*6.4. Discomfort and Disability*

SS can be disabling and associated with significant functional status impairment related to oral and/or ocular dryness, systemic activity, pain, fatigue and daytime somnolence, anxiety and depression symptoms [302–304]. Objective assessments of sicca syndrome correlated poorly with symptoms and remain generally stable over time [305]. Besides the associated symptoms, sicca syndrome also has a negative impact on smell, taste, pruritus, voice, swallowing and sexual function [306,307]. Fatigue and pain are both correlated with reduced quality of life and psychological distress [307]. Patients with widespread pain—34.9% of the cohort—were more frequently negative for anti-La/SSB, more frequently seronegative for all autoantibodies (ANA/SSA/SSB/RF) and had statistically fewer extraglandular manifestations in a Dutch study including 83 patients [308]. Another Italian study on 100 pSS patients demonstrated a prevalence of widespread pain of 22%, a phenotype statistically associated with fewer systemic and immunological manifestations (hypergammaglobulinemia, rheumatoid factor, focus-score ≥ 1) [309]. A subset of pSS patients therefore seem to develop a clinical phenotype with lower visceral involvement but with significant morbidity linked to glandular manifestations and a significant psychosomatic burden [302,310], bringing them closer to the notion of "Sicca Asthenia Polyalgia (SAP) Syndrome" [311–313]. At diagnosis, one in 4 patients is unable to work. This figure increases to more than 1 in 3 at 1 year. Work disability at 2 years is 40% and is related to fibromyalgia pattern, age and incapacity for work at diagnosis [314]. pSS has a high individual and societal cost, especially due to dental cost, symptomatic therapies and disease compensation [307].

EULAR SS Patient Reported Index (ESSPRI) is a consensus index calculated as the mean of 3 visual analogue scales (VAS)—self-assessment of dryness, (limb) pain and fatigue—allowing easy measurement of patients' symptoms in pSS [295]. By convention, patient-acceptable symptom state was defined by an ESSPRI <5/10 and the minimal clinically important improvement by a decrease of at least one point or 15%. The ESSPRI score is correlated with the Patient Global Assessment [PGA] [295] and with more complex and time-consuming scores such as the Profile of Fatigue and Discomfort [PROFAD] [295], Sicca Symptoms Inventory [SSI] [295], Health Assessment Questionnaire [HAQ] [315], Short Form 36 health survey [SF-36] [302], time trade-off values [TTO] and EuroQol5D VAS [316,317]. Very interestingly, a study using baseline data from 120 patients included in the TEARS study revealed that—even if there is a small correlation between ESSPRI and ESSDAI—ESSPRI is the only determinant associated with the quality of life score SF-36 in a multivariate model [318]. The ESSPRI score is therefore a good clinical screening and monitoring tool as well as a good surrogate endpoint to study the effectiveness of therapeutic interventions on pSS associated "Sicca Asthenia Polyalgia" Syndrome (Table 4).

It is therefore important, a fortiori in mild cases with low activity score but disabling sicca syndrome, to focus on improving the quality of life of patients through attentive and multimodal symptomatic management and to offer a multidisciplinary management program for the most disabled.

#### **7. Therapeutic**

Despite a better understanding of its pathophysiology, treatment of SS remains disappointing and essentially palliative. Systemic activity is treated by immunosuppressant drugs, based on scarce evidence. Manifestations linked to damage caused by local or systemic activity of pSS should be identified because they are by definition irreversible and cannot therefore be improved by immunosuppressive treatments. In the last 5 years, pSS management has been addressed by guidelines from EULAR [210], British Society of Rheumatology and National Institute for Health and Care Excellence (NICE) [319], Brazilian Society of Rheumatology [320], Research Team for Autoimmune Diseases [321] and Sjögren's Syndrome Foundation [322]. The main principles for care are summarized below.
