Adalimumab

Additional information

Pharmacokinetics and dosing

In a randomized, double-blind, dose-titration study involving patients (13 men, 47 women) with rheumatoid arthritis receiving either adalimumab (0.25, 0.5, 1, 3, or 5 mg/kg) or placebo, clearance across all doses of adalimumab was 30% higher in women (0.010 vs. 0.03 L/h, p<0.05). However, the difference appeared to be mainly due to differences in body weight (23%) between men and women. The number of men receiving adalimumab was small (10 men, 35 women) [1]. The original manufacturer report that no gender-related pharmacokinetic differences have been observed after correction for a patient’s body weight [2]. Pharmacokinetics shows no differences between men and women when corrected for bodyweight. However, in adults adalimumab is administrated as a fixed dose. No studies with a clinically relevant sex analysis regarding the dosing of adalimumab have been found.

Effects

Rheumatoid arthritisSeveral studies have shown that men have a better response to TNF inhibitors and 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 associated with male sex within the first 14.5 months of therapy with standard doses of TNF-inhibitors (infliximab, etanercept or adalimumab) in patients with rheumatoid arthritis [3]. Also, an open-label study involving patients with active RA treated with adalimumab 40 mg s.c. every other week (1246 men, 5227 women), showed that men had longer duration of remission (hazard ratio 1.28) [4]. A large observational study (593 men, 2032 women) evaluating the effectiveness of adalimumab 40 mg every other week in RA showed that men had a lower disease activity and higher self-reported functional capacity at 12 months of therapy [5]. A Swedish observational study (252 men, 446 women) showed that fewer women with RA receiving anti-rheumatic agents (mainly sulfasalazine or methotrexate) were in remission at follow-up at 2 and 5 years than men. Disease activity, assessed by the doctor, had decreased less in women than in men. However, women had a higher baseline disease activity [6]. Contrary to these findings, in another 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) [7].

Psoriatic arthritisPoorer treatment response among women treated with TNF inhibitors have also been described in patients with psoriatic arthritis. 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) [8]. Furthermore, a British observational controlled study (280 men, 316 women) showed that women treated with TNF inhibitors had lower response and remission rates at 6 months (OR 0.51 and 0.34, respectively) than men [9]. A later observational study included patients (35 men, 40 women) that initiated 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 [10]. In another, open-label uncontrolled study (221 men, 221 women), patients received adalimumab 40 mg every other week in addition to standard therapy for 12 weeks. Men had higher response rates (OR 2.24) [11].

Ankylosing spondylitisResponse to TNF inhibitors (infliximab, etanercept or adalimumab) in patients with ankylosing spondylitis has been evaluated in an observational study (152 men, 68 women). Men were more likely to have a better treatment response at 6 months of treatment (odds ratio 2.99) [12].

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, 1791 of these patients were started on adalimumab (1039 men, 752 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 [13].

Adverse effects

Sex differences in adverse drug reactions to immune suppressive medication (infliximab, adalimumab, certolizumab) have been analyzed in a review of medical records (386 men, 457 women). For patients treated with adalimumab, there were no significant differences between men and women in experience of adverse drug reactions. The most frequent adverse drug reaction to infliximab and adalimumab was allergic reactions, with a higher rate in women than men. No other sex-specific adverse drug reactions to TNF inhibitors were observed. As a result of adverse drug reactions, a higher proportion of women than men treated with TNFα-inhibitor stopped the treatment (19% vs. 9%). Also, a higher proportion of women than men switched to another TNF inhibitors (15% vs. 6%) [14].The risk of cutaneous adverse events was examined in an observational study that included 5 437 arthritis patients treated with TNF inhibitors (480 men, 848 women with adalimumab). Female sex was associated with a higher risk of cutaneous adverse events (incidence rate ratio 1.49) among all TNF inhibitor treated patients [15]. 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) [16]. 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 adalimumab (HR 2.91), as well as in etanercept and ustekinumab [17].

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 [18]. A subsequent study (402 men, 1510 women) confirmed these results, however some of the patients were included in both studies [19].

Several studies have shown that the delay to initiation of therapy for patients with rheumatoid arthritis is similar for men and women and that no differences in the proportion of men and women receiving biologic agents have been found [20,21].

Adherence to TNF inhibitors (etanercept, infliximab, adalimumab) in rheumatoid arthritis and Crohn’s disease was examined in a systematic review. Although there were some important differences, adherence was consistently lower in women [22]. Another systematic review of adherence, showed that female sex was a predictor of low adherence to TNF inhibitor therapy in inflammatory bowel disease [23]. In contrast to his, male sex has been shown to be a predictor of discontinuation of TNFα-inhibitor treatment (adalimumab, etanercept, infliximab) in Korean patients with ankylosing spondylitis (HR 0.327) [24].

Female sex was associated with development of anti-drug antibodies against adalimumab (n=24) or infliximab (n=) in a clinical study [25].