Tim Both

Reviewing primary Sjögren’s syndrome: Beyond the dryness - From pathophysiology to diagnosis and treatment

Primary Sjögrens syndrome (pSS) is a systemic autoimmune disease, characterized by lymphocytic infiltration of the secretory glands. This process leads to sicca syndrome, which is the combination of dryness of the eyes, oral cavity, pharynx, larynx and/or vagina. Extraglandular manifestations may also be prevalent in patients with pSS, including cutaneous, musculoskeletal, pulmonary, renal, hematological and neurological involvement. The pathogenesis of pSS is currently not well understood, but increased activation of B cells followed by immune complex formation and autoantibody production are thought to play important roles. pSS is diagnosed using the American-European consensus group (AECG) classification criteria which include subjective symptoms and objective tests such as histopathology and serology. The treatment of pSS warrants an organ based approach, for which local treatment (teardrops, moistures) and systemic therapy (including non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDS) and biologicals) can be considered. Biologicals used in the treatment of pSS mainly affect the total numbers of B cells (B cell depletion (Rituximab)) or target proteins required for B cell proliferation and/or activation (e.g. B cell activating factor (BAFF)) resulting in decreased B cell activity. The aim of this review is to provide physicians a general overview concerning the pathogenesis, diagnosis and management of pSS patients.

Everything you need to know about distal renal tubular acidosis in autoimmune disease

Abstract Renal acid–base homeostasis is a complex process, effectuated by bicarbonate reabsorption and acid secretion. Impairment of urinary acidification is called renal tubular acidosis (RTA). Distal renal tubular acidosis (dRTA) is the most common form of the RTA syndromes. Multiple pathophysiologic mechanisms, each associated with various etiologies, can lead to dRTA. The most important consequence of dRTA is (recurrent) nephrolithiasis. The diagnosis is based on a urinary acidification test. Potassium citrate is the treatment of choice.

Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome

OBJECTIVES Our objectives were to analyse the prevalence of distal renal tubular acidosis (dRTA) in primary SS (pSS) and to compare a novel urinary acidification test with furosemide and fludrocortisone (FF) with the gold standard ammonium chloride (NH4Cl) to detect dRTA. METHODS Urinary acidification was assessed in 57 pSS patients using NH4Cl and FF. A urinary acidification defect was defined as an inability to reach a urinary pH of <5.3 after NH4Cl. RESULTS The prevalence of complete dRTA (urinary acidification defect with acidosis) was 5% (3/57). All three patients had positive SSA/Ro and SSB/La autoantibodies and impaired kidney function. The prevalence of incomplete dRTA (urinary acidification defect without acidosis) was 25% (14/57). Compared with patients without dRTA, patients with incomplete dRTA had significantly lower venous pH and serum bicarbonate and higher urinary pH. SSB/La antibodies were more prevalent in the dRTA groups (P < 0.05). Compared with NH4Cl, the positive and negative predictive values of FF were 46% and 82%, respectively. Vomiting occurred more often during the urinary acidification test with NH4Cl than with FF (9 vs 0, P < 0.05). CONCLUSION Incomplete dRTA is common in pSS and causes mild acidaemia and higher urinary pH, which may contribute to bone demineralization and kidney stone formation. FF cannot replace NH4Cl in testing urinary acidification in pSS, but may be considered as a screening tool, given its reasonable negative predictive value and better tolerability.

Hydroxychloroquine affects bone resorption both in vitro and in vivo

We recently showed that patients with primary Sjögren syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favorable effects on BMD. The aim of the study was to evaluate whether HCQ modulates osteoclast function. Osteoclasts were cultured from PBMC‐sorted monocytes for 14 days and treated with different HCQ doses (controls 1 and 5 μg/ml). TRAP staining and resorption assays were performed to evaluate osteoclast differentiation and activity, respectively. Staining with an acidification marker (acridine orange) was performed to evaluate intracellular pH at multiple timepoints. Additionally, a fluorescent cholesterol uptake assay was performed to evaluate cholesterol trafficking. Serum bone resorption marker β‐CTx was evaluated in rheumatoid arthritis patients. HCQ inhibits the formation of multinuclear osteoclasts and leads to decreased bone resorption. Continuous HCQ treatment significantly decreases intracellular pH and significantly enhanced cholesterol uptake in mature osteoclasts along with increased expression of the lowdensity lipoprotein receptor. Serum β‐CTx was significantly decreased after 6 months of HCQ treatment. In agreement with our clinical data, we demonstrate that HCQ suppresses bone resorption in vitro and decreases the resorption marker β‐CTx in vivo. We also showed that HCQ decreases the intracellular pH in mature osteoclasts and stimulates cholesterol uptake, suggesting that HCQ induces osteoclastic lysosomal membrane permeabilization (LMP) leading to decreased resorption without changes in apoptosis. We hypothesize that skeletal health of patients with increased risk of osteoporosis and fractures may benefit from HCQ by preventing BMD loss.

Systemic interferon type I and type II signatures in primary Sjögren’s syndrome reveal differences in biological disease activity

Objective To assess the relationships between systemic IFN type I (IFN-I) and II (IFN-II) activity and disease manifestations in primary SS (pSS). Methods RT-PCR of multiple IFN-induced genes followed by principal component analysis of whole blood RNA of 50 pSS patients was used to identify indicator genes of systemic IFN-I and IFN-II activities. Systemic IFN activation levels were analysed in two independent European cohorts (n = 86 and 55, respectively) and their relationships with clinical features were analysed. Results Three groups could be stratified according to systemic IFN activity: IFN inactive (19-47%), IFN-I (53-81%) and IFN-I + II (35-55%). No patient had isolated IFN-II activation. IgG levels were highest in patients with IFN-I + II, followed by IFN-I and IFN inactive patients. The prevalence of anti-SSA and anti-SSB was higher among those with IFN activation. There was no difference in total-EULAR SS Disease Activity Index (ESSDAI) or ClinESSDAI between the three subject groups. For individual ESSDAI domains, only the biological domain scores differed between the three groups (higher among the IFN active groups). For patient reported outcomes, there were no differences in EULAR Sjögrens syndrome patient reported index (ESSPRI), fatigue or dryness between groups, but pain scores were lower in the IFN active groups. Systemic IFN-I but not IFN-I + II activity appeared to be relatively stable over time. Conclusions Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for trials targeting either IFN pathway.

Hydroxychloroquine decreases human MSC‐derived osteoblast differentiation and mineralization in vitro

We recently showed that patients with primary Sjögren Syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favourable effects on BMD. To study the direct effects of HCQ on human MSC‐derived osteoblast activity. Osteoblasts were cultured from human mesenchymal stromal cells (hMSCs). Cultures were treated with different HCQ doses (control, 1 and 5 µg/ml). Alkaline phosphatase activity and calcium measurements were performed to evaluate osteoblast differentiation and activity, respectively. Detailed microarray analysis was performed in 5 µg/ml HCQ‐treated cells and controls followed by qPCR validation. Additional cultures were performed using the cholesterol synthesis inhibitor simvastatin (SIM) to evaluate a potential mechanism of action. We showed that HCQ inhibits both MSC‐derived osteoblast differentiation and mineralization in vitro. Microarray analysis and additional PCR validation revealed a highly significant up‐regulation of the cholesterol biosynthesis, lysosomal and extracellular matrix pathways in the 5 µg/ml HCQ‐treated cells compared to controls. Besides, we demonstrated that 1 µM SIM also decreases MSC‐derived osteoblast differentiation and mineralization compared to controls. It appears that the positive effect of HCQ on BMD cannot be explained by a stimulating effect on the MSC‐derived osteoblast. The discrepancy between high BMD and decreased MSC‐derived osteoblast function due to HCQ treatment might be caused by systemic factors that stimulate bone formation and/or local factors that reduce bone resorption, which is lacking in cell cultures.

PRIS: Propofol Infusie Syndroom of Propofol Infectie Syndroom?

Sinds de publicatie van het rapport ‘To err is human’ is er veel aandacht voor patiëntveiligheid wereldwijd. De Raad van de Europese Unie heeft aanbevolen om patiëntveiligheid op te nemen in nationale gezondheidsbeleid en -programma’s. Uit Nederlands onderzoek blijkt dat in 2004 bij 2,3% van de opgenomen patiënten sprake was van potentieel vermijdbare schade. Naar aanleiding van dit onderzoek is het patiëntveiligheidsprogramma ‘Voorkom schade, werk veilig’ geı̈ntroduceerd met als doel de mogelijk vermijdbare schade in de Nederlandse ziekenhuizen terugbrengen met 50%, door ondermeer het voorkomen van lijnsepsis en verbetering van het klaarmaken en toediening van alle geneesmiddelen die worden geı̈njecteerd (bijv. intraveneus). In 2008 werden zeven patiënten in het Havenziekenhuis na een operatie ziek als gevolg van contaminatie van het toegediende anestheticum propofol. Bij twee patiënten werden gram-negatieve bacteriën gevonden. In de literatuur zijn eveneens casussen beschreven van propofol gecontamineerd met gram-negatieve bacteriën. Propofol is een zeer lipidenrijke emulsie die gevoelig is voor contaminatie. Behalve op de operatiekamer (OK) wordt propofol ook op de Intensive Care Unit (ICU) toegepast. Als sedativum wordt het hier vaak gedurende langere periode toegediend dan op de OK. Een ‘beruchte’ complicatie bij gebruik van propofol op de ICU is het propofol infusie syndroom (PRIS). In de literatuur wordt niet of nauwelijks gerapporteerd over gecontamineerde propofol op de ICU. Hierbij speelt de vraag op in hoeverre PRIS en contaminatie twee aparte ziekte-entiteiten zijn. Het doel van dit community project is dan ook te onderzoeken of er overeenkomsten zijn in de symptomatologie tussen PRIS en infusie van gecontamineerde propofol. Wordt PRIS mogelijk veroorzaakt door de toediening van gecontamineerde propofol? Daarnaast hebben we gekeken naar de micro-organismen die propofol kunnen contamineren en of de beschreven casus uit het Havenziekenhuis ook daadwerkelijk het beeld van een gram-negatieve sepsis vertoonden, aangezien dit slechts in twee gevallen met een bloedkweek bevestigd is.

Distal renal tubular acidosis in primary Sjögren syndrome

Primary Sjogren syndrome (pSS) is a chronic inflammatory disorder characterized by lymphocytic infiltration of exocrine glands. pSS can also cause distal renal tubular acidosis (dRTA). dRTA is a disorder in which patients are unable to acidify their urine because of impaired hydrogen ion secretion in the collecting duct.