Efficacy and safety of certolizumab pegol in pregnant women with uveitis. Recommendations on the management with immunosuppressive and biologic therapies in uveitis during pregnancy.

OBJECTIVES: Clinicians often face the challenge of providing effective and safe therapy for pregnant women with uveitis. Certolizumab pegol (CZP) differs from other anti-TNFα agents due to its limited placental transfer. In this study we assessed the efficacy of CZP in pregnant women with uveitis. We also provided information on outcomes of pregnant women and neonates exposed to CZP. METHODS: We carried out a multicentre study of women with uveitis who received CZP during pregnancy and their neonates. The main visual outcomes were visual acuity (VA), intraocular inflammation and corticosteroid-sparing effect. Pregnancy outcomes, maternal and neonatal infections and congenital malformations were also assessed. RESULTS: We studied 14 women (23 affected eyes); mean age of 34.3±5.5 years. The underlying diseases were spondyloarthritis (n=7), idiopathic (n=2), and Vogt-Koyanagi-Harada, rheumatoid arthritis, juvenile idiopathic arthritis, punctate inner choroidopathy and Behçet's disease (1 each). The patterns of ocular involvement were anterior (n=10), posterior (n=2), intermediate (n=1), panuveitis (n=1). Cystoid macular oedema was present in one patient (1 eye). Uveitis was bilateral in nine cases and chronic in seven patients. CZP was started before getting pregnant in ten patients and after conceiving in four. All patients achieved or maintained ocular remission throughout pregnancy. Fifteen healthy infants were born. Only one woman presented a mild infection during pregnancy. Neither infections nor malformations were observed in neonates after a follow-up of 6 months. Six infants were breastfed and all of them received scheduled vaccinations without complications. CONCLUSIONS: Certolizumab pegol is effective and safe in women with uveitis during pregnancy.

Clinical management of Anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review.

Tumor necrosis factor alpha inhibitors (anti-TNF-α) completely revolutionized the treatment of inflammatory bowel disease (IBD). However, anti-TNF-α-induced cutaneous side effects have been increasingly reported in the literature. Particularly, psoriasis and the recently recognized psoriasiform lesions are of particular concern, as anti-TNF-α agents are also used in the treatment of psoriasis, seemingly reflecting an immunological paradox. The clinical management of these cutaneous lesions is particularly challenging, owing to the potential need of anti-TNF-α discontinuation and scarcity of other therapeutic options. Therefore, optimization of current topical and systemic therapies and incorporation of new therapeutic agents is of great interest. Our aim is to review data in the literature regarding the clinical management of these cutaneous lesions and provide a therapeutic algorithm, supported by our experience as a tertiary referral center for IBD. Although in older reports no distinction was made, anti-TNF-α-induced psoriasiform lesions are not only more prevalent but also bear notable differences from classical psoriasis, possibly reflecting a different nosological entity. Onset of lesions has been related to periods of IBD remission, as supported by low levels of fecal calprotectin. Psoriasiform lesions can be adequately managed either by topical (glucocorticoids, calcineurin inhibitors, and antibiotics) or systemic (phototherapy, acitretin, glucocorticoids, and antibiotics) therapies and/or switch to other anti-TNF-α agents. Data referring to patients who were able to continue on the same IBD therapy ranged from 30.7 to 100%, reinforcing the importance of an adequate control of these lesions. The recently approved ustekinumab offers another step in the management of anti-TNF-α-intolerant patients.

Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development.

BACKGROUND & AIMS: Exposure to biologic and immunosuppressant agents during breastfeeding is controversial, and there are limited data on safety. We investigated whether biologics are detectable in breast milk from women receiving treatment for inflammatory bowel diseases (IBDs) and whether breastfeeding while receiving treatment is associated with infections or developmental delays. METHODS: We performed a multicenter prospective study of women with IBD and their infants, collecting breast milk samples (n = 72) from patients receiving biologic therapy from October 2013 to November 2015. Drug concentrations were measured in all breast milk samples at several time points within 48 hours of collection and within 168 hours for some samples. Child development was assessed using the Ages and Stages Questionnaire 3, completed by 824 women with IBD (treated or untreated) during pregnancy (620 breastfed, and 204 did not). Data on children's health and development were obtained from mothers and pediatricians, along with information on mothers' medication exposure, IBD history, activity, pregnancy, and postpartum complications. We used chi-squared method or Fisher exact test to determine associations between categorical values and compared differences in continuous outcomes between groups using analysis of variance models. The primary outcome was drug concentration of biologic agents in breast milk (from 72 women) at 1, 12, 24, and 48 hours after dosing and also at 72, 96, 120, and 168 hours for available samples. Secondary outcomes were a range of infant infections and Ages and Stages Questionnaire 3-defined developmental delays among all breastfed infants. RESULTS: We detected infliximab in breast milk samples from 19 of 29 treated women (maximum, 0.74 µg/mL), adalimumab in 2 of 21 treated women (maximum, 0.71 µg/mL), certolizumab in 3 of 13 treated women (maximum, 0.29 µg/mL), natalizumab in 1 of 2 treated women (maximum, 0.46 µg/mL), and ustekinumab in 4 of 6 treated women (maximum, 1.57 µg/mL); we did not detect golimumab in breast milk from the 1 woman receiving this drug. Rates of infection and developmental milestones at 12 months were similar in breastfed vs non-breastfed infants: any infection, 39% vs 39% in control individuals (P > .99) and milestone score, 87 vs 86 in control individuals (P = .9992). Rates of infection and developmental milestones did not differ among infants whose mothers received treatment with biologics, immunomodulators, or combination therapy compared with unexposed infants (whose mothers received treatment with mesalamines or steroids or no medication). CONCLUSIONS: In a study of women receiving treatment for IBD and their infants, we detected low concentrations of infliximab, adalimumab, certolizumab, natalizumab, and ustekinumab in breast milk samples. We found breastfed infants of mothers on biologics, immunomodulators, or combination therapies to have similar risks of infection and rates of milestone achievement compared with non-breastfed infants or infants unexposed to these drugs. Maternal use of biologic therapy appears compatible with breastfeeding. Clinicaltrials.gov no.: NCT00904878.

Risk of Serious Bacterial Infection Associated With Tumor Necrosis Factor-Alpha Inhibitors in Children and Young Adults With Inflammatory Bowel Disease.

Background: Prior studies evaluating the relationship between tumor necrosis factor-alpha inhibitors (TNFI) and infection were conducted in adults and had conflicting findings. We sought to examine the risk of serious infection associated with TNFIs compared with nonbiologic immunomodulators in children and young adults with inflammatory bowel disease (IBD) and to compare the risk among individual TNFIs. Methods: We conducted a cohort study using the Truven MarketScan Commercial Claims and Encounters database of patients age <30 years with a diagnosis of IBD who initiated treatment with a TNFI or immunomodulator (thiopurines or methotrexate) between 2009 and 2013. The outcome of interest was serious infection, defined as a nongastrointestinal bacterial infection requiring hospitalization. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for serious infection associated with TNFIs compared with immunomodulators. Results: We identified 10,838 children and young adults with IBD; 236 and 192 cases of serious infection were observed in 4502 TNFI initiators (5.25/100 person-years) and 6336 immunomodulator initiators (3.59/100 person-years), respectively. Compared with immunomodulators, TNFIs were associated with a higher risk of serious infection (HR, 1.36; 95% CI, 1.08-1.72). Among TNFI users, certolizumab showed a 3.38-fold (95% CI, 2.25-5.09) increased risk vs infliximab, and subcutaneously administered TNFIs also exhibited a higher risk (HR, 1.34; 95% CI, 1.18-1.53) than intravenous TNFIs. Conclusions: TNFIs pose a higher risk of serious infection compared with immunomodulators in children and young adults with IBD, and this risk differs among individual TNFIs and routes of administration.

Cost-utility analysis of certolizumab pegol in combination with methotrexate in patients with moderate-to-severe active rheumatoid arthritis in Greece.

We aimed to evaluate the cost-effectiveness of certolizumab pegol (CZP), a pegylated fc-free anti-TNF, as add-on therapy to methotrexate (MTX) versus etanercept, adalimumab, or golimumab in patients with moderate-to-severe active rheumatoid arthritis (RA) not responding to the conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). A Markov model (6-month cycle length) assessed health and cost outcomes of CZP versus other anti-TNFs recommended for RA in Greece over a patient's lifetime. Following discontinuation of first-line anti-TNF, patients switched to second anti-TNF and then to a biologic with another mode of action. Sequential use of csDMARDs followed third biologic. Clinical data and utilities were extracted from published literature. Analysis was conducted from third-party payer perspective in Greece. Costs (drug acquisition, administration, monitoring, and patient management) were considered for 2014. Results presented are incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY). Probabilistic sensitivity analysis (PSA) ascertained robustness of base-case findings. Base-case analysis indicated that CZP+MTX was more costly and more effective compared with Etanercept+MTX (base-case ICER: €3,177 per QALY), whilst versus adalimumab/golimumab, CZP was dominant (less costly, more effective). For all comparisons, CZP treatment resulted in greater improvements in life expectancy and QALYs. PSA indicated that at the willingness-to-pay threshold of €34,000/QALY, CZP+MTX was associated with a 71.6, 97.9, or 99.2% probability of being cost-effective versus etanercept, golimumab, or adalimumab, respectively, in combination with MTX. This analysis demonstrates CZP+MTX to be a cost-effective alternative over Etanercept+MTX and a dominant option over Adalimumab+MTX and Golimumab+MTX for management of RA in Greece.

Infections and Biological Therapy in Patients with Rheumatic Diseases.

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients with rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.