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ID PMID Title PublicationDate abstract
27841833 Impaired Pain Modulation in Fibromyalgia Patients in Response to Social Distress Manipulat 2017 Jul OBJECTIVES: Fibromyalgia (FM), a chronic pain condition, is associated with abnormalities in pain modulation. A growing body of evidence has shown that social distress modulates pain sensitivity. The current study aimed to assess the effects of social distress manipulation on pain in FM patients compared with positive (rheumatoid arthritis, RA) and negative (pain-free) controls. MATERIALS AND METHODS: FM, RA patients and pain-free controls (PFC) were recruited. Demographic, medical, and psychological data were collected. Each participant was exposed to 3 study conditions in a random order: the inclusion (positive social effects) and exclusion (negative social effects) conditions of Cyberball, a game that manipulates social distress, and a control condition. Pain sensitivity in response to nociceptive electrical and thermal (cold) stimuli was assessed before and during each study condition. RESULTS: In response to electrical stimuli, pain decreased in both the inclusion and exclusion conditions in PFC and RA groups, whereas inclusion conditions significantly increased pain in the FM group. Social manipulation (inclusion or exclusion) did not affect pain sensitivity as measured in response to thermal stimulation. DISCUSSION: These results are in line with previous studies demonstrating altered pain inhibition in FM patients, and suggest that unlike PFC or other non-"stress-related" chronic pain conditions, being socially included may increase pain perception in FM patients. Possible underlying mechanisms and clinical relevance are discussed.
28722815 Influence of Morphine and Naloxone on Pain Modulation in Rheumatoid Arthritis, Chronic Fat 2018 Apr BACKGROUND: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown. METHODS: A randomized, double-blind, placebo-controlled cross-over trial was carried out. Ten chronic fatigue syndrome (CFS)/fibromyalgia (FM) patients, 11 rheumatoid arthritis (RA) patients and 20 controls were randomly allocated to the experimental (10 mg morphine or 0.2 mg/mL Naloxone) and placebo (2 mL Aqua) group. Pressure pain thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned pain modulation (CPM) efficacy and deep tissue pain pressure were assessed by adding ischemic occlusion at the opposite upper arm. RESULTS: Deep tissue pain pressure was lower and temporal summation higher in CFS/FM (P = 0.002 respectively P = 0.010) and RA patients (P = 0.011 respectively P = 0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (P time = 0.034). Accordingly, PPTs increased after placebo (P time = 0.015), and no effects on the other pain parameters were objectified. There were no significant effects of naloxone nor nocebo on PPT, deep tissue pain, temporal summation or CPM in the control group. CONCLUSIONS: This study revealed anti-hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA.
28776300 Median time to low disease activity is shorter in tocilizumab combination therapy with csD 2017 Oct To analyse efficacy and safety of tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and/or tumour necrosis factor (TNF) inhibitors of the Swiss and Austrian patients from the ACT-SURE study. This is a sub-analysis of RA patients from Switzerland and Austria, who participated in the international phase 3b, open-label, ACT-SURE study. Patients with an inadequate response to csDMARDs or TNF antagonists receiving 8 mg/kg of IV tocilizumab every 4 weeks during a 24-week time period were included into the study. Therapy with one or more csDMARDs could be continued as combination therapy with tocilizumab (Combo) or stopped, resulting in tocilizumab monotherapy (Mono), at the treating physician's discretion. These two patient groups were analysed in separate and compared. Overall, 107 (22 on Mono vs. 85 on Combo) patients were treated with tocilizumab. The percentage of patients with at least one adverse event was significantly lower in the tocilizumab combination (58.8%) as compared to the monotherapy group (81.8%, p = 0.0458). No differences in ACR20/50/70/90 response rates were observed between both treatment groups at week 24 (Mono 63.6, 40.9, 22.7, and 18.2% vs. Combo 61.2, 43.5, 25.9, and 10.6%). The median time to low disease activity (LDA) was significantly shorter in patients treated with tocilizumab combination therapy (Mono 9.1, Combo 7.9 weeks, log rank p = 0.038). In this post hoc regional sub-analysis of the ACT-SURE study, no differences for disease activity were found comparing the two patient groups at week 24. However, median time to LDA was statistically shorter in patients treated with tocilizumab combination therapy as compared to tocilizumab monotherapy. Consequently, adding tocilizumab to csDMARD therapy rather than changing to tocilizumab monotherapy may be, in our opinion, the safest strategy to reach maximum effect in RA patients with active disease despite treatment with csDMARD. csDMARDs can be withdrawn either immediately due to adverse events or after at least low disease activity has been reached.
28749487 Autoimmune conditions and comorbid depression in pregnancy: examining the risk of preterm 2017 Oct OBJECTIVE: The objective of this study was to determine whether prenatal depression interacts with autoimmune conditions to further increase the risk of preterm birth or preeclampsia. STUDY DESIGN: Our sample included 3034 pregnant women with rheumatoid arthritis (RA), Crohn's disease (CD) or psoriasis, or controls that were prospectively enrolled into MothertoBaby pregnancy studies. We estimated the independent and joint effects of the three autoimmune conditions and depression on the select outcomes. RESULTS: We found an increased risk of preterm birth among women with RA (2.10; 95% confidence interval (CI) 1.54, 2.87), CD (1.87; 95% CI 1.25, 2.81) or psoriasis (1.88; 95% CI 1.27, 2.79) independent of depression status. RA was also independently associated with preeclampsia. Prenatal depression was not independently associated with preterm birth or preeclampsia, nor was there any synergism with autoimmune conditions. CONCLUSION: If these findings are confirmed, the absence of synergism should be encouraging news to the many women with select autoimmune conditions and depression in pregnancy.
28805099 Short-term daily teriparatide in patients with rheumatoid arthritis. 2018 May OBJECTIVE: The aim of this study was to compare the efficacy of six-month teriparatide treatment followed by six-month bisphosphonate therapy with 12-month bisphosphonate monotherapy in Japanese rheumatoid arthritis (RA) patients who had not been previously treated for osteoporosis. METHODS: A total of 34 RA patients with osteoporosis were enrolled. Thirteen patients received six-month teriparatide prior to six-month minodronate therapy (PTH group), and 21 patients received 12-month minodronate therapy (BP group). Bone mineral density (BMD), and bone turnover markers were measured prior to and 6 and 12 months after the initiation of treatment. RESULTS: Bone mineral density of the spine was significantly increased after 12 months of treatment in both groups. In the PTH group, the mean percent change of BMD of the spine was significantly higher at 12 months after the initiation of treatment, as compared to the BP group (PTH group: 9.9 ± 1.5%, BP group: 5.5 ± 0.7%). Femoral neck BMD was significantly increased only in the PTH group after 12 months. CONCLUSION: Therapy involving six-month teriparatide followed by six-month minodronate therapy increased spine BMD to a greater degree than 12-month minodronate monotherapy. The strategy of short-term administration of teriparatide for RA patients with osteoporosis might be useful when additional bisphosphonate therapy is considered.
28516890 Tocilizumab in the treatment of patients with rheumatoid arthritis in real clinical practi 2017 Nov OBJECTIVES: To describe the effectiveness and safety of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in a cohort of patients with rheumatoid arthritis (RA) recruited in clinical practice. METHODS: TRUST was an observational study in RA patients who started treatment with TCZ in the 6 months prior to site activation and were still on treatment at start of study; patients were followed up to 12 months after the first TCZ infusion. RESULTS: 322 RA patients were enrolled in 59 Italian centres (mean age: 55.8 years; mean disease duration: 120.5 months; baseline DAS28: 5.3). After 6 months of TCZ treatment, patients achieving low disease activity (DAS28 ≤3.2; 57.52%) or disease remission (DAS28 <2.6; 38.05%) were 216 out of 226 patients with available DAS28 (p<0.001). No statistically significant differences were found in mean DAS28 and HAQ score changes from baseline (start of TCZ treatment) to study end between patients previously inadequately responding to disease-modifyinganti-rheumatic drugs (DMARD-IR) or to DMARDs plus tumour necrosis factor inhibitors (DMARD +TNFi-IR): both patient populations responded to TCZ. A statistically significant decrease in mean VAS Fatigue score (48.4 vs. 34.7; p=0.0025) at month 6 was observed. In patients treated with TCZ as monotherapy (32.61%), DAS28, VAS fatigue and HAQ scores decreased from baseline to any post-baseline time point. Overall, 62 patients (19.3%) prematurely discontinued TCZ treatment, 24 (7.5%) for safety reasons. Drug-related adverse events occurred in 92 patients (28.6%) (mostly 3 hypercholesterolaemia and leucopenia) and drug-related serious adverse events in 11 patients (3.4%). CONCLUSIONS: This study confirms the good effectiveness and safety profile of TCZ in real life RA patient care.
29139090 Tofacitinib: A Review in Rheumatoid Arthritis. 2017 Dec Tofacitinib (Xeljanz(®)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months). Tofacitinib monotherapy inhibited progression of structural damage in methotrexate-naïve patients during ≤ 24 months' treatment, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months. Tofacitinib was generally well tolerated during ≤ 114 months' treatment, with most adverse events of mild or moderate severity. The tolerability profile of tofacitinib was generally similar to that of biological DMARDs (bDMARDs), with infections and infestations the most common adverse events (AEs) in tofacitinib recipients. However, the incidence of herpes zoster (HZ) was higher with tofacitinib than in the general RA population, although infections were clinically manageable. When added to background methotrexate, tofacitinib was noninferior to adalimumab in terms of efficacy, and both combination therapies had generally similar tolerability profiles. Although additional comparative studies are needed to more definitively position tofacitinib relative to bDMARDs and other targeted synthetic DMARDs, current evidence indicates that oral tofacitinib is a useful option for the treatment of patients with RA.
28424490 Direct recognition of LPS drive TLR4 expressing CD8(+) T cell activation in patients with 2017 Apr 19 Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8(+) T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8(+) T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8(+) T cells of RA patients and its role in skewing CD8(+) T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8(+) T cells directly correlates with disease severity. Moreover, these CD8(+) T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8(+) T cells in orchestrating RA through TLR4 mediated activation and differentiation.
28153828 Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatme 2017 Aug OBJECTIVES: To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. METHODS: MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. RESULTS: 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. CONCLUSIONS: In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP. TRIAL REGISTRATION NUMBER: NCT01451203.
28240592 Analysis of non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical 2017 Jul OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the incidence of non-melanoma skin cancer (NMSC) across the tofacitinib RA development programme. METHODS: NMSC events (through August 2013) were identified in patients receiving tofacitinib in two Phase (P)1, eight P2, six P3 and two long-term extension (LTE) studies. In P123 studies, tofacitinib was administered at various doses (1-30 mg twice daily [BID], 20 mg once daily), as monotherapy or with conventional synthetic disease-modifying anti-rheumatic drugs, mainly methotrexate. In LTE studies, patients from qualifying P123 studies received tofacitinib 5 or 10 mg BID. Crude incidence rates (IRs; patients with events/100 patient-years) for first NMSC event were evaluated across doses and over time. RESULTS: In the overall population, comprising data from 18 studies (15,103 patient-years), 83 of 6092 tofacitinib-treated patients had NMSC events. The IR for NMSC (0.55 [95% confidence interval, 0.45-0.69] overall population) was stable up to 84 months of observation. IRs for tofacitinib 5 and 10 mg BID in combined P123 trials were 0.61 (0.34-1.10) and 0.47 (0.24-0.90), respectively. Corresponding IRs for LTE studies were 0.41 (0.26-0.66) and 0.79 (0.60-1.05). CONCLUSIONS: The IR for NMSC across the tofacitinib RA clinical development programme was low and remained stable over time. The IR for NMSC in LTE studies was numerically but not significantly higher with tofacitinib 10 versus 5 mg BID; an inverse dose relationship was observed in P123 trials. Longer follow-up is required to confirm these results.
28314855 Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption. 2017 May 1 Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator differentially expressed in FDCP 6 homolog (Def6) as a novel inhibitor of osteoclastogenesis in physiological and inflammatory conditions. Def6 deficiency in Def6(-/-) mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer receptor activator for NF-κB ligand, and Def6(-/-) osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-α-induced osteoclastogenesis in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-α serum levels correlated negatively with Def6 expression levels in osteoclast precursors obtained from RA patients, and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, B lymphocyte-induced maturation protein-1, and c-Fos by regulating an endogenous IFN-β-mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.
28705782 Biologics in myelodysplastic syndrome-related systemic inflammatory and autoimmune disease 2017 Sep BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified. METHODS: In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics. RESULTS: We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection. CONCLUSION: This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.
28811354 Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension 2018 Jan OBJECTIVE: To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353). METHODS: After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose. RESULTS: In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128. CONCLUSION: In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.
29066221 Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. 2018 Mar 1,25-dihydroxyvitaminD(3) (1,25(OH)(2)D(3)), has potent anti-inflammatory effects, including suppression of IL-17 + and IFNγ+ T cells implicated in rheumatoid arthritis (RA), but efficacy at the site of active disease is unclear. To investigate this, T cells from synovial fluid (SF) and paired blood of patients with active RA were studied. 1,25(OH)(2)D(3) had significantly less suppressive effect on Th17 cells (IL-17+IFNγ-) and Th17.1 cells (IL-17+IFNγ+) from SF compared to those from blood, and had no effect on SF CD4(+) or CD8(+) IFNγ+ T cell frequencies. Memory T cells (CD45RO+) predominate in SF, and 1,25(OH)(2)D(3) had less effect on memory T cells relative to naïve (CD45RA+) T cells. RT-PCR and flow cytometry showed that this was not due to decreased expression of the vitamin D receptor or its transcription partners in memory T cells. Further studies using stimulated CD4(+) T cells sorted according to IL-17 and IFNγ expression confirmed the ability of 1,25(OH)(2)D(3) to suppress pre-existing cytokines. However, 1,25(OH)(2)D(3) was most effective at suppressing de novo IL-17 and IFNγ induction. Correspondingly, T cell responses to 1,25(OH)(2)D(3) correlated directly with capacity for phenotype change, which was lower in cells from SF compared to blood. These findings indicate that anti-inflammatory effects of 1,25(OH)(2)D(3) in active RA are impaired because of reduced effects on phenotype-committed, inflammatory memory T cells that are enriched in SF. Restoration of 1,25(OH)(2)D(3) responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.
28864936 A Case of Cutaneous Mycosis Caused by Scedosporium dehoogii on an Immunocompromised Patien 2018 Apr This report describes a 77-year-old man with cutaneous mycosis caused by Scedosporium dehoogii while taking oral betamethasone and tacrolimus for the treatment of rheumatoid arthritis. At examination in our clinic, the patient had multiple cystic lesions and nodules with slight tenderness, varying in size up to 4 cm, on his left knee and shin. He had not noticed any traumatic injury at the site of the lesions. Fungal cultures of samples taken from the abscesses, scales, and crusts of the lesions yielded white, later grayish brown, fluffy surfaced colonies. Partial sequencing of the β-tubulin gene confirmed the species of the isolate. The patient was initially treated with oral voriconazole and local hyperthermia, but experienced hepatic injury 2 weeks later. His treatment was changed to itraconazole (ITC) and local hyperthermia, followed by a combination of ITC and terbinafine. The patient recovered completely during the 12-month course of treatment.
28483768 Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: resul 2017 Sep OBJECTIVE: In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account. METHODS: Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case-control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model. RESULTS: During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)). In the case-control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)). CONCLUSIONS: Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.
28073800 Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence an 2017 Apr OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of myocardial infarction (MI) compared with subjects without RA, with the increased risk driven potentially by inflammation. Tumour necrosis factor inhibitors (TNFi) may modulate the risk and severity of MI. We compared the risk and severity of MI in patients treated with TNFi with that in those receiving synthetic disease-modifying antirheumatic drugs (sDMARDs). METHODS: This analysis included patients with RA recruited from 2001 to 2009 to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis starting TNFi (etanercept/infliximab/adalimumab) and a biologic-naïve comparator cohort receiving sDMARD. All patients were followed via physician and patient questionnaires and national death register linkage. Additionally, all patients were linked to the Myocardial Ischaemia National Audit Project, a national registry of hospitalisations for MI. Patients were censored at first verified MI, death, 90 days following TNFi discontinuation, last physician follow-up or 20 April 2010, whichever came first. The risk of first MI was compared between cohorts using COX regression, adjusted with propensity score deciles (PD). MI phenotype and severity were compared using descriptive statistics. 6-month mortality post MI was compared using logistic regression. RESULTS: 252 verified first MIs were analysed: 58 in 3058 patients receiving sDMARD and 194 in 11 200 patients receiving TNFi (median follow-up per person 3.5 years and 5.3 years, respectively). The PD-adjusted HR of MI in TNFi referent to sDMARD was 0.61 (95% CI 0.41 to 0.89). No statistically significant differences in MI severity or mortality were observed between treatment groups. CONCLUSIONS: Patients with RA receiving TNFi had a decreased risk of MI compared with patients with RA receiving sDMARD therapy over the medium term. This might be attributed to a direct action of TNFi on the atherosclerotic process or better overall disease control.
28762055 Gulf War illness (GWI) as a neuroimmune disease. 2017 Oct Gulf War illness (GWI) is a chronic disease characterized by the involvement of several organs, including the brain (Christova et al., Exp Brain Res doi: 10.1007/s00221-017-5010-8 , 2017). In a previous study (Georgopoulos et al., J Neural Eng 4:349-355, 2015), we identified six protective alleles from Class II human leukocyte antigen (HLA) genes, and more recently, we investigated the brain correlates of this protection (James et al., EBioMedicine 13:72-79, 2016). Those and other studies (Israeli, Lupus, 21:190-194, 2012) suggested an involvement of the immune system in GWI. In a recent study (Engdahl et al., EBioMedicine doi: 10.1016/j.ebiom.2016.08.030 , 2016), we showed that the brain pattern of synchronous neural interactions (SNI; Georgopoulos et al., J Neural Eng 4:349-355, 2007) in GWI is distinctly different from that in healthy controls. Here we focused on the SNI itself, as a basic measure of neural communication (irrespective of specific connections) and compared it between GWI and seven other diseases that cover a broad spectrum of etiology and pathophysiology. Specifically, we sought to determine which, if any, of those diseases might resemble GWI SNI, overall and within the HLA protective domain, and thus gain further knowledge regarding the nature of GWI brain abnormality. We studied a total of 962 participants from a healthy control population (N = 583) and eight different diseases, including GWI (N = 40), schizophrenia (SZ; N = 21), Alzheimer's disease (AD; N = 66), posttraumatic stress disorder (PTSD; N = 159), major depressive disorder (MDD; N = 10), relapsing-remitting multiple sclerosis (RRMS; N = 43), Sjögren's syndrome (SS; N = 32), and rheumatoid arthritis (RA; N = 8). They all underwent a resting-state magnetoencephalographic (MEG) scan to calculate SNIs. Data were analyzed using analysis of covariance (ANCOVA) with disease as fixed factor, and sex and age as covariates. We found that GWI SNIs differed significantly from control SZ, AD, PTSD and MDD but not from RRMS, SS and RA. In addition, we compared GWI to RRMS, SS and RA with respect to SNIs of MEG sensor pairs that were related to the HLA alleles protective for GWI (James et al., EBioMedicine 13:72-79, 2016). We found that GWI SNIs did not differ significantly from any of these three diseases but they did so from control SZ, AD, PTSD and MDD. These findings indicate that (a) GWI brain synchronicity does not differ significantly from that of known immune-related diseases (RRMS, SS, RA), and (b) that this SNI similarity is present within the HLA-related SNIs. In contrast, GWI SNIs differed significantly from those of the other diseases. We conclude that altered brain communication in GWI likely reflects immune-related processes, as postulated previously (James et al., EBioMedicine 13:72-79, 2016). By extension, these findings also indicate that functional brain abnormalities in RRMS, SS and RA might be, in part, due to lack of protective HLA alleles as documented for GWI (Georgopoulos et al., EBioMedicine 3:79-85, 2015).
28408801 Effects of β-d-mannuronic acid, as a novel non-steroidal anti-inflammatory medication wit 2017 Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis characterized by pain, swelling and destruction of joints, with a resultant disability. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can interfere with the disease process. In this study, the effect of β-d-mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive and anti-inflammatory effects together with antioxidant effects was evaluated on IL17, RORγt, IL4 and GATA3 gene expression in 12 RA patients. Previously, M2000 driven from sodium alginate (natural product; patented, DEU: 102016113018.4) has shown a notable efficacy in experimental models of multiple sclerosis, RA and nephrotic syndrome. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. M2000 was administered orally at a dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the expression levels of IL4, GATA3, IL17 and RORγt. The gene expression results showed that M2000 has a potent efficacy, so that it could not only significantly decrease IL17 and RORγt levels but also increase IL4 and GATA3 levels after 12 weeks of treatment. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments. In conclusion, M2000 as a natural novel agent has therapeutic and immunosuppressive properties on RA patients (identifier: IRCT2014011213739N2).
28982826 Beliefs about medicines and non-adherence in patients with stroke, diabetes mellitus and r 2017 Oct 5 OBJECTIVES: To investigate beliefs about medicines and their association with medicine adherence in patients with chronic diseases in China. DESIGN: A cross-sectional questionnaire-based study SETTING: Two large urban hospitals in Hefei and Tianjin, China PARTICIPANTS: Hospital inpatients (313 stroke patients) and outpatients (315 diabetic patients and 339 rheumatoid arthritis (RA) patients) were recruited between January 2014 and September 2014. OUTCOME MEASURES: The Beliefs about Medicines Questionnaire (BMQ), assessing patients' beliefs about the specific medicine (Specific-Necessity and Specific-Concerns) prescribed for their conditions (stroke/diabetes/RA) and more general background beliefs about pharmaceuticals as a class of treatment (BMQ-General Benefit, Harm and Overuse); the Perceived Sensitivity to Medicines scale (PSM) assessed patients' beliefs about how sensitive they were to the effects of medicines and the Medication Adherence Report Scale. The association between non-adherence and beliefs about medicines was assessed using a logistic regression model. RESULTS: Patients with diabetes mellitus had a stronger perceived need for treatment (mean (SD) Specific-Necessity score, 3.75 (0.40)) than patients with stroke (3.69 (0.53)) and RA (3.66 (0.44)) (p=0.049). Moderate correlations were observed between Specific-Concerns and General-Overuse, General-Harm and PSM (Pearson correlation coefficients, 0.39, 0.49 and 0.49, respectively, p<0.01). Three hundred and eleven patients were non-adherent to their medicine (159 (51.0%) in the stroke group, 60 (26.7%) in the diabetes mellitus group and 62 (19.8%) in the RA group, p<0.01). Across the whole sample, after adjusting for demographic characteristics, non-adherence was associated with patients who had higher concerns about their medicines (OR, 1.35, 95% CI 1.07 to 1.71) and patients who believed that they were personally sensitive to the effects of medications (OR 1.44, 95% CI 1.16 to 1.85). CONCLUSION: The BMQ is a useful tool to identify patients at risk of non-adherence. In the future, adherence intervention studies may use the BMQ to screen for patients who are at risk of non-adherence and to map interventional support.