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ID PMID Title PublicationDate abstract
29717662 The Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic Autoimmunity. 2018 Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described. Interestingly, increased BTK protein expression in patients with systemic autoimmune disease appears to be correlated with autoantibody production. In addition, BTK may promote autoimmunity as an important driver of an imbalance in B-T cell interaction. Because of this overwhelming evidence of a pathogenic role of BTK in autoimmunity, several clinical trials in rheumatoid arthritis and systemic lupus erythematosus patients with BTK inhibitors are currently running. Here, we review BTK function in different signaling pathways and in different cell lineages, focusing on the growing body of literature indicating a critical role for BTK in autoimmunity. We also discuss BTK and the promising results of BTK inhibition in animal models of autoimmune disease.
29659378 Osteoimmunology: Effects of Standard Orthopaedic Interventions on Inflammatory Response an 2018 May 15 Achieving fracture union is highly dependent on the initial inflammatory phase of fracture healing, which is influenced by both the local and systemic inflammatory environments. The rapidly emerging field of osteoimmunology involves the study of the interactions between the immune system and the skeletal system. Recent research has advanced the current state of knowledge regarding the effects of the surrounding soft-tissue injury, fracture hematoma, and the method of fracture fixation on the inflammatory phase of fracture healing. Acute systemic inflammation, as seen in patients with polytrauma, and chronic systemic inflammation, as seen in patients with diabetes or rheumatoid arthritis, affects the inflammatory phase of fracture healing. The use of NSAIDs can influence early fracture healing. Understanding the effects of standard orthopaedic interventions on the local and systemic inflammatory responses and early fracture healing is important for optimizing fracture union.
29607269 Mycophenolate Mofetil in a Lupus Patient with Pulmonary Hypertension. 2018 Jan 29 Pulmonary hypertension (PH) is a life-threatening complication of several, different connective tissue diseases, including systemic lupus erythematous (SLE), systemic sclerosis, and rheumatoid arthritis. PH can present early in SLE. The severity does not correlate with other organ disease activity or with disease duration. It is still debatable whether immunosuppressive therapy is useful for PH related to SLE or autoimmune connective tissue disease, as there are no large clinical trials. However, several case reports have shown improvement with cyclophosphamide and prednisone with or without vasodilator therapy. We present a case of SLE-related PH in which a dramatic improvement in mean pulmonary artery pressure and exercise capacity was noted after the institution of treatment with mycophenolate mofetil, resulting in a decrease in corticosteroid dose. Our observations support the potential value of mycophenolate mofetil therapy for PH in SLE.
29256764 Normalizing fibromyalgia as a chronic illness. 2018 Jan Fibromyalgia (FM) is a complex chronic disease that affects 3-10% of the general adult population and is principally characterized by widespread pain, and is often associated with disrupted sleep, fatigue, and comorbidities, among other symptoms. There are many gaps in our knowledge of FM, such that, compared with other chronic illnesses including diabetes, rheumatoid arthritis, and asthma, it is far behind in terms of provider understanding and therapeutic approaches. The experience that healthcare professionals (HCPs) historically gained in developing approaches to manage and treat patients with these chronic illnesses may help show how they can address similar problems in patients with FM. In this review, we examine some of the issues around the management and treatment of FM, and discuss how HCPs can implement appropriate strategies for the benefit of patients with FM. These issues include understanding that FM is a legitimate condition, the benefits of prompt diagnosis, use of non-drug and pharmacotherapies, patient and HCP education, watchful waiting, and assessing patients by FM domain so as not to focus exclusively on one symptom to the detriment of others. Developing successful approaches is of particular importance for HCPs in the primary care setting who are in the ideal position to provide long-term care for patients with FM. In this way, FM may be normalized as a chronic illness to the benefit of both patients and HCPs.
29211697 Cocaine/levamisole-associated autoimmune syndrome: a disease of neutrophil-mediated autoim 2018 Jan PURPOSE OF REVIEW: Levamisole was previously used for its immunomodulatory properties to treat rheumatoid arthritis and some cancers. However, because of serious side-effects, it was taken off the market in the United States. Recently, levamisole has reemerged as a popular cocaine adulterant. Some individuals who consume levamisole-adulterated cocaine can develop a life-threatening autoimmune syndrome. In this review, the medical consequences of levamisole exposure and postulated mechanisms by which levamisole induces these adverse effects are discussed. RECENT FINDINGS: Although agranulocytosis and cutaneous vasculitis are the major findings in patients who develop cocaine/levamisole-associated autoimmune syndrome (CLAAS), more recent experience indicates that other organ systems can be involved as well. Current studies point to neutrophil activation and neutrophil extracellular trap formation with subsequent antineutrophil cytoplasmic antibody-mediated tissue injury as a possible mechanism of CLAAS. SUMMARY: In the past decade, the detrimental effects of levamisole have reemerged because of its popularity as a cocaine adulterant. Although infrequent, some individuals develop a systemic autoimmune syndrome characterized by immune-mediated agranulocytosis and antineutrophil cytoplasmic antibody-mediated vasculitis. Mechanistically, neutrophil antigens appear to be a major player in inducing CLAAS. Prompt cessation of levamisole exposure is key to treatment, although relapses are frequent because of the addictive effects of cocaine and the high prevalence of levamisole within the cocaine supply.
29198867 Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inh 2018 Jan 15 BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
30071940 A case of exogenous ochronosis associated with hydroxychloroquine. 2018 Sep Exogenous ochronosis is characterized by hyperpigmented skin lesions that arise in association with local suppression of homogentisic acid oxidase enzyme. Although it generally develops in association with topical application of chemical agents, it can occasionally develop in association with antimalarial drugs. Here we present the case of a patient with rheumatoid arthritis who developed hyperpigmentation on the face and neck regions during hydroxychloroquine treatment. Hydroxychloroquine is being widely used in rheumatology practice, and cutaneous hyperpigmentation may develop as an adverse effect. In the present case, we emphasize the potential underlying mechanisms through which it may cause cutaneous hyperpigmentation and determine the clinical and histopathological findings of exogenous ochronosis.
30006857 [What rheumatologists can learn from pneumologists]. 2018 Aug BACKGROUND: Pulmonary involvement in patients with underlying autoimmune diseases poses a major diagnostic and therapeutic challenge to the treating physician. Due to the associated increased mortality risk, early diagnosis is crucial. OBJECTIVE: The incidence and mortality rate of connective tissue disease-related interstitial lung diseases (CTD-ILD) and pulmonary hypertension (PH) were evaluated in patients with rheumatic disease including clinical aspects, diagnostic procedure, prognosis and treatment recommendations. MATERIAL AND METHODS: An analysis of remarkable publications was carried out and guidelines are presented. RESULTS: The CTD-ILD and PH are frequent comorbidities with significantly increased mortality risk, especially in patients with systemic sclerosis (SSc). In primary fibrotic and non-inflammatory CTD-ILD, as occurs especially in patients with rheumatoid arthritis, immunosuppressive therapy is only partially effective. Currently, in some eligible patients only lung transplantation remains as a definitive therapy. CONCLUSION: The diagnostics and treatment of CTD-ILD and PH in patients with an underlying autoimmune disease requires an interdisciplinary approach. The effectiveness of antifibrotic treatment needs to be evaluated in the future.
29867550 Role of Toll-Like Receptor 4 on Osteoblast Metabolism and Function. 2018 Inflammation is a process whose main function is to fight against invading pathogens or foreign agents. Nonetheless, it is widely accepted that inflammation takes part in multiple processes in a physiological or pathophysiological context. Among these processes the inflammation has been closely related to bone metabolism. It is well-known that in systemic inflammatory diseases such as rheumatoid arthritis the inflammatory environment contributes to the reduction of the bone mineral density. This has been further evidenced in different animals models of osteoporosis where the deletion of key inflammatory molecules dramatically reduced the bone loss. On the contrary, it is also well-known that certain degree of inflammation is required to allow bone fractures healing. In fact, excessive use of anti-inflammatory drugs inhibits bone fracture consolidation. The innate immune responses (IIRs) contribute to the development and maintenance of the inflammation. These responses have been observed in cells of the musculoskeletal system. Chondrocytes and osteoblasts are equipped with the molecular repertoire necessary to setting up these IIR, including the expression of several toll-like receptors. Specifically, toll-like receptor 4 (TLR4) activation in mesenchymal stem cells, osteoblasts, and osteocytes has been involved in catabolic and anabolic process. Accordingly, in this review we have summarized the current knowledge about the physiology of TLR4, including its signaling, and its endogenous agonists. In addition we have focused on its role on osteoblast metabolism and function.
29772037 Janus Kinase Inhibitors: A Review of Their Emerging Applications in Dermatology. 2018 May The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.
29713102 Major Depressive Disorder Following Dermatomyositis: A Case Linking Depression with Inflam 2018 Mar 13 Major depressive disorder (MDD) is one of the most common psychiatric disorders. Recent studies have shown a strong association between MDD and peripheral inflammation, shown by a higher incidence of depression in patients with inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus. Dermatomyositis (DM), an idiopathic inflammatory connective tissue disease that is associated with inflammation, predominantly affects the skin and skeletal muscle. The association between DM and MDD in the context of inflammation has seldom been reported. Here we report a 30- year- old Caucasian female with symptoms of depression dating back to 2 years. These symptoms started after cutaneous manifestations of DM. In the past two years, her DM symptoms have worsened that paralleled an increase of depressive symptoms. Also, during the course of the patient's DM, we tracked elevated inflammatory markers including creatine kinase and aldolase, whereas C-reactive protein, C3, and C4 were in a high normal range which correlated with worsening of depression. Hence, a temporal relationship between the onset of MDD and DM symptoms suggests that inflammation may be a common mechanism linking these two conditions.
29329296 Identification and in silico analysis of functional SNPs of human TAGAP protein: A compreh 2018 Genetic polymorphisms in TAGAP gene have been associated with many diseases including rheumatoid arthritis, multiple sclerosis and other autoimmune disorders. Identifying functional SNPs in such disease associated genes is an uphill task hence before planning larger population study, it is better to scrutinize putative functional SNPs. In this study we used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of TAGAP protein that might be causing these diseases. Computational analysis was performed by five different in silico tools including SIFT, PROVEAN, PolyPhen-2, PhD-SNP and SNPs&GO. The study concludes that mutations of Glycine → Glutamic Acid at position 120, Glycine → Tryptophan at position 141 and Valine → Methionine at position 151 are major mutations in native TAGAP protein which might contribute to its malfunction and ultimately causing disease. The study also proposed 3D structures of native TAGAP protein and its three mutants. Future studies should consider these nsSNPs as main target mutations in various diseases involving TAGAP malfunction. This is the first comprehensive study, where TAGAP gene variants were analyzed using in silico tools hence will be of great help while considering large scale studies and also in developing precision medicines for cure of diseases related to these polymorphisms. Furthermore, animal models of various autoimmune diseases and having these mutations might be of help in exploring their precise roles.
29028650 Fast digestive proteins and sarcopenia of aging. 2018 Jan PURPOSE OF REVIEW: The speed of dietary protein digestion influences postprandial amino acid availability which is crucial for improving altered anabolic response of skeletal muscle one feature of sarcopenia during aging. RECENT FINDINGS: By analogy with carbohydrate and in reference to their absorption rate, dietary proteins can be classified as 'fast' or 'slow' proteins depending on matrix food structure and technological processes, which can influence amino acids availability and their subsequent metabolic actions. 'Fast' digestive proteins have been shown to stimulate muscle protein synthesis and to improve muscle function in several recent studies involving older patients. These new aspects may be applied for improving health through preservation or restoration of muscle protein mass and function in clinical situations (obesity, rheumatoid arthritis and cancer cachexia). SUMMARY: Using fast digestive proteins is of major interest to overcome 'anabolic resistance' of aging for limiting sarcopenia. Fast proteins' action on muscle anabolism may be stimulated by other nutrients like vitamin D or omega 3 fatty acids or by combination with exercise. The beneficial impact of the 'fast' protein concept beyond the amount of dietary protein on muscle preservation is a promising therapeutic perspective to improve mobility and quality of life of older patients affected with chronic disease.
30148930 [Necrotizing fasciitis caused by a Garengeot's hernia. Case report]. 2018 May Garengeot's hernia corresponds to the presence of the appendix within a femoral hernia, associated or not with acute appendicitis. The diagnosis of this uncommon situation is usually done during surgery. Furthermore, the clinical presentation as necrotizing fasciitis is a rare condition. We report a 54 years old obese hypertensive woman with rheumatoid arthritis of 40 years of evolution treated with methotrexate and prednisone. She consulted for pain and erythema in the right inguinal region. Laboratory revealed leukocytosis and an elevated C-reactive Protein. Suspecting a cellulitis, the patient was admitted for antimicrobial therapy. A pelvic magnetic resonance imaging showed a perforated acute appendicitis in an inguinal hernia with extensive pelvic cellulitis associated with signs of fasciitis. At surgery, an extensive groin and pubic fasciitis was evident, with a necrotic and perforated appendix within a femoral hernia. Surgical debridement, open appendectomy, and femoral hernioplasty without mesh were carried out. Vacuum-assisted closure was installed in the coverage defect. Three surgical debridement procedures were required for the closure of the wound. Two weeks after the first surgical procedure, the patient was discharged in good condition. During the follow-up, she evolved with a surgical wound dehiscence, which was managed with wound dressings until closure.
30127786 Lymphocyte Autophagy in Homeostasis, Activation, and Inflammatory Diseases. 2018 Autophagy is a catabolic mechanism, allowing the degradation of cytoplasmic content via lysosomal activity. Several forms of autophagy are described in mammals. Macroautophagy leads to integration of cytoplasmic portions into vesicles named autophagosomes that ultimately fuse with lysosomes. Chaperone-mediated autophagy is in contrast the direct translocation of protein in lysosomes. Macroautophagy is central to lymphocyte homeostasis. Although its role is controversial in lymphocyte development and in naive cell survival, it seems particularly involved in the maintenance of certain lymphocyte subtypes. Its importance in memory B and T cells biology has recently emerged. Moreover, some effector cells like plasma cells rely on autophagy for survival. Autophagy is central to glucose and lipid metabolism, and to the maintenance of organelles like mitochondria and endoplasmic reticulum. In addition macroautophagy, or individual components of its machinery, are also actors in antigen presentation by B cells, a crucial step to receive help from T cells, this crosstalk favoring their final differentiation into memory or plasma cells. Autophagy is deregulated in several autoimmune or autoinflammatory diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and Crohn's disease. Some treatments used in these pathologies impact autophagic activity, even if the causal link between autophagy regulation and the efficiency of the treatments has not yet been clearly established. In this review, we will first discuss the mechanisms linking autophagy to lymphocyte subtype survival and the signaling pathways involved. Finally, potential impacts of autophagy modulation in lymphocytes on the course of these diseases will be approached.
29594122 Comorbidities in Spondyloarthritis. 2018 Comorbidities in spondyloarthritis (SpA) add to the burden of disease by contributing to disease activity, functional and work disability, and mortality. Thus, awareness of comorbidities in SpA is crucial to improve their screening and management and to ultimately improve outcomes in those affected. Osteoporosis has been reported to be the most prevalent comorbidity in SpA, and its risk is increased in these patients, compared with the general population; the risk of vertebral fractures requires further evaluation. Cardiovascular risk is also increased in this population, both due to an increase of the traditional cardiovascular risk factors in these patients, but also due to the presence of inflammation. The role of non-steroidal anti-inflammatory drugs in this increased risk needs further elucidation, but there is consensus on the need to encourage smoking cessation and to perform periodic evaluation of cardiovascular risk in these patients, particularly in the case of change in treatment course. Concerning the risk of cancer, no increased risk inherent to SpA seems to exist. However, an increased neoplastic risk can occur due to SpA treatments, e.g., P-UVA. Data are sparse on the risk of infections compared with rheumatoid arthritis, but there appears to be no risk in the absence of TNF-inhibitor exposure. Regardless of which comorbidity, a gap exists between recommendations for their management and actual implementation in clinical practice, suggesting that there is still a need for improvement in this area. Systematic screening for these comorbidities should improve both short- and long-term outcomes in SpA patients.
30187141 Correction to: Sleep and physical activity: a cross-sectional objective profile of people 2018 Nov The original article can be found online.
30030862 Application of an electrochemiluminescence assay for quantification of E6011, an antifract 2019 Jan BACKGROUND: E6011, a humanized antifractalkine monoclonal antibody, is under development for the treatment of various inflammatory diseases, such as rheumatoid arthritis. A reproducible assay method has been developed for the determination of E6011 in monkey and human serum by electrochemiluminescence (ECL) assay. METHODS: E6011 in serum was captured by fractalkine and detected by ruthenium-labeled rabbit anti-E6011 Fab polyclonal antibodies for ECL detection. E6011 in serum was quantifiable from 0.02 and 0.1 μg/mL in monkey and human serum, respectively, with minimum required dilution of 500. The method was then validated in accordance with bioanalytical guidelines. RESULTS: Accuracy and precision of quality control samples at five concentrations in intra- and interbatch reproducibility demonstrated that relative error and relative standard deviation were within acceptable criteria. Recovery of E6011 was 92.9%-121.7% and 85.0%-109.3% in humans and monkeys. Dilution integrity, no prozone effects, and no impacts by antigen were also ensured. Parallelism was also confirmed using incurred clinical sample analysis. Various types of stability were assessed, which confirmed that E6011 in serum was stable for 367 and 735 days in monkey and human sera, respectively, under frozen conditions. CONCLUSION: The developed method was successfully applied supporting pharmacokinetic studies in monkeys and humans.
30568837 A case of a drug reaction to sulfasalazine in a patient infected with HIV. 2018 INTRODUCTION: The diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) in human immunodeficiency virus (HIV) patients on multiple drugs with concomitant disorders presents a diagnostic challenge. PATIENT PRESENTATION: We describe a case of a drug reaction to sulfasalazine in a 46 year old HIV-infected female with concurrent rheumatoid arthritis which presented atypically with a marked peripheral blood plasmacytosis mimicking a lymphoproliferative neoplasm. MANAGEMENT AND OUTCOME: A diagnosis of DRESS was made in conjunction with the laboratory and clinical presenting findings. Sulfasalazine was immediately discontinued. The mucocutaneous rash and systemic symptoms (which included fever, lymphadenopathy and multi-organ dysfunction) resolved with supportive treatment. This included topical and systemic corticosteroids. CONCLUSION: In conclusion, it is important to consider drug reactions when evaluating patients infected with HIV.
30429437 Expression of the Forkhead box transcription factor Foxo3a in human periapical granulomas. 2018 Dec 27 It has been reported that Forkhead box transcription factor class O3a (Foxo3a) is expressed in rheumatoid arthritis, a chronic inflammatory condition accompanied by bone resorption, and plays a role in its pathology. However, it has remained unclear whether Foxo3a is involved in the pathogenesis of periapical granulomas. The present study was performed to compare the expression of Foxo3a in periapical granulomas and healthy gingival tissues. Samples were obtained surgically from patients, and subjected to hematoxylin-eosin staining for histopathologic diagnosis. Two-color immunofluorescence staining was also performed using antibodies against Foxo3a and markers for three types of inflammatory cells: neutrophils, T lymphocytes, and B lymphocytes. This revealed that Foxo3a was expressed in all three cell types in periapical granulomas but not in healthy gingival tissues. Foxo3a was expressed in 82.1%, 78.3%, and 77.5% of neutrophils, T lymphocytes, and B lymphocytes, respectively, and statistical analysis using the Kruskal-Wallis test followed by the Steel-Dwass test showed no significant difference of Foxo3a expression among the three cell types. Our results suggest that Foxo3a transcription factors may be involved in the pathogenesis of periapical granulomas.