Primary Sjögren’s Syndrome (pSS) is the second most prevalent systemic autoimmune disease characterized by ocular and oral dryness, musculoskeletal pain, profound fatigue, and an increased risk of lymphoma.1 Although the symptoms are identifiable, pSS remains incurable due to its heterogeneity and the lack of knowledge relating to its mechanism. Nonetheless, there has been an influx of potential targeted therapies giving hope to pSS patients. At the International Conference of Chinese Rheumatologists (ICCR) 2019, organized by the Hong Kong Society of Rheumatology, Prof. Wan-Fai Ng from the Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom, presented the limitations of the current pSS therapies, and the advantages of adopting a stratification strategy.
pSS is a chronic immune-mediated inflammatory disease currently causing patients to suffer from substantial morbidity and reduced quality of life due to the absence of an effective treatment.1 Significant efforts in characterizing and understanding the pathogenesis of pSS are ongoing. However, the relationship between dysregulated biological pathways and clinical symptoms is often difficult to establish, owing to the complexity and heterogeneity of the disease. The pipeline of pSS treatment consists of novel biologics and small molecular entities. Despite the availability of various treatment options, defining the appropriate clinical endpoints to measure the effectiveness of these treatments remains a challenge. Consequently, numerous targeted therapies have failed to demonstrate significant benefits in the defined primary and secondary endpoints.
For example, studies have shown that biologic drugs such as rituximab, anakinra, lanalumad (VAY736), IL-2, abatacept, and baminercept elicit a less significant improvement in the primary endpoints. However, there were substantial improvements in other key indicators. Recent investigations revealed that pSS patients administered with anakinra experienced reduced fatigue by 50%, while Ianalumab (VAY736) could sustain B cell depletion and baminercept illustrated ability in inhibiting the lymphotoxin-β pathway.
Prof. Ng explained the findings of rituximab in the phase 3 study for French (TEARS) and British (TRACTISS) trials, “I think, we actually need to look at this study more deeply. If you look at the TRACTISS study, you will see that rituximab did actually improve the salivary flow although it did not actually meet the primary endpoint. Whatever this is clinically significant or not, is debatable, and at least, there are some improvements.” Similarly, in the TEARS study, there was also some evidence of improvement in terms of cortisol. In short, treatment-induced improvements to the symptoms associated with pSS is possible, despite the lack of significant changes by the selected primary endpoint.
To date, RSLV-132, a human RNase fused to the Fc domain of human IgG, is the first in class biologics targeted therapy for pSS. Interestingly, results from a phase 2, randomized, double-blinded trial, consisting of 30 patients on RSLV-132, demonstrated improved symptoms of fatigue as compared to placebo. Data from the PRO-F scale measuring the mental fatigue conditions, showed an improvement of 1.53 points compared to the worsening of 0.06 points in the placebo group (p=0.046). Additionally, there was also a significant improvement in the RSLV-132 group in their Digital Symbol Substitution Test performance, with a reduction of 16.4 seconds in completing the test, compared to an increase of 2.8 seconds in the placebo group (p=0.024).3
“My own personal opinion is that the future for pSS therapy is very promising,” expressed Prof. Ng, based on his optimism towards the future of personalized pSS medicine. Most importantly, a proper definition of optimal clinical outcome measures from a more extensive and adequately powered study is crucial in encouraging the innovation of new biological therapies. Additionally, during an interview with Omnihealth Practice, Prof. Ng emphasized the importance of a stratification approach centered on identifying, characterizing and validating the clinical subgroups for pSS. He explained, “Stratification is a point to really think about and what do you want to stratify for? Are you stratifying patients in terms of how you can treat them or in terms of the risk?”
Performing stratification during drug development allows the prediction of biological responses. Besides, patient stratification enables predicting the occurrence of a specific pSS symptom. Subsequently, formulating this approach into clinical management requires the establishment of a registry containing patients’ information of the early age onset of the illness, predicting the likelihood of the patient developing significant complications based on a scoring system and the levels of Anti-Ro, C3/4, IgG and MSG. Uncovering clinically relevant endpoints and adopting a suitable stratification strategy are critical for an effective pSS treatment. Furthermore, non-pharmacological approaches, such as supervised walking exercises and non-vagus nerve stimulation, might serve as alternative solutions towards managing the pSS patient’s symptoms.