Karen Schreiber

BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids

Centre for Rheumatology Research, UCL Division of Medicine, University College London, London, Department of Rheumatology, University Hospitals of Leicester, Leicester, Womens Health, University College London Hospital, London, Obstetrics and Gynaecology, Frimley Park Hospital, Surrey, Department of Rheumatology, University Hospital Birmingham NHS Foundation Trust, Birmingham, Department of Rheumatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet, Denmark, Department of Rheumatology, Burton Hospitals NHS Trust, Burtonupon-Trent, Rheumatic and Musculoskeletal Disease Unit, Our Lady’s Hospice and Care Services, Dublin, Ireland, Department of Rheumatology, University College London Hospital, London, Department of Rheumatology, Aneurin Bevan University Health Board, Newport, UK, Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust and Division of Immunity and Infection, University of Birmingham, Birmingham, UK

Thrombotic risk assessment in antiphospholipid syndrome: the role of new antibody specificities and thrombin generation assay.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by the presence of antiphospholipid antibodies (aPL) in subjects presenting with thrombosis and/or pregnancy loss. The currently used classification criteria were updated in the international consensus held in Sidney in 2005. Vascular events seem to result of local procoagulative alterations upon triggers influence (the so called “second-hit theory”), while placental thrombosis and complement activation seem to lead to pregnancy morbidity. The laboratory tests suggested by the current classification criteria include lupus anticoagulant, a functional coagulation assay, and anticardiolipin and anti-β2-glycoprotein-I antibodies, generally detected by solid phase enzyme-linked immunosorbent assay. The real challenge for treating physicians is understanding what is the actual weight of aPL in provoking clinical manifestations in each case. As thrombosis has a multi-factorial cause, each patient needs a risk-stratified approach. In this review we discuss the role of thrombotic risk assessment in primary and secondary prevention of venous and arterial thromboembolic disease in patients with APS, focusing on new antibody specificities, available risk scoring models and new coagulation assays.

Improvement in fatigue during natalizumab treatment is linked to improvement in depression and day-time sleepiness

Background: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing–remitting MS patients showed a clinically meaningful decrease in fatigue over 1 year of treatment with natalizumab. Objective: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness. Methods: Patients were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of the two latter symptoms and changes in fatigue was analyzed. Results: After 1 year of natalizumab treatment, the majority of patients (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of patients without depression increased by 17% while proportions of mildly depressed patients or patients with potential major depression decreased by 5 and 12%, respectively. Proportion of patients classified as not being sleepy increased by 13% while proportions of sleepy and very sleepy patients decreased by 11 and 2%, respectively. Most importantly, improved depression and sleepiness were significantly related to improved fatigue. Conclusion: Our findings highlight the importance of patient-reported outcomes in identifying potential benefits of drug treatment beyond its well-established effects on disease activity and disability progression.

HYdroxychloroquine to Improve Pregnancy Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) Protocol: A Multinational Randomized Controlled Trial of Hydroxychloroquine versus Placebo in Addition to Standard Treatment in Pregnant Women with Antiphospholipid Syndrome or Antibodies

Women with antiphospholipid antibodies (aPL) are at risk of adverse pregnancy outcomes, including recurrent first-trimester pregnancy loss and late pregnancy complications such as preeclampsia, HELLP (hemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, premature delivery, intrauterine growth restriction, placental abruption, and intrauterine death. Current standard care in obstetric antiphospholipid syndrome includes aspirin and heparin and has resulted in live-birth rates of approximately 70%. However, 30% continue to have pregnancy complications. Hydroxychloroquine (HCQ) is suggested as a new treatment approach, but no randomized controlled trials (RCTs) have assessed its efficacy. This study aims to assess pregnancy outcome in women with aPL treated with HCQ versus placebo in addition to standard treatment. The HYdroxychloroquine to improve Pregnancy outcome in women with AnTIphospholipid Antibodies (HYPATIA) study is a phase IV multicenter RCT, in which pregnant women with persistent aPL will receive either HCQ or placebo in addition to their usual medication. The primary endpoint is a composite of aPL-related adverse pregnancy outcomes: one or more pregnancy loss(es) (either   10 weeks of gestation) and premature birth before 34 weeks due to any of the following preeclampsia, eclampsia, or recognized features of placental insufficiency. The HYPATIA study is expected to provide evidence on the effect of HCQ in pregnant women with persistent aPL.

The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies

Objectives HCQ has been described as having a beneficial effect in patients with APS but its mechanism of action is unclear. We hypothesized that HCQ may have effects on subnormal angiogenesis, inflammation and haemostatic biomarkers seen in APS. The aim of our study was to assess laboratory markers [annexin A5 (AnxA5) anticoagulant activity, tissue factor (TF) levels, thromboelastography (TEG), CRP, Bb, C3a and VEGF] in HCQ-naïve patients with aPL at baseline and after commencing HCQ. Methods Twenty-two patients with aPL [20 female, 2 male, median age 55 (range 18-70) years] had blood taken pre- and 3 months after starting HCQ 200 mg daily. Results Soluble TF levels were significantly reduced comparing baseline and 3 months after HCQ commencement [401.8 (152.8) vs 300.9 (108) pg/ml (P = 0.010)]. No significant changes were found in the following [reported as pre- and post-HCQ commencement, mean (s.d.)]: AnxA5 anticoagulant ratio [187.1 (29.5) vs 193 (31) (P = 0.157)], anti-domain1 β2 glycoprotein1 IgG activity [1.8 (2) vs 1.2 (1.4) μg/ml (P = 0.105)], complement C3a-des-Arg [147.8 (84.5) vs 154.4 (88.1) ng/ml (P = 0.905)], complement Bb [1.3 (0.7) vs 1.1 (0.7) μg/ml (P = 0.422)], VEGF [68.8 (40) vs 59.4 (19.6) pg/ml (P = 0.454)] and CRP [7 (3.5) vs 7 (3.9) μg/ml (P = 0.917)]. TEG results including TEG reaction time, achievement of clot firmness, TEG maximum amplitude and TEG percentage lysis 30 and 60 min after maximum amplitude showed no significant difference. Conclusion HCQ significantly reduced soluble TF levels in patients with aPL. No significant change was observed in AnxA5 activity, anti-domain 1 IgG activity, TEG, CRP, complement Bb and C3a-des-Arg, and VEGF. Further studies of a larger patient cohort are needed.

Progressive multiple sclerosis, cognitive function, and quality of life

Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS.

Current insights in obstetric antiphospholipid syndrome

Purpose of review Antiphospholipid syndrome (APS) is defined as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). In this review, we will highlight the most important clinical presentations of APS with a focus on the obstetric morbidity, the current management strategies and the outlook for the future. Recent findings The use of aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS have a successful pregnancy outcome. Unfortunately, the current standard of care does not prevent all pregnancy complications as the current treatment fails in 20–30% of APS pregnancies. This therefore highlights the need for alternative treatments to improve obstetrical outcome. Other treatment options are currently explored and retrospective studies show that pravastatin for example is beneficial in women with aPL-related early preeclampsia. Moreover, the immunmodulator hydroxychloroquine may play a beneficial role in the prevention of aPL-related pregnancy complications. Summary APS is among the most frequent acquired risk factors for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischaemic placental dysfunction, such as fetal growth restriction, preeclampsia, premature birth and intrauterine death. Current treatment is mainly based on aspirin and heparin. Studies to inform on alternative treatment options are urgently needed.

Functional neuroimaging of recovery from motor conversion disorder: A case report

ABSTRACT A patient with motor conversion disorder presented with a functional paresis of the left hand. After exclusion of structural brain damage, she was repeatedly examined with whole‐brain functional magnetic resonance imaging, while she performed visually paced finger‐tapping tasks. The dorsal premotor cortex showed a bilateral deactivation in the acute‐subacute phase. Recovery from unilateral hand paresis was associated with a gradual increase in task‐based activation of the dorsal premotor cortex bilaterally. The right medial prefrontal cortex displayed the opposite pattern, showing initial task‐based activation that gradually diminished with recovery. The inverse dynamics of premotor and medial prefrontal activity over time were found during unimanual finger‐tapping with the affected and non‐affected hand as well as during bimanual finger‐tapping. These observations suggest that reduced premotor and increased medial prefrontal activity reflect an effector‐independent cortical dysfunction in conversion paresis which gradually disappears in parallel with clinical remission of paresis. The results link the medial prefrontal and dorsal premotor areas to the generation of intentional actions. We hypothesise that an excessive ‘veto’ signal generated in medial prefrontal cortex along with decreased premotor activity might constitute the functional substrate of conversion disorder. This notion warrants further examination in a larger group of affected patients. HighlightsWe mapped finger‐tapping activity in a patient recovering from conversion paresis.Activity of dorsal premotor cortex gradually emerged during repeated fMRI sessions.Conversely, medial prefrontal activity tapered off with recovery from paresis.The pattern was also expressed during finger‐tapping with the non‐affected hand.It may represent a substrate of cortical dysfunction in conversion disorder.

Clinical utility of anti-MOG antibody testing in a Danish cohort

BACKGROUND Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet. METHODS In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy. RESULTS We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy. CONCLUSION A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated.

Antiphospholipid Antibodies and Syndrome: Complexities in Diagnosis and Management

Antiphospholipid syndrome (APS) is characterised by arterial and/or venous thromboses and/or obstetric morbidity (obstetric APS) in patients persistently positive for antiphospholipid antibodies (aPL). The classification criteria for APS have been defined in the original Sapporo criteria, which more recently have been updated in the Sydney criteria (ss) (Miyakis et al. 2006).