Infliximab

Additional information

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 [1]. However, another study found no sex differences in infliximab volume of distribution or clearance [2].

Infliximab is dosed per kilogram bodyweight.

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].

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 (odds ratio 0.60) or etanercept (odds ratio 0.61) [4]. 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 [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].

Crohn disease

The 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 (hazard ratio 0.34) and a lower likelihood of failure to achieve sustained clinical benefit of infliximab therapy (hazard ratio 0.49) [10]. The better response to TNFα-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 (odds ratio 2.24; 95%CI 1.09-4.60). 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 [11].

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) [12].

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%) [13].

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) [14]. 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) [15].

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) [16].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (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 [17]. 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) [18].

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 [19, 20].

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 [21]. Another systematic review of adherence, showed that female sex was a predictor of low adherence to TNFα- inhibitor therapy in inflammatory bowel disease [22]. In patients with rheumatoid arthritis, a study showed that women were more likely to discontinue infliximab therapy (hazard ratio 1.24) [23]. 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) [24].

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) [25].