Pregnancy

Observational studies and case reports of women exposed to TNF inhibitors during pregnancy sugges<sup>t</sup> that their pregnancy outcomes, including rates of preterm birth, spontaneous miscarriage, and congenital anomalies, are similar to those in women with RA who have not received a TNFi [41].

Complete immunoglobulin G (IgG) antibodies—maternal as well as therapeutic—cross placenta via active transport facilitated by the neonatal fragment crystallizable (Fc) receptor on the placenta. IgG1 is the most effectively transported of the four subclasses of IgG (G1–G4) [42]. This is relevant to adalimumab, golimumab, and infliximab which are complete IgG1 anti-TNF. Etanercept is comprised of the Fc domain of human IgG1 fused with the extracellular ligand binding domain of human tumor necrosis factor receptor-2. Transplacental transport via the neonatal Fc receptor would theoretically be plausible. In contrast to the complete IgG1 anti-TNF antibodies certolizumab pegol differs structurally as it is a humanized PEG (polyethylene glycol)-ylated antibody Fab' fragment lacking the IgG1 Fc portion. Without the Fc portion it should, in theory, not be transported actively across the placenta [43]. So passive diffusion would be the only option for any detectable concentrations in exposed infants. This was shown in two trials. Based on these trials the EMA has approved a label change for CZP, making it the first anti-TNF for potential use in women with chronic rheumatic disease during both pregnancy and breastfeeding [44].

TNFi may have different structures, morphology, pharmacokinetic properties, and activity, but their clinical efficiency is comparable. If drug survival and safety are similar or different is still a matter of debate.

#### *3.2. Interleukin 1 Inhibitor*

Anakinra was first approved in the US in 2001 and in Europe in March 2002. It is a recombinant human IL-1 receptor antagonist with a short half-life (4–6 h), administered subcutaneously at a dose of 100 mg once a day. It was first developed for use in RA and showed some effects in early trials. A big systematic review of the literature in 2009 showed only a moderate effectiveness [45,46]. Anakinra plays not a very grea<sup>t</sup> role in RA therapy; today, it is much more effective in the therapy of auto-inflammatory diseases, gout, or polyserositis [45–50].

Adverse effects include injection site reactions characterized by itching, pain, and redness at the site of medication injection and lasting days to weeks. Between one and ten percent of people have severe infections, decreased white blood cells, or decreased platelets [51].
