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ID PMID Title PublicationDate abstract
29125905 Arthritis After Cancer Immunotherapy: Symptom Duration and Treatment Response. 2019 Mar OBJECTIVE: Musculoskeletal manifestations of immune-related adverse events (irAEs) after checkpoint inhibitor immunotherapy for cancer remain incompletely characterized and poorly understood. A recently published case series suggested that immunotherapy-induced arthritis is an aggressive process requiring high-dose corticosteroids. METHODS: This was a retrospective chart review of all patients with musculoskeletal irAEs first seen by one of the authors between 2014 and 2016. All patients had been treated for a malignancy with immune checkpoint inhibitors targeting PD-1 (nivolumab, pembrolizumab), PD-L1 (durvalumab), and/or CTLA-4 (ipilimumab, tremelimumab) at Memorial Sloan Kettering Cancer Center. RESULTS: We identified 10 patients with a mean ± SD age of 63.2 ± 9.7 years. Seven were treated with a combination of checkpoint inhibitors and 3 with nivolumab monotherapy. Four patients developed inflammatory polyarthritis, 4 oligoarthritis, and 2 tenosynovitis. Six were antinuclear antibody positive and 2 had anti-cyclic citrullinated peptide antibodies. Mean ± SD time from the first dose of immunotherapy until joint involvement was 6.3 ± 4.3 months. All 10 patients were treated with systemic corticosteroids, but 6 of 10 required ≤20 mg per day of prednisone. Five patients received steroid-sparing agents. Mean ± SD time until resolution of joint symptoms after the last dose of immunotherapy was 9.2 ± 6.1 months. CONCLUSION: Musculoskeletal irAEs can manifest as a rheumatoid arthritis-like polyarthritis, oligoarthritis, tenosynovitis, or polymyalgia rheumatica. Musculoskeletal symptoms can last more than a year, but they can generally be managed with low to moderate doses of corticosteroids.
30946325 Risk of Parkinson disease in Sjögren syndrome administered ineffective immunosuppressant 2019 Apr To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.
31267034 Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a 2019 Jul 2 Cathepsin S (CTSS) is highly increased in Sjögren's syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS's utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14-15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14-15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.
30411528 Clinical features and potential relevant factors of renal involvement in primary Sjögren' 2019 Feb OBJECTIVE: To investigate distinct features of renal involvement in patients with primary Sjögren's syndrome (pSS) and to identify potential factors associated with renal involvement. METHODS: Four hundred and thrity-four pSS patients from the Rheumatology Department of the First Affiliated Hospital of Wenzhou Medical University from 2013 to 2017 were included in a cross-sectional study. Patients with renal involvement were compared with their age- and gender-matched controls (pSS without renal involvement). Demographic, clinical, histological, nephritic, immunological features of renal involvement in pSS were systematically analyzed. Possible factors related to renal involvement were identified using multivariate logistic regression analyses. RESULTS: One hundred and ninety-two pSS patients (88.48%) with renal involvement were women with mean age of nearly 58 years and mean disease duration of above 4 years. Clinical manifestation, serologic and immunological features and renal biopsy class of the pSS patients with renal involvement were presented. By multivariate analyses, xerophthalmia, histological positivity for lower salivary gland biopsy (LSGB), anti-SSA/Ro52-positive, reduced complement 3 (C3) levels, hypoalbuminemia and anemia retained significant association with renal involvement in pSS (all P < 0.05). CONCLUSION: In addition to LSGB pattern, anti-SSA/Ro52-positivity, reduced C3 levels, hypoalbuminemia and anemia, also indicate significant association with renal involvement in pSS. Therefore, early vigilance is required for patients with these clinical manifestations.
30955252 Trajectories of pain predict disabilities affecting daily living in arthritis. 2019 Sep PURPOSE: To examine the interplay between pain and disability in arthritis when adjusting for patient heterogeneity in pain progression. There is consistent evidence to suggest that people experience osteoarthritis heterogeneously, with subgroups of people having different trajectories of pain. However, at present it is unclear how these pain trajectories are related to functional disability. We ask the question: Do levels of disability track changes in pain across different pain trajectories? METHODS: Secondary analysis of a subset (n = 889) from a cohort of older English adults, representative of the general population (the English Longitudinal Study of Ageing). The relationship between pain and functional disability was compared in three domains of disability: mobility, activities of daily living (ADL) and instrumental ADL. These represent increasingly complex forms of self-care required for independent living. Data analysis compared the heterogeneous analysis of pain (different trajectories) and disability compared to treating pain as a simpler homogenous construct. RESULTS: On a population level, pain was significantly positively correlated with increased disability in all three domains, and the relationship remained stable over time. However, when heterogeneity was examined respondents whose pain improved did not show a corresponding improvement in disability in two domains (ADL and mobility). CONCLUSIONS: These findings highlight how, for some people, alleviating pain, the main symptom of arthritis, might not prevent the persistence or progression of disability. Even when pain improves, further interventions that improve disability are likely to be required. Statement of contribution What is already known on this subject? Pain and functional limitation in daily living are common symptoms of arthritis. Arthritis pain is heterogeneous - there are trajectories of people whose pain gets better or worse. However, to date no study has looked at the relationship between trajectories of arthritis pain and functional disability outside of the minority of people with rheumatoid arthritis. What does this study add? Treating pain as heterogeneous explained disability better than treating pain as a single entity. Respondents in a trajectory of worsening pain reported functional disability in two domains (mobility and activities of daily living) also got worse over time. People in a trajectory of decreasing pain over time did not experience a reduction in disability, despite pain being the most common reason for why people limit their daily functioning. This suggests further intervention is required for people with arthritis, even when the most visible symptoms have been alleviated.
31885670 Study on the Multitarget Mechanism and Key Active Ingredients of Herba Siegesbeckiae and V 2019 BACKGROUND: Herba Siegesbeckiae (HS, Xixiancao in Chinese) is widely used to treat inflammatory joint diseases such as rheumatoid arthritis (RA) and arthritis, and its molecular mechanisms and active ingredients have not been completely elucidated. METHODS: In this study, the small molecule ligand library of HS was built based on Traditional Chinese Medicine Systems Pharmacology (TCMSP). The essential oil from HS was extracted through hydrodistillation and analyzed by Gas Chromatography-Mass Spectrometer (GC-MS). The target of RA was screened based on Comparative Toxicogenomics Database (CTD). The key genes were output by the four algorithms' maximum neighborhood component (MNC), degree, maximal clique centrality (MCC), and stress in cytoHubba in Cytoscape, while biological functions and pathways were also analyzed. The key active ingredients and mechanism of HS and essential oil against RA were verified by molecular docking technology (Sybyl 2.1.1) in treating RA. The interaction between 6 active ingredients (degree ≥ 5) and CSF2, IL1β, TNF, and IL6 was researched based on the software Ligplot. RESULTS: There were 31 small molecule constituents of HS and 16 main chemical components of essential oil (relative content >1%) of HS. There were 47 chemical components in HS. Networks showed that 9 core targets (TNF, IL1β, CSF2, IFNG, CTLA4, IL18, CD26, CXCL8, and IL6) of RA were based on Venn diagrams. In addition, molecular docking simulation indicated that CSF2, IL1β, TNF, and IL6 had good binding activity with the corresponding compounds (degree > 10).The 6 compounds (degree ≥ 5) of HS and essential oil had good interaction with 5 or more targets. CONCLUSION: This study validated and predicted the mechanism and key active ingredients of HS and volatile oil in treating RA. Additionally, this study provided a good foundation for further experimental studies.
30006919 Prevalence of overlap of antineutrophil cytoplasmic antibody associated vasculitis with sy 2019 Jan We aimed to estimate the frequency of overlap of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with systemic autoimmune diseases. Retrospective single-center study to identify patients with AAV diagnosis and concomitant autoimmune systemic diseases, simultaneously, before or after the diagnosis of AAV. Sociodemographic characteristics, such as comorbidities; follow-up time; type of AAV; disease duration; relapses; treatment and response; clinical, serological, and histological characteristics; disease activity and damage; prognosis; dialysis requirements, and death were assessed. Twenty-eight of two hundred and forty-seven patients (11.3%) with AAV had a concomitant diagnosis of autoimmune disease. The predominant AAV type was renal-limited vasculitis (39%), followed by granulomatosis with polyangiitis (29%), mycroscopic polyangiitis (25%), and eosinophilic granulomatosis with polyangiitis (7%). Mean age at AAV diagnosis was 50 ± 17 years and 24/28 were ANCA positive. The main clinical manifestations were renal (79%), otorhinolaryngologic (43%), and pulmonary and peripheral neuropathy (32%). Sixteen patients (57%) experienced partial or total remission at a median follow-up of 34 months, and four patients (14%) died. The most frequent autoimmune disease overlapped was rheumatoid arthritis (39%), followed by Sjögren's syndrome and systemic sclerosis (14%), mixed connective tissue disease (11%), systemic lupus erythematosus and juvenile idiopathic arthritis (7%), and ankylosing spondylitis and IgG4-related disease (4%). In nine patients (32%), both diagnoses were simultaneous; in the rest, median time elapsed between the autoimmune disease and AAV diagnosis was 173 months. The prevalence of overlap AAV with other autoimmune diseases was low. The most common AAV phenotype was renal-limited vasculitis, and the most frequent overlap disease was rheumatoid arthritis.
31657698 Polyarthritis and its differential diagnosis. 2019 Oct Polyarthritis is a term used when at least five joints are affected with arthritis. Several different diseases ranging from rheumatoid arthritis to infection diseases can lead to polyarthritis. Anamnesis, physical examination, laboratory findings and imaging methods are important tools to differential diagnosis.
31181879 Diagnostic utility of PET/CT in a patient with miliary tuberculosis. 2019 Jun 11 A 63-year-old male presented with loss of appetite, subfebrile fever, swelling of the right hand and dyspnea on exertion for three months. Past medical history revealed methotrexate treatment of six months for rheumatoid arthritis. Chest radiography and computed tomography (CT) revealed diffuse miliary nodules. PET/CT scan demonstrated diffuse FDG uptake in both lungs, in the spleen, in the right hand, the mediastinal and the axillary lymph nodes. MR of the right hand showed inflammatory arthritis. Histopathology of the right hand tru-cut biopsy revealed degenerative changes. Culture of the hand biopsy tissue was positive for mycobacterium tuberculosis. PET/CT may determine the biopsy and the sampling sites for the early diagnosis of patients with suspected miliary tuberculosis where lesion identification on other modalities may be difficult or unfeasible. High sensitivity for inflammatory diseases makes PET/CT a useful diagnostic utility for enabling early diagnosis in miliary tuberculosis which is a diagnostic predicament.
31657699 Are there any differences among psoriasis, psoriatic arthritis and rheumatoid arthritis in 2019 Oct OBJECTIVE: Although the frequency of metabolic syndrome has been studied separately in psoriasis, psoriatic arthritis (PsA), and rheumatoid arthritis (RA) patients, there is no study that compares the prevalence of metabolic syndrome in all three diseases. The purpose of this study is to evaluate the relationship between metabolic syndrome (MetS) and chronic low-grade inflammatory diseases, and to determine the frequency of MetS and insulin resistance in psoriasis and PsA as compared to RA. METHODS: A total of 155 patients were included in this cross-sectional study. Fifty patients who were diagnosed with psoriasis, 55 PsA patients who were diagnosed according to the CASPAR criteria, and 50 seropositive RA patients who were diagnosed according to the ACR/EULAR 2010 classification criteria were included in this study. MetS was diagnosed by the 2005 criteria of International Diabetes Federation. The cardiovascular risk factors and parameters associated with MetS were evaluated. RESULTS: The patients' mean age was significantly higher in the RA. MetS was determined in 33.5% of all patients and MetS and insulin resistance showed no significant difference among the three groups (psoriasis: 36%, PsA: 29%, RA: 36%; p: 0.684 and psoriasis: 70%, PsA: 64%, RA: 66%, respectively; p: 0.785). Triglyceride levels were higher in psoriasis and PsA as compared to the RA (psoriasis: 34%, PsA: 32.7%, RA: 16%, respectively; p: 0.045). The frequency of hypertension was 38% in the RA, which was higher than PsA and psoriasis (p: 0.011). CONCLUSION: In all three groups, the prevalence of MetS was shown to be higher than the general population. The lack of difference between these groups may be due to the small number of patients, the retrospective study design, and the inequality of the population with respect to age and gender.
31426853 Resveratrol reduces store-operated Ca(2+) entry and enhances the apoptosis of fibroblast-l 2019 Aug 19 BACKGROUND: Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process. RESULTS: In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model. CONCLUSION: These results indicated that resveratrol reduced store-operated Ca(2+) entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1-STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.
31165299 The use of leukocytes' secretome to individually target biological therapy in autoimmune a 2019 Jun 5 BACKGROUND: Biological agents have allowed remarkable improvement in controlling autoimmune arthropathies, although none of the numerous biologics readily available represent a universal treatment standard. Moreover, classical and genetic predictors are currently unsatisfactory to predict individual response to a biologic, and the best treatment selection is still based on a trial-and-error approach. Here, we report a clinical case demonstrating the usefulness of examining the leukocytes' secretome of patients. We set up and standardized a protocol that examines a patient's immune responses to establish the secretome of the blood mononuclear leukocytes and personalize the biotherapy. CASE PRESENTATION: A 24-year-old woman was diagnosed with active early rheumatoid arthritis. The initial treatment regimen (prednisone, methotrexate, hydroxychloroquine, naproxen) was inefficient, as well as the anti-TNF adalimumab. The diagnosis was revised as possible rheumatoid arthritis-like psoriatic arthritis and adalimumab was replaced by abatacept (IgG1 Fc-CTLA-4) to no avail. Five years later, abatacept was replaced by the anti-IL-12/IL-23 ustekinumab with no objective control over the symptoms. The patient was thus enrolled in a prospective study based on the quantification of cytokines secreted by peripheral blood leukocytes stimulated with well-known immune activators of pattern recognition receptors and cytokine signalling. The results of this study revealed that plasma concentrations of cytokines were similar between the patient and healthy donors. In comparison to leukocytes from healthy donors, the patient's secretome showed a unique overproduction of IL-6. The anti-IL-6 receptor tocilizumab was, therefore, administered with a rapid improvement of her active psoriatic arthritis that remained dependent on low prednisone dosage. Clinical parameters progressively returned to normal levels and her quality of life was greatly improved, despite the major delay to begin the present personalized treatment. CONCLUSIONS: An efficient way to effectively treat patients with complex autoimmune arthropathies, and avoid irreversible disability, is to know their leukocytes' secretome to identify abnormally secreted cytokines and personalize their biotherapy, as exemplified by this case report.
31231554 Therapeutic effects of a novel BAFF blocker on arthritis. 2019 B-cell targeted therapy is effective for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA), although there are setbacks in RA clinical trials. In this study, we designed a novel B-cell activating factor (BAFF) antagonist: BAFF-Trap, a recombinant glycoprotein with BAFF-binding domains of two BAFF receptors (TACI and Br3) linked to Fc domain of human IgG1. Unlike TACI-Fc, BAFF-Trap bound BAFF but not APRIL (a proliferation-inducing ligand), and significantly suppressed the development of collagen-induced arthritis and adjuvant-induced arthritis. Furthermore, BAFF-Trap inhibited proinflammatory cytokine expression, ameliorated joint damage and suppressed B- and T-cell activation. BAFF-Trap reduced dendritic cells in joints, and increased regulatory T cell, regulatory B-cell, and M2 macrophage. The function of BAFF-Trap was related to inhibition of canonical and noncanonical NF-κB activation. Thus, BAFF-Trap may be a valuable agent for the effective treatment of RA.
30772483 Do recent research studies validate the medicinal plants used in British Columbia, Canada 2019 May 23 ETHNOPHARMACOLOGICAL RELEVANCE: There are insufficient safe and effective treatments for chronic pain in pets. In cases such as osteoarthritis there is no commercially available cure and veterinarians use NSAIDs to manage pain. Pet owners may have to plan for a lifetime of plant-based treatment for the conditions that lead to chronic pain in pets. Phytopharmacotherapies have the advantage of being less toxic, cheap or free, readily available, are more likely to be safe for long-term use and have the potential to reset the immune system to normal functioning. AIM OF THE STUDY: To examine the recently published medicinal plant research that matches unpublished data on ethnoveterinary medicines (EVM) used for pets in Canada (British Columbia) to see if the EVM data can provide a lead to the development of necessary drugs. MATERIALS AND METHODS: In 2003 semi-structured interviews were conducted with 60 participants who were organic farmers or holisitic medicinal/veterinary practitioners obtained using a purposive sample. A draft manual prepared from the data was then evaluated by participants at a participatory workshop that discussed the plant-based treatments. A copy of the final version of the manual was given to all research participants. In 2018, the recently published research matching the EVM data was reviewed to see if the EVM practices could serve as a lead for further research. RESULTS AND CONCLUSION: Medicinal plants are used to treat a range of conditions. The injuries treated in pets in British Columbia included abscesses (resulting from an initial injury), sprains and abrasions. Dogs were also treated with medicinal plants for rheumatoid arthritis, joint pain and articular cartilage injuries. More than 40 plants were used. Anal gland problems were treated with Allium sativum L., Aloe vera L., Calendula officinalis L., Plantago major L., Ulmus fulva Michx., Urtica dioica L. and Usnea longissima Ach. Arctium lappa, Hydrangea arborescens and Lactuca muralis were used for rheumatoid arthritis and joint pain in pets. Asthma was treated with: Linum usitatissimum L., Borago officinalis L., Verbascum thapsus L., Cucurbita pepo L., Lobelia inflata L., and Zingiber officinale Roscoe. Pets with heart problems were treated with Crataegus oxyacantha L., Cedronella canariensis (L.) Willd. ex Webb & Berth, Equisetum palustre L., Cypripedium calceolus L., Pinus ponderosa Douglas ex Lawson, Humulus lupulus L., Valeriana officinalis L., Lobelia inflata L., Stachys officinalis (L.) Trev., and Viscum album L. The following plants were used for epilepsy, motion sickness and anxiety- Avena sativa L., Valeriana officinalis, Lactuca muralis (L.) Fresen., Scutellaria lateriflora L., Satureja hortensis L., and Passiflora incarnata L. Plants used for cancer treatment included Phytolacca decandra, Ganoderma lucidum, Lentinula edodes, Rumex acetosella, Arctium lappa, Ulmus fulva, Rheum palmatum, Frangula purshiana, Zingiber officinale, Glycyrrhiza glabra, Ulmus fulva, Althea officinalis, Rheum palmatum, Rumex crispus and Plantago psyllium. Trifolium pratense was used for tumours in the prostate gland. Also used were Artemisia annua, Taraxacum officinale and Rumex crispus. This review of plants used in EVM was possible because phytotherapy research of the plants described in this paper has continued because few new pharmaceutical drugs have been developed for chronic pain and because treatments like glucocorticoid therapy do not heal. Phytotherapuetic products are also being investigated to address the overuse of antibiotics. There have also been recent studies conducted on plant-based functional foods and health supplements for pets, however there are still gaps in the knowledge base for the plants Stillingia sylvatica, Verbascum thapsus, Yucca schidigera and Iris versicolor and these need further investigation.
30506262 Intravenous anesthetic ketamine attenuates complete Freund's adjuvant-induced arthritis in 2019 Feb BACKGROUND: The current study was intended to investigate the effect of ketamine (KET) on complete Freund's adjuvant (CFA)-induced arthritis in rats. METHODS: The CFA was administered in the hind paw of the rats for the induction of adjuvant-induced arthritis. The paw swelling of experimental animals was measured as hind paw volume. Hematoxylin and eosin staining was estimated and pathological changes in the joint tissues were observed under a light microscope. Furthermore, the bicinchoninic acid assay was used for protein quantification. The antibody-reactive bands were visualized using enhanced chemiluminescence. RESULTS: The present study showed that KET significantly reduces the severity of arthritis in CFA mice. The therapeutic effects were linked with reduced joint swelling and destruction, as evidenced by analyzing rat paws. The KET also revealed to attenuate the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). In western blot analysis, KET inhibit phosphorylation of MAPKs, IκBα and nuclear translocation NF-κB in the inflammatory joints of AIA rats. Moreover, KET showed to induce apoptosis via mitochondrial signalling pathways (Bcl2, Bax, cytochrome C, cleaved caspase-3 and cleaved caapse-9). CONCLUSION: Taken together, KET show significant anti-rheumatoid arthritis activity via multiple mechanisms and may thus have therapeutic benefits for RA.
30940693 Exposure-Effect Relationships in Established Rat Adjuvant-Induced and Collagen-Induced Art 2019 Jun The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis. A range of doses of indomethacin (a nonsteroidal anti-inflammatory drug), and three disease-modifying antirheumatic drugs (DMARDs), methotrexate, etanercept, and tofacitinib, were evaluated in AIA and CIA rats. Dexamethasone was included in this study as a positive control. The area under the ankle diameter-time profile (AUC(ankle)) and ankle histopathology summed scores (AHSS) were used as efficacy endpoints for activity against disease symptoms (joint inflammation) and disease progression (joint damage), respectively. Translational PK-PD analysis was performed to rank order preclinical efficacy endpoints at clinically relevant concentrations. For each drug tested, inhibition of AUC(ankle) and AHSS scores was generally comparable in both magnitude and rank order. Overall, based on both AUC(ankle) and the AHSS inhibition, the rank ordering of preclinical activity for the DMARDs evaluated was tofacitinib > etanercept ≥ methotrexate. This ranking of preclinical efficacy was consistent with reported clinical efficacy. Of interest, indomethacin showed equal or often better efficacy than the three DMARDs evaluated on inhibiting AHSS despite having limited ability to prevent joint damage clinically in patients. The translational value of performing PK-PD analysis of arthritis models in rats is discussed.
31842626 PTEN negatively regulates the expression of pro-inflammatory cytokines and chemokines of f 2019 Dec Rheumatoid arthritis (RA) is characterized by tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. The latest studies proved phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the surviving, proliferation and pro-inflammatory cytokines in RA. The purpose of this study was to explore the function and underlying mechanisms of PTEN in RA pro-inflammatory cytokines and chemokines of fibroblast-like synoviocytes (FLSs). Increased level of PTEN was observed in adjuvant-induced arthritis (AIA) FLSs in comparison to normal rats. Increased concentrations of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), chemokines (CCL-2 and CCL-3), VCAM-1 and VEGF-α expression were observed in FLSs with PTEN inhibitor bpv or PTEN-RNAi. Moreover, co-incubation FLSs with overexpression vector with PTEN-GV141 reduced the expression of pro-inflammatory cytokines, chemokines, VCAM-1 and VEGF-α in AIA. Interestingly, we also found DNA methylation could regulate PTEN expression and activation of AKT signaling was with a change of PTEN. Altogether, our findings in the present study suggested that PTEN might play a pivotal role during pro-inflammatory cytokines and chemokines of FLSs through activation of AKT signaling pathway. In addition, PTEN expression may be regulated by DNA methylation in the pathogenesis of AIA.
30782174 Similar alteration for mental and physical aspects in health-related quality of life over 2019 Feb 19 INTRODUCTION: Health-related quality of life (HRQoL) is a priority for patients. The objectives were to describe the changes in HRQoL over 5-8 years in patients with early arthritis (EA) or early inflammatory back pain (IBP) and to explore factors associated to HRQoL. PATIENTS AND METHODS: In 2 prospective observational French cohorts (ESPOIR for EA patients and DESIR for early IBP patients), HRQoL was assessed regularly over 5-8 years, using the SF36 physical and mental composite scores (PCS and MCS, range 0-100). Disease activity was assessed by DAS28-ESR and ASDAS-CRP. Univariate and multivariate linear mixed-effect models and trajectory-based mapping were applied. RESULTS: In all, 1347 patients (701 EA and 646 early IBP) were analysed: mean age 48.4 ± 12.2 and 33.9 ± 8.7 years respectively; mean disease duration 3.4 ± 1.7 and 18.2 ± 10.8 months; and 76.3% and 55.0% females. At baseline, in EA, mean PCS and MCS were respectively 40.2 ± 9.1 and 40.4 ± 11.2 and, in early IBP, were respectively 38.5 ± 8.5 and 39.8 ± 10.9. Over follow-up, HRQoL mean levels improved mostly over the first 6 months (p <  0.001). Two trajectories were evidenced in both diseases. The 'good HRQoL' trajectory groups, i.e. 54-61% of patients, reached levels of HRQoL close to population norms. DAS28-ESR and ASDAS-CRP over time were related to PCS (range of explained variance 9-43%, p <  0.001 in the mixed models) but not to MCS. CONCLUSION: HRQoL was altered similarly for both physical and mental aspects in EA and early IBP. Disease activity only partly explained HRQoL: the drivers of HRQoL should be further explored.
31093599 TNF Inhibitor-Induced Psoriasis: Proposed Algorithm for Treatment and Management. 2019 Apr Tumor necrosis factor a (TNF-α)-targeted therapies have expanded the therapeutic options for patients with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis (PsA) and have significantly improved patients' quality of life. Paradoxically, anti-TNF-α agents may induce psoriatic eruptions or worsen preexisting psoriatic skin disease. Currently, there is no standard approach for the management of TNF inhibitor-induced psoriasis. Here, we conduct a literature review on TNF inhibitor-induced psoriasis and introduce a novel treatment algorithm for maintaining otherwise effective anti-TNF therapy versus switching to a different class as appropriate in the management of patients with IBD, RA, psoriasis, or PsA.
31648078 The role of sphingosine 1-phosphate metabolism in bone and joint pathologies and ectopic c 2020 Jan Sphingolipids display important functions in various pathologies such as cancer, obesity, diabetes, cardiovascular or neurodegenerative diseases. Sphingosine, sphingosine 1-phosphate (S1P), and ceramide are the central molecules of sphingolipid metabolism. Sphingosine kinases 1 and 2 (SK1 and SK2) catalyze the conversion of the sphingolipid metabolite sphingosine into S1P. The balance between the levels of S1P and its metabolic precursors ceramide and sphingosine has been considered as a switch that could determine whether a cell proliferates or dies. This balance, also called « sphingolipid rheostat », is mainly under the control of SKs. Several studies have recently pointed out the contribution of SK/S1P metabolic pathway in skeletal development, mineralization and bone homeostasis. Indeed, SK/S1P metabolism participates in different diseases including rheumatoid arthritis, spondyloarthritis, osteoarthritis, osteoporosis, cancer-derived bone metastasis or calcification disorders as vascular calcification. In this review, we will summarize the most important data regarding the implication of SK/S1P axis in bone and joint diseases and ectopic calcification, and discuss the therapeutic potential of targeting SK/S1P metabolism for the treatment of these pathologies.