*7.1. Sicca Syndrome and Non-Visceral Manifestations*

Despite the dysimmune origin of the disease, no immunosuppressive treatment has demonstrated sufficient efficacy associated with a satisfactory risk–benefit balance in the treatment of sicca syndrome and non-visceral aspecific manifestations (non-inflammatory widespread chronic pain, fatigue). Treatment is mainly focused on symptom management and prevention or treatment of complications resulting from exocrinopathy (Table 5).

Therapeutic approach to oral dryness must be driven by baseline objective and subjective severity of hyposialia and xerostomia. To this end, current guidelines recommend evaluating baseline SG function by measuring unstimulated (UWSF) and stimulated salivary flow (SWSF) or using salivary scintigraphy. Subjective xerostomia impact is captured by a simple Visual Analogue Scale, as part

of the ESSPRI score. EULAR guidelines propose an algorithmic approach to the management of dry mouth: patients with an UWSF < 0.1 mL/min are categorized based on their SWSF as mild (>0.7 mL/min), moderate (0.1–0.7 mL/min) or severe dysfunction (<0.1 mL/min). Self-care advice and non-pharmacological stimulation are proposed to mild cases as first line therapy [210]. Pharmacological stimulation (pilocarpine per os or as a mouthwash, cevimeline per os) is the treatment of choice in moderate cases (with residual SG function) or in mild dysfunction patients who failed to respond to basic recommendations, in addition to first line therapy. Saliva substitutes are reserved for patients with no residual function or as a third line treatment in non-responding patients.


**Table 5.** Current treatment for sicca-related manifestations.

The stomatological complications of exocrinopathy affecting the SG are cavities formation, periodontal disease, candida infections and glandular swellings linked to abscess or to a lithiasic disease. It is therefore strongly recommended that patient adopts impeccable dental hygiene and be evaluated at least 2 times per year by a dental professional. Local fluoride-based treatments can be administrated. Candida simple infection (visible white plaques) are treated with Nystatin mouthwash for 7 days. One-week prophylactic treatment may be repeated every 8 weeks in the event of recurrence. Erythematous infection of tongue or oral cavity is treated with Fluconazole 50 mg for 10 days. Angular cheilitis is treated with Miconazole topically on each side of the mouth for 2 weeks. Presence of abscess or lithiasic involvement can be treated with antibiotic treatment and stomatologist involvement is indicated. If no infectious or mechanical cause is found in case of gland swelling, a distinction must be made between primary neoplasia, systemic activity of the disease (as scored in ESSDAI, treated by glucocorticoid in loco by sialendoscopy, per os or intra-muscular) and the appearance of a lymphomatous complication.

The management of dry eyes must also be guided by the objective and subjective severity of keratoconjunctivitis sicca (KCS), resulting from damage to corneal and conjunctival epithelium secondary to accelerated tear-film break-up and hyperosmolar tear composition. EULAR guidelines

propose an algorithmic approach based on Ocular Staining Score (OSS) score and Ocular Surface Disease Index (OSDI) questionnaire to classify patients as non-severe or severe KCS [210]. The British Society of Rheumatology recommended a classification into 3 categories (mild, moderate and severe dry eyes) based on the Schirmer's test, Break Up Time (BUT) and ocular staining [319]. First line therapy for all patients with dry eyes is the instillation of preservative-free artificial tears containing methylcellulose or hyaluronate, and ointment at night. In DREAM studies, use of supplements of n-3 fatty acids for 12 month and beyond does not improve OSDI, staining scores, BUT or Schirmer test compared to olive oil in dry eyes patients [323,324]. Although these treatments are not associated with an improvement in objective parameters, substantial subjective improvement in both groups suggests that daily olive oil teaspoon should be used in dry eye management [325]. Although the origin of the dryness is the decrease in the production of tears, a dysfunction of the Meibomian glands can also be associated and must be treated by daily eyelid massage with hot pad or liposomal spray to reconstitute the lipid layer preventing the evaporation of the tear film. In patients with persistent Meibomian inflammation and blepharitis, doxycycline 50 mg once daily for a minimum of 3 months is effective as a metallomatrix proteinase inhibitor. In case of refractory case of severe KCS, local treatment using NSAID-, glucocorticoid- or cyclosporin-containing eyedrops can be used under the strict supervision of an ophthalmologist. Rescue therapies by serum eye drops, oral or topical muscarinic agonists, lifitegrast-containing eyedrops or lacrimal plugs insertion must be evaluated in specialized settings.

Only two Disease Modifying Anti-Rheumatic Drug (DMARDs) have demonstrated a significant effect on sicca syndrome: Methotrexate in a small uncontrolled trial [326], and Mizoribine (a Japanese DMARD) in 2 cohort studies [327,328]. With regard to biological therapies, infliximab, etanercept, belimumab and tocilizumab have failed to demonstrate a favourable effect on exocrine glandular function in their respective RCTs. "Abatacept Sjögren Active Patients" (ASAP) proof-of-concept trial on abatacept showed a significant improvement in ESSPRI and BUT, but not on SWSF while another trial showed no effect on ESSPRI and SWSF. Some randomized trials, but not all, find an improvement in exocrine function and dryness with rituximab. In TEARS study, a study using 120 patients, aims for a >30% improvement in at least 2 VAS in 4 (fatigue, pain, dryness and PGA) at 6–16–24 weeks, primary endpoint is only reached at week 6, and this effect is no longer found thereafter. Dryness VAS is statistically different from the placebo group from week 6 to 24, but no group achieved a clinically significant decrease. The other large trial, TRACTISS, studying the effect of rituximab on 133 patients with a primary endpoint of >30% improvement oral dryness and fatigue VAS at 48w, did not show significant improvements in any outcome measure, except unstimulated salivary flow. However, this intervention does not seem cost-effective. The clinical significance of those differences remains to be determined and is interpreted according to the various guidelines. Only the Sjögren's Syndrome Foundation proposes to use rituximab as rescue therapy for sicca syndrome [322].

In pSS patients, complaints regarding general non-specific symptoms (non-inflammatory musculoskeletal pain and fatigue) mimicking a fibromyalgia picture are common and can be challenging for the clinician. In this context, differential diagnosis is important. Non-specific manifestation of another condition (e.g., hypothyroidism, hypocortisolism, osteoarthritis, depression, neoplasia) or resulting from a misleading manifestation linked to the systemic activity of the disease (e.g., myositis, inflammatory arthralgia or arthritis, hypokalaemia or osteomalacia due to tubular involvement, small fibre neuropathy or lymphoma) must be ruled out. When no secondary cause is identified, this fibromyalgia-like presentation can be treated as such [329]. These can be quantified and monitored using the ESSPRI score or standardized scores such as the Profile of Fatigue and the Brief Pain Inventory. Education and management according to the biopsychosocial model of chronic pain, lifestyle adaptation, sleep management strategies and the practice of moderate physical activity are the cornerstones of the management of fatigue and pain. Many patients report benefit from joining a SS support group. If drug treatment is necessary, it will consist of the prescription of conventional painkillers (short-term acetaminophen or NSAID). Antidepressants and anticonvulsants may be considered as co-analgesic medications in chronic musculoskeletal or neuropathic pain, keeping in mind the anticholinergic effect

of these drugs, which can worsen sicca syndrome. Opioids are not suitable treatments for chronic pain patients. DHEA supplementation is not recommended.

As a rule of thumb, systemic immunomodulatory drugs should not be used to treat non-specific systemic manifestations because evidence is scarce. In currently available biotherapies, abatacept and belimumab failed to demonstrate an effect on fatigue and pain VAS. Data on rituximab are conflicting: 3 RCTs showed an improvement in fatigue VAS, results not found in the large TRACTISS trial. A phase 2 RCT on a total of 17 patients failed to demonstrate >20% improvement of fatigue VAS at 24 weeks, fatigue VAS improvement at 24w or >30% improvement of fatigue VAS at 24w. The authors only report a statistically significant improvement in fatigue VAS in treated group compared to baseline, while the placebo group did not reach a statistically significant difference [330]. In two other studies, patients with early pSS and active disease treated with RTX displayed a significant improvement in fatigue VAS compared to placebo from different time points post-treatment [331,332]. All RCTs have shown that rituximab is not associated with an improvement in pain VAS. An RCT investigating the effect of anakinra on fatigue, although not reaching its primary endpoint, shows a significant improvement in VAS fatigue [333]. Off-label use of DMARD or biological treatments, even as a rescue therapy, is currently not mainstream recommendation in this indication. However, some guidelines suggest a trial of hydroxychloroquine in patients with recurrent musculoskeletal complaints or fatigue, mainly based on "experience-based medicine". In its 2015 guidelines, Sjögren's Syndrome Committee of Brazilian Society of Rheumatology highlighted the possibility of using rituximab as rescue therapy for fatigue (but not sicca syndrome) management [320].
