Background
Chronic spontaneous urticaria (CSU) is defined as spontaneous occurrence of wheals and/or angioedema for ≥6 weeks. Omalizumab is a monoclonal anti‐IgE antibody effective in refractory CSU, ...but its mechanism of action and markers predictive of response remain not completely defined.
Objectives
To correlate baseline levels of two proposed biomarkers, total IgE (bIgE) and d‐dimer (bd‐dimer), and clinical parameters to omalizumab response and to relapses after drug withdrawal.
Methods
In this retrospective Italian multicentre study, clinical data were collected in 470 CSU patients, and bIgE and bd‐dimer were measured in 340 and 342 patients, respectively. Disease activity was determined by Urticaria Activity Score 7 (UAS7) at week 1 and 12 after omalizumab starting. Relapses were evaluated during a 2‐ and 3‐month interval after a first and a second course of treatment, respectively.
Results
bIgE correlated to a good response to omalizumab since levels were significantly higher in responders than non‐responders (P = 0.0002). Conversely, bd‐dimer did not correlate to response. There was no correlation between both bIgE and d‐dimer and either first or second relapse. Disease duration was significantly longer in patients who experienced either first or second relapse (P < 0.0001 and P = 0.0105, respectively), while baseline UAS7 correlated only to first relapse (P = 0.0023).
Conclusions
Our study confirms bIgE as a reliable biomarker predicting response to omalizumab in CSU, while it does not support the usefulness of bd‐dimer unlike previous findings. CSU duration before omalizumab and baseline UAS7 may be clinical markers of relapse risk.
Summary
Background
Secukinumab is administered at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter.
Objectives
To investigate the efficacy of secukinumab ...administered without the initial loading dose in patients with psoriasis.
Methods
This was a retrospective observational study including adult patients with psoriasis (n = 156) treated with secukinumab 300 mg administered either according to the labelled dose (n = 75) or without the initial loading dose (n = 81). Efficacy was evaluated by comparing the Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates at week 8, 12, 16, 32 and 48.
Results
For patients who received the labelled dose vs. those who did not, PASI 75 response rates were achieved at week 8, 12, 16, 32 and 48 by 60% vs. 40% (P < 0·01), 72% vs. 61% (P < 0·01), 77% vs. 75%, 85% vs. 77% and 79% vs. 78%, respectively. PASI 90 responses were achieved at the same time points by 45% vs. 31% (P < 0·01), 49% vs. 40% (P < 0·01), 54% vs. 47%, 55% vs. 47% and 57% vs. 54% for those who received the labelled dose vs. those who did not, respectively. A greater proportion of patients receiving secukinumab without the loading dose discontinued treatment because of inefficacy (25% vs. 13%, P < 0·05), particularly those with body weight greater than 80 kg.
Conclusions
Secukinumab administered without the loading dose is associated with a higher proportion of primary inefficacy, and achieved inferior results compared with the labelled dose at week 8 and week 12, but showed similar efficacy thereafter.
What's already known about this topic?
Secukinumab is an interleukin (IL)‐17A inhibitor for chronic plaque psoriasis administered by subcutaneous injections at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter (maintenance dose).
Dose adjustment is common in clinical practice, and can consist of dose reduction when a prolonged remission is obtained or a dose increase in order to improve efficacy.
What does this study add?
The efficacy of secukinumab administered without the initial weekly loading dose was significantly inferior compared with the labelled dose in the short term, but was similar after week 16 and up to week 48.
A greater proportion of patients receiving secukinumab without the loading dose showed primary inefficacy, particularly those with body weight greater than 80 kg.
Linked Comment: Aichelburg and Tanew. Br J Dermatol 2020; 182:18–19.
To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS).
The percent brain volume change (PBVC) was computed on existing longitudinal (2 time ...points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68).
There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.
This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.
Summary Background A 24-week phase II trial has shown that 0·3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of ...active lesions. We assessed the effect of oral daily 0·3 and 0·6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study. Methods The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18–50 years, were randomly assigned to placebo (n=102), laquinimod 0·3 mg a day (n=98), or 0·6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week −4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov , number NCT00349193. Findings Compared with placebo, treatment with laquinimod 0·6 mg per day showed a 40·4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4·2 SD 9·2 vs 2·6 5·3, p=0·0048); treatment with 0·3 mg per day showed no significant effects (3·9 5·5 vs placebo, p=0·6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome—ie, a thrombotic venous outflow obstruction of the liver—occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0·6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation. Interpretation In patients with relapsing-remitting multiple sclerosis, 0·6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated. Funding Teva Pharmaceutical Industries.
Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. In this study, we ...prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.
In recent years, criteria for the diagnosis of multiple sclerosis (MS) have changed, mainly due to the incorporation of new MRI criteria. While the new criteria are a logical step forward, they are ...complex and-not surprisingly-a good working knowledge of them is not always evident among neurologists and neuroradiologists. In some circumstances, several MRI examinations are needed to achieve an accurate and prompt diagnosis. This provides an incentive for continued efforts to refine the incorporation of MRI-derived information into the diagnostic workup of patients presenting with a clinically isolated syndrome. Within the European multicenter collaborative research network that studies MRI in MS (MAGNIMS), a workshop was held in London in November 2007 to review information that may simplify the existing MS diagnostic criteria, while maintaining a high specificity that is essential to minimize false positive diagnoses. New data that are now published were reviewed and discussed and together with a new proposal are integrated in this position paper.
Background:
Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.
Objectives:
The Magnetic Imaging in MS ...(MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.
Methods:
Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).
Results:
In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.
Conclusions:
Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.
BackgroundThe approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new ...opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.MethodsWe collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.ResultsA total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).ConclusionsSativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.
Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those ...for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.
The correlation between conventional MRI lesion load accumulation and multiple sclerosis clinical evolution is only modest. The assessment of brain parenchymal volume and of its changes over time may ...provide adjunctive MRI markers reflecting the more disabling aspects of multiple sclerosis pathology. Magnetization transfer (MT) MRI is sensitive to ‘occult’ multiple sclerosis‐related brain damage and might also contribute to overcome the clinical/MRI paradox. In this study, we assessed the value of conventional and MT MRI‐derived metrics in predicting the medium‐term clinical evolution of patients with different multiple sclerosis phenotypes. We studied 73 patients, with relapsing–remitting multiple sclerosis (n = 34), secondary progressive multiple sclerosis (n = 19) and clinically isolated syndromes suggestive of multiple sclerosis (n = 20), and 16 healthy subjects. Brain dual‐echo, T1‐weighted (only in patients) and MT MRI scans were obtained at baseline and after 12 months. T2‐hyperintense and T1‐hypointense lesion volumes, normalized brain volume and average lesion MT ratio (MTR) were measured. MTR histograms from the whole brain tissue were also obtained. Clinical multiple sclerosis evolution and neurological disability were re‐assessed in all patients after a median follow‐up of 4.5 years. A multivariate analysis was performed to establish which clinical and MRI‐derived variables were significant predictors of neurological deterioration at the end of the study period. At the end of follow‐up, 34 patients showed significant neurological deterioration. The final multivariable model included average brain MTR percentage change after one year P = 0.02, odds ratio (OR) = 0.86 and baseline T2‐hyperintense lesion volume (P = 0.04, OR=1.04) as independent predictors of medium‐term disability accumulation (r2 = 0.23). In this cohort of patients, abnormal values of average brain MTR changes showed a relatively high specificity (76.9%) and positive predictive value (59.1%) for Expanded Disability Status Scale score deterioration in individual cases. In patients with multiple sclerosis, a comprehensive estimation of the short‐term changes of both conventional and MT MRI‐detectable lesion burden might provide useful prognostic information for the medium‐term clinical disease evolution.
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