Beyond the dryness of Sjögren’s syndrome : renal complications and bone metabolism

In this thesis, we addressed three clinical important issues: 1) the prevalence and consequences of distal renal tubular acidosis in Primary Sjögren’s syndrome patients; 2) the effect of Primary Sjögren’s syndrome on bone metabolism; 3) the effect of hydroxychloroquine on bone metabolism. __Part 1__ includes the clinical studies of this thesis and is dedicated to the evaluation of distal renal tubular acidosis and its consequences in Primary Sjögren’s syndrome and the effect of Primary Sjögren’s syndrome on bone. __Part 2__ includes the laboratory studies of this thesis in which we demonstrate the effects of hydroxychloroquine on human bone cells both in vivo and in vitro

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

Primary Sjögren’s 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,

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 reveale

Bone Mineral Density in Sjögren Syndrome Patients with and Without Distal Renal Tubular Acidosis

Primary Sjögren’s syndrome (pSS) can be complicated by distal renal tubular acidosis (dRTA), which may contribute to low bone mineral density (BMD). Our objective was to evaluate BMD in pSS patients with and without dRTA as compared with healthy controls. BMD of lumbar spine (LS) and femoral neck (FN) was measured in 54 pSS patients and 162 healthy age- and sex-matched controls by dual-energy X-ray absorptiometry (DXA). dRTA was defined as inability to reach urinary pH <5.3 after an ammonium chloride (NH4Cl) test. LS- and FN-BMD were significantly higher in pSS patients compared with controls (1.18 ± 0.21 g/cm2 for patients vs. 1.10 ± 0.18 g/cm2 for controls, P = 0.00

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

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

Inflammatory bowel disease in primary immunodeficiency disorders is a heterogeneous clinical entity requiring an individualized treatment strategy

Objective: To describe the prevalence, clinical presentation and current treatment regimens of inflammatory bowel disease (IBD) in patients with primary immunodeficiency disorders (PI

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