*Pregnancy*

There is only limited information about the use of RTX during pregnancy. Rituximab has been detected in high concentrations in umbilical cord blood. There are case reports available, but in most cases, the mother took RTX due to hematologic malignancies. Congenital anomalies were not reported. As for all babies indirectly exposed to immunosuppressant biologics during pregnancy, immunization with live vaccines should be postponed until the age of 6 months [66].

#### **6. Targeted Synthetic DMARDS: JAK-Inhibitors**

Recently, with the Janus–Kinase (JAK) Inhibitors, a new group of drugs for the treatment of rheumatoid arthritis was introduced. These targeted, synthetic DMARDS (tsDMARDS) are e ffective in inflammatory diseases by intracellularly blocking tyrosine kinase [67].

The JAK are cytoplasmic protein tyrosine kinases that are critical for signal transduction to the nucleus from the common gamma chain of the plasma membrane receptors for interleukin (IL)-2, -4, -7, -9, -15, and -21. JAK are receptor-associated intracellular proteins, with a tyrosine-kinase component. They are important downstream mediators of many pro-inflammatory cytokines, e.g., interferons or interleukin 6. Once a ligand binds to its receptor, the intracellular kinase is phosphorylated, which further leads to the phosphorylation and activation of the signal transducer and activator of transcription (STAT)-pathway. Accordingly, blocking these enzymes with a targeted molecule a ffects multiple inflammatory pathways [65,66]. How JAKs transmit signals from cytokines and thereby activates gene transcription is shown in Figure 2.

**Figure 2.** Cytokines bind to the receptors, which then undergo a change in their configuration into a dimeric structure, thereby activating their ability to work as a kinase. Consequently, they phosphorylate the STAT molecules (Signal Transducer and Activator of Transcription). Phosphorylated STATs also form dimeres that travel to the cell core, where they activate transcription processes, which further fuel inflammatory processes.

Pharmacological aspects: JAK-inhibitors are referred to as small molecules, meaning that these compounds carry a low molecular weight and bind to a macromolecular target, altering their activity and function [68,69].

To date, two JAK-inhibitors are approved for therapeutic use in rheumatoid arthritis: Tofacitinib and Baricitinib.

Tofacitinib was approved by the FDA (Food and Drug Administration) in the US in 2012. In 2017, the European Medicines Agency (EMA) approved the drug for use in the European Union. Tofacitinib is an inhibitor of JAK 1 and 3, with only little a ffinity to JAK 2 and Tyrosine-Kinase 2. It has been shown e ffective in moderate and severe rheumatoid arthritis in monotherapy or in combination with methotrexate. Several phase III clinical trials showed e fficacy in DMARD naïve patients as well as in patients with insu fficient responses to csDMARDs and even bDMARDS. Tofacitinib is taken orally twice daily with a dosage of 5 mg. The elimination is mostly hepatic; therefore, an adaption to impaired kidney function is not necessary up to a GFR > 30 mL/min. Consequently, the treatment of patients with end-stage renal failure with a GFR < 30 mL/min with Tofacitinib is possible with reduced dosage [70,71].

The second JAK-inhibitor currently approved is Baricitinib which is an inhibitor of JAK 1 and 2. It was approved by the FDA as well as the EMA in 2017. Baricitinib can be administered as monotherapy or in combination with methotrexate. Several phase III clinical trials showed e fficacy in the treatment of DMARD naïve patients as well as in patients with insu fficient responses to csDMARDS or even bDMARDS [72–75].

Baricitinib is taken orally once daily. There are two dosages available: 4 mg or 2 mg. The elimination for Baricitinib is mostly renal, which makes it necessary to reduce the dosage for patients with impaired kidney function (estimated GFR 30–60 mL/min) from 4 mg to 2 mg daily. For patients with an estimated GFR < 30 mL/min, the use of Baricitinib is not recommended [2].

According to the EULAR-Guidelines, both JAK-Inhibitors can be used in rheumatoid arthritis once a therapy with csDMARDs has been insu fficient or had to be discontinued due to adverse events. Both Tofacitinib and Baricitinib have been shown to be more e fficient than a placebo in the treatment of rheumatoid arthritisl; both could show non-inferiority compared with the TNF-inhibitor Adalimumab [2,71,73].

## *Side E*ff*ects*

Tofacitinib: Increased susceptibility to infections including especially herpes zoster are the most common side e ffects of Tofacitinib as well as headaches, hypertension, nausea, and diarrhoea. Elevated levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, and liver enzymes have also been reported. In a post-marketing study, higher dosages of Tofacitinib showed an increased risk of deep vein thrombosis and pulmonary embolism. The recommended dosage of 5 mg twice daily should, therefore, not be exceeded [76,77].

Baricitinib: The most common side e ffect of Baricitinib was an increase of cholesterol levels. Elevated cholesterol levels return to normal once the medication is paused or be treated with statins effectively. This has been seen with other immunosuppressants as well. Other side e ffects include upper respiratory tract infections and nausea. Other infections, such as herpes zoster or pneumonia are also associated to Baricitinib. Patients treated with Baricitinib (0.3%) show significant neutropenia [78,79].

Screening pre-treatment: Active or latent infections with hepatitis or tuberculosis should be ruled out before initiating treatment with JAK-inhibitors. Blood cell counts and liver and kidney function also need to be evaluated prior to treatment.

Screening during treatment: neutrophil levels, lymphocyte levels, hemoglobin, and kidney and liver function should be screened; 8–12 weeks after the initiation of treatment, HDL, LDL, overall cholesterol, and triglycerides should also be screened.

Contraindications: JAK-inhibitors should not be prescribed for patients with neutropenia (<1/nL), active tuberculosis or severe infections, or severe liver impairment and during pregnancy. A combination with other bDMARDs or strong immunodepressants as azathioprine, cyclosporine, or tacrolimus should be avoided due to the elevated risk of infection and the lack of experience.

Use during Pregnancy: drugs from the JAK-inhibitor family have not been tested in pregnan<sup>t</sup> women yet. As both drugs are small molecules, it seems likely that cross the placenta. Women taking JAK-inhibitors should be instructed to use safe contraceptive methods throughout the treatment and up to one week (Baricitinib) to four weeks (Tofacitinib) after a discontinuation of the drug.

Perioperative management: Although there are not enough long-term data for a conclusive recommendation on perioperative management, JAK-inhibitors in general have a short elimination-time. It therefore seems possible to continue treatment until shortly before surgery. The therapy should then be paused until proper wound-healing is achieved.

Ongoing development: Two selective JAK-1-Inhibitors are currently undergoing Phase 3 trials for clinical approval: Upadacitinib and Filgotinib. Both drugs show promising results in terms of efficacy and safety. Another JAK-inhibitor currently being evaluated in Phase 3 trials is the selective JAK-3-Inhibitor Peficitinib, with limited data available so far [80,81].

## **7. Conclusions**

The therapeutic strategies of RA have improved dramatically over the past 3 decades. At that time, only a few drugs were available and therapy started late in disease course. With the T2T strategy and the possibility to choose from different mode of actions, the aim of stable remission can be reached and joint destruction can be prevented. Equally important to the choice of drugs is to diagnose the disease early and to start therapy within 6–12 weeks after disease onset. Early arthritis clinics headed by experienced rheumatologists are a good tool to achieve this. T2T further improves the prognosis of RA.

**Author Contributions:** Concept—H.-M.L., B.M.K., J.G. and D.K. Design—B.M.K., J.G. and D.K. Supervision—H.-M.L.; Literature Search—B.M.K., J.G. and D.K.; Writing Manuscript—B.M.K., J.G. and D.K.; Critical Review—H.-M.L. All authors read and approved the final manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
