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ID PMID Title PublicationDate abstract
30075746 Role of the mTOR pathway in minor salivary gland changes in Sjogren's syndrome and systemi 2018 Aug 4 BACKGROUND: To examine the activity of the mammalian target of rapamycin (mTOR) pathway and its regulators, transforming growth factor (TGF)-β1 and phosphatase and tensin homolog (PTEN), in minor salivary gland biopsies of Sjogren's syndrome (SS) and systemic sclerosis (SSc) patients. METHODS: We retrospectively evaluated SS, SSc, and SS-SSc overlap patients admitted to our outpatient rheumatology clinic between January 2007 and December 2015 who underwent a minor salivary gland biopsy. Patient demographics and some clinical features were obtained from hospital records. Immunohistochemistry was used to analyze total mTOR, total PTEN, and TGF-β1 expression in the biopsied tissues. The biopsy specimens were also examined for the presence and degree of fibrosis. RESULTS: Minor salivary gland biopsies of 58 SS, 14 SSc, and 23 SS-SSc overlap patients were included in the study. There was no significant difference in mTOR expression between these groups (P = 0.622). PTEN protein was expressed in 87.2% of patients with SS, 57.9% with overlap syndrome, and 100% of the SSC patients, and these differences were statistically different (P = 0.023). Although ductal epithelial TGF-β1 expression was similar between the groups (P = 0.345), acinar cell expression was found to be more frequent in the SSc (72.7%) and overlap patients (85.7%) in comparison with the SS cases (58.2%; P = 0.004). CONCLUSION: mTOR may be one of the common pathways in the pathology of both SS and SSc. Hence, there may be a role for mTOR inhibitors in the treatment of both diseases. Additionally, PTEN and TGF-β1 expression may be a distinctive feature of SSc.
30544839 Neurological and Inflammatory Manifestations in Sjögren's Syndrome: The Role of the Kynur 2018 Dec 8 For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren's syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular surface (OS), and salivary glands (SG) are linked to the central nervous system (CNS) at the brainstem and hippocampus. Once compromised, these CNS sites may be responsible for autonomic and functional disturbances that are related to major and EGM in SS. Recent studies have confirmed that the kynurenine metabolic pathway (KP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating indoleamine 2,3-dioxygenase (IDO) in SS. This pathway interferes with serotonergic and glutamatergic neurotransmission, mostly in the hippocampus and other structures of the CNS. Therefore, it is plausible that KP induces neurological manifestations and contributes to the discrepancy between symptoms and signs, including manifestations of hyperalgesia and depression in SS patients with weaker signs of sicca, for example. Observations from clinical studies in acquired immune deficiency syndrome (AIDS), graft-versus-host disease, and lupus, as well as from experimental studies, support this hypothesis. However, the obtained results for SS are controversial, as discussed in this study. Therapeutic strategies have been reexamined and new options designed and tested to regulate the KP. In the future, the confirmation and application of this concept may help to elucidate the mosaic of SS manifestations.
29223133 How stress contributes to autoimmunity-lessons from Sjögren's syndrome. 2018 Jan A large body of clinical evidence on the association between stressful life events and autoimmune diseases suggests that stress may play an important role in the pathogenesis of these disorders. In this article, we discuss the effects of stress, not on the immune system but on specific cell populations against which the autoimmune reactivity is directed. Using Sjögren's syndrome as a model autoimmune disease, we review the role of stress in the initiation and perpetuation of autoimmune reactivity. We present data that reveal the effects of stress on salivary gland epithelial cells, suggesting that stress can become immunogenic through its various effects on salivary gland epithelium.
29251022 Impact of double positive for anti-centromere and anti-SS-a/Ro antibodies on clinicopathol 2018 Sep OBJECTIVES: The purpose of our study was to define the clinical characteristics of anti-centromere antibody and anti-SS-A/Ro antibody (ACA/SS-A) double positive Sjögren's syndrome (SS) and to clarify the clinical impact of these antibodies. METHODS: We examined 108 patients (6 males, mean age 57.9 years) with SS who underwent labial salivary gland biopsy. The patients were divided into four groups by ACA and anti-SS-A/Ro antibody positivity. Symptoms, laboratory and pathological data, and scleroderma-related data were compared among the groups. RESULTS: The cohort consisted of 16 ACA/SS-A double positive, 20 ACA single positive, 67 SS-A single positive, and 5 ACA/SS-A double negative SS. ACA/SS-A double positive SS were significantly older than SS-A single positive SS (mean age 71.1 vs. 53.1 years). They had higher EULAR Sjögren's syndrome disease activity index (ESSDAI) at diagnosis (mean 3.81 vs. 0.50) and higher serum IgG (mean 2009 vs. 1389 mg/dL) than ACA single positive SS. No patients developed skin sclerosis during a mean follow-up period of 45.6 months (range: 1-178). CONCLUSION: These results demonstrate that ACA/SS-A double positive SS is distinct from ACA single positive and SSA single positive SS. The combination of ACA and anti-SS-A/Ro antibody in SS should deserve greater attention in clinical practice.
29615973 Evidence for Ongoing Modeling-Based Bone Formation in Human Femoral Head Trabeculae via Fo 2018 Bone modeling is a biological process of bone formation that adapts bone size and shape to mechanical loads, especially during childhood and adolescence. Bone modeling in cortical bone can be easily detected using sequential radiographic images, while its assessment in trabecular bone is challenging. Here, we performed histomorphometric analysis in 21 bone specimens from biopsies collected during hip arthroplasty, and we proposed the criteria for histologically identifying an active modeling-based bone formation, which we call a "forming minimodeling structure" (FMiS). Evidence of FMiSs was found in 9 of 20 specimens (45%). In histomorphometric analysis, bone volume was significant higher in specimens displaying FMiSs compared with the specimens without these structures (BV/TV, 31.7 ± 10.2 vs. 23.1 ± 3.9%; p < 0.05). Osteoid parameters were raised in FMiS-containing bone specimens (OV/BV, 2.1 ± 1.6 vs. 0.6 ± 0.3%; p < 0.001, OS/BS, 23.6 ± 15.5 vs. 7.6 ± 4.2%; p < 0.001, and O.Th, 7.4 µm ± 2.0 vs. 5.2 ± 1.0; p < 0.05). Our results showed that the modeling-based bone formation on trabecular bone surfaces occurs even during adulthood. As FMiSs can represent histological evidence of modeling-based bone formation, understanding of this physiology in relation to bone homeostasis is crucial.
28673789 Efficacy and safety of biological DMARDs modulating B cells in primary Sjögren's syndrome 2018 Jan OBJECTIVE: In this review, we summarise the clinical efficacy and safety of B-cell targeted therapies for primary Sjögren's syndrome (pSS). METHODS: A systematic literature review was conducted using databases including MEDLINE, EMBASE and Cochrane. Only articles reporting controlled or prospective studies of b-DMARDs modulating B cells in treatment of pSS were selected. The highest-quality studies were selected for meta-analysis. The primary outcome of interest was clinical efficacy at week 24 on fatigue, dryness, Schirmer test, salivary flow rate and the full ESSDAI score including biological domain. For the efficacy criteria used, the difference between rituximab and placebo groups was expressed as mean difference (MD). RESULTS: Eighteen articles (13 of rituximab, 3 of belimumab, 1 of epratuzumab and 1 of baminercept) were identified for detailed evaluation. 4 controlled randomised trials of rituximab treatment vs. placebo involving 300 patients were included for quantitative analysis. No significant differences were observed between groups in the meta-analysis of mean improvements between baseline and week 24 in fatigue VAS [MD -3,24 95% CI (-30,21 to 23,72)], oral dryness VAS [MD -8,41 95% CI (-35,06 to 18,24)], salivary flow rate [MD 0,04 95% CI (-0,03 to 0,11)] and Schirmer test [MD 0,35 95% CI (-2,13 to 2,82)]. Rituximab was relatively safe compared to placebo. CONCLUSION: Our review shows that rituximab is not effective in pSS with the designs and outcomes proposed in the trials. Controlled randomised trials are needed to prove the efficacy of belimumab and epratuzumab in this indication. The randomised controlled trial evaluating baminercept failed to achieve its primary endpoint.
30029059 Myeloid-derived suppressor cells exacerbate Sjögren's syndrome by inhibiting Th2 immune r 2018 Sep Myeloid-derived suppressor cells (MDSCs) can regulate various aspects of immune responses based on their potent immune-suppressive activity. Studies reported that MDSCs participated in many autoimmune diseases. However, the role of MDSCs in Sjögren's syndrome (SS) is unknown. In this study, we determined the frequencies and function of MDSCs in non-obese diabetic (NOD) mice and SS patients. The NOD mice were adoptively transferred with MDSCs or treated with anti-Gr1 antibody. Results showed that peripheral MDSCs increased significantly with the development of SS-like syndrome in NOD mice and the percentage of MDSCs was higher in SS patients than healthy controls. The SS-like syndrome aggravated after transfer of MDSCs in NOD mice. The deletion of MDSCs in NOD mice alleviated SS-like syndrome. Mechanistically, MDSCs down-regulated the percentages of Th2 cells in NOD mice and SS patients. In summary, our findings suggested that MDSCs exacerbated Sjögren's syndrome by inhibiting Th2 cells.
29310465 Predictive role of tear protein expression in the early diagnosis of Sjögren's syndrome. 2018 Sep Background The contribution of tear protein expression in patients with presumed diagnosis of Sjögren syndrome is underestimated. We aimed to evaluate the role of tear proteins in the Sjögren syndrome early diagnosis. Methods Charts from 110 patients suspected of Sjögren syndrome were analysed and the subsequent diagnosis retrieved. Subjective symptoms (ocular surface disease index, OSDI), tear film break-up time (TFBUT), Schirmer test, Jones test, tear clearance (TC), corneal (NEI score) and conjunctival staining (van Bjerstelveldt score), esthesiometry, cytology, tear protein analysis (total protein [TP] content, lysozyme-C [LYS-C], lactoferrin [LACTO], lipocalin-1 [LIPOC-1] and albumin [ALB]) were analysed. The diagnostic performance with area under the curve (AUC) and odds ratio (OR) for each parameter were calculated. Results Thirty-five patients (31.8%) had been diagnosed as affected by Sjögren syndrome. Clinical tests showed lower diagnostic performance (OSDI > 44 [AUC 0.57], Schirmer ≤ 5 mm [0.59], TFBUT ≤ 3 s [0.72], TC > 1/16 [0.68], Jones ≤ 4 mm [0.68], corneal staining > 2 [0.51], conjunctival staining > 2 [0.78]) compared with tear proteins (LYS-C ≤ 1.5 mg/mL [0.79], LACTO ≤ 20% [0.94], LIPOC-1 ≤ 10% [0.89], ALB ≥ 15% [0.79]). LYS-C, LACTO, LIPOC-1 and ALB showed a significant association in predicting Sjögren syndrome vs. not-Sjögren syndrome dry eye (OR, respectively, 4.9, 5.5, 7.2, 6.7). Conclusions Tear proteins' concentrations showed a significant higher accuracy compared with the traditional ocular clinical tests for reaching Sjögren syndrome's diagnosis. In particular, LACTO and LIPOC-1 provided an excellent diagnostic performance and thus could likely be considered promising biomarkers of Sjögren syndrome.
30179908 Chemokine Receptor 4 Expression in Primary Sjögren's Syndrome. 2018 Nov Ga-pentixafor is a novel radioligand of C-X-C motif chemokine receptor 4. A 55-year-old woman with a history of primary Sjögren's syndrome underwent Ga-pentixafor PET/CT for staging of lymphoma originating from mucosa-associated lymphoid tissue. Whereas no lymphoma manifestation could be detected, imaging revealed bilateral intense radiotracer uptake in both parotid and submandibular salivary glands, consistent with inflammatory cell infiltration.
29527903 Update of the SEPD position statement on the use of biosimilars for inflammatory bowel dis 2018 Jun In 2013, the European Medicines Agency (EMA) approved the biosimilar infliximab (CT-P13) for the full range of indications of the originator product, based on data from two trials conducted in rheumatoid arthritis and ankylosing spondylitis. The same year, our Society published a position statement that was later reviewed.
29380732 Fulminant presentation of oral mucosal leishmaniasis as severe stomatitis and periodontiti 2018 Jan This case report shows an atypical presentation of mucosal leishmaniasis infantum in the oral cavity resulting in severe stomatitis and periodontitis. The patient was immunocompromised because of rheumatoid arthritis for which he used prednisone and methotrexate. He was treated with intravenous liposomal amphotericin B and recovered within four weeks.
30213699 The role of dietary sodium in autoimmune diseases: The salty truth. 2018 Nov Autoimmune diseases are a group of heterogeneous condition that occur secondary to the intrinsic loss of tolerance to self- antigens. In genetically susceptible individuals, the complex interplay of environmental factors and epigenetic deregulations have been proposed to drive disease etiopathogenesis. Various environmental variables have been identified including viral infections, exposure to pollutants, stress and dietary factors. Sodium, a major constituent of salt is essential for mammalian physiology. However, high salt intake may play a role in the development of autoimmune diseases. Several lines of evidence point toward the role of high sodium intake in reversing the suppressive effects of Regulatory T cells (Tregs) and instead promoting cellular shift toward T-helper (Th)-1 and Th17 pro-inflammatory phenotypes. These effects have been attributed to cascade of events that ultimately results in downstream activation of serum glucocorticoid kinase 1 (Sgk1). In vivo, various autoimmune animal models have confirmed the role of high sodium diet in the emergence and the exacerbation of autoimmune conditions including for instance Experimental Autoimmune Encephalomyelitis model for multiple sclerosis, MRL/lpr mouse model for lupus nephritis, collagen induced arthritis model for rheumatoid arthritis, and dextran sulfate sodium induced colitis, and TNBS-induced colitis models for Crohn's disease. Clinical epidemiological studies are scarce. High sodium intake was associated with increased risk of rheumatoid arthritis disease emergence. In multiple sclerosis, some studies suggest a relation to clinical exacerbation rates however other studies did not corroborate these results. Taken together, high dietary salt intake plays a role in the spectrum of autoimmune disease etiology. Further research is warranted to better characterize such relationship and assist in identifying individuals that would benefit from dietary salt restriction.
29896077 Therapeutic potentials of superoxide dismutase. 2018 May Superoxide dismutases (SODs) constitute a very important antioxidant defense against oxidative stress in the body. The enzyme acts as a good therapeutic agent against reactive oxygen species-mediated diseases. The present review describes the therapeutic effects of SOD in various physiological and pathological conditions such as cancer, inflammatory diseases, cystic fibrosis, ischemia, aging, rheumatoid arthritis, neurodegenerative diseases, and diabetes. However, the enzyme has certain limitations in clinical applications. Therefore, SOD conjugates and mimetics have been developed to increase its therapeutic efficiency. Here, an overview is provided of some in vivo therapeutic effects observed with SOD.
30071937 Severe gangrene in a patient with anti-RNP positive limited cutaneous systemic sclerosis/r 2018 Dec In this paper, we describe a case of a male patient with anti-U1RNP positive limited cutaneous systemic sclerosis/rheumatoid arthritis overlap syndrome, who presented acutely with rapidly progressive digital ischemia, which lead to extensive gangrene. Management with conventional vasodilator therapy was unsuccessful. There were constitutional symptoms and a marked inflammatory response in the absence of evidence of infection, implying a component of vasculitis underlying the presentation. Treatment with immunosuppression and intravenous immunoglobulin led to resolution of the inflammatory process with no further progression of tissue necrosis. Here we discuss pertinent issues raised by the case, including the management of digital ischemia and gangrene in this context and the relevance of the anti-U1RNP in systemic sclerosis overlap syndromes.
29563778 Support needs for medication use and the suitability of eHealth technologies to address th 2018 OBJECTIVE: The objectives of this study were to explore the needs of patients with rheumatoid arthritis (RA) regarding support for medication use and to gain insight into their perspective on the suitability of eHealth technologies to address these needs. METHODS: Three focus groups were conducted with 28 patients with RA. Audio recordings made during the focus groups were transcribed verbatim. Two researchers independently performed an inductive, thematic analysis on the data (ie, the transcripts and field notes). RESULTS: The following three themes that described support needs of patients with RA for medication use were identified in the data: 1) informational support; 2) practical support; and 3) emotional support. Informational support reflected the provision of information and facts, including advice, suggestions, and feedback from health care providers. Practical support included the reinforcement of practical skills as well as the provision of medication aids and pharmacy services. Emotional support reflected a trusted patient-health care provider relationship, characterized by good communication. Although potential advantages of eHealth technologies to address the patients' support needs were recognized, concerns over matters such as personal interaction with health care providers, privacy and data security, and the quality and reliability of online information were prevalent. CONCLUSION: Patients with RA have informational, practical, and emotional support needs for medication use. Informational support seems to be most important. From the patients' perspective, eHealth technologies may have the potential to address these needs. However, these technologies are regarded as a complement to, rather than a replacement of, current practices.
30144075 Role and translational implication of galectins in arthritis pathophysiology and treatment 2019 Feb Galectins are members of the animal lectin family that bind to the β-galactoside-containing carbohydrate moieties of glycoconjugates. They seem to have an important role in the pathophysiology of several diseases, including arthritis. Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic conditions with few or no available therapies. In this context, galectins could provide a novel opportunity, but the precise role and mechanism of their involvement in arthritis are still not fully understood. This descriptive systematic literature review summarizes in vitro, in vivo, and clinical studies that analyzed and examined the role and mechanism of action of galectins in arthritis to highlight and clarify their possible translation implication. This review yielded promising evidence that individual galectins, in particular galectin-1, -3, and -9, could play positive or negative roles in the pathogenesis of arthritis, especially in RA and OA. It also emphasized the cell-dependent role of these galectins. This is particularly true for galectin-1, which was shown to have a protective anti-inflammatory role in RA, while it seemed to be associated with cartilage degeneration in OA. In summary, this review underlined that manipulation of certain galectins can suppress or aggravate disease symptoms in arthritis animal models, demonstrating the therapeutic potential of galectins for the treatment of RA and OA. Nevertheless, despite the fact that galectin therapy and therapies acting on galectin expression seem to be an interesting and important opportunity for research, we highlighted that further investigation is necessary to carefully evaluate their potential clinical implications in arthritis.
29930803 Stevens-Johnsons syndrome or drug-induced lupus - a clinical dilemma: A case report and re 2018 Jul Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.
30369262 Autoimmune, rheumatic, chronic inflammatory diseases: Neutrophil extracellular traps on pa 2018 Sep Rheumatic diseases are a group of inflammatory conditions that affect joints and connective tissues and are often accompanied by pain and restriction of motility. In many of these diseases, autoantibodies develop that react with molecules/structures commonly found hidden in neutrophils. Neutrophil extracellular trap (NET) formation and release is considered a defense mechanism against pathogens or endogenous danger signals and it has been associated with initial inflammatory responses. NETs are also endowed with an important resolution potential based on its intrinsic enzymatic activity, but in the case they are not timely removed from the crime scene they might modulate subsequent immune responses and contribute to the pathogenesis of chronic inflammatory diseases. In this review, we will summarize the actual knowledge about the multifaceted roles of NETs in the etiology and pathogenesis of rheumatic autoimmune diseases.
29890824 Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d 2018 Jun Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the β-hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.
29423640 Effectiveness of custom-made foot orthoses for treating forefoot pain: a systematic review 2018 Aug PURPOSE: Pain in and around the metatarsal heads, the metatarsal phalangeal joints and the surrounding soft tissues is called metatarsalgia. Non-operative treatment of metatarsalgia includes foot orthoses. Foot orthoses may be classified as standard or custom-made. A systematic review was carried out to determine whether custom-made foot orthoses are effective for treating forefoot pain. METHODS: The MEDLINE, CINAHL, The Cochrane Library and PEDro databases were searched for relevant articles reporting patients undergoing treatment for forefoot pain by means of custom-made foot orthoses. Two reviewers independently reviewed all titles and abstracts and extracted the available data. The study eligibility criteria were randomised controlled clinical trials that included participants with forefoot pain treated with custom-made foot orthoses and that reported levels of forefoot pain after the use of orthoses. The data consisted of patient demographics, pathologies related to forefoot pain, type of foot orthoses used, follow-up period and clinical outcomes. RESULTS: Nine studies were selected which had a total of 487 participants. The pathologies evaluated were rheumatoid arthritis, hallux abductus valgus and isolated and secondary metatarsalgia. The use of custom-made foot orthoses was the intervention that exerted the most significant reduction of the level of pain in the forefoot in most of the studies. CONCLUSIONS: The use of custom-made foot orthoses improved the level of forefoot pain in rheumatoid arthritis, hallux abductus valgus and secondary metatarsalgia as it increases sole pressures.