Etanercept

Number: 0315

Policy

Note: There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Otezla (apremilast), Remicade (infliximab), Renflexis (infliximab-abda) Simponi (golimumab), Simponi Aria (golimumab intravenous), Stelara (ustekinumab), Tremfya (guselkumab), Xeljanz and Xeljanz XR (tofacitinib) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because Actemra (tocilizumab), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab), Skyrizi (risankizumab-rzaa) and Tysabri (natalizumab) brands of targeted immune modulators are more costly than the least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, these brands of targeted immune modulator will be considered medically necessary only if the member has a contraindication, intolerance or ineffective response to the following numbers of trials of least cost brands of targeted immune modulators by indication:

• Ankylosing spondylitis – two least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria)
• Crohn’s disease – one least cost brand (not including Renflexis) (i.e., Entyvio, Inflectra, Remicade, Stelara)
• Juvenile idiopathic arthritis – trial of Enbrel (etanercept)
• Plaque psoriasis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Stelara, Tremfya)
• Psoriatic arthritis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Simponi, Simponi Aria, Stelara, Xeljanz, Xeljanz XR)
• Rheumatoid arthritis – three least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria, Xeljanz/Xeljanz XR)
• Ulcerative colitis – one least cost brand (not including Renflexis) (i.e., Entyvio, Inflectra, Remicade, Simponi, Xeljanz)

Note: Cimzia (certolizumab), Cosentyx (secukinumab), Ilaris (canakinumab), Kevzara (sarilumab), Olumiant (baricitinib), Siliq (brodalumab), and Taltz (ixekizumab) brands of targeted immune modulators do not require a trial of a least cost brand of targeted immune modulator; there may, however, be a higher copayment where these brands are covered under pharmacy plans with a tiered formulary. Please check benefit plan descriptions. If the least costly targeted immune modulators do not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. Also note that Renflexis is not a least cost brand for Crohn’s disease and ulcerative colitis indications.

1. Medically Necessary Indications

   Aetna considers Enbrel (etanercept) medically necessary for any of 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)Footnotes* within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factorsFootnotes** for TB that are continuing therapy with biologics:
   
   

   1. Adult Rheumatoid Arthritis:

      Etanercept is considered medically necessary for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in members with moderately to severely active rheumatoid arthritis who have had an ineffective response to methotrexate, or if methotrexate is contraindicated or not tolerated, has had an ineffective response to another non-biologic disease-modifying anti-rheumatic drug (conventional DMARD) (i.e. azathioprine, hydroxychloroquine, leflunomide, sulfasalazine).

   2. Juvenile Rheumatoid Arthritis:

      Etanercept is considered medically necessary for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in persons aged 2 and older.

   3. Active Psoriatic Arthritis:

      For medical necessity criteria, see CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators.

   4. Ankylosing Spondylitis or Axial Spondyloarthritis:

      Etanercept is considered medically necessary for members with moderate to severe ankylosing spondylitis or axial spondyloarthropathy (an early form of ankylosing spondylitis) who have failed treatment with 2 or more non-steroidal anti-inflammatory drugs (NSAIDS) (e.g. ibuprofen, meloxicam, naproxen).  

   5. Reactive Arthritis:

      Etanercept is considered medically necessary for members with refractory reactive arthritis (also known as Reiter’s syndrome) who have failed NSAIDS, methotrexate, steroids, and sulfasalazine.

   6. Behcet's Disease:

      Etanercept is considered medically necessary for treatment of mucocutaneous manifestations (oral ulcers, nodular skin lesions) of Behcet's disease refractory to glucocorticoids and azathioprine.

   7. Chronic Moderate to Severe Psoriasis

      For medical necessity criteria, see CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators

2. Combination with other biologics

   Aetna considers use of etanercept (Enbrel) with other biologicals (such as Humira, Remicade, Orencia, or Kineret) or secukinumab (Cosentyx) as experimental and investigational.
   
   

3. Erelzi (Etanercept-szzs; a Biosimilar to Enbrel)

   Aetna considers Erelzi (etanercept-szzs), a biosimilar to Enbrel, medically necessary for the treatment of the following indications where the member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnotes* within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factorsFootnotes** for TB that are continuing therapy with biologics:
    
   
   1. Active ankylosing spondylitis
   2. Active psoriatic arthritis, including use in combination with methotrexate (MTX) in members with psoriatic arthritis who do not respond adequately to MTX alone
   3. Chronic moderate-to-severe plaque psoriasis in adults (18 years or older) who are candidates for systemic therapy or phototherapy
   4. Moderate-to-severe polyarticular juvenile idiopathic arthritis (2 years or older)
   5. Moderate-to-severe rheumatoid arthritis for members who have had an ineffective response to methotrexate, or if methotrexate is contraindicated or not tolerated, has had an ineffective response to another non-biologic disease-modifying anti-rheumatic drug (conventional DMARD) (i.e. azathioprine, hydroxychloroquine, leflunomide, sulfasalazine).

4. Experimental Indications

   Aetna considers Enbrel (etanercept) and its biosimilars experimental and investigational for all other indications, including any of the following (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
   • Graft-versus-host disease
   • Hand osteoarthritis
   • Hidradenitis suppurativa
   • 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
   • Pyoderma gangrenosum
   • SAPHO syndrome
   • Sarcoidosis
   • Sjogren's syndrome
   • Stevens-Johnson 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. 
       

5. Biomarkers

   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.
   
   

Footnotes* Etanercept and etanercept-szzs are contraindicated and considered not medically necessary for persons with active TB or untreated latent disease. If the screening test for TB is positive, there must be documentation of further testing to confirm there is no active disease. Do not administer etanercept or etancercept-szzs to persons with active TB infection. If there is latent disease, TB treatment must be started before initiation of etanercept or etanercept-szzs.

Footnotes** Risk factors for TB include: persons with close contact to people with infectious TB disease; persons who have recently emigrated from areas of the world with high rates of TB (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); children less than 5 years of age who have a positive TB test; groups with high rates of TB transmission (e.g., homeless persons, injection drug users, and persons with HIV infection); persons who work or reside with people who are at an increased risk for active TB (e.g., hospitals, long-term care facilities, correctional facilities, and homeless shelters) (CDC, 2012).

See also CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions, CPB 0341 - Infliximab, CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions, CPB 0595 - Kineret (Anakinra), and CPB 0655 - Adalimumab (Humira).

Background

Enbrel (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 (etanercept) is indicated for the treatment of moderate to severe active rheumatoid arthritis, moderate to severe active polyarticular juvenile idiopathic arthritis in patients ages two and older, psoriatic arthritis, active ankylosing spondylitis and moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The patient selection criteria were adapted from the U.S. Food and Drug Administration (FDA)-approved labeling of Enbrel (etanercept), off-label indications accepted by the U.S. Pharmacopoeial Convention, and from published studies of etanercept’s effectiveness.  Although there is evidence of the effectiveness of both tumor necrosis factor (TNF) inhibitors etanercept and infliximab (Remicade) in Crohn’s disease arthritis, only infliximab has been shown to also improve the underlying Crohn’s disease.

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 FDA-approved labeling for Enbrel includes black-box warnings about the risk of infections with etanercept.  The labeling states that, in post-marketing reports, serious infections and sepsis, including fatalities, have been reported with the use of etanercept.  Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.  The labeling states that rare cases of tuberculosis (TB) have been observed in patients treated with TNF antagonists, including etanercept.  The labeling recommends that patients who develop a new infection while undergoing treatment with etanercept should be monitored closely.  Administration of etanercept should be discontinued if a patient develops a serious infection or sepsis.  The labeling states that treatment with etanercept should not be initiated in patients with active infections including chronic or localized infections.  The labeling recommends that physicians should exercise caution when considering the use of etanercept in patients with a history of recurring infections or with underlying conditions which may predispose patients to infections, such as advanced or poorly controlled diabetes.  The labeling notes that, in a 24-week study of concurrent etanercept and anakinra therapy, the rate of serious infections in the combination arm (7 %) was higher than with etanercept alone (0 %).  The combination of etanercept and anakinra did not result in higher ACR response rates compared to etanercept alone.  The labeling states that concurrent therapy with etancerpt and anakinra is not recommended.

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel.

It is recommended that the prescription be written by or on the advice of a dermatologist, pediatric rheumatologist, or rheumatologist depending on the condition or an individual highly familiar with prescribing and monitoring of etanercept therapy.

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 Specialised 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.

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.

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.

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 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 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.

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.

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.

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.

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.

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.

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.

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 “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. 

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.

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”.

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

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.

The above policy is based on the following references: