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ID PMID Title PublicationDate abstract
28154368 Adult-Onset Still's Disease: Still a Serious Health Problem (a Case Report and Literature 2017 Feb 3 BACKGROUND Adult-onset Still's Disease (AOSD) is a rare systemic inflammatory disease accompanied by a triad of spiking fever, maculopapular exanthema, and arthralgia. To date, there is no definite laboratory or imaging test available for diagnosing AOSD, and the diagnosis is one of exclusion, which can be very challenging. CASE REPORT We report on the case of a 53-year-old female who presented with fever, arthralgia, and abdominal pain. Her initial laboratory tests showed elevated AST and ALT, and normal leukocytes with bandemia. During her hospitalization, we evaluated the patient for other potential differential diagnoses. After an extensive workup, the patient was diagnosed with AOSD based on Yamaguchi criteria. Her serum ferritin levels were measured and found to be markedly elevated, which is a non-specific finding in AOSD patients. CONCLUSIONS This case highlights the important role of a detailed history and physical examination for timely diagnosis of AOSD to prevent complications and improve patient's prognosis.
28636885 Differential changes in the pharmacokinetics of statins in collagen-induced arthritis rats 2017 Oct 15 The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.
28429194 Photobiomodulation therapy associated with treadmill training in the oxidative stress in a 2017 Jul Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by chronic and systemic inflammation, which leads to the destruction of the cartilage and bone and affects tissues in multiple joints. Oxidative stress has been implicated with regards to involvement in various disease conditions, such as diabetes mellitus and neurodegenerative, respiratory, cardiovascular, and RA diseases. In vivo experimental studies using photobiomodulation therapy (PBMT) have shown positive effects in reducing lipid peroxidation and in increasing antioxidant activity. The regular practice of physical exercise has also been reported to be a beneficial treatment capable of reducing oxidative damage. Thus, the aim of this study was to analyze the effects of photobiomodulation therapy at 2- and 4-J doses associated with physical exercise on oxidative stress in an experimental model of RA in protein expression involving superoxide dismutase (SOD), glutathione peroxidase (GPX), and/or catalase (CAT) on thiobarbituric acid reactive substances (TBARS). In this study, 24 male Wistar rats divided into four groups were submitted to an RA model (i.e., collagen-induced arthritis, CIA), with the first immunization performed at the base of the tail on days 0 and 7 were included. After 28 days, a third intraarticular dose was administered in both knees of the animals. After the last induction, PBMT was started immediately, transcutaneously at two points (i.e., the medial and lateral), with a total of 15 applications. Treadmill exercise was also started the day after the last induction, and lasted for 5 weeks. With respect to results, we obtained the decreases in the lipid peroxidation and the increases of the antioxidant activities of SOD, GPX and CAT, with physical exercise associated to PBMT in doses of 2 and 4 J. In conclusion, physical exercise associated with PBMT decreases lipid peroxidation and increases antioxidant activity.
29164007 Adult-Onset Still's Disease: Is This Truly a Diagnosis of Exclusion? 2017 Nov Adult-onset Still's Disease is a rare, idiopathic, inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and daily fevers as well as lymphadenopathy, pharyngitis, splenomegaly, myalgias, and serositis. The inciting etiology of this syndrome is unknown, though it has been hypothesized that infection triggers an autoimmune response. The Yamaguchi Criteria, the most sensitive and widely used diagnostic criteria, requires both a minimum set of criteria to be met as well other potential etiologies to be excluded. By definition, evidence of concomitant infection, malignancy, vasculitis, or connective tissue disease precludes the diagnosis of Adult-onset Still's Disease from being made. We present a very rare case of a patient who met all diagnostic criteria for Adult-onset Still's Disease, had a protracted course refractory to numerous immunosuppressant treatments, and also had evidence of coxsackie B infection with fourfold rise in viral titers on two occasions (both associated with disease flare). Although coxsackie B virus has been linked to Adult-onset Still's Disease at disease presentation, this case is unique in its protracted course and serological evidence of infection temporally related to disease flare. While accepted diagnostic criteria call for this disease to be a diagnosis of exclusion, our case supports the fact that ongoing infection may in fact be an important antigenic driver in persistent and refractory Adult-onset Still's Disease.
28268160 Primary Sjögren's syndrome and bronchiolitis. An unusual association. 2018 Jul Sjögren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands. It has been reported that the association between SS and respiratory involvement occurs in 11% and 45% of cases, and can be the initial manifestation of the disease. The diagnosis is based on the integration of clinical, immunological and histopathological criteria. This paper examines a 58-year-old man with SS, severe dyspnea and recurrent exacerbations associated with bronchiolitis-bronchiectasis. The absence of anti-Ro and anti-La antibodies associated with severe bronchiolitis is a clinical presentation that is poorly characterized in this group of patients; moreover, how to treat them remains unclear.
28428095 Sjogren's syndrome: Clinical aspects. 2017 Sep Sjogren's syndrome (SS) is the 2nd most common chronic autoimmune rheumatic disease and associated with a high burden of illness. Morbidity arises not only from untreated xerostomia and keratoconjunctivitis sicca but also from extra-glandular manifestations including the development of non-Hodgkin's B cell lymphomas. Proper diagnosis of SS requires objective evidence of dry eyes and/or objective evidence of dry mouth as well as proof of autoimmunity. The recent development of new international classification criteria and clinical practice guidelines for SS should not only enhance the existing standards of care but also facilitate further studies to improve future diagnosis and outcomes.
28337967 One year in review 2017: primary Sjögren's syndrome. 2017 Mar Primary Sjögren's syndrome (pSS) is a complex and heterogeneous disease. Last year, a great deal of basic and clinical research was carried out in pSS. Following the previous reviews of this publishing series, we will herewith provide a critical digest of the most recent literature on pSS pathogenesis, clinical manifestations and treatment. More specifically, we will focus on the heterogeneity of the disease, on the underlying pathogenetic pathways and on the possible new targeted treatments on the horizon.
29033912 The Infectious Basis of ACPA-Positive Rheumatoid Arthritis. 2017 Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrullinated protein autoantibodies (ACPAs). ACPAs precedes the onset of clinical and subclinical RA. There are strong data for three infectious agents as autoimmunity triggers in RA, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans causes of periodontal disease (PD), and Epstein-Barr virus (EBV). P. gingivalis expresses arginine gingipains, that cleave proteins at the arginine residues, and peptidyl arginine deiminase (PPAD), which citrullinates arginine residues of proteins, thus forming neoantigens that lead to ACPA production. Peripheral blood plasmablasts from ACPA+RA patients produce ACPAs the majority of which react against P. gingivalis. A. actinocycetemcomitans produces leukotoxin A, a toxin that forms pores in the neutrophil membranes and leads to citrullination and release of citrullinated autoantigens in the gums. EBV can infect B cells and epithelial cells and resides as latent infection in resting B cells. Abs against citrullinated peptides derived from EBV nuclear antigen appear years before RA and cross-react with human citrullinated fibrin. Citrullinated proteins are potential arthritogenic autoantigens in RA. The conversion of arginine to citrulline increases the peptide binding affinity to HLA-DRB1SE. Also, citrullinated fibrinogen induces arthritis in HLA-DRB1(*)0401 transgenic mice, and transfer of their splenic T cells causes arthritis to recipient mice.
28722479 Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis 2017 Jul AIM: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation. RESULTS: Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity. CONCLUSION: Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis.
28794078 Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or s 2017 Aug 9 OBJECTIVES: SB4 (Benepali, Brenzys) is a biosimilar of reference etanercept (ETN). In a randomised, double-blind, 52-week study, SB4 demonstrated comparable efficacy and safety to ETN in patients with rheumatoid arthritis (RA). The open-label extension period evaluated long-term efficacy, safety and immunogenicity when continuing SB4 versus switching from ETN to SB4. METHODS: In the randomised, double-blind phase, patients received weekly subcutaneous administration of 50 mg SB4 or ETN with background methotrexate for up to 52 weeks. Patients in the Czech Republic and Poland who completed the 52-week visit were enrolled in the open-label extension period and received SB4 for 48 additional weeks. Efficacy, safety and immunogenicity were assessed up to week 100. RESULTS: Of 245 patients entering the extension period, 126 continued to receive SB4 (SB4/SB4) and 119 switched to SB4 (ETN/SB4). American College of Rheumatology (ACR) response rates were sustained and comparable between SB4/SB4 and ETN/SB4 with ACR20 response rates at week 100 of 77.9% and 79.1%, respectively. Other efficacy results, including radiographic progression, were also comparable between the groups. After week 52, rates of treatment-emergent adverse events were 47.6% (SB4/SB4) and 48.7% (ETN/SB4); one patient/group developed non-neutralising antidrug antibodies. No cases of active tuberculosis or injection-site reactions were reported during the extension period. One patient (SB4/SB4) died of hepatic cancer. CONCLUSIONS: SB4 was effective and well tolerated over 2 years in patients with RA. Efficacy, safety and immunogenicity were comparable between the SB4/SB4 and ETN/SB4 groups, showing no risk associated with switching patients from ETN to SB4. TRIAL REGISTRATION NUMBER: NCT01895309; 2012-005026-30.
28768982 Multicentric Reticulohistiocytosis with Dermatomyositis-like Eruptions. 2017 A 68-year-old man presented with polyarthritis, proximal muscle weakness, and erythema of the face, arms, neck, and anterior chest that resembled the V-neck sign. Initially, dermatomyositis (DM) was considered because of the erythema, polyarthritis, and muscle weakness. He also had mediastinal and hilar lymphadenopathy on contrast-enhanced computed tomography. Unexpectedly, a biopsy of the forehead skin revealed numerous multinucleated giant cells. A biopsy of a solitary nodule on the dorsum of his right middle finger revealed similar multinucleated giant cells with ground-glass cytoplasm, leading to the diagnosis of multicentric reticulohistiocytosis (MRH). Although MRH is rare, it should be remembered that MRH can mimic DM.
28955489 Mortality in patients with interstitial lung disease treated with rituximab or TNFi as a f 2017 OBJECTIVES: Guidelines cautioned prescribing of tumour necrosis factor inhibitors (TNFi) to patients with rheumatoid arthritis and interstitial lung disease (RA-ILD) after reports of new or worsening of ILD. Less is known about outcomes among patients with RA-ILD who receive rituximab (RTX). This study compares mortality in patients with RA-ILD who received RTX or TNFi as their first biologic. METHODS: Participants with RA-ILD recruited to the British Society for Rheumatology Biologics Register for RA were included. Death rates were calculated and risk comparisons were made using Cox regression. Causes of death, including the frequency in which ILD was recorded on death certificates were examined. RESULTS: 43 patients on RTX and 309 on TNFi were included. RTX recipients had shorter disease duration and less disability. Death rates were 94.8 (95%CI: 74.4 to 118.7) and 53.0 (22.9 to 104.6) per 1000 person years, respectively. The adjusted mortality risk was halved in the RTX cohort, but the difference was not statistically significant (HR 0.53, 95% CI: 0.26 to 1.10). ILD was the underlying cause of death in 1 of 7 RTX deaths (14%) and 12 of 76 TNFi deaths (16%). CONCLUSIONS: Patients with RA-ILD who received RTX had lower mortality rates compared to TNFi. The absence of information on ILD severity or subtype prevents conclusions of which drug represents the best choice in patients with RA-ILD and active arthritis.
28928392 Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target f 2017 Sep 19 Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-targeting inhibitory small molecule, MALT1 selective inhibitor 2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1H-1,2,4-triazol-1-yl]phenylacetamide (MI-2) strongly suppresses the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine tumour necrosis factor α. Furthermore, MI-2 ameliorates pathologic bone erosion and synovitis in an in vivo mouse model of collagen-induced arthritis. Mechanistically, MI-2 blocked expression of the master osteoclast regulator - nuclear factor of activated T cells 1 (NFATc1) - by inhibiting nuclear factor κB (NF-κB), which is a critical regulator of NFATc1. These findings highlight the important regulatory role of MALT1 in the NF-κB-NFATc1-signalling axis during osteoclastogenesis and suggest that targeting MALT1 is a promising treatment option for rheumatoid arthritis.
28723802 Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult- 2017 Jul RATIONALE: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, fever spikes, arthralgia, and lymphadenopathy. AOSD usually has a good prognosis, but it can sometimes be fatal, especially when it is complicated by systemic inflammatory response syndrome (SIRS) and multiple organ failure. PATIENT CONCERNS: A previously healthy 26-year-old woman was referred to our hospital for persistent high fever and mild systemic edema. Five days later, the patient presented with dyspnea, hypotension, and anuria. Anasarca developed with massive pleural effusion, ascites, and systemic edema, resulting in an increase of 47 kg in body weight. DIAGNOSES: The patient was diagnosed as AOSD after infection, malignancy, hematologic disorders, and other autoimmune diseases were excluded. INTERVENTIONS: We administered tocilizumab, an IL-6 receptor inhibitor, intravenously in addition to cyclosporine, prednisolone, plasma exchange, and continuous hemodiafiltration. OUTCOMES: The patient's systemic condition improved. After stabilization by all medications, the patient was managed and responded to tocilizumab alone. To the best of our knowledge, this was the first case of severe SIRS complicating AOSD that was successfully treated with an anti- IL-6 receptor antibody. LESSONS: SIRS should not be overlooked in a patient with steroid-resistant AOSD and edema. Inhibitors of the IL-6 receptor can be used safely and effectively to control AOSD complicated with severe SIRS.
28549428 Rheumatoid factors do not predict cardiovascular disease and mortality in the general popu 2017 May 26 BACKGROUND: Rheumatoid Factors (RF) are antibodies directed against the Fc portion of IgG and are involved in clearance of immune complexes. While RF can develop in a wide range of conditions, higher RF levels indicate a greater risk for a severe disease course in Rheumatoid Arthritis (RA) patients including cardiovascular complications and premature death. We investigated whether RF also constitute a risk factor for these outcomes in the general population. METHODS: We included 2,323 participants (46% male, mean age 50 years) free of CVD at baseline in 1972. RF positivity was defined as a score of ≥2 by latex agglutination (scale 0-5). All outcomes during 42-year follow-up were obtained from state-wide registries. The predictive value of RF for coronary heart disease, all cardiovascular disease and all-cause mortality was estimated by adjusted hazard ratios (HR) from Cox regression models. RESULTS: After adjustment for standard risk factors, RF positivity was not predictive of future CHD (HR 1.05, p = 0.61), CVD (HR 1,04, p = 0.63) or mortality (HR 1.03, p = 0.70) in the full CVD-free cohort. In an interaction model, RF in 41 out of 355 participants with an RA history was not predictive of CHD (HR 0.92, p = 0.77) or CVD events (HR 1.15, p = 0.51), but there was a borderline significant association with overall mortality (HR 1.41, CI 0.97-2.04, p = 0.07). CONCLUSIONS: RF detected by Latex agglutination do not independently predict future CHD, CVD or death in the general population. However, the presence of RF in the context of a history of RA is associated with a moderate, borderline significant increase in the long term adjusted risk for all-cause mortality.
28499370 Is hydroxychloroquine effective in treating primary Sjogren's syndrome: a systematic revie 2017 May 12 BACKGROUND: To systematically review and assess the efficacy and safety of hydroxychloroquine (HCQ) for treating primary Sjogren's syndrome (pSS). METHODS: Five electronic databases (Pubmed, EMBASE, Web of science, Ovid, Cochrane Library) were searched for randomized controlled trials and retrospective or prospective studies published in English that reported the effect of HCQ on pSS. The subjective symptoms (sicca symptoms, fatigue and pain) and the objective indexes (erythrocyte sedimentation rate and Schirmer test) were assessed as main outcome measures. A meta-analysis and descriptive study on the efficacy and safety of HCQ were conducted. The estimate of the effect of HCQ treatment was expressed as a proportion together with 95% confidence interval, and plotted on a forest plot. RESULTS: Four trials with totals of 215 SS patients, including two randomized controlled trials, one double blind crossover trial and one retrospective open-label study, were analyzed in this review. For dry mouth and dry eyes, the effectiveness of HCQ treatment was essentially the same as placebo treatment. For fatigue, the effectiveness of HCQ was lower than placebo. The efficacy of HCQ in treating pain associated with pSS was superior to that of the placebo. There was no significant difference between HCQ-treated groups and controls in terms of Schirmer test results, but HCQ could reduce the erythrocyte sedimentation rate compare with placebo. A descriptive safety assessment showed that gastrointestinal adverse effects were the most common adverse effects associated with HCQ. CONCLUSIONS: This systematic review showed that there is no significant difference between HCQ and placebo in the treatment of dry mouth and dry eye in pSS. Well-designed, randomized, controlled trials are needed to provide higher-quality evidence to confirm our findings, and future studies should focus on some other index or extraglandular measures, such as cutaneous manifestations, to further explore the therapeutic effect of HCQ in pSS.
27444892 Primary Sjögren's syndrome: clinical phenotypes, outcome and the development of biomarker 2017 Feb Primary Sjögren's syndrome is a complex, autoimmune disease with distinct clinical phenotypes and variable outcomes. The systemic form of the disease is characterized by immune complex-mediated manifestations and is complicated by lymphoma as a result of a polyclonal B cell hyperactivity that is evolving into B cell malignancy. In the past decades, well-established clinical and serological markers have been described in the literature to identify high-risk patients and predict lymphoma development. However, specific biological treatments have proven ineffective to control the disease. Significant research effort has been made to reveal the major underlying biological events in this subgroup and identify biomarkers for early diagnosis, prognosis and response to treatment. In this review, we summarize the current data for the proposed histological, molecular and genetic biomarkers.
29076903 Imaging Characteristics of Chemotherapy Related Adult-Onset Still Disease. 2017 Dec A 60-year-old man with lymphoma completed chemotherapy on October 21, 2016, with complete remission. He then received rituximab maintenance therapy. Since March 2017, he has had progressive fatigue, myalgias, rash, weight loss, diarrhea, and recurrent low-grade fever. Subsequent bone marrow biopsy and FDG PET/CT demonstrated no active lymphoma. An In-white blood cell scan showed abnormal tracer uptake on 20-hour postinjection, but not on 3-hour postinjection images, including innumerable skeleton muscle foci, multiple cutaneous foci, and persistent diffuse increased uptake in the lungs. Diagnosis of adult-onset Still disease was made accordingly. The patient's cytopenia was deemed a chemotherapy-related adverse effect.
28532233 Updates on Sjögren's syndrome: from proteomics to protein biomarkers. 2017 Jun Primary Sjögren's syndrome (pSS) is a complex heterogeneous autoimmune disorder, typically affecting exocrine glands. Recently, a great interest has arisen in searching for novel biomarkers able to improve the diagnostic work-up of the disease as well as the general assessment and the prognostic stratification of pSS patients. From this perspective, salivary proteomics has appeared as a promising tool considering that salivary proteins may closely reflect the underlying disease processes in the salivary glands. Areas covered: Here we will provide an update on the state of the art of proteomics in pSS, focusing in particular on putative novel biomarkers for the disease. There is a special focus on candidate salivary protein and their role in non-invasive diagnosis of pSS. Expert commentary: Proteomics represents an emerging throughput omics-based approach for use in diagnosis of pSS. The studies that have been presented in this review have provided major contributions towards the identification of putative protein biomarkers, that once validated, could be able not only to contribute to a non-invasive diagnosis of pSS but also to the stratification of different disease subsets, ultimately allowing a better comprehension of the disease.
28861079 Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Inter 2017 Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14(+) monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients.