What is etanercept?
Etanercept belongs to the class of biological medicines called tumour necrosis factor (TNF) inhibitors. TNF is a cytokine — a messenger chemical. The trade name for the original drug is Enbrel®. Etanercept biosimilars are also available in some countries, including etanercept-ykro (Eticovo™, FDA-approved in 2019) and etanercept-szzs (Erelzi™, 2016).
Etanercept is approved for the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis in adults. It is approved for the treatment of psoriasis and juvenile idiopathic arthritis in children and adolescents aged 2–17 years. In the USA, etanercept is also approved for use in moderate to severe chronic plaque psoriasis in children and adolescents aged 4–17 years.
In New Zealand, PHARMAC has approved funding for severe treatment-resistant psoriasis in adults on Special Authority application. In children older than 4 years, it is approved for use for up to 24 weeks.
How does etanercept work?
Etanercept is genetically engineered from human protein. It works by directly binding to TNF molecules in the blood and diseased tissue. Etanercept-bound TNF cannot bind to or activate TNF receptors. TNF-alpha helps the body fight infection and cancer, but when overproduced it can have harmful effects. In psoriasis, there is overproduction to TNF.
How effective is etanercept in psoriasis?
Randomised, double-blind, placebo-controlled studies of etanercept in moderate-to-severe chronic plaque psoriasis showed that it significantly decreased disease activity (PASI score) with a favourable safety profile.
In this randomised double-blind multicentre trial, 752 patients with psoriasis and psoriatic arthritis as evaluated by dermatologists and rheumatologists, were randomised to receive etanercept 50 mg twice weekly (n=379) or 50 mg once weekly (n=373) for 12 weeks by subcutaneous injection .
All participants then received open-label etanercept 50 mg once weekly for 12 additional weeks, while remaining blinded to the regimen.
Patients who had both moderate to severe plaque psoriasis and psoriatic arthritis were enrolled from 98 international sites into this randomised multicentre study. The study consisted of a 12 week double-blind treatment period followed by a 12-week open-label treatment period and a two-week post-treatment follow-up.
Efficacy and safety analyses were carried out on the modified intention-to-treat population which included all randomised participants who took at least one dose of test drug and had at least one post-baseline efficacy evaluation.
752 participants (379 in the etanercept 50 mg twice weekly/once-weekly group and 373 in the etanercept 50 mg once weekly/once weekly group) comprised the modified intention to treat population and 92% (695) completed the study.
At week 12, 46% (176/379) of participants receiving etanercept 50 mg twice weekly achieved a physician's global assessment of psoriasis of "clear" or "almost clear" compared with 32% (119/373) in the group treated with 50 mg once weekly (P<0.001). By week 24, the proportions were similar (56% (214/379) v 50% (187/373), P=0.104).
The mean percentage improvement from baseline in the physician’s global assessment of psoriasis at week 12 was significantly greater in the twice-weekly/once weekly group than in the once-weekly/once weekly group (52% v 45%, P<0.001). At week 24, the mean percentage improvement from baseline in physician’s global assessment of psoriasis was similar for both groups (57% v 55%, P=0.420).
At week 12, a significantly greater proportion of participants in the etanercept 50 mg twice weekly/once weekly group than in the 50 mg once weekly/once weekly group achieved at least 75% improvement in (PASI) psoriasis area and severity index (55% (207/377) v 36% (135/371) P<0.001; and 70% (265/377) v 62% (231/371) at week 24, P<0.026).
Joint and tendon disease manifestations improved from baseline in both groups to a similar extent.
Etanercept was well tolerated in both treatment groups over 24 weeks; we found no significant differences between the groups in the incidence of adverse events. The most commonly reported treatment-emergent adverse events were upper respiratory tract infection, injection site reaction, pharyngitis, and headache.
A total of 15 (4%) participants in the twice-weekly/once-weekly group and 11 (3%) in the once-weekly/once weekly group reported serious adverse events, including serious infections and malignancies.
It was concluded that a regimen of 50 mg once weekly seems to be appropriate for treatment of joint and tendon symptoms in patients with active psoriasis and psoriatic arthritis; 50 mg twice weekly may allow for more rapid clearance of skin lesions than with 50 mg once weekly. The choice of regimen should be determined by the clinical needs of the individual patient.
Quality of life – PRESTA trial
A separate analysis of the PRESTA trial examined employment status, job duties, and sick days, among this patient population. A pharmacoeconomic questionnaire was administered at baseline, week 12 and week 24 of treatment. The questionnaire included employment status and changing job responsibilities and sick time taken due to psoriasis or psoriatic arthritis (PsA) .
For patients with moderate-to-severe plaque psoriasis and PsA, etanercept treatment resulted in reducing job responsibility changes due to disease and in reducing sick time.
Employment was at least maintained from baseline to week 24 in both dose groups (56% [twice weekly/once weekly] and 60% [once weekly/once weekly] at baseline, 61% and 60%, respectively, at week 24). Among employed participants, the proportion of patients whose job responsibilities changed due to psoriatic arthritis decreased significantly from baseline to week 24 (17–23% to 5–8%; p<0.01). Similar results were seen with job responsibility changes due to psoriasis (11–14% to 4%; p<0.01). The number of monthly sick days also decreased from baseline to week 24 (2.4 days for both treatment groups to 0.7 (twice weekly/once weekly) and 1.1 (once weekly/once weekly); p≤0.03 for each).
This trial investigated the efficacy and safety of two dose regimens of etanercept when used with as-needed adjunctive topical therapy .
Patients were randomised to etanercept 50 mg once weekly or 50 mg twice weekly double-blind for 12 weeks, followed by 50 mg once-weekly open-label through week 24.
Mild topical corticosteroids were permitted on scalp, axillae, and groin for the first 12 weeks; topical medications (corticosteroids of all potencies, vitamin D analogues, and combination products) were allowed as needed during the second 12 weeks at physicians' discretion, consistent with "real-world" therapeutic practice.
At week 24, PASI 75 was achieved in 59.9% and 78.2% of patients in the once-weekly/once weekly and twice-weekly/once weekly groups, respectively. Mean percentage PASI improvement in these groups was 58.5% and 74.1% at week 12 and 70.7% and 81.3% at week 24. Although permitted from weeks 12 to 24, topical agents were used in only 27.7% and 22.6% in the once-weekly/once weekly and twice-weekly/once weekly groups, respectively by week 24.
Both etanercept regimens were efficacious in moderate-to-severe psoriasis, although the twice-weekly/once-weekly regimen consistently provided higher response rates than the once-weekly/once-weekly regimen.
Subset Analysis – PRISTINE trial
These results were confirmed in a subset analysis of patients from Latin America, Asia, and Central Europe participating in the PRISTINE trial .
At week 8, 26.7% in the etanercept once-weekly group and 44.0% in the twice-weekly group achieved PASI 75.
PASI 75 increased to 39.5% and 62.8% in the once-weekly/once-weekly group and to 66.7% and 83.3% in the twice-weekly/once-weekly group, at weeks 12 and 24, respectively.
Treatment with etanercept 50 mg provided rapid relief of psoriasis symptoms in patients from Asia, Central Europe, and Latin America.
A more rapid response was observed in patients who received twice-weekly treatment for the first 12 weeks; this response was sustained even after the reduction to once-weekly dosing for the subsequent 12 weeks. Response rates were similar to those observed in the overall PRISTINE population.
Quality of Life – PRISTINE trial
The objective of this study was to examine pruritus and QoL (Quality of life) in patients with moderate-to-severe psoriasis treated with etanercept in the PRISTINE clinical trial .
Patients were randomized (1:1, double-blind) to etanercept 50 mg once weekly or 50 mg twice weekly for 12 weeks, followed by 50 mg once weekly for 12 weeks.
Pruritus was reported as 0 (no itching) to 5 (severe itching). Associations were examined between pruritus and Psoriasis Area and Severity Index, Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Screening (HADS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Euro-Qol 5D (EQ-5D) and Medical Outcomes Study (MOS) Sleep Index II.
Pruritus improved significantly with etanercept therapy and was strongly associated with improvements in QoL.
Patients with the most severe itching at baseline (score of 5) had a mean score of 1.7 at week 24 post-treatment. Overall, patients with clinically meaningful pruritus improvement at week 24 reported greater improvement in QoL measures than other patients.
A separate analysis of the PRISTINE trial also confirmed improvement in sleep with etanercept and optional adjunctive topical therapy in patients with moderate to severe psoriasis. Sleep impairment was measured by the Medical Outcomes Study (MOS) sleep questionnaire Index II (population norm = 25.8; minimum clinically important difference = 5.1).
Patients with moderate-to-severe psoriasis were randomized to etanercept 50 mg once weekly (once weekly/once weekly) or 50 mg twice weekly (twice weekly/once weekly) for weeks 1–12, followed by 50 mg once weekly for weeks 13–24; a broad range of topical therapies were permitted during weeks 13–24 .
Mean baseline MOS-Sleep scores were 34.0 for both groups. At week 12 of treatment, MOS-Sleep scores improved to 30.8 and 30.1, and at week 24, to 28.4 and 28.2 respectively, in the once-weekly and twice-weekly groups.
Sleep improvement was associated with improved EQ-5D utility and FACIT-Fatigue (P < 0.001).
How is etanercept given?
Etanercept is given by subcutaneous injection. The usual dose for psoriasis is 50 mg twice weekly for the first twelve weeks, then once weekly. After initial counselling and training by a health professional on how to prepare and inject the drug, patients can usually self-administer at home using a pre-filled syringe or autoinjector. Injections are usually into the thigh, abdomen, or upper arm. A different site should be used at each injection to reduce soreness and prevent the skin from becoming tender, red, bruised, or hard.
Etanercept can be given alone or if necessary, in combination with topical treatments, methotrexate, and/or phototherapy.
The recommended dose of etanercept in adults is 50 mg per week, given once weekly (single 50 mg injection) or twice weekly (single 25 mg injections given 3–4 days apart) as a subcutaneous injection.
Elderly RA patients (age ≥ 65 years) show similar safety, efficacy and pharmacokinetic profiles compared to younger adult patients treated receiving etanercept. Dose adjustment is not needed for the elderly.
In children, aged 4 years and above, the dose is 0.8 mg/kg up to a maximum dose of 50 mg once weekly as a subcutaneous injection for up to 24 weeks. Treatment should be discontinued in patients who do not show a significant PASI response after 12 weeks.
Etanercept injections need to be kept cold, including when travelling. See travel letter, which explains the need to carry the medication as hand luggage.
Precautions necessary for patients on etanercept
Careful assessment is required before treatment with etanercept. Regular follow-up visits to monitor the safety and efficacy of treatment are also necessary.
Because etanercept works by selectively targeting a cytokine involved in psoriatic arthritis and/or psoriasis, theoretically it should have little effect on the rest of the body's immune system. Even so, caution must be taken when considering its use in patients prone to infections or in those with chronic or recurrent infections. It should not be used in patients with sepsis or active infections in case it makes these worse.
There is a particular concern that etanercept may reactivate tuberculosis (TB), viral hepatitis B and C, and increase the risk of the human immunodeficiency virus (HIV), listeria and legionella infections.
Etanercept should not be started during pregnancy (category B2) or breastfeeding.
Patients who require major surgery may be advised to stop etanercept temporarily 2 to 3 weeks prior to a planned operation. It can be started again 2 weeks after surgery, providing no infection is present.
Screening tests prior to etanercept
Screening tests recommended prior to starting etanercept usually include full blood count, liver enzymes, serum creatinine, urine analysis, antinuclear antibody (ANA), pregnancy test if relevant (urine or serum), HAV/HBV/HCV and HIV status.
Tuberculosis screening includes chest X-ray, and Mantoux intradermal test or QuantiFERON-TB Gold blood indirect test.
Vaccinations and etanercept
Immunisation status should be reviewed prior to starting etanercept. If necessary, vaccines should be updated. Annual influenza vaccination is recommended.
As they may induce illness in immunodeficient individuals, live vaccines should not be used during treatment with etanercept. Currently, available live attenuated viral vaccines include measles, mumps, rubella, varicella, yellow fever, influenza (intranasal vaccine) and the oral polio vaccine. Live attenuated bacterial vaccines include BCG and oral typhoid vaccine.
What are the side effects and risks of etanercept?
Etanercept appears to be very well tolerated. Mild to moderate injection site reactions (redness, swelling, itching, pain) appear to be the most common side effect. These tend to occur in the first month and then become less frequent. Cool compresses and 1% hydrocortisone ointment may help to alleviate injection site discomfort. Some people complain of itchy skin, and weight gain has been reported.
If any of the following symptoms or signs are severe or do not go away, you should contact your doctor:
- Coughing, wheezing, breathlessness or chest pain
- Nausea and/or vomiting and/or abdominal pain
- Fever, headache, chills or other signs of infection
- A hot, red, swollen area on the skin
- Bleeding or bruising
- Unexpected weight loss
- Sore eyes (uveitis has been described as a possible uncommon adverse reaction to etanercept).
Severe cutaneous reactions to etanercept have rarely been reported, including urticaria, angioedema, anaphylaxis and Stevens-Johnson syndrome / toxic epidermal necrolysis. Etanercept has been reported to cause drug-induced vitiligo.
Patients treated with etanercept may be at slightly greater risk of lymphoma and possibly other malignancies compared to the untreated population. In most cases, the patients have also been taking other medicines that suppress the immune system such as azathioprine or mercaptopurine.
Other conditions that have been reported in patients on etanercept include demyelinating diseases such as multiple sclerosis (MS), cardiac failure and bone marrow suppression. New onset of autoimmune diseases may occur; these may be associated with the underlying skin disease or its treatment.
Drug interactions with etanercept
Concurrent administration of etanercept and anakinra (a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist) has been associated with an increased risk of serious infection, an increased risk of neutropenia, and no additional benefit compared to etanercept alone.
The safety and efficacy of anakinra used in combination with etanercept have not been established. Therefore, the combination of etanercept and anakinra is contraindicated .
In clinical studies, concurrent administration of abatacept and etanercept resulted in increased incidences of serious adverse events, including infections. This combination has not demonstrated increased clinical benefit; and as such is not recommended.
In clinical trials, no apparent interactions have been observed when etanercept was administered with glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics.
Etanercept does not significantly affect digoxin or warfarin exposure.
The use of etanercept in patients receiving concurrent cyclophosphamide therapy (e.g. Wegener’s Granulomatosis) is not recommended.
Monitoring while on etanercept
It is recommended that patients on biological medications have routine blood tests every 6 months or so, including full blood count and liver function tests. TB testing should also be repeated from time to time.
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).