Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study

Objectives: To assess long-term golimumab efficacy/safety in patients with active psoriatic arthritis (PsA).<p></p> Methods Adult PsA patients (≥3 swollen, ≥3 tender joints, active psoriasis) were randomly assigned to subcutaneous injections of placebo, golimumab 50 mg or 100 mg every 4 weeks (q4wks) through week 20. All patients received golimumab 50 or 100 mg beginning week 24. Findings through 2 years are reported. Efficacy evaluations included ≥20% improvement in American College of Rheumatology (ACR20) response, good/moderate response in Disease Activity Scores incorporating 28 joints and C-reactive protein (DAS28-CRP), ≥75% improvement in Psoriasis Area and Severity Index (PASI75) and changes in PsA-modified Sharp/van der Heijde scores (SHS).<p></p> Results: Golimumab treatment through 2 years was effective in maintaining clinical response (response rates: ACR20 63%–70%, DAS28-CRP 77%–86%, PASI75 56%–72%) and inhibiting radiographic progression (mean change in PsA-modified SHS in golimumab-treated patients: −0.36), with no clear difference between doses. No new safety signals were identified through 2 years. With the study's tuberculosis screening and prophylactic measures, no patient developed active tuberculosis through 2 years.<p></p> Conclusions: Golimumab 50 and 100 mg for up to 2 years yielded sustained clinical and radiographic efficacy when administered to patients with active PsA. Increasing the golimumab dose from 50 to 100 mg q4wks added limited benefit. Golimumab safety through up to 2 years was consistent with other antitumour necrosis factor α agents used to treat PsA. Treatment of patients with latent tuberculosis identified at baseline appeared to be effective in inhibiting the development of active tuberculosis.<p></p&gt

Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

ObjectiveTo evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).MethodsThis was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.ResultsIn total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.ConclusionsDenosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD

A Review of Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a systemic autoimmune disorder that induces ankylosis of the spine (fusion of the vertebrae at their various joints) and inflammatory arthritis of peripheral joints among other symptoms. Overexpression of cytokines, the presence of genetic mutations not exclusive to the human leucocyte antigen (HLA)-B27 region, and environmental factors all have large roles in the progressive development of AS. Although a definitive pathology continues to be sought after, researchers believe the adaptive immune system in AS patients attacks fibrocartilaginous entheses (supportive connective tissue between bone and attached structures like tendon, ligament, and fascia). AS markedly reduces proper systemic functioning in several areas of human physiology, including the musculoskeletal, cardiovascular, neurological, psychiatric, and reproductive systems in both genders. A diagnosis for this disease requires the presentation of several qualifying symptoms, namely chronic inflammatory back pain, peripheral joint arthritis, enthesitis (inflammation of the enthesis not associated with a joint), uveitis (inflammation of the uvea or inner eye layer), and positive response to non-steroidal anti-inflammatory drugs (NSAIDs), with radiological support through x-ray or magnetic resonance imaging (MRI). Upon an AS diagnosis, patients should engage in healthy lifestyle changes, non-impact exercise, and taking NSAIDs as the first pharmacological treatment. Symptoms unresolved by NSAIDs are then treated with disease modifying antirheumatic drugs (DMARDs) and/or biologic medications like a monoclonal TNFα antibody to prevent further disease progression. Continued research to understand the association between AS and interleukin (IL)-17/IL-23 is needed for development of additional biologic treatments

Targeting of cytochrome b2 into the mitochondrial intermembrane space

Cytochrome b2 contains 2-fold targeting information: an amino-terminal signal for targeting to the mitochondrial matrix, followed by a second cleavable sorting signal that functions in directing the precursor into the mitochondrial intermembrane space. The role of the second sorting sequence was analyzed by replacing one, two or all of the three positively charged amino acid residues which are present at the amino-terminal side of the hydrophobic core by uncharged residues or an acidic residue. With a number of these mutant precursor proteins, processing to the mature form was reduced or completely abolished and at the same time targeting to the matrix space occurred. The accumulation in the matrix depended on a high level of intramitochondrial ATP. At low levels of matrix ATP, the mutant proteins were sorted into the intermembrane space like the wild-type precursors. The results: (i) suggest the existence of one or more matrix components that specifically recognize the second sorting signal and thereby trigger the translocation into the intermembrane space; (ii) indicate that the mutant signals have reduced ability to interact with the recognition component(s) and then embark on the default pathway into the matrix by interacting with mitochondrial hsp70 in conjunction with matrix ATP; (iii) strongly argue against a mechanism by which the hydrophobic segment of the sorting sequence stops translocation in the hydrophobic phase of the inner membrane

Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model.

Molecules from animal venoms are promising candidates for the development of new drugs. Previous in vitro studies have shown that the venom of the spider Phoneutria nigriventer (PnV) is a potential source of antineoplastic components with activity in glioblastoma (GB) cell lines. In the present work, the effects of PnV on tumor development were established in vivo using a xenogeneic model. Human GB (NG97, the most responsive line in the previous study) cells were inoculated (s.c.) on the back of RAG-/- mice. PnV (100 µg/Kg) was administrated every 48 h (i.p.) for 14 days and several endpoints were evaluated: tumor growth and metabolism (by microPET/CT, using 18F-FDG), tumor weight and volume, histopathology, blood analysis, percentage and profile of macrophages, neutrophils and NK cells isolated from the spleen (by flow cytometry) and the presence of macrophages (Iba-1 positive) within/surrounding the tumor. The effect of venom was also evaluated on macrophages in vitro. Tumors from PnV-treated animals were smaller and did not uptake detectable amounts of 18F-FDG, compared to control (untreated). PnV-tumor was necrotic, lacking the histopathological characteristics typical of GB. Since in classic chemotherapies it is observed a decrease in immune response, methotrexate (MTX) was used only to compare the PnV effects on innate immune cells with a highly immunosuppressive antineoplastic drug. The venom increased monocytes, neutrophils and NK cells, and this effect was the opposite of that observed in the animals treated with MTX. PnV increased the number of macrophages in the tumor, while did not increase in the spleen, suggesting that PnV-activated macrophages were led preferentially to the tumor. Macrophages were activated in vitro by the venom, becoming more phagocytic; these results confirm that this cell is a target of PnV components. Spleen and in vitro PnV-activated macrophages were different of M1, since they did not produce pro- and anti-inflammatory cytokines. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. The identification, optimization and synthesis of antineoplastic drugs from PnV molecules may lead to a new multitarget chemotherapy. Glioblastoma is associated with high morbidity and mortality; therefore, research to develop new treatments has great social relevance. Natural products and their derivatives represent over one-third of all new molecular entities approved by FDA. However, arthropod venoms are underexploited, although they are a rich source of new molecules. A recent in vitro screening of the Phoneutria nigriventer spider venom (PnV) antitumor effects by our group has shown that the venom significantly affected glioblastoma cell lines. Therefore, it would be relevant to establish the effects of PnV on tumor development in vivo, considering the complex neoplastic microenvironment. The venom was effective at impairing tumor development in murine xenogeneic model, activating the innate immune response and increasing tumor infiltrating macrophages. In addition, PnV activated macrophages in vitro for a different profile of M1. These activated PnV-macrophages have potential to fight the tumor without promoting tumorigenesis. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. We aim to synthesize and carry out a formulation with these antineoplastic molecules for clinical trials. Spider venom biomolecules induced smaller and necrotic xenogeneic GB; spider venom activated the innate immune system; venom increased blood monocytes and the migration of macrophages to the tumor; activated PnV-macrophages have a profile different of M1 and have a potential to fight the tumor without promote tumorigenesis

Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis

Biologics May Prevent Cardiovascular Events in Rheumatoid Arthritis by Inhibiting Coronary Plaque Formation and Stabilizing High-Risk Lesions.

ObjectiveTo evaluate whether biologic disease-modifying antirheumatic drugs (DMARDs) decrease cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) and whether biologic DMARDs might have a beneficial effect on coronary plaque formation or progression.MethodsIn this single-center observational cohort study, 150 patients underwent computed tomographic angiography for evaluation of coronary atherosclerosis (total, noncalcified, mixed/calcified, and low-attenuation plaque); 101 had repeat assessments within a mean ± SD of 6.9 ± 0.3 years to evaluate plaque progression. All CVD events were prospectively recorded, including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication, and hospitalization for heart failure. The Framingham-D'Agostino score was used to assess cardiovascular risk. The segment stenosis score was used to measure plaque burden. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsAfter adjustment for the segment stenosis score, the Framingham-D'Agostino score, and time-varying Disease Activity Score in 28 joints using the C-reactive protein level using marginal structural models, current biologic DMARD use was associated with lower long-term CVD risk (OR 0.15 [95% CI 0.04-0.60]). Noncalcified and low-attenuation plaque presence moderated the effect of biologic DMARDs on CVD risk; specifically, biologic DMARD use was associated with lower CVD risk in patients with noncalcified or low-attenuation plaque at baseline (OR 0.21 [95% CI 0.04-0.99] and OR 0.08 [95% CI 0.01-0.70], respectively), but not in those without noncalcified or low-attenuation plaque. Per-segment plaque progression analyses showed that biologic DMARD exposure was associated with transition of noncalcified to mixed/calcified plaque (OR 4.00 [95% CI 1.05-15.32]). Biologic DMARD exposure predicted a lower likelihood of new plaque forming in segments without plaque among patients without mixed/calcified plaque in other coronary segments (OR 0.40 [95% CI 0.17-0.93]), but not among those with calcification. Biologic DMARD treatment also predicted low-attenuation plaque loss (P = 0.042).ConclusionOur findings indicate that in RA, biologic DMARD use is associated with reduced CVD risk, protective calcification of noncalcified lesions, and lower likelihood of new plaque formation in patients with early atherosclerosis

Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients.

OBJECTIVE:Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. METHODS:Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. RESULTS:Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. CONCLUSION:Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment

Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48