Infliximab

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

Infliximab pharmacokinetics has been analyzed in patients with inflammatory bowel disease. Patients received 5 mg/kg infusions at weeks 0, 2, 4 and 8 followed by every 8 weeks. The study showed that volume of distribution was higher in men than in women [4]. However, another study found no sex differences in infliximab volume of distribution or clearance [5]. Infliximab is dosed per kilogram bodyweight.

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) [6]. A register-based study (3 465 men, 10 971 women) with rheumatoid arthritis patients treated with TNF inhibitors (29% infliximab) 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) [7]. 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) [8]. Another register study (824 men, 2487 women) also showed that women with RA were less likely to achieve remission than men at 6 months following therapy with infliximab (OR 0.60) or etanercept (OR 0.61) [9].A clinical trial in Japanese patients (39 men, 312 women) showed that male sex was related to response of infliximab given in standard doses to patients with RA [10].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 [11]. In contrast, 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) [12].

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) [13]. 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 [14].

Crohn's diseaseThe efficacy of long-term infliximab therapy in patients with Crohn disease has been examined in an observational cohort study (86 men, 124 women). Multivariate analysis showed that men had a lower likelihood of failure to respond to infliximab induction therapy (HR 0.34) and a lower likelihood of failure to achieve sustained clinical benefit of infliximab therapy (HR 0.49) [15]. The better response to TNF-inhibitors in males is also described in children with Crohn disease. The efficacy of infliximab in children has been examined retrospectively from hospital records (123 boys, 71 girls). Infliximab was prescribed as monotherapy or in combination with immunomodulators (thiopurines or methotrexate). Boys were more likely than girls to have a complete response (OR 2.24). However, male sex was the only factor associated with secondary loss of response, defined as complete loss of benefit from infliximab, despite adjustment of dose and/or dosing interval. The sex differences persisted when controlling for induction response and Tanner stage (state of puberty). This benefit could not be explained by differences in weight-adjusted or BMI-adjusted infliximab dose [16].

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 (OR 2.99) [17].

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 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 TNF inhibitor stopped the treatment (19% vs. 9%). Also, a higher proportion of women than men switched to another TNF inhibitor (15% vs. 6%) [18].The risk of cutaneous adverse events was examined in an observational study that included 5 437 arthritis patients treated with TNF inhibitors (1002 men, 1502 women with infliximab). Female sex was associated with a higher risk of cutaneous adverse events (incidence rate ratio 1.49) among all TNF inhibitor treated patients [19]. 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) [20].Reactions from infliximab infusion in children with Crohn disease or Ulcerative colitis has been retrospectively analyzed (55 boys, 56 girls). The incidence of reactions was 14% in girls and 2% in boys (p=0.03) [21].

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 [22]. A subsequent study (402 men, 1510 women) confirmed these results, however some of the patients were included in both studies [23].

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 [24, 25].

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 [26]. Another systematic review of adherence, showed that female sex was a predictor of low adherence to TNF inhibitor therapy in inflammatory bowel disease [27]. In patients with rheumatoid arthritis, a study showed that women were more likely to discontinue infliximab therapy (HR 1.24) [28]. In contrast to his, male sex has been shown to be a predictor of discontinuation of TNF inhibitor treatment (adalimumab, etanercept, infliximab) in Korean patients with ankylosing spondylitis (HR 0.327) [29].

Female sex was associated with development of anti-drug antibodies against adalimumab (n=5) and infliximab (n=12) in a clinical study of rheumatic patients [30].