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. 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 sex-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 arthritis

Several 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 TNFα-inhibitors (infliximab, etanercept or adalimumab) [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, a large observational study of patients with established RA (353 men, 1212 women) showed that sex did not predict the response to TNFα-inhibitors (infliximab, etanercept or adalimumab) [7].

Psoriatic arthritis

Poorer treatment response among women treated with TNFα inhibitors have also been described in patients with psoriatic arthritis. In a British observational controlled study (280 men, 316 women), multivariate analysis showed that women treated with TNFα-inhibitors had lower response and remission rates at 6 months (odds ratio 0.51 and 0.34, respectively) than men [8]. A Danish register study showed that women had shorter treatment duration and men had better clinical response (odds ratio 1.5) [9]. 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 (odds ratio 2.24) [10].

Ankylosing spondylitis

Response to TNFα-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) [11].

Adverse effects

Sex differences in adverse drug reactions to immune suppressive medication have been analyzed in a review of medical records (386 men, 457 women). For patients treated with infliximab, more women than men suffered from adverse drug reaction (odds ratio 2.2, 95%CI 1.2-4.1). 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 TNFα-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 TNFα-inhibitor (15% vs. 6%) [12].

The incidence of cutaneous adverse events in patients with chronic inflammatory arthritis who receive TNFα-inhibitors (infliximab, etanercept or adalimumab) has been evaluated in a prospective study (92 men, 165 women). After 60 months of follow-up, 27.6% had experienced some type of adverse event involving the skin. Of those, 81.7% were women.  Female sex was the main risk factor associated with cutaneous adverse events (odds ratio 2.84, 95%CI 1.90-5.63) [13]. An observational register study (2123 men, 3311 women) found an incidence rate ratio of cutaneous adverse events of 1.49 in women treated with TNFα-inhibitors (infliximab, etanercept or adalimumab) [14].

Reproductive health issues

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

Other information

Disease characteristics at initiation of TNFα-inhibitor treatment (infliximab, etanercept or adalimumab) in men and women with rheumatoid arthritis have been analyzed in a Swedish register study (2204 men, 7098 women). The register includes data assessed both by patients and the physician. Women with rheumatoid arthritis were initiated on TNFα-inhibitor therapy at a higher level of disease when measured by patient, but at the same level as men when measured by physician [15]. Same results were shown in another similar register study (402 men, 1510 women). This may indicate that physicians were not taking the patient’s experiences into account in their decision of treatment. However, there were no differences between men and women in the choice of biologic agent (etanercept, adalimumab, infliximab, rituximab, abatacept, golimumab, certolizumab pegol, anakinra, tocilizumab, or ustekinumab) [16].

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 [17, 18].

A systematic review of adherence to TNFα-inhibitors (infliximab, etanercept or adalimumab) in Crohn disease and rheumatoid arthritis showed that the most consistent factor associated with lower adherence was female sex [19]. Another systematic review of adherence, showed that female sex was a predictor of low adherence to TNFα- inhibitor therapy in inflammatory bowel disease [20]. In contrast to his, male sex has been shown to be a predictor of discontinuation of TNFα-inhibitor treatment in Korean patients with ankylosing spondylitis (hazard ratio 0.327) [21].

A study has evaluated the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of TNFα-inhibitors (infliximab, etanercept, or adalimumab) in patients with rheumatic diseases (21 men, 37 women). The only factor associated with development of anti-drug antibodies was female sex (odds ratio 8.3) [22].