocortisone, giving a 17 % absolute benefit in favor of fluocinonide (95 % confidence interval [CI]: 0.0 to 0.34, NNT (number needed to treat) 6).  In the second trial, acitretin (50 mg/day) was compared with hydroxychloroquine (400 mg/day) in 58 people in a parallel trial of 8 weeks duration.  There was marked improvement or clearing in 46 % of people using acitretin and in 50 % of those on hydroxychloroquine, but there was no significant difference between the 2 interventions.  The adverse effects were more frequent and more severe in the acitretin group.  In this trial, clearing of erythema was measured and found to be better in the hydroxychloroquine group (risk ratio [RR] 0.61, 95 % CI: 0.36 to 1.06).  The authors concluded that fluocinonide cream may be more effective than hydrocortisone in treating people with discoid lupus erythematosus.  Hydroxychloroquine and acitretin appear to be of equal efficacy, although adverse effects are more frequent and more severe with acitretin.  There is not enough reliable evidence about other drugs (including etanercept) used to treat discoid lupus erythematosus.

DNA Methylation as a Biomarker of Response to Etanercept

Plant and colleagues (2016) stated that biologic drug therapies represent a huge advance in the treatment of RA.  However, very good disease control is only achieved in 30 % of patients, making identification of biomarkers of response a research priority.  These researchers hypothesized that differential DNA methylation patterns may provide biomarkers predictive of response to TNFi therapy in patients with RA.  An epigenome-wide association study was performed on pre-treatment whole blood DNA from patients with RA.  Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected.  Differentially methylated positions (DMPs) were identified using linear regression.  Variance of methylation at DMPs was assessed for correlation with cis-acting SNPs.  A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.  A total of 5 DMPs between responder groups were identified with a false discovery rate (FDR) less than 5 %.  The top 2 DMPs mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, p = 1.39E-08 and cg26401028, 1.96E-08).  The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 DMPs (2.63E-07 and 1.05E-06, respectively).  Further the A allele of rs3468 was correlated with EULAR non-response in the discovery cohort (n = 56; p = 0.03) and in the independent replication cohort (n = 1,204; p = 0.003).  The authors identified DNA methylation as a potential biomarker of TNFi response and reported the association between response and the LRPAP1 gene that encodes a chaperone of low-density lipoprotein receptor-related protein-1.  They stated that additional replication experiments in independent sample collections are needed.

Dyshidrotic Eczema

An UpToDate review on “Acute palmoplantar eczema (dyshidrotic eczema)” (Adams and Marks, 2014) does not mention the use of etanercept as a therapeutic option.

Erythema Nodosum Leprosum

Chowdhry and colleagues (2016) stated that erythema nodosum leprosum (ENL) is a common complication of lepromatous leprosy.  Some patients unresponsive to conventional, 1st-line therapeutics develop recurrent, recalcitrant ENL.  These investigators reported a case of severe refractory ENL that was successfully treated with etanercept.  The authors concluded that biologics may be considered as therapeutic alternatives in management of severe, recalcitrant ENL.  This was a single case study; its findings need to be validated by future studies.

Etanercept Biosimilar (Erelzi)

On August 30, 2016, the FDA approved Erelzi (etanercept-szzs), a biosimilar to Enbrel (etanercept) for multiple inflammatory diseases:

• Active ankylosing spondylitis
• Active psoriatic arthritis, including use in combination with methotrexate (MTX) in psoriatic arthritis patients who do not respond adequately to MTX alone
• Chronic moderate-to-severe plaque psoriasis in adults (18 years or older) who are candidates for systemic therapy or phototherapy
• Moderate-to-severe polyarticular juvenile idiopathic arthritis (2 years or older)
• Moderate-to-severe rheumatoid arthritis, either as a standalone therapy or in combination with MTX.

In a phase-III, multi-center, double-blind, randomized, parallel-group study, Matsumo and colleagues (2017) evaluated the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of safety and efficacy, including immunogenicity, in patients with active RA despite methotrexate treatment.  This 54-week study was conducted in Japan and Korea.  The primary efficacy end-point was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24.  American College of Rheumatology 20 % (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated.  A total of 374 patients were randomized to LBEC0101 (n = 187) or ETN-RP (n = 187).  The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95 % CI: -3.198 to -2.820) in the LBEC0101 group and -2.86 (95 % CI: -3.051 to -2.667) in the ETN-RP group.  The estimated between-group difference was -0.15 and its 95 % CI was -0.377 to 0.078, which was within the pre-specified equivalence margin of -0.6 to 0.6.  ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3 % versus ETN-RP 86.7 %).  The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0 % versus ETN-RP 92.5 %), although fewer patients in the LBEC0101 group (1.6 %) than the ETN-RP group (9.6 %) developed ADAs.  The authors concluded that clinical efficacy of LBEC0101 was equivalent to that of ETN-RP; LBEC0101 was well-tolerated and had a comparable safety profile to ETN-RP.

Egeberg and associates (2017) examined safety, efficacy and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab and ustekinumab) and compared originators with biosimilars (i.e., Enbrel with Benepali, and Remicade with Remsima).  The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics.  These investigators examined patients treated between January 1, 2007 and March 31, 2017.  They used Kaplan-Meier survival curves and Cox regression to examine drug survival patterns.  A total of 3,495 treatment series (2,161 patients) were included (adalimumab n = 1,332; etanercept n = 579; infliximab n = 333; ustekinumab n = 1,055; and secukinumab n = 196).  Secukinumab had the highest number of PASI 100 (100 % improvement from baseline Psoriasis Area and Severity Index) respondents, but also the lowest drug survival among all the biologics.  Ustekinumab had the highest drug survival overall.  There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept.  Treatment with higher than approved dosages was frequent for all drugs except for adalimumab and secukinumab; AEs (predominantly infections) were most frequent for secukinumab compared with the other agents.  The authors concluded that ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, although most patients on secukinumab were non-naive.  They stated that switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable; AEs occurred most frequently with secukinumab.

As of October 2019, Erelzi had not been made available in the U.S. due to patent litigation (Novartis, 2019).

Etanercept Biosimilar SB4 (Benepali)

Codreanu and associates (2019) compared the safety and efficacy of biosimilar etanercept (SB4 [Benepali]) to original ETN in a real-life national cohort of RA.  Data from RA patients were retrieved electronically from the Romanian Registry of Rheumatic Diseases (RRBR), which contains all patients receiving biologics in the country.  The study included 242 patients with safety and efficacy data after 6 months of treatment: 123 (50.8 %) with ETN, 119 (49.2 %) with SB4.  There were no significant differences after 6 months regarding composite scores of RA activity between patients on ETN and SB4 (e.g., DAS28 remission: 18.7 % in ETN group and 17.6 % in SB4 group, p = 0.823; Boolean remission: 11.4 % in ETN group and 11.8 % in SB4 group, p = 0.926).  There were 11 AEs in the ETN subgroup (including 3 severe AE: lower respiratory tract infection [LRTI], enterocolitis and anaphylaxis) and 12 AEs in SB4 subgroup (including 4 severe AE: LRTI, vasculitis, anaphylaxis and rash).  The authors concluded that biosimilar and original ETN showed similar safety and efficacy after the first 6 months of treatment in RA patients from a national registry, which brought further evidence for bio-similarity in unselected patients in real-world setting.

Ebbers and colleagues (2019) stated that in 2016, SB4 became the 1st ETN biosimilar to obtain marketing authorization in Europe.  Despite robust analytical and clinical comparisons, outstanding questions remain on SB4 use in routine practice.  These investigators carried out a systematic search for publications on real-world evidence of SB4 safety, effectiveness, and drug survival using search terms (SB4 OR Benepali OR biosimilar etanercept OR innovator etanercept) in the BIOSIS Toxicology, BIOSIS Previews, Embase® and Medline databases up to January 17, 2019.  Of 959 articles identified, 8 journal articles, 2 journal letters and 23 congress abstracts were selected on criteria of original real-world evidence with a clinical focus.  As expected with real-world evidence, quality scoring showed that the evidence had high external validity but lower internal validity.  A total of 13,552 patients were described across 9 European countries and all approved SB4 indications: 2,499 were ETN-naïve and 11,053 switched from ETN-RP to SB4 (switchers).  Switch acceptance rates (a combination of clinicians offering and patients accepting initiation on SB4) ranged between 51.6 % and 99.0 %; patient support programs positively contributed to acceptance.  Disease activity was generally similar pre- and post-switch (typically 3-month time-frame).  Retention rates across studies were at least 75 % (up to 12 months follow-up); no new safety signals were identified.  Differences in discontinuation rates versus historic controls reported in some studies may have been influenced by differences in treatment practices, lack of clinician confidence and nocebo effects.  The authors concluded that nearly 2,500 ETN-naïve patients have been initiated on SB4 and outcomes were similar to those patients receiving ETN-RP.  The authors concluded that this systematic review of real-world evidence provided additional reassurance that SB4 is as safe and effective as ETN-RP in both switched and naïve patients.

Familial Mediterranean Fever

In a Cochrane review, Wu and colleagues (2015) evaluated the safety and effectiveness of interventions for reducing inflammation in people with familial Mediterranean fever.  These researchers used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP.  In addition, they searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.  Date of last search was May 21, 2014.  Randomized controlled studies of people with diagnosis of familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard (a herbal dietary supplement) and NSIADs) with placebo or no treatment, or comparing active drugs to each other were selected for analysis.  These investigators independently selected studies, extracted data and assessed risk of bias.  They pooled data to present the RR or mean difference with their 95 % CI.  They assessed overall evidence quality according to the GRADE approach.  These researchers  included 4 randomized placebo-controlled studies with a total of 75 participants (aged 3 to 53 years); 3 were of cross-over and 1 of parallel design; 2 studies used the active intervention of oral colchicine (0.6 mg 3 times daily or 0.5 mg twice-daily), 1 study used oral ImmunoGuard and the 4th used rilonacept as a subcutaneous injection.  The duration of each study arm ranged from 1 to 3 months.  The 2 most recent studies were generally well-designed, except for an unclear risk of detection bias in one of these.  However, some inadequacy existed in the other 2 older studies, where each had an unclear risk of selection bias, a high risk of attrition bias, an unclear risk of reporting bias and a high risk of other potential bias (baseline characteristics such as mutation status and disease severity were not described); one of these studies additionally had an unclear risk of detection bias.  The authors aimed to report on the number of participants experiencing an attack, the timing of attacks, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.  Based on 1 study (15 participants), there was a significant reduction in the number of people experiencing attacks at 3 months when colchicine was administered at a dose of 0.6 mg 3 times daily (14 % versus 100 %), RR 0.21 (95 % CI: 0.05 to 0.95); however, the GRADE evidence quality was low.  Based on 2 further studies, there was no significant reduction in the number of participants experiencing attacks at 2 months when colchicine was administered at a dose of 0.5 mg twice-daily (22 participants) in people with familial Mediterranean fever, or at 3 months when rilonacept was used in individuals who were colchicine-resistant or colchicine-intolerant (14 participants).  In the ImmunoGuard study (24 participants) acute phase response indicators (including erythrocyte sedimentation rate, white blood cell count and C-reactive protein) were not reduced after 1month treatment.  The authors concluded that there were limited randomized controlled studies assessing interventions for people with familial Mediterranean fever.  Based on the evidence, colchicine appeared to reduce the number of people experiencing attacks; however, only a few low-quality randomized controlled studies contributed data for analysis.  They stated that further randomized controlled studies examining active interventions, not only colchicine, are needed before a comprehensive conclusion regarding the safety and effectiveness of interventions for reducing inflammation in familial Mediterranean fever can be drawn.

Graft-Versus-Host Disease (GVHD)

Uhlving et al (2012) stated that bronchiolitis obliterans (BO) following allogeneic hematopoietic SCT (HSCT) is a serious complication affecting 1.7 to 26.0 % of the patients, with a reported mortality rate of 21 to 100 %.  It is considered a manifestation of chronic graft-versus-host disease (GVHD), but the knowledge of etiology and pathogenesis is still limited.  Diagnostic criteria are being developed and will allow more uniform and comparable research activities between centers.  At present, no randomized controlled trials have been completed that could demonstrate an effective treatment.  Steroids in combination with other immunosuppressive drugs still constitute the backbone of the treatment strategy, and results from the authors’ and other centers suggested that monthly infusions of high-dose pulse intravenous methylprednisolone (HDPM) might stabilize the disease and hinder progression.

The British Committee for Standards in Haematology’s guideline on “Diagnosis and management of chronic graft-versus-host disease” (Dignan et al, 2012) stated that there is insufficient evidence at present to recommend the use of etanercept in the management of chronic GVHD.  Furthermore, an UpToDate review on “Chronic lung transplant rejection: Bronchiolitis obliterans” (Reilly, 2013) does not mention the use of etanercept as a therapeutic tool.

An UpToDate review on "Treatment of acute grave-verus-host disease" (Chao, 2020) state that in one set of studies, patients (n=61) with new onset GVHD treated with etanercept plus steroids were significantly more likely to attain complete response (CR) after 28 days than those treated with steroids alone. This difference was observed in hematopoietic cell transplant (HCT) recipients of related donors (79 versus 39 percent) as well as unrelated donors (53 versus 26 percent). The higher CR rate seen in those receiving etanercept translated into significantly superior survival at 100 days following initiation of treatment (82 versus 66 percent).

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2020) provide a category 2A recommendation for acute, for which therapy for steroid-refractory acute graft-versus-host-disease (GVHD) is often used in conjunction with the original immunosuppressive agent, or chronic GVHD as additional therapy in conjunction with systemic corticosteroids following no response (steroid-refractory disease) to first-line therapy options.

Granuloma Annulare

Chen et al (2019) stated that granuloma annulare (GA), a benign inflammatory skin disease, is considered a Th1-type delayed hypersensitivity reaction.  Localized GA is likely to resolve spontaneously, whereas disseminated GA (DGA) may persist for decades and could be resistant to treatment.  Biologics including TNF-alpha inhibitors have been proposed and used as salvage therapy for GA and other related diseases, interstitial granulomatous dermatitis (IGD), and actinic granuloma (AG).  These investigators carried out a systematic review using the combination of search terms "granuloma annulare", "interstitial granulomatous dermatitis" or "actinic granuloma" and either "biologics", "etanercept", "adalimumab", "infliximab", "ustekinumab", "ixekizumab", "secukinumab", "guselkumab", "golimumab", "brodalumab", "tildrakizumab" or "certolizumab" from the years 1970 to 2017.  Review of the literature demonstrated that 79.3 % of the patients with GA, IGD, or AG who had been treated with TNF-alpha inhibitor therapy reported a clinical response.  Only 1 of the 5 patients demonstrated a response to etanercept.  The authors concluded that TNF-alpha inhibitor therapy has been used to treat chronic GA, IGD, and AG that involved extensive body surface areas.  However, the literature was limited to case-series studies lacking control groups.  These researchers stated that RCTs are needed to establish evidence-based treatment of GA and related cutaneous, granulomatous conditions. 

An UpToDate review on “Granuloma annulare: Management” (Brodell, 2023) stated that “Limited data suggest adalimumab and infliximab may be effective for GA.  Although improvement in GA with etanercept has been reported, etanercept generally appears to be ineffective in GA”.

Hand Osteoarthritis

Kloppenburg and colleagues (2018) stated that hand OA is a prevalent disease with limited therapeutic options.  In a proof-of-concept study, these investigators examined TNF as treatment target in patients with proven joint inflammation.  This 1-year, randomized, multi-center, double-blind trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand OA.  Patients flaring after non-steroidal anti-inflammatory drug (NSAID) wash-out were randomized to etanercept (24 weeks 50 mg/week, thereafter 25 mg/week) or placebo.  The primary outcome was VAS pain at 24 weeks; secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n = 54) and MRIs (n = 20)).  Of 90 patients randomized to etanercept (n = 45) or placebo (n = 45), respectively, 12 and 10 discontinued prematurely.  More patients on placebo discontinued due to inefficacy (6 versus 3), but fewer due to adverse effects (1 versus 6).  The mean between-group difference (MD) in VAS pain was not statistically significantly different (-5.7 (95 % CI: -15.9 to 4.5), p = 0.27 at 24 weeks; - 8.5 (95 % CI: -18.6 to 1.6), p = 0.10 at 1 year; favoring etanercept).  In pre-specified per-protocol analyses of completers with pain and inflammation at baseline (n = 61), MD was -11.8 (95 % CI: -23.0 to -0.5) (p = 0.04) at 1  year.  Etanercept-treated joints showed more radiographic re-modelling (delta GUSS: MD 2.9 (95 % CI: 0.5 to 5.4), p = 0.02) and less MRI bone marrow lesions (MD -0.22 (95 % CI: -0.35 to -0.09), p = 0.001); this was more pronounced in joints with baseline inflammation.  The authors concluded that anti-TNF did not relieve pain effectively after 24 weeks in erosive OA.  Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies are needed to confirm this.

Kawasaki Disease

Standard therapy of acute Kawasaki disease (KD) includes intravenous immunoglobulin (IVIG) and high-dose aspirin, but a substantial number of patients are refractory and require additional treatment.  Tumor necrosis factor-alpha levels are elevated in children with KD, suggesting a role for etanercept in treatment.  In a prospective open-label trial, Choueiter and colleagues (2010) examined the safety and pharmacokinetics of etanercept in children with acute KD (age range of 6 months to 5 years; n = 17) who met clinical criteria and with fever less than or equal to 10 days.  All patients received IVIG and high-dose aspirin.  They received etanercept immediately after IVIG infusion and then twice-weekly.  For the initial safety evaluation, the first 5 patients received 0.4 mg/kg/dose.  Subsequent subjects received 0.8 mg/kg/dose.  A total of 15 patients completed the study.  The pharmacokinetics were similar to that in older children in published series.  No serious adverse events related to etanercept occurred.  No patient demonstrated prolonged or recrudescent fever requiring re-treatment with IVIG.  No patient showed an increase in coronary artery diameter or new coronary artery dilation/cardiac dysfunction.  The authors concluded that etanercept appears to be safe and well-tolerated in children with KD.  They stated that these findings support performance of a placebo-controlled trial.

Keloids

Berman et al (2008) evaluated the tolerability and efficacy of etanercept as compared to triamcinolone acetonide (TAC) for the treatment of keloids.  A total of 20 subjects were randomly assigned to receive monthly intralesional injections of either 25 mg of etanercept or 20 mg of TAC for 2 months.  Keloids were evaluated at baseline, week 4, and week 8 by subjects and investigators in a blinded fashion using physical, clinical, and cosmetic parameters.  Photographs were taken and adverse events were noted during each evaluation.  Etanercept improved 5/12 parameters including significant pruritus reduction, while TAC improved 11/12 parameters at week 8, although no statistical difference was observed as compared to baseline.  There was no significant difference between the 2 treatment groups.  Both treatments were safe and well- tolerated.  The authors concluded that etanercept was safe, well-tolerated, improved several keloid parameters, and reduced pruritus to a greater degree than TAC therapy.  However, they stated that further studies are needed before it can be recommended for the treatment of keloids.

Knee Osteoarthritis

Langerhans Cell Histiocytosis

Flores Legarreta and colleagues (2018) noted that TNF-alpha (TNF-α) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in plasma of patients with active LCH.  It has been postulated that TNF-α may play a role in the pathophysiology of LCH.  In a phase-II clinical trial, these researchers determined the efficacy of etanercept for patients with refractory or relapsed LCH.  A total of 5 LCH patients who had failed at least 2 prior treatments (range of 2 to 9) received etanercept at a dose of 0.4 mg/kg twice-weekly for up to a total of 24 doses.  Disease response was assessed at 4 and 8 weeks.  None of the 5 patients had improvement in their disease with etanercept treatment; 3 progressed at week 4 and 1 progressed at week 8; 1 subject died after 3 weeks of treatment from disease progression.  During the study, only 1 drug-related toxicity was noted which spontaneously resolved.  The study was concluded early due to lack of response to etanercept and insufficient accrual rate.  The authors concluded that these findings suggested that etanercept as given in this study may not be effective for relapsed or refractory LCH.  However, the number of patients treated was not adequate enough to power this study and it is possible that a different dose and regimen of etanercept may be needed to successfully treat this disease.

Neurocysticercosis

Nash and colleagues (2019) stated that manifestations of neurocysticercosis (NCC) are primarily due to host inflammatory responses directed at drug-damaged or naturally degenerating metacestodes (cysts) of the tapeworm Taenia solium.  Prolonged high-dose corticosteroids are often needed to control this inflammation in complicated disease, and frequently causing severe side effects.  Studies evaluating alternatives to corticosteroids are lacking.  These investigators described the clinical course of NCC in 16 patients prescribed etanercept (ETN) to control inflammation resulting from anthelmintic treatment.  A total of 12 patients with extra-parenchymal NCC were administered ETN with corticosteroids (11/12, 91.7 %) and/or methotrexate (9/12, 75.0 %).  The median age of the sub-group with extra-parenchymal NCC was 40 years (range of 26 to 57 years) and 66.7 % were men.  They were administered ETN for a median period of 311 days (range of 31 to 461 days) and then followed for a median of 3.4 years (range of 0.3 to 6.6 years).  Among 9 assessable patients, all improved clinically after starting ETN and 1 deteriorated transiently.  Of the remaining 3, 1 was lost to follow-up and 2 had improved but had not completed their assigned course; 4 additional persons with recurrent perilesional edema (PE) episodes were given ETN for a median of 400.5 days (range of 366 to 854 days) and followed post-ETN for a median of 1.7 years (range of 0.2 to 2.4 years).  All PE patients improved and 2 successfully tapered corticosteroids.  The authors concluded that etanercept therapy was associated with clinical improvement, stable disease, and absence of recurrence.  These researchers stated that taken together with etanercept’s acceptable safety profile, these findings suggested its utility as a corticosteroid-sparing/replacement medication.  Moreover, they stated that randomized control trials (RCTs) of ETN are needed to evaluate and establish efficacy.

The authors stated that there are some disadvantages using ETN in this population.  First, the drug is expensive, particularly in comparison with corticosteroids.  Second, it requires subcutaneous injections.  Third, similar to patients treated with high-dose corticosteroids, there is increased susceptibility to re-activation or new infection with TB, fungal infections (such as histoplasmosis), and susceptibility to other systemic infections, as well as other side effects, although these infections did not occur in this cohort.

Ocular Inflammatory Disorders

1. infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behcet's disease,
2. infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis,
3. infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with sero-negative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation, and
4. infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.

Periodic Fever Syndromes

Schoindre and colleagues (2009) stated that TNF receptor-associated periodic syndrome (TRAPS) is a highly polymorphic auto-inflammatory syndrome related to mutations in the TNFRSF1A gene encoding the type 1 TNF receptor.  Arthralgia and non-erosive synovitis are among the most common manifestations.  These investigators reported the case of a 73-year old woman who presented with chronic erosive joint disease that progressed by flare-ups.  Moderate non-specific abdominal and cutaneous abnormalities were noted, suggesting TRAPS.  This diagnosis was confirmed when genetic tests identified the R92Q mutation in the TNFRSF1A gene.  Although steroid therapy was effective in alleviating the symptoms, combination therapy with methotrexate and etanercept neither decreased the frequency of the flare-ups nor slowed the pace of joint destruction.  Treatment with anakinra is being considered.  The authors noted that this is the first reported case of joint destruction related to TRAPS.

Plaque Psoriais (PsO) and Psoriatic Arthritis (PsA)

Enbrel received FDA approval to treat signs and symptoms of psoriatic arthritis in 2002. In April 2004, Enbrel (Immunex Corporation) gained FDA approval for the treatment of chronic moderate-to-severe chronic plaque psoriasis. FDA approval was based on the results of 2 phase III clinical studies involving adults with psoriasis who were treated for up to 12 months.  These studies reported nearly half (46 %) of those who received etanercept had a 75 % or greater improvement on the PASI after 3 months of treatment.  That response was sustained for an additional 3 months at the lower dose (25 mg once-weekly).

According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006), etanercept, administered at a dose not exceeding 25 mg twice-weekly is recommended for the treatment of adults with plaque psoriasis only when their disease is severe and they have failed to respond to standard systemic therapies, as described above.

According to NICE guidelines, etanercept treatment should be discontinued in patients whose psoriasis has not responded adequately at 12 weeks.  Further treatment cycles are not recommended in these patients.

Guidelines from the British Association of Dermatologists (2005) stated that etanercept should be considered first choice for patients with significant, uncontrolled psoriatic arthritis, and for patients with stable psoriasis where a decision to treat with an tumor necrosis factor inhibitor has been made.

The FDA approved the supplemental Biologics License Application (sBLA) for the expanded use of etanercept) to treat pediatric patients (ages 4-17) with chronic moderate-to-severe plaque psoriasis (Amgen, 2016). The approval was based on results from a Phase 3 one-year study and its five-year open-label extension study to evaluate the safety and efficacy of etanercept in pediatric patients, ages 4 to 17, with chronic moderate-to-severe plaque psoriasis. In addition to demonstrating efficacy, the adverse events were similar to those seen in previous studies in adults with moderate-to-severe plaque psoriasis. 

Paller, et al. (2008) sought to assess the efficacy and safety of etanercept in children and adolescents with moderate-to-severe plaque psoriasis. In a 48-week study, 211 patients with psoriasis (4 to 17 years of age) were initially randomly assigned to a double-blind trial of 12 once-weekly subcutaneous injections of placebo or 0.8 mg of etanercept per kilogram of body weight (to a maximum of 50 mg), followed by 24 weeks of once-weekly open-label etanercept. At week 36, 138 patients underwent a second randomization to placebo or etanercept to investigate the effects of withdrawal and retreatment. The primary end point was 75% or greater improvement from baseline in the psoriasis area-and-severity index (PASI 75) at week 12. Secondary end points included PASI 50, PASI 90, physician's global assessment of clear or almost clear of disease, and safety assessments. At week 12, 57% of patients receiving etanercept achieved PASI 75, as compared with 11% of those receiving placebo (P<0.001). A significantly higher proportion of patients in the etanercept group than in the placebo group had PASI 50 (75% vs. 23%), PASI 90 (27% vs. 7%), and a physician's global assessment of clear or almost clear (53% vs. 13%) at week 12 (P<0.001). At week 36, after 24 weeks of open-label etanercept, rates of PASI 75 were 68% and 65% for patients initially assigned to etanercept and placebo, respectively. During the withdrawal period from week 36 to week 48, response was lost by 29 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept; all resolved without sequelae. The investigators concluded that etanercept significantly reduced disease severity in children and adolescents with moderate-to-severe plaque psoriasis.

Paller, et al. (2016) reported on an extension study to evaluate long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. The investigators reported on a 5-year, open-label extension study enrolled patients aged 4 to 17 years who had participated in a 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections, and rates of 75% and 90% improvement in Psoriasis Area and Severity Index score and clear/almost clear on static physician global assessment. Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 serious AEs; only 1 (cellulitis) was considered treatment-related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement in Psoriasis Area and Severity Index score (∼ 60%-70%) and 90% improvement in Psoriasis Area and Severity Index score  (∼ 30%-40%) and static physician global assessment status clear/almost clear (∼40%-50%) were maintained through week 264. The investigators noted that one limitation of this study was that the number of patients remaining on study at week 264 was small. The investigators concluded that etanercept in pediatric patients was generally well tolerated and efficacy was maintained in those who remained in the study for up to 264 weeks.

In October 2023, the FDA approved etanercept (Enbrel) for the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients 2 years of age and older. Previously, etanercept was limited to adults with active psoriatic arthritis (PsA). FDA approval is based on the safety and efficacy data from "adequate and well-controlled studies" of etanercept in adults with PsA; pharmacokinetic (PK) data from adults with PsA, RA, and PsO; and PK data from pediatrics with active JIA and PsO. Safety of etanercept in JPsA is supported by a clinical study in 69 pediatrics with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years (Constantin et al, 2016; Immunex, 2023).

Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a rare ulcerative inflammatory condition of unknown etiology.  Therapy for PG involves local wound care along with topical and systemic anti-inflammatory and other immunodulatory agents.  Charles et al (2007) assessed the safety and effectiveness of etanercept in the treatment of PG ulcers.  A retrospective analysis was performed on 7 patients with 11 refractory PG ulcers treated with subcutaneous injections of etanercept (25 to 50 mg twice-weekly).  All 7 patients with PG responded well to etanercept.  Eight of the 11 ulcers (73 %) completely healed with the mean time of (12.5 weeks), while the other 3 ulcers had marked reduction in size (within 8 to 18 weeks).  Etanercept was well-tolerated.  No serious side-effects were reported.  Only 1 patient discontinued the drug secondary to side-effects.  The authors concluded that etanercept is an alternative treatment option for patients with refractory ulcers due to PG.  The findings of this small study need to be validated by well-designed studies.

An UpToDate review on "Pyoderma gangrenosum: Treatment and prognosis" (Schadt, 2020) state that in addition to infliximab, other biologic TNF-alpha inhibitors may be beneficial in pyoderma gangrenosum (PG). Improvement in PG with etanercept (25 to 50 mg twice weekly) has been reported in a small retrospective series and case report. However, in the author's experience, adalimumab seems to be more efficacious than etanercept. However, in theory, other biologic TNF-alpha inhibitors might be useful for PG, particularly in patients with PG-associated diseases that are treated with these agents. 

Radicular Pain

In a review on recent advancements in the treatment of lumbar radicular pain, Burnett and Day (2008) stated that recent studies have shown promising results in the treatment of both acute and chronic lumbar radicular pain with TNF-alpha antagonists such as etanercept and infliximab, as well as with interleukin receptor antagonists.

In a prospective randomized study, Ohtori et al (2012) examined the effect of etanercept on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis.  A total of 80 patients with low back and radicular leg pain were investigated.  These researchers diagnosed the patients by physical examination, and X-ray and magnetic resonance imaging.  In 40 patients, these investigators administered epidurally 2.0 ml of lidocaine and 10 mg of etanercept onto the affected spinal nerve, and 2.0 ml of lidocaine and 3.3 mg of dexamethasone was used in 40 patients.  Low back pain, leg pain, and leg numbness were evaluated using a VAS and ODI score before and for 1 month after epidural administration.  Low back pain, leg pain, and leg numbness in the 2 groups were not significantly different before epidural administration.  Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, 1, 2, and 4 weeks: p < 0.05), low back pain (3 days, 1 and 2 weeks: p < 0.05), and leg numbness (3 days, 1 and 2 weeks: p < 0.05).  No adverse event was observed in either group.  The authors concluded that these findings indicated that epidural administration of a TNF-α inhibitor onto the spinal nerve produced pain relief, but no adverse event.  They stated that TNF-α inhibitors may be useful tools for the treatment of radicular pain caused by spinal stenosis.  Drawbacks of this study included relatively small sample size, short-term follow-up, and the use of combination therapies of lidocaine and etanercept.

In a multi-center, randomized trial, Cohen et al (2012) examined if epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.  Randomization was computer-generated and stratified by site.  Pharmacists prepared the syringes.  Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment.  A total of 84 adults with lumbosacral radiculopathy of less than 6 months' duration were included in this study.  Two epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks were administered.  The primary outcome measure was leg pain 1 month after the second injection.  All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.  The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95 % CI: -2.79 to 0.27]; p = 0.11) or etanercept (mean difference, -1.01 [CI: -2.60 to 0.58]; p = 0.21).  For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI: -1.85 to 0.81]; p = 0.44) and etanercept (mean difference, -0.92 [CI:-2.28 to 0.44]; p = 0.18) were observed.  The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids versus etanercept (mean difference, -16.16 [CI: -26.05 to -6.27]; p = 0.002), steroids versus saline (mean difference, -5.87 [CI: -15.59 to 3.85]; p = 0.23), and etanercept versus saline (mean difference, 10.29 [CI: 0.55 to 20.04]; p = 0.04).  More patients treated with epidural steroids (75 %) reported 50 % or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50 %) or etanercept (42 %) (p = 0.09).  The authors concluded that epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.

An UpToDate review on “Acute lumbosacral radiculopathy: Prognosis and treatment” (Levin et al, 2014) does not mention the use of etanercept as a therapeutic option.  Also, an UpToDate review on “Subacute and chronic low back pain: Pharmacologic and noninterventional treatment” (Chou, 2014a) states that “Systemic anti-tumor necrosis factor (TNF)-alpha therapy, which is primarily used in the treatment of inflammatory rheumatologic and bowel disease, does not appear to have a role for patients with chronic low back pain.  This was suggested in the FIRST II trial (n = 40), which found no differences in pain or functional outcomes between a single intravenous infusion of infliximab or saline infusion at three-month and one-year follow-up.  Epidural and intradiscal injections of anti-TNF-alpha therapy have also been evaluated.  Furthermore, an UpToDate review on “Subacute and chronic low back pain: Nonsurgical interventional treatment” (Chou, 2014b) states that “There is insufficient evidence to recommend the use of epidural injections of etanercept (tumor necrosis factor alpha inhibitor) for lumbosacral radiculopathy”.

Rheumatoid Arthritis

Guidelines on rheumatoid arthritis (RA) from the American College of Rheumatology (ACR) (Saag et al, 2008) stated that patients with early RA with low or moderate disease activity (in study) were not considered candidates for biologic therapy.  The use of anti-TNF agents in combination with methotrexate was recommended if high disease activity was present for less than 3 months with features of a poor prognosis.

The American College of Rheumatology (ACR) conducted a systematic review to synthesize the evidence for the benefits and harms of various treatment options. Their goal was to develop evidence-based, pharmacologic treatment guideline for rheumatoid arthritis. The 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis provided “strong” recommendations for established RA and symptomatic early RA.

For established RA, the guidelines state “if the disease activity is low, in patients who have never taken a DMARD, the recommendation is to use DMARD monotherapy (methotrexate preferred) over TNFi”. “If disease activity remains moderate or high despite DMARD monotherapy, the recommendation is to use combination traditional [conventional] DMARDs or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. Recommendations for patients with symptomatic early RA state that “if disease activity is low, in patients who have never taken a DMARD, use DMARD monotherapy (methotrexate preferred) over double or triple therapy”.  “If disease activity remains moderate or high despite DMARD monotherapy (with our without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with our without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. A strong recommendation means that the panel was confident that the desirable effects of following the recommendation outweigh the undesirable effects (or vice versa), so the course of action would apply to most patients, and only a small proportion would not want to follow the recommendation (Singh et al., 2016). 

SAPHO Syndrome

Zhang and Gao (2016) examine the effectiveness of TNF-α inhibitors in the treatment of SAPHO (synovitis acne pustulosis hyperostosis osteitis) syndrome.  Two cases of refractory SAPHO syndrome were successfully treated with etanercept.  Pain scores, laboratory parameters and functional index were used to judge the effectiveness; literature was also systemically reviewed.  Both patients achieved marked clinical remission.  There was no obvious toxic or AEs.  The authors concluded that etanercept had rapid and definite effectiveness in the treatment of patients with refractory SAPHO syndrome.  This was a small case-series study (n = 2); and the authors stated that further follow-ups are needed to determine long-term outcomes of these patients.

Sarcoidosis

Crommelin et al (2014) noted that sarcoidosis is a systemic disease with an incidence of 1 to 40 per 100,000 persons per year.  It predominantly affects people in the age of 20 to 40 years.  Disease course varies from mild self-limiting to chronic debilitating and life-threatening disease.  Since the cause of sarcoidosis is unknown, curative therapy is not available.  Immunosuppressive drugs may, however, control the symptoms of the disease.  The hallmark of sarcoidosis is the formation of granulomas that are most commonly found in lungs and lymph nodes.  As TNF plays an important role in both formation and maintenance of these granulomas, as well as in the immune response, anti-TNF biologicals such as infliximab and adalimumab are considered a last resort therapeutic option.  Clinical effectiveness, however, varies considerably and data showing which patients would benefit most from this expensive therapy are scarce.

Ogbue and colleagues (2020) noted that sarcoidosis and uveitis are chronic inflammatory conditions with potentially debilitating effects on quality of life (QOL).  Steroids form the mainstay standard therapy in both conditions.  Biologic agents are considered to be appropriate alternatives for treatment in steroid-refractory sarcoidosis and uveitis due to the role of TNF in mediating the inflammatory cascade observed in both conditions.  These investigators carried out a thorough literature search using PubMed to compare the extent of use, safety, and efficacy of individual anti-TNF agents in the management of these conditions.  This review consisted of 2 systematic reviews with meta-analysis, 13 observational studies, and 15 case-series/reports.  Infliximab had the widest range of organ-system usage in extra-pulmonary sarcoidosis but is equivalent to adalimumab in terms of efficacy.  In uveitis, adalimumab was found to be the most effective agent for maintaining disease remission in adults and children with chronic non-infectious uveitis.  Etanercept was neither used widely, nor was it effective in the management of either condition.  In terms of safety profile, biologic agents were found to be well-tolerated and had a similar safety profile.  The author concluded that more randomized clinical trials are needed to inform evidence-based use of biologic agents in these conditions.

Sciatica

In a pilot study, Genevay and colleagues (2004) examined the effectiveness of etanercept in patients with severe sciatica.  A total of 10 consecutive patients received 3 s.c. injections of etanercept (25 mg every 3 days) in addition to standard analgesia.  Response was evaluated at day 10 (T1) and week 6 (T2) using a VAS for leg pain (VASL) and for low back pain (VASB), and 2 validated functional scores: the ODI and the Roland Morris disability questionnaire (RMDQ).  The control group consisted of 10 patients with severe sciatica, who took part in an observational study on intravenous methylprednisolone.  In the etanercept group, all variables improved: VASB from 36 to 7; VASL from 74 to 12; RMDQ from 17.8 to 5.8, and ODI from 75.4 to 17.3; all p < 0.001.  Pain (VASL and VASB: p < 0.001) and ODI (p < 0.05) were significantly better in the etanercept group than in the methylprednisolone group.  The authors concluded that in this open, historical group-controlled study, patients with severe sciatica had sustained improvement after a short treatment with etanercept that was better than standard care plus a short course of methylprednisolone.  These results suggested that inhibition of TNF-alpha is beneficial in the treatment of sciatica and support a pathological role for TNF-alpha in the pathogenesis of sciatica.  They stated that these results need to be confirmed by a randomized controlled trial.

In a double-blind, placebo-controlled, dose-response study, Cohen and associates (2009) evaluated the effectiveness of trans-foraminal epidural etanercept for the treatment of sciatica.  A total of 24 patients with subacute lumbo-sacral radiculopathy were randomly assigned to receive 2 trans-foraminal epidural injections of 2, 4, or 6 mg of etanercept 2 weeks apart in successive groups of 8.  In each group, 2 patients received epidural saline.  A parallel epidural canine safety study was conducted using the same injection doses and paradigm as in the clinical study.  The animal and human safety studies revealed no behavioral, neurological, or histological evidence of drug-related toxicity.  In the clinical arm, significant improvements in leg and back pain were collectively noted for the etanercept-treated patients, but not for the saline group, 1 month after treatment.  One patient in the saline group (17 %), 6 patients in the 2-mg group (100 %), and 4 patients each in the 4-mg and 6-mg groups (67 %) reported at least 50 % reduction in leg pain and a positive global perceived effect 1 month after treatment.  Six months after treatment, the beneficial effects persisted in all but 1 patient.  The authors concluded that epidural etanercept holds promise as a treatment for lumbo-sacral radiculopathy.

In a triple-blinded randomized controlled study, Okoro et al (2010) examined the treatment effect of etanercept in acute sciatica secondary to lumbar disc herniation.  Inclusion criteria were acute unilateral radicular leg pain secondary to herniated nucleus pulposus confirmed on magnetic resonance imaging scan.  Exclusions were previous back surgery, spinal stenosis and any contra-indications to the use of etanercept such as immunosuppression.  The patient, the injector, and assessor were blinded to the agent being used.  Follow-up was at 6 weeks and 3 months post-treatment; ODI and VAS were among the assessment criteria.  A total of 15 patients were recruited in a 4 year-period with a 3 months follow-up of 80 %.  The etanercept group had 8 patients whereas the placebo group had 7.  The average ODI for the etanercept group pre-intervention was higher than that in the placebo group (53.6 versus 50.4) and this remained the same after 6 weeks (46.1 versus 31.2) and 3 months of follow-up (37 versus 35).  Visual analog score was also higher in the etanercept group versus placebo; pre-injection (8.6 versus 7.4), 6 weeks (5.0 versus 3.8), and 3 months (4.8 versus 4.5).  The authors concluded that small numbers of trial subjects limited statistical analysis.  The trend appears to show no benefit to the use of etanercept over placebo in the pharmacologic treatment of sciatica.

1. 0.5-mg,
2. 2.5-mg,
3. 12.5-mg etanercept, or
4. placebo. 

Subjects received 2 transforaminal epidural injections, 2 weeks apart, and were assessed for effectiveness up to 26 weeks after the second injection.  The primary outcome measure was the change in mean daily worst leg pain (WLP).  Secondary outcomes included average leg pain, worst back pain, average back pain, in-clinic pain, ODI, patient global impression of change, and tolerability.  Forty-three of the 49 randomized patients completed the study.  Patients receiving 0.5-mg etanercept showed a clinically and statistically significant (p < 0.1) reduction in mean daily WLP compared with the placebo cohort from 2 to 26 weeks for both the per protocol population (-5.13 versus -1.95; p = 0.066) and the intention-to-treat population (-4.40 versus -1.84; p = 0.058).  Fifty percent of these subjects reported a 100 % reduction in WLP 4 weeks post-treatment compared with 0 % of subjects in the placebo cohort.  Improvements in all secondary outcomes were also observed in the 0.5-mg etanercept cohort.  The overall incidence of adverse events was similar in placebo and all etanercept cohorts.  The authors concluded that 2 transforaminal injections of etanercept provided clinically significant reductions in mean daily WLP and worst back pain compared with placebo for subjects with symptomatic LDH.  They stated that epidural etanercept may offer patients with sciatica a safe and effective non-operative treatment.

Stevens-Johnson Syndrome

Lerch and co-workers (2018) stated that Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs; and SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms.  The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of less than 10 %; TEN is defined as skin involvement of greater than 30 %, and SJS/TEN overlap as 10t o 30 % skin involvement.  The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology.  The mortality rates for SJS and TEN have decreased in the last decades.  Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment.  Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, NSAIDs of the oxicam type, allopurinol, nevirapine, and chlormezanone.  Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents.  The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens.  The understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified.  However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs.  In SJS/TEN, the most common complications are ocular, cutaneous, or renal.  Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role.  However, in the acute phase, septicemia is a leading cause of morbidity and fatality.  Pulmonary and hepatic involvement is frequent.  The acute management of SJS/TEN requires a multi-disciplinary approach.  Immediate withdrawal of potentially causative drugs is mandatory.  Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance.  The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.

Gavigan and associates (2018) reported the case of an 11-year old girl with SJS/TEN overlap, most likely triggered by sulfamethoxazole-trimethoprim, who was treated with the combination of methylprednisolone, cyclosporine, and etanercept.  Her condition stabilized and her skin involvement did not progress after the addition of etanercept.  The authors concluded that to their knowledge, this was the first report of etanercept for pediatric SJS/TEN.

Wang and colleagues (2019) noted that SJS/TEN are spectrum of rare, acute and life-threatening delayed-type drug hypersensitivity reactions that are associated with high mortality rates.  However, no therapeutic standard has been proposed for SJS/TEN.  These investigators reported a case of a patient diagnosed with SJS whose disease progression was halted by a single-dose of etanercept and was treated successfully.

Furthermore, an UpToDate review on “Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae” (High, 2019) states that “Etanercept, given in a single 50 mg subcutaneous injection, has been used successfully in a small number of patients … Although this study adds further evidence to support the use of etanercept for SJS/TEN, additional studies are needed to determine the optimal dose and duration of treatment, particularly in patients with severe and rapidly progressing disease”.

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2022) includes a category 2A recommendation for the use of etanercept for management of Stevens-Johnson syndrome or toxic epidermal necrolysis as immunosuppressive therapy.

Stroke

Tobinick et al (2012) systematically examined the clinical response following peri-spinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and traumatic brain injury (TBI).  After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with peri-spinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.  The treated cohort included 629 consecutive patients.  Charts of 617 patients following stroke and 12 patients following TBI were reviewed.  The mean age of the stroke patients was 65.8 years +/- 13.15 (range of 13 to 97).  The mean interval between treatment with PSE and stroke was 42.0 +/- 57.84 months (range of 0.5 to 419); for TBI the mean interval was 115.2 +/- 160.22 months (range of 4 to 537).  Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioral function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence.  Improvements in multiple domains were typical.  Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI.  In the TBI cohort, motor impairment and spasticity were statistically significantly reduced. Irrespective of the methodological limitations, the present results provided clinical evidence that stroke and TBI may lead to a persistent and ongoing neuro-inflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.  The authors concluded that excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI.  Peri-spinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI.  The therapeutic window extends beyond a decade after stroke and TBI.  They stated that randomized clinical trials will be necessary to further quantify and characterize the clinical response.

On behalf of the American Academy of Neurology (AAN), Gronseth and Messe (2016) reviewed evidence regarding the safety, effectiveness, and tolerability of etanercept used to treat patients with post-stroke disability.  These investigators searched Medline and the Cochrane Central Register of Controlled Trials for studies of adult patients with post-stroke disability treated with etanercept in order to improve their functional status.  They rated each study for risk of bias (Class I to IV) using the AAN therapeutic classification of evidence scheme.  Practice recommendations were formulated on the basis of the strength of the evidence and assessments of potential benefits, potential harms, and patient preferences.  A total of 2 case series were identified, and both reported clinical improvements 3 weeks following treatment across a wide range of functional domains.  However, both studies were rated Class IV because of poor methodological quality (i.e., high risk of bias).  The authors concluded that for patients with post-stroke disability, the evidence is insufficient to support or refute a benefit of etanercept for the treatment of post-stroke disability.  The AAN recommended that clinicians should counsel patients considering etanercept for treatment of post-stroke disability that the evidence is insufficient to determine the treatment's effectiveness and that it may be associated with adverse outcomes and high cost (Level U).

Transplantation-Related Lung Injury after Hematopoietic Stem Cell Transplantation

Hohlfelder et al (2015) noted that although some data suggested favorable outcomes with use of etanercept for treatment of transplantation-related lung injury, concerns, such as development of new infections, still exist.  These investigators evaluated the safety and effectiveness of etanercept for this indication.  Adult patients receiving at least 1 dose of etanercept for the treatment of pulmonary complications in patients after hematopoietic stem cell transplant from January 2005 to December 2010 were retrospectively evaluated.  Outcomes included hospital mortality, incidence of new infection after etanercept administration, and time from administration of 1st dose of etanercept to infection.  A total of 17 patients who received etanercept at the authors’ institution from January 2005 to December 2010 were included.  Four patients (24 %) survived their hospital stay, and 3 patients (18 %) were alive at both 100 days and 1 year from the initiation of etanercept therapy.  Four patients (24 %) developed at least 1 confirmed new infection after the initiation of etanercept therapy.  Both moderate and long-term survival in this cohort was low.  The authors concluded that caution and careful assessment of the risks and benefits of therapy should be taken before initiation of etanercept for transplantation-related lung injury.

Uveitis

An UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2013) stated that “The role of tumor necrosis factor-alpha (TNF) inhibitors such as infliximab, adalimumab, or etanercept in the management of patients with uveitis is uncertain.  Further data from controlled trials are needed to clarify the indications and risks of TNF inhibition in the treatment of ocular inflammatory disease”.

Cordero-Coma et al (2013) established evidence-based recommendations regarding the use of TNF-α agents for managing uveitis patients.  Medline was searched via OVID (1950 to October Week 3, 2011) using a Cochrane highly sensitive search (phases 1 and 2).  Additional literature searches were also conducted including the following databases: the Cochrane, LILACS and the TRIP Database.  A total of 54 studies met all of the inclusion criteria and were included in this review.  A different level of recommendation and evidence is assigned to each anti-TNF-α agent.  The overall rate of reported side effects with anti-TNF-α agents for the treatment of uveitis that required discontinuation of therapy was 2.2 % (26/1,147 patients).  The authors concluded that based on the evidence gathered, infliximab and adalimumab seem to be effective in the management of immune-mediated uveitis.  Moreover, they stated that further randomized studies evaluating the effectiveness of these agents are needed.  It is the most common cause of inflammatory eye disease, with an estimated prevalence of 115 cases per 100,000 persons.  Endogenous or associated with a systemic disease, non-infectious uveitis accounts for approximately 75 % of total cases comprising of a heterogeneous group of inflammatory conditions responsible for about 10 % of legal blindness in developed nations.  Endogenous uveitides are thought to have an autoimmune component mediated by T lymphocytes specific to intra-ocular antigens that have failed to successfully pass basic processes designed to maintain self-tolerance. 

Ogbue and colleagues (2020) noted that sarcoidosis and uveitis are chronic inflammatory conditions with potentially debilitating effects on quality of life (QOL).  Steroids form the mainstay standard therapy in both conditions.  Biologic agents are considered to be appropriate alternatives for treatment in steroid-refractory sarcoidosis and uveitis due to the role of TNF in mediating the inflammatory cascade observed in both conditions.  These investigators carried out a thorough literature search using PubMed to compare the extent of use, safety, and efficacy of individual anti-TNF agents in the management of these conditions.  This review consisted of 2 systematic reviews with meta-analysis, 13 observational studies, and 15 case-series/reports.  Infliximab had the widest range of organ-system usage in extra-pulmonary sarcoidosis but is equivalent to adalimumab in terms of efficacy.  In uveitis, adalimumab was found to be the most effective agent for maintaining disease remission in adults and children with chronic non-infectious uveitis.  Etanercept was neither used widely, nor was it effective in the management of either condition.  In terms of safety profile, biologic agents were found to be well-tolerated and had a similar safety profile.  The author concluded that more randomized clinical trials are needed to inform evidence-based use of biologic agents in these conditions.

Wound Healing

Kirsner (2010) stated that TNF-alpha antagonists (e.g., etanercept) are now being extensively evaluated in the setting of chronic wound healing.  Preliminary studies and case reports provided evidence of the clinical potential of these compounds in PG, and further investigations are warranted.

Appendix

Appendix A: Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Leflunomide, Cyclosporine, or Acitretin

• Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease
• Drug interaction
• Risk of treatment-related toxicity
• Pregnancy or currently planning pregnancy
• Breastfeeding
• Significant comorbidity prohibits use of systemic agents (e.g., liver or kidney disease, blood dyscrasias, uncontrolled hypertension)
• Hypersensitivity
• History of intolerance or adverse event

Appendix B: Risk Factors for Articular Juvenile Idiopathic Arthritis

• Positive rheumatoid factor
• Positive anti-cyclic citrullinated peptide antibodies
• Pre-existing joint damage

Source: Wieczorek and Walecka (2018)

References