Small-molecule inhibitors and the salivary gland epithelium in Sjögren’s syndrome

ABSTRACT

Introduction: The salivary gland (SG) in primary Sjögren’s syndrome (pSS) is characterized by its lack of function (hyposalivation) and lymphocytic invasion. Small-molecule inhibitors (SMIs) are a new class of drugs, whose diminutive size permits diffusion into cells. SMIs targeting components of the immune system are eagerly being trialed for their potential therapeutic utility in pSS. Neglected until now, however, is a discussion of the potential effects of SMIs on the SG epithelium.

Areas covered: We begin by reminding the reader of the SG epithelial compartment, its complicity in inflammatory milieu formation in pSS, and categories of SMIs which merit attention. We discuss each SMI category, including pre-clinical data concerning pSS and likely consequences of their application on the SG epithelium.

Expert opinion: Recovery of saliva production in pSS requires restoring the function of the SG epithelium, not solely on inflammation resolution. Many SMIs, for example, those blocking JAK-STAT signaling, interfere with critical epithelial cell pathways, most notably EGF signaling. If the effect of SMIs on SG epithelium is ignored, recovery of SG function will be challenging. We predict that NFκB signaling blockade will impart the least SG epithelium damage whilst reducing inflammation and facilitating recovery from hyposalivation in pSS.

KEYWORDS:

• Epithelium
• hyposalivation
• inflammation
• NFκB signaling
• salivary gland
• Sjögren’s syndrome
• small-molecule inhibitors
• toll-like receptor

Article Highlights

• Recovery of saliva production in patients with pSS requires rescue of the saliva-producing SG epithelium, not solely resolution of inflammation.

• Small molecular inhibitors (SMIs) targeting TLR, NFκB, and JAK-STAT signaling, in addition to the autophagy machinery and Rho kinases are all either currently in clinical trials with pSS patients, or likely to be in the near future.

• The cross-talk between these inflammatory pathways, particularly TLR and JAK-STAT signaling, and mechanisms governing SG epithelial cell homeostasis is significant. This implies that application of some SMIs for treatment of pSS patients may be detrimental to SG function.

• From the SMIs currently available and studies performed, blockade of NFκB signaling using SMIs may represent the option with the least collateral damage to the SG epithelium.

• There is a general lack of basic studies concerning the effect of SMIs on the SG, which will hamper our ability to choose the most appropriate treatment modality.

• In order to model SMI induced damage on the whole SG epithelium, not only the ductal cells, organoid cultures will likely become a crucial tool.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors is funded by an investigator driven grants from Bristol-Myers Squibb and ReumaNederland [LLP29 T015–052].