Effect of short-interval rituximab and high-dose corticosteroids on kidney function in systemic sclerosis: Long-term experience of a single centre.

INTRODUCTION: Scleroderma renal crisis (SRC) is a rare but one of the most recognised complications of systemic sclerosis (SSc). Corticosteroid (CS) use has been considered as a major risk factor for SRC. Several studies reported the efficacy of rituximab (RTX) with an acceptable safety profile in SSc. However, data on the long-term effect of high-dose CS concomitant to RTX on kidney function are lacking. METHODS: We retrospectively analysed SSc patients (n = 35) treated with a lower dosage and short-interval RTX and concomitant high-dose CS at the Department of Internal Medicine at the Medical University of Graz between 2010 and 2019. The kidney function was assessed using the estimated glomerular filtration rate (eGFR) at every RTX admission. The annual decline of kidney function was evaluated by linear mixed model analysis. RESULTS: At the RTX initiation, one patient had a decreased kidney function indicated by eGFR < 60 mL/min/1.73 m2 (median: 96 mL/min/1.73 m2 ; interquartile range (IQR): 43-136). Patients received RTX and complementary high-dose CS for a median follow-up time of 3.4 years (range 0.6-9.5). A linear mixed model analysis with the patient as random effect and time from first RTX as fixed effect estimated an annual decline of 1.98 mL/min/1.73 m2 of the eGFR (95% confidence interval: [-2.24, -1.72]; P <.001). During the follow-up period, no patient experienced SRC or a significant drop in kidney function. CONCLUSIONS: A regular, high-dose CS given contemporary to RTX seems to be a safe option for kidney function in patients with SSc. Our findings provide additional knowledge in risk evaluation and planning of individualised therapies or designing clinical studies using RTX.

Evaluation of subcutaneous glucose monitoring systems under routine environmental conditions in patients with type 1 diabetes.

Continuous and flash glucose monitoring (GM) systems have been established in diabetes care. We compared the sensor performance of 3 commercially available GM systems. A total of 12 patients with type 1 diabetes were included in a single-centre, open-label study in which the sensor performance of the Abbott FreeStyle libre (Abbott), Dexcom G4 Platinum (Dexcom) and Medtronic MiniMed 640G (Medtronic) systems over 12 hours was compared during mimicked real-life conditions (meals, exercise, hypo- and hyperglycaemia). Sensor performance was determined by fulfilment of ISO 15197:2013 criteria, calculating mean absolute relative difference (MARD), and was also illustrated using Parkes error grid and Bland-Altman plots. Sensor performance during changes in metabolic variables (lactate, betahydroxybutyrate, glucagon, non-esterified-fatty-acids) was determined by Spearman's rank correlation coefficient testing. The systems fulfilled ISO 15197:2013 criteria by 73.2% (Abbott), 56.1% (Dexcom) and 52.0% (Medtronic). The MARDs ± standard deviation in the entire glycaemic range were 13.2% ± 10.9% (Abbott), 16.8% ± 12.3% (Dexcom) and 21.4% ± 17.6% (Medtronic), respectively. All sensors performed less accurately during hypoglycaemia and best during hyperglycaemia. We did not observe an influence of metabolic variables on sensor performance.

Patients' recollection about the onset of Sjögren's disease - a mixed methods study on the patients' perspective.

BACKGROUND: Little is known about the symptoms at the onset of Sjögren's Disease (SjD) and it is unclear whether SjD starts with characteristic symptoms that could be differentiated from dryness of other origin (sicca syndrome). The aim of this study was to investigate patients' recollection of initial events and first symptoms of SjD. The second aim was to verify and quantify these aspects in a representative cohort. METHODS: All SjD patients fulfilled the EULAR/ACR 2016 classification criteria. In the first part of the study, consecutive SjD patients were recruited for individual, semi-structured interviews. All interviews were audio-recorded and transcribed verbatim, and an inductive thematic data analysis was performed. In the second part, the identified aspects of the qualitative analysis were grouped into a checklist with ten items. RESULTS: One-hundred and thirty-four patients participated in the study. 31 SjD patients completed the qualitative part. Major aspects emerged of how patients experienced the beginning and first symptoms of SjD: (1) "classic" SjD symptoms (fatigue, pain, dryness) (2), sicca symptoms started after initial swelling of parotid and/or lymph nodes (3), after hormonal transition or infections before the onset of SjD symptoms. In the second part of the study, the previous identified major aspects were verified in an independent cohort of 103 SjD patients. The main symptom before diagnosis was dryness (n = 77, 74.8%) with migratory joint pain (n = 51, 49.5%) and fatigue (n = 47, 45.6%). In 38.8% (n = 40), patients reported a swelling/inflammation of the parotid gland at the onset of disease. CONCLUSIONS: We describe patients' recollection of the onset of SjD. Raising awareness of the symptoms identified among physicians and among the general public may allow earlier diagnosis of SjD.

Sjögren syndrome: looking forward to the future.

Primary Sjögren's syndrome (pSS) is a heterogeneous disease characterised by a wide spectrum of manifestations that vary according to the different stages of the disease and among different subsets of patients. The aim of this qualitative literature review is to summarise the recent advances that have been reported in pSS, ranging from the early phases to the established disease and its complications. We analysed the diagnostic, prognostic, and management aspects of pSS, with a look into future clinical and research developments. The early phases of pSS, usually antedating diagnosis, allow us to investigate the pathophysiology and risk factors of the overt disease, thus allowing better and timely patient stratification. Salivary gland ultrasound (SGUS) is emerging as a valid complementary, or even alternative, tool for histopathology in the diagnosis of pSS, due to a standardised scoring system with good agreement and performance. Other promising innovations include the application of artificial intelligence to SGUS, ultrasound-guided core needle biopsy, and a wide array of novel diagnostic and prognostic biomarkers. Stratifying pSS patients through the integration of clinical, laboratory, imaging, and histopathological data; differentiating between activity-related and damage-related manifestations; and identifying patients at higher risk of lymphoma development are essential steps for an optimal management and individualised treatment approach. As new treatment options are emerging for both glandular and systemic manifestations, there is a need for a more reliable treatment response evaluation. pSS is a complex and heterogeneous disease, and many distinct aspects should be considered in the different stages of the disease and subsets of patients. In recent years, efforts have been made to improve our understanding of the disease, and certainly in the coming years, some of these novelties will become part of our routine clinical practice, thus improving the management of pSS patients.

Effect of Liraglutide Treatment on Whole-body Glucose Fluxes in C-peptide-Positive Type 1 Diabetes During Hypoglycemia.

CONTEXT: The effect of liraglutide in C-peptide-positive (C-pos) type 1 diabetes (T1D) patients during hypoglycemia remains unclear. OBJECTIVE: To investigate the effect of a 12-week liraglutide treatment on the body glucose fluxes during a hypoglycemic clamp in C-pos T1D patients and its impact on the alpha- and beta-cell responses during hypoglycemia. DESIGN: This was a randomized, double-blind, crossover study. Each C-pos T1D patient was allocated to the treatment sequence liraglutide/placebo or placebo/liraglutide with daily injections for 12 weeks adjunct to insulin treatment, separated by a 4-week washout period. SETTING AND PARTICIPANTS: Fourteen T1D patients with fasting C-peptide ≥ 0.1 nmol/L. INTERVENTION(S): All patients underwent a hyperinsulinemic-stepwise-hypoglycemic clamp with isotope tracer [plasma glucose (PG) plateaus: 5.5, 3.5, 2.5, and 3.9 mmol/L] after a 3-month liraglutide (1.2 mg) or placebo treatment. MAIN OUTCOME MEASURE(S): The responses of endogenous glucose production (EGP) and rate of peripheral glucose disposal (Rd) were similar for liraglutide and placebo treatment during the clamp. RESULTS: The numbers of hypoglycemic events were similar in both groups. At the clamp, mean glucagon levels were significantly lower at PG plateau 5.5 mmol/L in the liraglutide than in the placebo group but showed similar responses to hypoglycemia in both groups. Mean C-peptide levels were significantly higher at PG-plateaus 5.5 and 3.5 mmol/L after liraglutide treatment, but this effect was not reflected in EGP and Rd. Hemoglobin A1c and body weight were lower, and a trend for reduced insulin was seen after liraglutide treatment. CONCLUSIONS: The results indicate that 3 months of liraglutide treatment does not promote or prolong hypoglycemia in C-pos T1D patients.

Go Ask Your Patients! PSS-QoL Reported Perception of Dryness Correlates With Lacrimal and Salivary Flow in Primary Sjögren's Syndrome.

Introduction/Objectives: The patient perspective is an essential outcome parameter in the quest for effective therapy in primary Sjögren's Syndrome (PSS). The EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is recommended by EULAR to quantify patient's symptom burden and has been used in several clinical trials. Surprisingly, the patient's perception of dryness quantified with ESSPRI does not correlate with objective measures of salivary or lacrimal flow. Thus, we evaluated a newly developed assessment tool-the Primary Sjögren's Syndrome Quality of Life Questionnaire (PSS-QoL)-for quantifying symptoms of dryness in comparison with the ESSPRI and objective measurements of salivary and lacrimal flow. Methods: Data of patients from the PSS registry of the Medical University of Graz fulfilling the 2016 ACR/EULAR classification criteria for PSS were analyzed. The patient perspective was analyzed by PSS-QoL, ESSPRI, Xerostomia Inventory (XI) and Ocular Surface Disease Index (OSDI). Sicca signs were measured with Schirmer's test, unstimulated salivary flow test (USF) and stimulated salivary flow test (SSF). ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) and EGA (Evaluator Global Assessment, numeric rating scale from 0 to 10) were obtained. In addition, free light chains (FLC) κ and λ, rheumatoid factor (RF) IgM and IgA were determined. Results: Data from 123 PSS patients were analyzed; 91.9% (n = 113) were female, with a mean disease duration of 6.2 (±5.3) years and mean age of 60.1 (±12.4) years. PSS-QoL-dryness revealed significant negative correlations with Schirmer's test (r = -0.31, p < 0.05) and SSF-test (r = -0.390, p < 0.01). In contrast, we found no significant correlation between ESSPRI-dryness and any objective dryness test. Lower perceived dryness was associated with higher immunological activity determined by increased levels of IgG, FLC and RF-IgA. Whereas patients with only subjective signs of dryness had lower immunological activity. Discussion: Patients' perception of dryness assessed by PSS-QoL correlates with objective measurements of salivary gland function while ESSPRI-dryness did not. Based on the PSS-QoL and objective measures of dryness two distinct groups of PSS patients could be distinguished, which may have implications in daily practice and future clinical studies.

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.

Impact of C-Peptide Status on the Response of Glucagon and Endogenous Glucose Production to Induced Hypoglycemia in T1DM.

Context: Complete loss of ß-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia. Objective: We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM. Design and Setting: We conducted an open, comparative trial. Patients: Ten C-peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled. Intervention: Plasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique. Main Outcome Measure: Impact of C-peptide status on glucagon response and EGP during hypoglycemia. Results: Glucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 ± 4.6 vs 4.19 ± 2.4 pmol/L, P = 0.016, mean ± standard deviation) but comparable EGP rates (2.13 ± 0.2 vs 2.04 ± 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients. Conclusions: Glucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved ß-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM.