Pregnancy

There have been no adequate studies for the safety of Anakinra in Pregnancy, although several case reports of women with adult-onset Still's disease treated through pregnancy resulted in healthy neonates [52].

#### **4. Interleukin 6 and Interleukin 6 Receptor Inhibitors**

Interleukin-6 (IL-6) was identified in 1986 as a key cytokine in the pathogenesis of RA with proinflammatory activity. It is able to enhance the production of acute-phase proteins involved in the systemic inflammation process. Tocilizumab (TCZ) is the first humanized recombinant IgG1monoclonal antibody that binds to both the soluble and membrane-bound IL-6 receptor, blocking its action and leading to the decrease of the inflammatory response cascade. Its half-life (10–13 days) allows its administration intravenously (8 mg/kg) every 4 weeks. A subcutaneous formulation of TCZ (162 mg/week) has been approved, with an efficacy and safety profile comparable to intravenous administration [52,53]. A second agent, Sarilumab is a human immunoglobulin G1 anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor alpha [54].

Events of gastrointestinal (GI) perforations have been reported in Phase III clinical trials, primarily as complications of diverticulitis, including generalized purulent peritonitis, lower GI perforation, fistula, and abscess. Tocilizumab or Sarilumab should be used with caution in patients who may be at increased risk for GI perforation. Patients presenting with new-onset abdominal symptoms should be evaluated promptly for the early identification of GI perforation. It is important to keep in mind that, during IL-6 blockade, C-reactive protein or other acute phase reactants will increase slowly and less pronounced [55,56].

Other side e ffects are neutropenia or thrombocytopenia as well as hyperlipidemia. Also, serious infections and liver enzyme elevations were observed and can require dose adjustments or drug discontinuation [56].

## *4.1. Pregnancy*

Based upon animal data, tocilizumab may cause fetal harm, but there are no adequate studies of its e ffects on human pregnancy to allow an assessment of its risk. There are a few case series available. No teratogenic e ffects were observed. In a case series of 50 pregnancies exposed to tocilizumab with known outcomes, 36 resulted in live births, while there were five low-birthweight infants born and one case of neonatal asphyxia [57,58].

#### *4.2. CD80*/*86-CD 28 Inhibitor*

Abatacept is a fusion protein constituted by an immunoglobulin fused to the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA-4). This is a molecule that binds with a high a ffinity to the CD80/86 ligand on antigen-presenting cells. Therefore, abatacept is able to block the interaction between the antigen-presenting cell's CD80/86 ligand and the CD28 ligand on the T cell [59]. This results in decreased T cell proliferation and cytokine production. Abatacept is administered intravenously once every 4 weeks or subcutaneously once a week [60,61].

Adverse e ffects including cases of hypersensitivity and anaphylaxis or anaphylactoid reactions have been reported with iv administration. As in other bDMARDs, serious infections (including tuberculosis and sepsis) have been reported, particularly in patients receiving concomitant immunosuppressive therapy [59].

The use of CTLA-4 Inhibitors due to its T cell inhibition a ffect defenses against malignancies. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. Abatacept itself seems not to further increase this risk [62].
