Jolien F. van Nimwegen

The impact of primary Sjögren’s syndrome on female sexual function

OBJECTIVE Prevalence of vaginal dryness and dyspareunia is high in women with primary SS (pSS). Our aim was to compare sexual function and sexual distress in women with pSS with healthy controls, as well as to assess parameters that are associated with sexual dysfunction and distress in pSS. METHODS Forty-six women fulfilling the American-European Consensus Group criteria for pSS [mean age 46.3 years (s.d. 10.5)] and 43 age-matched healthy controls were included. Participants completed self-administered questionnaires, namely the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), Multidimensional Fatigue Inventory (MFI), Hospital Anxiety and Depression Scale (HADS), Maudsley Marital Questionnaire (MMQ) and RAND 36-item Health Survey (RAND-36). In addition, the European League Against Rheumatism Sjögrens Syndrome Disease Activity Index (ESSDAI) and Patient Reported Index (ESSPRI) were recorded in patients. RESULTS Women with pSS had impaired sexual function compared with healthy controls (median FSFI 20.6 vs 30.3, P < 0.001), as reflected by significantly lower scores in the domains of desire, arousal, orgasm, lubrication and pain. Furthermore, pSS patients experienced more sexual distress (median FSDS 7 vs 4, P < 0.05) and were sexually active less frequently than controls (76% vs 93%, P < 0.05). Sexual dysfunction correlated significantly with patient-reported symptoms of pSS (ESSPRI), symptoms of fatigue (MFI), depressive symptoms (HADS), relationship dissatisfaction (MMQ) and lower mental quality of life (RAND-36), but not with systemic disease activity (ESSDAI). CONCLUSION Women with pSS have impaired sexual function and more sexual distress compared with healthy controls. Sexual function and distress are influenced by vaginal dryness and patient-reported symptoms of pSS as well as psychosocial factors.

Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjögren’s syndrome

Objective To assess the validity of ultrasound of major salivary glands (sUS) compared with parotid and labial gland biopsies, sialometry, anti-SSA/Ro antibody status and classification criteria in patients clinically suspected with primary Sjögren’s syndrome (pSS). Methods 103 consecutive outpatients with clinically suspected pSS underwent sUS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and clearness of salivary gland border were scored according to the Hocevar scoring system. Total ultrasound score was calculated as the sum of these domains (range 0–48). Results Absolute agreement between sUS and parotid (83%) and labial (79%) gland biopsy outcome was good. Negative sUS predicts negative parotid gland biopsy, and positive sUS predicts positive labial gland biopsy. Compared with the American European Consensus Group (AECG) classification, sUS showed an absolute agreement of 82%, sensitivity of 71% and specificity of 92%. Compared with the American College of Rheumatology (ACR) classification, absolute agreement was 86%, sensitivity was 77% and specificity was 92%. Compared with the ACR-European League Against Rheumatism (EULAR) classification, absolute agreement was 80%, sensitivity was 67% and specificity was 94%. Positive sUS predicts classification, but negative sUS does not exclude classification. The combination of positive sUS with presence of anti-SSA/Ro antibodies or negative sUS with absence of anti-SSA/Ro antibodies showed a high predictive value for classification as pSS or non-pSS. Conclusion In our prospective inception cohort study derived from daily clinical practice, absolute agreement between sUS and salivary gland biopsies was slightly higher for parotid compared with labial gland biopsies. The combination of positive sUS and presence of anti-SSA/Ro antibodies highly predicts classification according to the AECG, ACR and ACR-EULAR classification criteria.

The value of rituximab treatment in primary Sjögren's syndrome

The rationale for B cell depletion therapy with rituximab in primary Sjögrens syndrome relies upon the well-established role of B cell hyperactivity in immunopathogenesis. In line with this notion, several biomarkers of B cell activity are significantly affected by treatment, both in the target organs and periphery. In contrast to most biological outcomes, clinical outcomes are not consistent between studies. Although two large RCTs did not meet their primary endpoint, several beneficial clinical effects of treatment have been shown. As discussed in this review, differences in study design and patient characteristics could explain the variation in results. Interestingly, a newly developed composite endpoint of subjective and objective outcomes did show a significant effect of rituximab in one of the large RCTs. Response predictors need to be identified to define more targeted inclusion criteria and achieve precision medicine. The positive effects seen on biological and clinical parameters warrant future studies to investigate this promising treatment modality.

Safety of treatments for primary Sjogren's syndrome

ABSTRACT Introduction: Primary Sjögren’s syndrome (pSS) is a disabling auto-immune disease, affecting exocrine glands and several organs. Areas covered: In this review we analyze the safety of therapies used in pSS. Symptomatic treatment is widely applied due to the good supportive effect and good safety profile. Systemic stimulation of tears and saliva can be successful in pSS. However, cumbersome adverse events can influence the tolerability of this therapy. Evidence for the effectiveness of synthetic DMARDs therapies in pSS is limited, while there is a risk of adverse events. Several studies on biologic DMARD treatment of pSS patients have shown promising efficacy and safety results. Expert opinion: The safety of symptomatic treatment of pSS is very good. However, systemic therapy is necessary to achieve long-term relieve and prevention of organ-damage. Synthetic DMARDs have not shown much efficacy in earlier studies, and their benefits do not weigh up to the possible harms, while biologic DMARDs show promising results regarding efficacy and cause mostly mild adverse events. Many questions remain unanswered regarding safety of DMARDs in pSS. There is a need for well designed studies, in which safety should be evaluated in a uniform manner to be able to compare the results between studies.

Scoring hypoechogenic areas in one parotid and one submandibular gland increases feasibility of ultrasound in primary Sjögren’s syndrome

Objective To assess whether ultrasonographic scoring of (i) both parotid and submandibular salivary glands and (ii) all individual components of the Hocevar scoring system, is needed for classifying patients as primary Sjögren’s syndrome (pSS). Methods Ultrasound examination of the major salivary glands (sUS) was performed in 204 consecutive patients clinically suspected (n=171) or diagnosed (n=33) with pSS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and salivary gland posterior border were scored in left and right parotid and submandibular glands. Logistic regression analyses were performed to assess which glands and sUS components contributed significantly to classification as pSS or non-pSS according to the 2016 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) criteria. Results 116 (57%) patients were classified as pSS, the remaining as non-pSS. Instead of scoring both sides (area under the curve; AUC=0.856, Nagelkerke R2=0.526), multivariate analysis showed that sUS scoring of only right (AUC=0.850; R2=0.518) or left (AUC=0.852; R2=0.511) parotid and submandibular glands is sufficient to predict ACR-EULAR classification. Moreover, all individual components of the Hocevar scoring system significantly predicted classification. Multivariate analysis showed that parenchymal echogenicity and hypoechogenic areas contributed independently to ACR-EULAR classification (AUC=0.857; R2=0.539). Scoring these components in one parotid and one submandibular gland highly predicted ACR-EULAR classification (AUC=0.855; R2=0.539). Scoring only hypoechogenic areas on one side showed almost similar results (AUC=0.846; R2=0.498). Conclusion sUS examination of parotid and submandibular glands on one side is sufficient to predict classification of patients according to the ACR-EULAR criteria. To further increase feasibility of sUS in outpatient clinics worldwide, only hypoechogenic areas can be scored.

Validation of the ACR-EULAR criteria for primary Sjogren's syndrome in a Dutch prospective diagnostic cohort

Objectives To validate the ACR-EULAR classification criteria for primary SS (pSS), and compare them to the American-European Consensus Group (AECG) and ACR criteria in a Dutch prospective diagnostic cohort. Methods Consecutive patients (n = 129) referred for suspicion of pSS underwent a multidisciplinary evaluation, including a labial and/or parotid gland biopsy. Patients with an incomplete work-up (n = 8) or associated systemic auto-immune disease (n = 7) were excluded. The ACR-EULAR classification was compared with expert classification, AECG and ACR classification. Additionally, the accuracy of individual ACR-EULAR items in discriminating pSS from non-pSS was evaluated. The validity of criteria sets was described separately using parotid or labial gland biopsy results for classification. Results Of the 114 evaluated patients, the expert panel classified 34 (30%) as pSS and 80 (70%) as non-pSS. Using labial gland biopsy results, ACR-EULAR classification showed 87% absolute agreement (κ = 0.73) with expert classification, with a sensitivity of 97% and specificity of 83%. Using the parotid gland biopsy results, the ACR-EULAR criteria performed excellently as well. Focus score, anti-SSA titre and ocular staining score showed good to excellent accuracy, whereas unstimulated whole saliva and Schirmers test had poor accuracy. The ACR-EULAR and AECG criteria had equal validity. Compared with ACR classification, ACR-EULAR classification showed higher sensitivity but lower specificity. Conclusion The ACR-EULAR criteria showed good agreement with expert classification, but some patients may be misclassified as pSS. Unstimulated whole saliva and Schirmers test showed poor discriminative value. The ACR-EULAR criteria performed equally to the AECG criteria, and had higher sensitivity but lower specificity than the ACR criteria.

Can ultrasound of the major salivary glands assess histopathological changes induced by treatment with rituximab in primary Sjögren’s syndrome?

With great interest we have read the recent publication by Fisher et al ,1 entitled ‘Effect of rituximab on a salivary gland ultrasound score in primary Sjogren’s syndrome: results of the TRACTISS randomised double-blind multicenter substudy’ in which the authors demonstrated a significant improvement in total ultrasound score (TUS) after rituximab treatment compared with placebo at weeks 16 and 48 in 52 patients with primary Sjogren’s syndrome (pSS). We and others have shown that treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, affects the histopathology of the salivary glands and results in a decrease in area of lymphocytic infiltrate in the labial and parotid glands.2–5 This reduction in infiltrated area, that is, up to 50%, is mainly caused by B cell depletion.2 Rituximab treatment also causes a significant loss of germinal centres.2 Interestingly, rituximab treatment also leads to a significant restoration of the ductal epithelium glandular tissue itself. This is illustrated by a significant decrease in number and severity of lymphoepithelial lesions (LELs) in parotid gland tissue 12 weeks after rituximab treatment.2 6 The normalisation of the epithelium appears to be a direct consequence of depletion of intraepithelial B cells.7 Significant improvement of the parotid gland ultrasound score of patients with pSS has been observed before in another randomised controlled trial (RCT) with rituximab, the Tolerance and Efficacy of Rituximab in Primary Sjogren’s Syndrome (TEARS) study.8 This is an RCT with rituximab versus placebo, performed by a French group. Together with the improvement of the histopathology of the gland, it might not be a surprise that Fisher et al 1 also observed a significant improvement in TUS. This newly …

Serum immunoglobulin free light chains are sensitive biomarkers for monitoring disease activity and treatment response in primary Sjögren’s syndrome

Objectives Serum immunoglobulin free light chains (FLCs) are frequently elevated in B-cell-mediated autoimmune diseases, including primary SS (pSS). The objective of this study was to assess if serum FLCs can contribute to classification, mucosa-associated lymphoid tissue (MALT) lymphoma detection, monitoring of disease activity and treatment response in pSS. Methods Serum samples of 100 consecutive patients suspected of pSS were included. Forty-five patients fulfilled ACR-EULAR criteria for pSS. Additionally, samples of 17 pSS patients with MALT lymphoma and longitudinal samples of pSS patients treated with rituximab (n = 20), placebo (n = 10) or abatacept (n = 15) were included. Serum FLCκ/FLCλ was measured by nephelometry or turbidimetry. Results At diagnosis, FLCκ and FLCλ serum levels were significantly higher in pSS compared with non-SS sicca patients. The FLCκ/FLCλ ratio was abnormal in 11% of pSS patients. In established MALT-pSS patients, without recent rituximab treatment (n = 12), 50% had abnormal FLCκ/FLCλ ratios. FLC measurement had no additional value for pSS classification, compared with IgG and anti-SSA. FLC levels correlated significantly with systemic disease activity, assessed by EULAR SS Disease Activity Index (ESSDAI) and clinical ESSDAI, both cross-sectionally and longitudinally following treatment. Treatment with rituximab or abatacept significantly lowered FLC levels. FLCs show a large sensitivity to change and relative changes induced by treatment were higher compared with IgG. Conclusion Serum FLCs are elevated in pSS, and abnormal FLCκ/FLCλ ratios may be indicative for the presence of MALT lymhoma. FLC levels can be used as a biomarker for systemic disease activity and monitoring treatment responses. FLCs are sensitive to change and have more favorable kinetics than IgG.