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Etanercept

Classification: A

Drug products: Benepali, Enbrel®, Erelzi

ATC code: L04AB01

Substances: etanercept

Summary

Specific evidence on sex and gender differences for etanercept is lacking. Studies on etanercept in different indications have shown worse treatment response and a higher rate of treatment discontinuation in women. The causes of these discrepancies are unknown. The incidence of cutaneous adverse events during TNF inhibitor treatment is higher in women than in men. Register data have shown that women with rheumatoid arthritis are initiated on TNF inhibitor treatment at a higher level of self-reported disease activity but at the same physician-reported disease activity.

Additional information

The prevalence of rheumatoid arthritis in the adult Swedish population is 0.7% and it is two-to-three times more common in women than in men [1]. The prevalence of ankylosing spondylitis in the Swedish adult population is 0.2%, with more men than women affected (0.23% vs. 0.14%) [2]. The overall prevalence of psoriasis in the adult Swedish population is 1.2%, psoriatic arthritis affects about 20% of these patients. In both psoriasis and psoriatic arthritis men and women are affected equally [3].

Pharmacokinetics and dosing

Pharmacokinetic parameters were examined in a study that combined samples from patients with rheumatoid arthritis in an open-label pharmacokinetic study (10 men, 15 women), with patients from a randomized clinical trial (11 men, 66 women). There was no difference between men and women in the clearance or half-life of etanercept, although given the low number of men included, small differences could not be ruled out [4]. In a larger pharmacokinetics study, data from three randomized controlled trials on etanercept in psoriasis were pooled together (718 men, 359 women). Clearance was 12% higher in women than in men but given the large overall variability in clearance the authors did not consider this to be of any clinical significance [5]. The prescribing information states that in clinical studies pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients [6].

Effects

Rheumatoid arthritisSeveral studies have shown that men have a greater chance to achieve remission in rheumatoid arthritis (RA). A large observational study involving RA patients (165 men, 840 women) found a relative risk of 1.51 for remission in men within the first 14.5 months of therapy with standard doses of TNF-inhibitors (infliximab, etanercept or adalimumab) [7]. A register-based study (3 465 men, 10 971 women) with RA patients treated with TNF inhibitors (33% etanercept) examined factors predictive of sustained remission. Female sex was associated with a lower chance of achieving sustained remission (Odds ratio (OR) 0.59) and sustained low disease activity (OR 0.65,) [8]. Similar results were reported in a meta-analysis which found an OR of 0.53  for women to achieve sustained remission with TNF inhibitor therapy in RA (3729 patients, 77% women) [9]. In a smaller observational study of patients with established RA (353 men, 1212 women) patient’s sex did not predict the response to TNF inhibitors (infliximab, etanercept or adalimumab) [10].

Axial spondyloarthritis and psoriatic arthritisA register-based study on spondyloarthritis patients (1601 men, 919 women) initiating TNF inhibitor therapy (etanercept n=745) examined factors that influenced drug discontinuation. Risk of drug discontinuation was lower in men than in women (hazard ratio (HR) 0.66) [11].  An observational study on patients with axial spondyloarthritis (236 men, 104 women) assessed the influence of patient’s sex on response to TNF inhibitor treatment (etanercept n=96) and disease remission. The probability of achieving partial remission was two to three times higher in men than in women [12].Predictors of response to TNF inhibitors in patients with ankylosing spondylitis and psoriatic arthritis were analyzed in a systematic review and meta-analysis that included 56 observational studies and randomized trials. In ankylosing spondylitis, male sex was associated with an OR of 1.57 for achieving clinical response as measured by the Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50). In psoriatic arthritis, men showed better response than women in five out of eight studies that included data on demographics but was not identified as a predictor of response [13]. A later observational study included patients (35 men, 40 women) initiated on TNF inhibitor treatment (etanercept, golimumab and adalimumab) and were followed prospectively. After twelve months, minimal disease activity was achieved in 61% of the patients. Male sex was associated with two to three times higher odds of achieving response, no difference was seen between the different TNF inhibitors [14].A systematic literature review found eight studies that examined differences between men and women in treatment discontinuation of TNF inhibitors in psoriatic arthritis. A higher risk of treatment discontinuation for women was reported in the majority of the included studies (n=3950 patients, about 45% women) [15].

PsoriasisAn observational study on patients with psoriasis that initiated biologic treatment (etanercept, adalimumab or ustekinumab) examined factors associated with response. The study included 3079 patients with data on baseline and six-month disease activity, 713 of these patients were started on etanercept (430 men, 283 women). Among all patients, female sex was associated with reduced odds of achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) (OR 0.78,). Chance of achieving PASI90 was lower for etanercept-treated compared to adalimumab-treated (OR 0.25). However, there was some evidence of a comparatively better response to etanercept for women, than men [16].

Adverse effects

The risk of cutaneous adverse events was examined in an observational study that included 5 437 arthritis patients treated with TNF inhibitors (644 men, 961 women with etanercept). Female sex was associated with a higher risk of cutaneous adverse events (incidence rate ratio 1.49) among all TNF inhibitor treated patients [17]. A similar observational study examined the incidence of cutaneous adverse events among TNF inhibitor-treated patients with chronic inflammatory arthritis (92 men, 165 women). After five years of follow-up, 71 (27.6%) patients experienced some type of adverse event involving the skin. Female sex was strongly linked to risk of cutaneous adverse events (OR 2.84) [18]. Another observational study examined drug discontinuation in biologics-treated psoriasis (etanercept, adalimumab or ustekinumab). The study included 226 men and 145 women and found that female sex predicted drug discontinuation due to adverse events in etanercept (HR 2.33), as well as in adalimumab and ustekinumab [19].

 

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A register-based study (2204 men, 7098 women) examined differences in disease characteristics at initiation of TNF inhibitors (etanercept, adalimumab and infliximab) between men and women. In women with rheumatoid arthritis, TNF inhibitor therapy was initiated at a higher level of patient reported disease activity than men. Except for slightly higher levels of c-reactive protein among men, physician-reported disease activity did not differ between the sexes [20]. A subsequent study (402 men, 1510 women) confirmed these results, however some of the patients were included in both studies [21].

Several studies have shown that the delay to initiation of therapy for patients with RA is similar for men and women and that no differences in the proportion of men and women receiving biologic agents have been found [22, 23].

Adherence to TNF inhibitors (etanercept, infliximab, adalimumab) in RA and Crohn’s disease was examined in a systematic review. Although there were some important differences, adherence was consistently lower in women [24].

Patients with rheumatic disease treated with etanercept (n=24) did not develop anti-drug antibodies in a clinical study. However, female sex was associated with development of anti-drug antibodies against adalimumab and infliximab [25].

Updated: 2022-11-08

Date of litterature search: 2022-10-07

References

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  2. Exarchou S, Lindström U, Askling J, Eriksson JK, Forsblad-d'Elia H, Neovius M et al. The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study. Arthritis Res Ther. 2015;17(1):118. PubMed
  3. Löfvendahl S, Theander E, Svensson Å, Carlsson KS, Englund M, Petersson IF. Validity of diagnostic codes and prevalence of physician-diagnosed psoriasis and psoriatic arthritis in southern Sweden--a population-based register study. PLoS One. 2014;9(5):e98024. PubMed
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  17. Hernández MV, Sanmartí R, Cañete JD, Descalzo MA, Alsina M, Carmona L et al. Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: study using the Spanish registry of adverse events of biological therapies in rheumatic diseases. Arthritis Care Res (Hoboken). 2013;65:2024-31. PubMed
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Authors: Hjalmar Wadström

Reviewed by: Diana Rydberg, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson