*7.5. Targeted Therapies: Revolution or Disillusion?*

Targeted therapies have revolutionized Rheumatology in recent years, especially in chronic inflammatory rheumatism—such as in RA—and, to a lesser extent, systemic diseases such as SLE and vasculitis. In terms of pSS, many targeted therapies have been tested or are currently in the pipeline. Unfortunately, a revolution like the one known in the field of RA has not yet occurred. These targeted drugs are shown in Figure 4 and summarized in Tables 6–12.

Given their predominant role in the production of autoantibodies, germinal centres and the evolution towards lymphoma, B cell depletion is one of the therapeutic mechanisms studied in pSS (Tables 6–8). In addition to the mixed results of the anti-CD20 Rituximab RCTs, other targeted drugs have been studied. Epratuzumab, an anti-CD22 B cell depleting therapy studied in SLE patients had a positive effect on the systemic activity of SLE patients with Sjögren syndrome in a post-hoc analysis of EMBODY trial [337]. However, an RCT should be designed to assess the effect of the therapy on both ESSDAI and ESSPRI in pSS patients. Other B cell depletion strategies aiming at blocking the BAFF

pathway showed a positive effect on the ESSDAI and ESSPRI scores at 28–52 weeks [338,339]. However, the confirmation of these promising results against a placebo is necessary. Other strategies targeting BAFF pathway are also under investigation: a TACI-antibody fusion protein called RC18, rituximab + belimumab combo therapy, Tibulizumab—a dual anti-BAFF (belimumab) and anti-IL-17 antibody (Ixekizumab)—and Ianalumab (anti-BAFF receptor). The results of these different studies are expected during 2020. B cell targeting drugs by Bruton tyrosine kinase inhibitor (4 molecules), LTßR fusion protein, PI3Kδ inhibitor (3 molecules) and Cathepsin S inhibitor are currently being evaluated with inconclusive results to date. Bortezomib, a proteasome inhibitor used for the treatment of multiple myeloma, has been successfully used in 2 cases of refractory pSS reports but has never been studied on a larger scale [236,340].

**Figure 4.** Synoptic view of targeted drugs (being) studied in pSS. Therapeutic classes are in bold. Biotherapies and small molecules are in black if they have been the subject of one or more trials in pSS or in grey if they exist but have not been tested in pSS. Names in strikethrough are drugs whose development has been stopped because of unacceptable side effects or because of portfolio prioritization.

T-cells play a central role in the modulation and polarization of the local autoimmune reaction within lymphocyte infiltrates in the exocrine glands. They are also used as therapeutic target by biotherapies interfering with the T-cell co-stimulation (Table 9). To date, there is no convincing result to recommend these treatments in pSS, but most studies targeting the CD40-ligand (CD154)/CD40 pathway are in progress. Therapies targeting T-cell trafficking, such as Fingolimod or Natalizumab, have not been studied in pSS.

With regard to anti-cytokine targeted therapies, RCTs using anti-TNF (infliximab and etanercept) and anti-IL6 receptor (tocilizumab) are negative (Table 11). Anakinra demonstrated a statistically significant decrease in fatigue VAS, without however reaching its primary clinical endpoint. The development of GSK2618960—an anti-IL-7Rα biotherapy—was stopped by the company due to the prioritization of their portfolio. So far, only one RCT studying the effect of Ustekinumab—an anti-IL-12/IL-23 antibody—on ESSDAI score at week 24 as primary endpoint is expected to give results in 2022 [341].

In a phase II trial, Filgotinib—a Jak1 inhibitor—and Lanraplenib—a SIK inhibitor—failed to demonstrate a significant effect on the ESSDAI and ESSPRI scores [342]. Finally, innovative therapies targeting plasmacytoid dendritic cells, immune complexes by RNase1-Fc fusion protein or the induction of T-reg cells by low-dose IL-2 injections are being evaluated. These various therapies are reviewed in Table 12.


targeteddrugsinpSSpart1:monoclonalantibodiesdirectedagainstBcellspecificClusterofDifferentiation

D-VAS or F-VAS, BILAG = British Isles Lupus Assessment Group index, BICLA =

serious adverse effects, SGUS = salivary gland ultrasound, Ig =

immunoglobulin,



=

BILAG-based

 Combined Lupus Assessment, ESSPRI = EULAR SS Patient Reported Index, SAEs =

decrease/increase,

 Δ =

difference.


*J. Clin. Med.* **2020**, *9*, 2299


 cell targeted drugs in pSS part 3: drugs targeting other B cells survival and function pathways.

> **Table 8.**

B

152

#### *J. Clin. Med.* **2020**, *9*, 2299

