Increasing smoking intensity is associated with increased disease activity in axial spondyloarthritis.

A history of ever-smoking appears to be associated with a more severe disease phenotype in axial spondyloarthritis (axSpA). However, evidence is sparse for the effect of increased smoking exposure on disease outcomes or whether smoking reduction or cessation improves outcomes. The aim of this study was to explore whether a dose-response relationship exists between pack-years and disease activity and functional impairment in axSpA. Consecutive patients meeting ASAS criteria for axial SpA were recruited from a spondyloarthritis service. The associations between pack-years of smoking and: (1) disease activity (BASDAI/ASDAS), (2) spinal pain, (3) functional impairment (BASFI) and (4) inflammatory markers were explored using multivariable linear models, adjusted for age, gender and use of TNF inhibition (TNFi) therapy. Pack-years were categorised into four groups (40) and analysed with light smoking (40, β = 2.6 (0.54, 3.56)), higher BASFI (21-40, β = 2.1 (0.42, 4.80); >40, β = 3.2 (0.76, 5.71)), and higher ASDAS (21-40, β = 0.82 (0.14, 1.51)). This cross-sectional study demonstrated that smoking is associated with increased axSpA severity markers in a dose-response manner. Particular effort should be made to restrict smoking exposure early before accruing a significant number of pack-years

Behçet's syndrome in children and young people in the United Kingdom & Republic of Ireland: a prospective epidemiological study

OBJECTIVES: To define the incidence and prevalence of Behçet's syndrome (BS) in children and young people (CYP) up to the age of 16 years in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: A prospective epidemiological study was undertaken with the support of the British Paediatric Surveillance Unit (BPSU) and the British Society of Paediatric Dermatologists (BSPD). Consultants reported anonymised cases of BS seen. A follow-up study at one year examined progression of disease and treatment. RESULTS: Over a two-year period, 56 cases met International Criteria for Behçet's Disease. For children under 16 years of age, the two-year period prevalence estimate was 4.2 per million (95% CI 3.2-5.4) and the incidence was 0.96 per million person years (95% CI 0.66-1.41). Mucocutaneous disease was the most common phenotype (56/100%), with ocular (10/56; 17.9%), neurological (2/56; 3.6%) and vascular involvement (3/56; 5.4%) being less common. Median age at onset was 6.34 years and at diagnosis was 11.72 years. There were slightly more female than male children reported (32/56; 55.6%). The majority of cases (85.7%) were white Caucasian. Apart from genital ulcers, which were more common in females, there were no significant differences in frequency of manifestations between male or females, nor between ethnicities. Over 83% of cases had three or more non-primary care healthcare professionals involved in their care. CONCLUSION: BS is extremely rare in CYP in the UK and ROI and most have mucocutaneous disease. Healthcare needs are complex, and coordinated care is key

Serine 162, an essential residue for the mitochondrial localization, stability and anti-apoptotic function of mcl-1.

Mcl-1 is an anti-apoptotic member of the Bcl-2 family that plays a key role in normal development, but also in pathologies such as cancer. It has some unusual properties compared to other anti-apoptotic members of the Bcl-2 family, and its expression and function are dynamically regulated by a variety of post-transcriptional and post-translational processes. Of note, Mcl-1 protein has a very short half life, and its stability and function may be regulated by reversible phosphorylation. There is also evidence to suggest that it may be localized to different subcellular compartments. The aim of this work was to determine whether residues within the PEST region of Mcl-1 that may undergo reversible phosphorylation, also regulate its subcellular distribution. We show that EGFP:Mcl-1 localizes mainly to the mitochondria of HeLa cells, with some additional cytoplasmic and nuclear localization. The mutations, S64A, S64E, S121A, S159A, T163A and T163E did not significantly affect the localization of Mcl-1. However, mutation of Ser162 to the phospho-null residue, Alanine resulted in an essentially nuclear localization, with some cytoplasmic but no mitochondrial localization. This mutant Mcl-1 protein, S162A, showed significantly decreased stability and it decreased the ability to protect against Bak-induced apoptosis. These data identify a new molecular determinant of Mcl-1 function, localization and stability that may be important for understanding the role of this protein in disease

Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab with methotrexate, in rheumatoid arthritis: A phase IIIB/IV trial

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objective To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR). Methods ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores. Results Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points. Conclusion Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning. Trial registration number NCT02187055

Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons

Editorial

Early arthritis management in Africa: moving on to a realit