More severe parotid gland histopathology in paediatric-onset than in adult-onset Sjögren's disease.

OBJECTIVES: The aim of this study was to assess the histopathological features of the parotid glands in patients with paediatric-onset Sjögren's disease (pedSjD) in comparison to patients with adult-onset Sjögren's disease (adSjD). METHODS: This study was performed in Groningen, the Netherlands. Patients with pedSjD from a diagnostic paediatric cohort (n=19), patients with adSjD from a diagnostic adult cohort (n=32) and patients with adSjD who participated in a clinical trial (n=42) with a baseline parotid gland biopsy were included. Parotid gland biopsies were analysed after (immuno)histological staining for SjD-related histopathological markers and compared between groups. RESULTS: All characteristic histopathological features of adSjD were also observed in pedSjD. There were no significant differences in lymphoepithelial lesions or immunoglobulin A (IgA)/IgG plasma cell shift between the pedSjD and the adSjD cohorts. However, compared with the diagnostic adSjD cohort (with comparable total EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores), pedSjD showed more severe lymphocytic infiltration as reflected by a higher focus score (p=0.003), a higher relative surface area of CD45+ infiltrate (p=0.041), higher numbers of B and T lymphocytes/mm2 (p=0.004 and p=0.029, respectively), a higher B/T lymphocyte ratio (p=0.013), higher numbers of CD21+ follicular dendritic cell networks/mm2 (p=0.029) and germinal centres (GC)/mm2 (p=0.002). Compared with the trial adSjD cohort, with significant higher total ESSDAI scores (p=0.001), only the B/T lymphocyte ratio and numbers of GC/mm2 were significantly higher in the pedSjD cohort (p=0.023 and p=0.018, respectively). CONCLUSION: Patients with pedSjD exhibit more pronounced histopathological features compared with patients with adSjD at diagnosis. Notably, the histopathology of patients with pedSjD aligns more closely with that observed in an adSjD clinical trial cohort, with even stronger B lymphocyte involvement.

Regenerative treatments for scleroderma in cutaneous manifestations of the face: a systematic review.

OBJECTIVES: Scleroderma is a heterogeneous chronic autoimmune disease affecting connective tissue, characterised by chronic inflammation and fibrosis, particularly affecting internal organs and skin. Orofacial involvement is common, leading to facial atrophy, mask-like appearance and difficulties in function that significantly impact patients' quality of life. This systematic review evaluates different autologous regenerative treatments of facial manifestations of scleroderma, aiming to provide comprehensive understanding of their effectiveness in reducing fibrosis, and thereby improving function and skin quality. METHODS: A search in PubMed, Embase, Web of Science Core Collection, Cochrane CENTRAL, and CINAHL was conducted. Studies assessing autologous regenerative treatments in cutaneous manifestations of the face in scleroderma patients were included. Outcomes of interest were treatment characteristics, characterisation of biomaterials, outcome measurements and patient satisfaction. Methodological quality was assessed with the Effective Public Health Practice Project tool. RESULTS: In total 18 studies were included. Methodological quality of studies was weak (n=15) and moderate (n=3). Treatments consisted of autologous fat grafting, platelet-rich plasma, stromal vascular fraction, and adipose-derived stem cells. In general, most studies showed improvements of symptoms, but no treatment was considered superior. CONCLUSIONS: Autologous regenerative treatments hold potential for alleviating cutaneous manifestations of the face in scleroderma. Further clinical trials should be well-designed to improve the quality of clinical evidence.

Added value of the salivary gland ultrasonography OMERACT score in the ACR/EULAR classification criteria for Sjögren's disease.

OBJECTIVES: To assess whether addition of the salivary gland ultrasonography (SGUS) OMERACT score influences the performance of the 2016 ACR/EULAR classification criteria for Sjögren's disease (SjD) in daily clinical practice. METHODS: Patients visiting the Sjögren Expertise centre in the University Medical Center Groningen for a diagnostic trajectory because of a suspicion of SjD were included. SGUS was performed of both parotid and submandibular glands. ROC analysis was used to assess the accuracy to predict clinical diagnosis of SjD with the SGUS OMERACT score, and by adding the SGUS OMERACT score to the ACR/EULAR criteria. Furthermore, the performance of the SGUS OMERACT and total SGUS Hocevar score were compared. RESULTS: In total, 419 consecutive patients were included. ROC analysis of the highest SGUS OMERACT score out of all four salivary glands (range 0-3) showed good accuracy (AUC 0.849) to predict clinical diagnosis of SjD, comparable to the accuracy of the total SGUS OMERACT score (range 0-12; AUC 0.868) and total Hocevar score (range 0-48; AUC 0.864). When incorporating the highest SGUS OMERACT score (cut-off score of ≥2) as additional item in the ACR/EULAR criteria, accuracy remained excellent (AUC 0.974), and clinical diagnosis could be predicted with a sensitivity of 96.4% and specificity of 86.5%. CONCLUSION: The accuracy of the ACR/EULAR classification criteria for predicting the clinical diagnosis of SjD remained excellent after incorporating the SGUS OMERACT score and extends the diagnostic options in patients suspected with SjD.

Increased Diagnostic Accuracy of the Labial Gland Biopsy in Primary Sjögren Syndrome When Multiple Histopathological Features Are Included.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of the labial salivary gland biopsy based on multiple histopathological features in patients with suspected primary Sjögren syndrome (pSS). METHODS: Patients from a diagnostic sicca cohort with clinically suspected pSS who underwent a labial gland biopsy were included. Patients were categorized as having pSS or non-Sjögren syndrome sicca (non-SS sicca) based on vignettes scored by an expert panel. Labial gland biopsies were analyzed for the presence of four histopathological features: focus score (FS) ≥1, prelymphoepithelial and lymphoepithelial lesions, immunoglobulin G plasma cell shift, and germinal centers. Sensitivity and specificity of histologic features were calculated, and the optimal cutoff value for the number of histopathological features needed to diagnose pSS was determined with receiver operating curve analysis. RESULTS: A total of 38 patients were categorized as having pSS and 65 as having non-SS sicca. In labial gland biopsies of patients with pSS, the prevalence of FS ≥1 was 82%, followed by 68% for pre-lymphoepithelial and lymphoepithelial lesions, 63% for plasma cell shift, and 24% for germinal centers. Although FS ≥1 showed the highest sensitivity for patients with pSS (82%), specificity was higher for the other three features (98%-100%). The presence of two or more (of four) histopathological features had almost comparable sensitivity to FS alone, but specificity increased with 12% to 100%. For fulfillment of American College of Rheumatology/EULAR criteria, specificity increased from 84% to 95% when an abnormal biopsy was defined by the presence of two or more histopathological features instead of FS ≥1 only. CONCLUSION: The diagnostic accuracy of the labial gland biopsy increases when other histopathological features besides FS are taken into account, by reducing the number of false-positive biopsies.

Can ultrasound of the major salivary glands differentiate Sjögren's disease from its major mimics?

OBJECTIVES: Ultrasound of the major salivary glands (SGUS) is widely used to assess the major salivary glands in Sjögren's disease (SjD). Little is known, however, regarding the diagnostic accuracy of SGUS to differentiate SjD from its mimics. This study aims to investigate the diagnostic accuracy of SGUS in differentiating SjD from other diseases with salivary gland involvement. METHODS: SGUS was performed in 20 consecutive patients with SjD and 20 consecutive patients with well-established systemic disease, i.e., with either sarcoidosis, amyloidosis, HIV infection or chronic HCV infection. Images were scored independently by two blinded observers using the Hocevar scoring system. Diagnostic accuracy to discriminate between the patient (sub-)groups was explored. RESULTS: The accuracy of SGUS to differentiate SjD from other systemic diseases was excellent (area under ROC curve of 0.91). The optimal cut-off value to define positive or negative ultrasound for SS was 15. Sensitivity, specificity, positive predictive value and negative predictive value were high, varying from 85-90%, and diagnostic odds ratio was 51. SGUS was positive in the vast majority of SjD patients (n=18), but also in 2 patients with HIV infection and one patient with sarcoidosis. SGUS score differed significantly between patients with SjD and other systemic diseases (median 27 vs. 10, p<0.001) as well as between SjD patients and patients with either sarcoidosis, amyloidosis, HIV or HCV infection (all p<0.05). CONCLUSIONS: This study indicates that SGUS has a potentially high diagnostic accuracy to discriminate SjD from systemic diseases which can also cause salivary gland involvement.

Longitudinal evaluation of major salivary gland functioning in Sjögren's disease patients in a prospective standard-of-care cohort.

OBJECTIVES: To evaluate changes in major salivary gland functioning over time using salivary gland ultrasonography (SGUS), salivary flow measurements (sialometry), and patient-reported outcome measures (PROMs) in patients diagnosed with primary Sjögren's disease (SjD). METHODS: Consecutive outpatients from the ongoing prospective REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort, all fulfilling the ACR-EULAR classification criteria for SjD, were included. SGUS images assessed with the Hocevar and OMERACT scoring system, unstimulated and stimulated whole saliva (UWS/SWS), unstimulated and stimulated submandibular/sublingual saliva (uSMSLS/sSMSLS) and parotid saliva, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) general dryness, oral dryness, and Xerostomia Inventory were assessed at baseline (BL), 2-year (Y2) and 5-year (Y5) follow-up. RESULTS: In total, BL and Y2 data were available for 253 patients and 75 patients had already reached Y5. At group level, SGUS Hocevar (i.e., mean±SD: 22±10 at BL, 22±10 at Y2 and 23±10 at Y5), OMERACT scores, UWS, SWS and PROMs remained stable over time (all p>0.05). Slightly decreased uSMSLS (p=0.025) and sSMSLS (p=0.004) were observed at Y5. At individual patient level, a similar proportion showed an increase or decrease of ≥25% for Hocevar, UWS and SWS. At baseline, poor associations were observed between SGUS and PROMs and fair associations between sialometry and PROMs. Over time, changes in objective assessments did not correlate with changes in PROMs. CONCLUSIONS: Overall, major salivary gland functioning assessed with SGUS, sialometry and PROMs did not change significantly up to 5 years of follow-up in a standard-of-care cohort of SjD patients from daily clinical practice.

Patient Acceptable Symptom State (PASS) in patients with primary Sjögren's syndrome in daily clinical practice.

OBJECTIVES: To explore Patient Acceptable Symptom State (PASS) in a standard of care cohort of patients with primary Sjögren's syndrome (pSS) and to compare patient characteristics including EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) between PASS and non-PASS groups. METHODS: All pSS patients fulfilling ACR/EULAR classification criteria from the Registry of Sjögren's Syndrome LongiTudinal (RESULT) cohort, who had available PASS data at baseline were included. Patient-reported outcomes included the PASS question: "Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?"; yes: PASS / no: non-PASS. RESULTS: Of the 278 included pSS patients, 199 (72%) had an acceptable symptom state according to the PASS question, and median ESSPRI was 6 (IQR 4-7). In the PASS group, 118 (59%) patients had an unacceptable symptom state according to ESSPRI (score ≥5). In multivariable regression analyses, ESSPRI and disease duration were independently associated with presence of PASS. The accuracy of ESSPRI to predict PASS was fair (AUC of 0.78). The cut-off point of ESSPRI for presence of PASS with the highest Youden's index was 7.2 (sensitivity 85%, specificity 56%), followed by 5.2 (sensitivity 48%, specificity 90%). CONCLUSIONS: The majority of pSS patients reported being in an acceptable symptom state according to the PASS question, despite high ESSPRI scores. In our standard of care cohort, the optimal cut-off point of ESSPRI to predict PASS is different when focusing on sensitivity (±7) or specificity (±5).

Can salivary gland ultrasonography replace salivary gland biopsy in the diagnosis of Sjögren's syndrome?

Ultrasound is a promising diagnostic method when it comes to assessing the involvement of major salivary glands in patients with primary Sjögren's syndrome (pSS). A matter of debate is whether ultrasound of the major salivary glands (SGUS) can replace a salivary gland biopsy in the diagnosis or classification of pSS. The intra- and inter-observer reliability of SGUS was found to be good, especially when focusing on hypoechogenic areas and homogeneity, and comparable to the reliability of histopathologic characteristics of salivary gland biopsies of pSS patients. However, replacing salivary gland biopsy by SGUS led to substantial decrease of the accuracy of the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria with clinical diagnosis as the gold standard. When SGUS was added as an additional item to the criteria, the accuracy of the criteria remained high, offering at the same time the clinicians a wider array of tools to assess patients. Combination of SGUS and anti-SSA antibodies was shown to be highly predictive of the classification of a patient suspected of pSS, making routine salivary gland biopsy debatable.

Treatment of resistant Raynaud's phenomenon with single-port thoracoscopic sympathicotomy: One-year follow-up.

OBJECTIVE: Follow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS). METHODS: Eight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and number and duration of RP attacks were reported over a 2-week period. Perfusion was assessed with a cooling and recovery procedure at baseline and one year after SPTS. Furthermore, laser speckle contrast analysis, pulse wave velocity, heart rate variability and nailfold capillary microscopy were performed. RESULTS: One year after SPTS the duration of the attacks of was reduced with 1.9 h in the left hand versus 0.3 h in the right hand. Furthermore, three aspects of the questionnaire showed a significant improvement (role limitations due to physical health (p = 0.017), pain (p = 0.027) and physical functioning (p = 0.025)). The total area under the curve of the total cooling and recovery procedure of the left hand was larger one year after surgery (101 (75-140) at baseline versus 118 (95-190) one year post-operatively, p = 0.012), implying a better perfusion in the fingers. This was mainly due to the improvement during the recovery phase (21 (1-41) at baseline versus 38 (24-43) one year post-operatively, p = 0.028). CONCLUSION: One year after unilateral R3 SPTS the benefit with regard to the majority of outcome variables persisted, though some effects seem to attenuate. Long-term effects and long-term follow-up results will be investigated in an on-going study. CLINICAL TRIAL REGISTRATION NUMBER: NCT02680509.

Capillary microscopy is a potential screening method for connective tissue disease in children with Raynaud's phenomenon.

BACKGROUND: Nailfold capillary microscopy (NCM) is a cornerstone in the diagnosis of Systemic Sclerosis (SSc) in adulthood. Although Raynaud's phenomenon (RP) is very common in childhood, studies on diagnostic methods to differentiate between primary RP (PRP) and secondary RP (SRP) at a young age are scarce. The aim of this study was to determine the value of NCM in differentiating between PRP and SRP in children and adolescents with RP. METHODS: In this nested case-control study, 83 patients diagnosed with RP and having underwent NCM in childhood were retrospectively included. Based on whether they were diagnosed with a connective tissue disease (CTD) during follow-up, patients were classified as PRP or SRP. NCM was performed by a vascular technician. PRP and SRP patients were compared on demographics, NCM and serology. Variables associated with SRP were included in a multivariate logistic regression model. Predictive values were calculated for NCM, ANA positivity and the combination of NCM and ANA positivity. RESULTS: At the time of the NCM, the mean age of the RP patients was 15.4 ± 2.3 years. Of these patients, 78.3% were classified as PRP and 21.7% as SRP at mean follow-up of 6.4 ± 3.20 years. CTDs were miscellaneous, with only one patient having developed SSc. Of the NCM parameters, only capillary loss was associated with SRP (p = 0.01). In a multivariate logistic regression model including ANA, capillary loss was not a predictor of SRP. In a model without ANAs, capillary loss was an independent predictor (OR = 3.98, CI 95% 1.22-12.99). Capillary loss had a sensitivity of 44.4% and a specificity of 84.4% for SRP. ANA combined with capillary loss had a sensitivity of 66.7% and a specificity of 85.7%. CONCLUSION: Whereas RP in adulthood is most strongly associated with SSc, children with RP seem to be at risk for developing other CTDs with less apparent NCM abnormalities. Of all NCM findings, only capillary loss was predictive for SRP. NCM did not add to the predictive value of ANA screening. However, with a specificity of 84.4% and being non-invasive, NCM shows potential as a screening method for SRP. More research with a larger study population is required before drawing conclusions.

Long-term abatacept treatment for 48 weeks in patients with primary Sjögren's syndrome: The open-label extension phase of the ASAP-III trial.

OBJECTIVE: To investigate treatment efficacy of long-term abatacept treatment in pSS patients. METHODS: The single-centre ASAP-III trial consisted of two phases: the randomised, double-blind, placebo-controlled phase (1:1 randomisation) from baseline to week 24, of which results have been published previously, and the open-label extension phase from week 24 to 48, in which all patients received abatacept. Main inclusion criteria were fulfilment of the AECG criteria, positive gland biopsy, disease duration ≤ 7 years and ESSDAI ≥ 5. Long-term treatment effects of abatacept on clinical, patient-reported, glandular and laboratory outcome measures were assessed in patients treated with abatacept from baseline to week 48. Furthermore, Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) response (response on ≥3 of 5 items) was analysed. RESULTS: In patients on abatacept treatment for 48 weeks (n = 40), median ESSDAI improved from baseline 14.0 (IQR 9.0-16.8) to 4.0 (2.0-8.0) at week 48 (p < 0.001), with 50% of patients reaching low disease activity (ESSDAI < 5) at week 48. Median ESSPRI improved from 7.0 (IQR 5.4-7.7) to 5.0 (3.7-6.7) (p < 0.001). Significant improvement was also seen in dry eye and laboratory tests. Combining response at multiple clinically relevant items, 73% of patients were CRESS responders at week 48. Additional improvement was seen between week 24 and week 48 of abatacept treatment. CONCLUSION: In the open-label extension phase of the ASAP-III trial, improvement was seen up to 48 weeks of abatacept treatment in clinical, patient-reported, dry eye and laboratory outcomes. The majority of patients were CRESS responders at week 48.

Histopathology, salivary flow and ultrasonography of the parotid gland: three complementary measurements in primary Sjögren's syndrome.

OBJECTIVE: The involvement of salivary glands in primary SS (pSS) can be assessed in different ways: histopathology, salivary flow and ultrasonography. To understand the relative value of these different approaches, it is crucial to understand the relationship between them. As we routinely perform these three modalities in the parotid gland for disease evaluation, our aim was to investigate the construct validity between these modalities in one and the same gland. METHODS: Consecutive sicca patients underwent a multidisciplinary diagnostic workup including parotid gland biopsy, collection of parotid gland-specific saliva and parotid gland ultrasonography. Patients who were classified as pSS according to the ACR-EULAR criteria were included. Construct validity was assessed using Spearman's correlation coefficients. RESULTS: The 41 included pSS patients completed a full workup within a mean time interval of 2.6 months. Correlations between histopathological features and stimulated parotid salivary flow were fair (ρ = -0.123 for focus score and ρ = -0.259 for percentage of CD45+ infiltrate). Likewise, poor correlations were observed between stimulated parotid salivary flow and parotid ultrasonography (ρ = -0.196). Moderate to good associations were found between the histopathological items focus score and the percentage of CD45+ infiltrate, with parotid US scores (total US score: ρ = 0.510 and ρ = 0.560; highest for homogeneity: ρ = 0.574 and ρ = 0.633). CONCLUSION: Although pSS-associated ultrasonographic findings did correlate with histopathological features, the three modalities that evaluate salivary gland involvement assess different (or at best partly related) constructs. Therefore histopathology, salivary flow and ultrasonography are complementary measurements and cannot directly replace each other in the workup of pSS.

Differences in presentation between paediatric- and adult-onset primary Sjögren's syndrome patients.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a rare disease in paediatric patients. Presenting symptoms differ from those in adult patients. The aim of this study was to evaluate presenting symptoms, classification criteria and clinical assessments, including salivary gland ultrasonography (SGUS), at disease onset in paediatric and adult patients with pSS. METHODS: Data of 23 paediatric- and 33 adult-onset patients with pSS were obtained from our standardised multidisciplinary REpSULT and RESULT cohorts, respectively. Clinical, patient-reported, serological, functional, biopsy and SGUS parameters were compared. RESULTS: In paediatric-onset pSS (pedSS) patients, recurrent parotid gland swelling (91% vs. 49%, p<0.001) and fever (30% vs. 3%, p=0.006) were more often present than in adult-onset patients. In contrast, sicca symptoms of mouth (52% vs. 79%, p=0.046) and eyes (26% vs. 73%, p<0.001) were less common in pedSS patients. In paediatric patients, the entry criteria of the ACR/EULAR classification were most often met due to activity in the glandular domain of the ESSDAI. When applying the ACR/EULAR classification criteria, only 78% of pedSS fulfilled these criteria compared to 100% of adult patients. Abnormal glandular function tests had a greater contribution to fulfilling the criteria in adults, while the biopsy had a greater contribution in paediatric patients. Anti-SSA/Ro serology had similar contribution for both cohorts. SGUS Hocevar score was significantly higher in paediatric compared to adult patients (median 25 vs. 18, p=0.004). CONCLUSION: PedSS has a different presentation than adult-onset pSS. Recurrent parotid gland swelling in paediatric patients should alert clinicians to the potential presence of pSS.

[Sympathicotomy in patients with drug resistant Raynaud's phenomenon]. / Sympathicotomie bij medicatieresistent fenomeen van Raynaud.

Raynaud's phenomenon (RP) is a disorder of the microvasculature which causes poor blood flow to the digits. This disorder is common in young females and may be associated with several underlying connective tissue diseases including systemic sclerosis. Although RP may have a tremendous impact on quality of life, treatment options are limited. Conventional medical treatment mainly consists of vasodilatory drugs, which are not effective in all patients and may induce undesired side effects. The current clinical lesson describes three patients with severe RP who all underwent a novel, minimally invasive, single-port thoracoscopic sympathicotomy (SPTS). Although this procedure seems promising in patients with treatment-resistant RP, as shown with patients A and B, future research has yet to show what the long-term effects are.

Clinical Phenotyping of Primary Sjögren Syndrome Patients Using Salivary Gland Ultrasonography: Data From the RESULT Cohort.

OBJECTIVE: To investigate salivary gland ultrasound (SGUS) abnormalities in relation to clinical phenotype and patient characteristics, disease activity, and disease damage in patients with primary Sjögren syndrome (pSS). METHODS: Consecutive outpatients included in our REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort were selected. Patients with pSS who were included were classified according to the American College of Rheumatology/European League Against Rheumatism (EULAR) criteria and underwent full ultrasonographic examination (Hocevar score 0-48) at baseline. Total SGUS scores of ≥ 15 were considered positive. Patient characteristics, disease activity, and disease damage were compared between the different SGUS groups. RESULTS: In total, 172 of 186 patients with pSS were eligible, of whom 136 (79%) were SGUS positive. Compared with patients who were SGUS negative, SGUS-positive patients had significantly longer disease duration, higher EULAR Sjögren Syndrome Disease Activity Index, higher Sjögren Syndrome Disease Damage Index, and were more likely to have a positive parotid gland biopsy, anti-SSA/SSB antibodies, and abnormal unstimulated whole saliva (UWS) and ocular staining score (OSS), and higher levels of IgG and rheumatoid factor. Regarding patient-reported outcome measurements (PROM), patients who were SGUS positive scored significantly lower on the EULAR Sjögren Syndrome Patient-Reported Index for fatigue and pain, and more often found their disease state acceptable compared with patients who were SGUS negative. SGUS total score showed significant associations with various clinical and serological variables, and with PROM. Highest associations were found for UWS (ρ = -0.551) and OSS (ρ = 0.532). CONCLUSION: Patients who were SGUS positive show a distinct clinical phenotype in all aspects of the disease compared with patients who were SGUS negative: clinical, functional, serological, and PROM. SGUS could be a helpful tool in selecting patients for clinical trials and estimating treatment need.

How do patients with systemic sclerosis experience currently provided healthcare and how should we measure its quality?

OBJECTIVES: To gain insight into SSc patients' perspective on quality of care and to survey their preferred quality indicators. METHODS: An online questionnaire about healthcare setting, perceived quality of care (CQ index) and quality indicators, was sent to 2093 patients from 13 Dutch hospitals. RESULTS: Six hundred and fifty patients (mean age 59 years, 75% women, 32% limited cutaneous SSc, 20% diffuse cutaneous SSc) completed the questionnaire. Mean time to diagnosis was 4.3 years (s.d. 6.9) and was longer in women compared with men (4.8 (s.d. 7.3) vs 2.5 (s.d. 5.0) years). Treatment took place in a SSc expert centre for 58%, regional centre for 29% or in both for 39% of patients. Thirteen percent of patients was not aware of whether their hospital was specialized in SSc. The perceived quality of care was rated with a mean score of 3.2 (s.d. 0.5) (range 1.0-4.0). There were no relevant differences between expert and regional centres. The three prioritized process indicators were: good patient-physician interaction (80%), structural multidisciplinary collaboration (46%) and receiving treatment according to SSc guidelines (44%). Absence of disease progression (66%), organ involvement (33%) and digital ulcers (27%) were the three highest rated outcome indicators. CONCLUSION: The perceived quality of care evaluated in our study was fair to good. No differences between expert and regional centres were observed. Our prioritized process and outcome indicators can be added to indicators suggested by SSc experts in earlier studies and can be used to evaluate the quality of care in SSc.

Incorporation of Salivary Gland Ultrasonography Into the American College of Rheumatology/European League Against Rheumatism Criteria for Primary Sjögren's Syndrome.

OBJECTIVE: To assess whether the addition of salivary gland ultrasonography (SGUS) or replacement of current criteria items by SGUS influences the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for primary Sjögren's syndrome. METHODS: Included were consecutive patients with complete data on all ACR/EULAR items (n = 243) who underwent SGUS in our primary Sjögren's syndrome expertise center. Clinical diagnosis by the treating physician was used as the gold standard. Separate analyses were performed for patients who underwent labial or parotid gland biopsies. The average score for hypoechogenic areas in 1 parotid and 1 submandibular gland was determined (range 0-3). Next, performance of the ACR/EULAR criteria was evaluated after addition of SGUS or replacement of current items by SGUS. RESULTS: Receiver operating characteristic analysis showed an optimal cutoff value of ≥1.5 for SGUS. The optimal weight for SGUS positivity was 1. Cutoff for ACR/EULAR fulfilment remained ≥4. In patients who underwent a labial gland biopsy (n = 124), the original criteria showed an area under the curve (AUC) of 0.965, sensitivity of 95.9%, and specificity of 92.2%. After the addition of SGUS, the AUC was 0.966, with a sensitivity of 97.3% and specificity of 90.2%. In patients who underwent a parotid gland biopsy (n = 198), similar results were found. Sensitivity of the criteria decreased substantially when SGUS replaced salivary gland biopsy or anti-SSA antibodies, while performance remained equal when SGUS replaced the ocular staining score, Schirmer's test, or unstimulated whole saliva flow. CONCLUSION: Validity of the ACR/EULAR criteria remains high after incorporation of SGUS. With SGUS, clinicians are offered a larger array of tests to evaluate fulfillment of the ACR/EULAR criteria.

Abatacept treatment for patients with early active primary Sjögren's syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study).

BACKGROUND: Several small open-label studies have suggested efficacy of abatacept-a co-stimulation inhibitor-in patients with primary Sjögren's syndrome. These promising results warranted further evaluation. We therefore aimed to further assess the safety and efficacy of abatacept compared with placebo in patients with primary Sjögren's syndrome. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial at the University Medical Center Groningen (Groningen, Netherlands). We included patients with primary Sjögren's syndrome fulfilling the American-European Consensus Group criteria, aged 18 years or older, with positive salivary gland biopsies, time from diagnosis of 7 years or less, and a European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or more. Independent pharmacists randomly allocated patients (1:1) to either the abatacept group or placebo group using a computer-generated sequence stratified by previous use of disease-modifying anti-rheumatic drugs. Patients received at-home subcutaneous injections of abatacept (125 mg) or placebo once a week for 24 weeks. The primary outcome was the between-group difference in ESSDAI score at week 24. Efficacy was analysed in patients who received at least one drug dose and for whom post-baseline data were collected. Safety was analysed in all patients who received at least one drug dose. FINDINGS: Between Aug 14, 2014, and Aug 23, 2018, 580 patients were reviewed for eligibility, of which 80 patients were randomly assigned to receive study treatment. Efficacy was analysed in 40 patients receiving abatacept and 39 patients receiving placebo (one patient in this group was lost to follow-up). The primary outcome did not significantly differ between the treatment groups. The adjusted mean difference in ESSDAI score at week 24 between the abatacept group and placebo group was -1·3 (95% CI -4·1 to 1·6). No deaths or treatment-related serious adverse events occurred. In 38 (95%) of 40 patients in the abatacept group, 103 adverse events occurred, including one serious adverse event and 46 infections. In 38 (95%) of 40 patients in the placebo group, 87 adverse events occurred, including four serious adverse events and 49 infections. INTERPRETATION: On the basis of this trial, we cannot recommend abatacept treatment as standard of care to reduce systemic disease activity in patients with primary Sjögren's syndrome. Further studies should evaluate whether patients with specific clinical manifestations and biological characteristics might benefit from abatacept treatment. FUNDING: Bristol-Myers Squibb.

Abnormal Nailfold Capillaroscopy Is Common in Patients with Connective Tissue Disease and Associated with Abnormal Pulmonary Function Tests.

OBJECTIVE: To assess the presence of a systemic sclerosis (SSc) pattern on nailfold capillary microscopy (NCM) in patients with Raynaud phenomenon (RP) and to explore its association with abnormal pulmonary function tests (PFT). METHODS: NCM patterns were assessed in 759 consecutive patients with RP. Patterns were classified as normal (n = 354), nonspecific (n = 159), or SSc pattern (n = 246). Abnormal PFT was defined as forced vital or diffusion capacity < 70%. Patients were classified as primary RP (n = 245), or secondary: no definite diagnosis (n = 391), SSc (n = 40), primary Sjögren syndrome (pSS; n = 30), systemic lupus erythematosus (SLE; n = 30), mixed connective tissue disease (MCTD; n = 7), rheumatoid arthritis (RA; n = 15). RESULTS: An SSc pattern on NCM was frequently observed in most patients with a definite diagnosis: SSc (88%), pSS (33%), SLE (17%), MCTD (71%), and RA (13%). In patients without definite diagnosis, 17% had a normal NCM pattern, 35% nonspecific, and 48% SSc pattern. Abnormal PFT was more frequent in patients with an SSc pattern (35.9% vs 19.5%, p = 0.002), even when corrected for SSc diagnosis (p = 0.003). Absence of an SSc pattern had high negative predictive value (88%); positive predictive values were low. CONCLUSION: SSc pattern on NCM is common in patients with RP, and in those with connective tissue diseases other than SSc. It is associated with a higher prevalence of abnormal PFT, independent of the presence of an SSc diagnosis. Although these data need validation in a prospective setting, they underline the importance of NCM in RP and putative value to stratify the risk of pulmonary involvement in early stages of disease.