What's New in Ocular and Oral Aspects of Sjögren's Syndrome and Do New Treatments Work?

Nurhan Sutcliffe; Alberto Recchioni; Shireen Hilmi; Saaeha Rauz; Anwar R. Tappuni


Rheumatology. 2021;60(3):1034-1041. 

In This Article

New Treatments for Ocular SS

One of the newly suggested treatment options in DED is intense pulsed light (IPL). Using intense pulses of non-coherent light (xenon light flashes) varying from 500 to 1200 nm, IPL has been demonstrated to improve tear film quality (increased resistance to evaporation) while reducing symptoms in dry eye patients.[28] However, the mechanism of action of IPL is unclear, but it seems to improve MG de-obstruction (heating and liquefaction of the lipids), Demodex eradication, secretion of non-inflammatory molecules and reduction of MMP-9 levels in the tear film. In a study by Mejia et al.,[29] the researchers found improved DED metrics such as symptoms, tear breakup time, Schirmer test and ocular staining score after completing three IPL sessions. The authors stated that IPL treatment could have improved the DED metrics due to a photochemical effect on the mitochondria. Those cells could have reacted to the non-coherent light treatment, producing a proliferation of acini cells, leading to increased cellular oxygenation.

Like the IPL treatment, which is believed to promote cellular proliferation in the eyelids, new studies are attempting to understand if the MGs can be regenerated in those patients with MGD. Recently Hwang et al.[30] found that increased MGD dropout levels could potentially be a cause of DED in SS patients. Additionally, the authors reported that reduced lipid layer thickness, which directly influences the quality of the tear film, was correlated with a decrease in MGD.

Xie et al.[31] discovered biomarkers for human MG progenitor and differentiated cells. These include leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) and deoxyribonuclease 2. They both have a plastic expression that can be enhanced to obtain proliferation or differentiation of MGs. This has promoted interest in future in vivo studies assessing MG regeneration. These studies could have a clinical impact in the management of EDE in SS, where patients with primary and secondary disease have been found to have MG orifice metaplasia, obstructed ducts and reduced quality of the secreted lipids.[32]

Another device that has demonstrated its efficacy in the general treatment of MGD in SS is the LipiFlow (TearScience, Morrisville, NC, USA).[33] The principle behind this technology is to bring together the benefits from manual gland expression with melting of the meibum oil accumulated within the glands and its ducts. The machine is able to deliver continuous massage to the eyelids while heating to a temperature of 42.5°C. A 12 min treatment per eye can improve the expressibility of the MG, tear breakup time and ocular symptoms for a duration of 3–12 months.[34,35] The treatment can be added to the current patients' management plan (e.g. tear lubricant or eye drops) and would be specifically beneficial in those cases where a reduction in lipid production is observed (unstable tear film and reduced tear breakup time) or where other lipid-based treatments are not completely successful (e.g. liposomal spray or lipid eye drops).[36] Patients access to both IPL and LipiFlow treatments is still limited, but many private practices are implementing these treatment devices in their offices, as they can also be useful for treating mild–moderate DED (non-SS).

Chloroquine and hydroxychloroquine are widely adopted immune-modulating drugs used in conditions such as SS, RA, SLE and amoebic hepatitis for alleviating musculoskeletal pain and fatigue.[37] Topical application of chloroquine (0.03%) for a duration of 21 days has been shown to be efficacious in moderate DED, positively impacting the inflammatory status of the tear film, leading to improvement in ocular staining, DED symptoms and tear film volume.[38,39] Systemic oral chloroquine and its derivatives are known to increase the risk of retinal toxicity depending on the daily dosage, concentration and duration of the treatment.[40,41] A therapeutic concentration of 0.03% and limited time of use (3 weeks) is highly unlikely to deliver toxic levels after systemic or intraocular absorption. Nevertheless, further studies are required to understand the possible side effects when chloroquine is used for longer periods on the surface of the eye and whether there is intraocular penetration and systemic absorption that might impact on the retina.[42]

Another topical drug considered for treating DED in SS and non-SS patients is the topical ciclosporin A (CsA). CsA is a T cell immunosuppressive that has been demonstrated in several studies to work at low doses to reduce the inflammatory response that causes DED.[43,44] However, due to the nature of its chemistry (e.g. poor solubility in the tear film), new compounds have been designed and tested to overcome this issue: the nanoemulsion solution Cyporin N (Taejoon Pharm, Seoul, Korea) is a new CsA formulation at 0.05% concentration that has been shown to improve ocular staining (both conjunctival and corneal), tear film breakup time and symptomatology after 12 weeks of study.[45]

Recently a new phase 2b trial started investigating the effect of a new drug application formerly known as AR-15512 [transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) agonist; Aerie Pharmaceuticals, Durham, NC, USA). AR-15512 is a potent and selective agonist of the TRPM8 cold thermoreceptor ion channel, which controls tear production and the blink rate. The aim of this trial is to understand if the drug is able to restore tear film volume in patients with dry eye by acting over this mechanism. Previously, Avizorex Pharma (Spain) completed a phase 2a trial that has demonstrated positive results. Unfortunately, data from this study are not yet published.

As previously mentioned, evaporative DED due to MGD is one of the most common causes of DED. A novel phase 3 trial of NOV3 (Novaliq, Heidelberg, Germany) was due to start by the end of 2020 to assess the efficacy, safety and tolerability of this novel ophthalmic solution. NOV3 aims to stabilize the lipid layer of the tear film while penetrating on the MG orifices to help dissolve the thickened/obstructed meibum.

Finally, while IPL and LipiFlow treatments are already available in the private sector for mild–severe DED and even for SS patients, confirmatory studies with larger sample sizes and longer terms are required to understand the impact of topical chloroquine, newer ciclosporin formulations (e.g. nanoemulsion) and advanced drugs in the treatment of DED in SS patients.[37]