Stick or twist? Cost-effectiveness of siponimod compared with continuing existing disease-modifying therapies in the treatment of active secondary progressive multiple sclerosis in the UK.

OBJECTIVE: Identification of the phenotypic transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) is often delayed due to disease complexity and an unwillingness to withdraw RRMS disease-modifying therapies (DMTs), driven by limited SPMS treatment options. Despite the paucity of clinical evidence for efficacy in patients with SPMS, DMTs licensed for RRMS are frequently continued into the early stages of SPMS. The cost-effectiveness of oral siponimod, an active SPMS DMT, versus continued oral or infused RRMS DMTs for patients with active SPMS, was evaluated. METHODS: A cohort Markov model based on disease progression through Expanded Disability Status Scale health states, with annual cycles and lifetime horizon, was employed to determine the cost-effectiveness of siponimod from a UK National Health Service (NHS) perspective for patients with active SPMS. Baseline characteristics, health state utility values, hazard ratios for time to 6-month confirmed disability progression, annualized relapse rate ratios and adverse events for siponimod were obtained from the phase 3 EXPAND clinical trial, supplemented by published literature. Published costs, resource use data and comparator efficacy data were obtained from the literature and, in the absence of data, reasonable assumptions were made. RESULTS: Quality-adjusted life years (QALYs) were greater for siponimod versus all comparators (3.45 versus 2.69-2.83). Incremental cost-effectiveness ratios (ICERs), calculated as cost per QALY, for siponimod versus natalizumab (dominant), ocrelizumab (£4,760), fingolimod (£10,033) and dimethyl fumarate (£15,837) indicated that siponimod was cost-effective at the commonly accepted willingness-to-pay threshold of £30,000/QALY. CONCLUSIONS: Recognition of active SPMS and treatment of this phenotype with siponimod offers a cost-effective and clinically beneficial treatment approach compared with the continuation of oral or infused RRMS DMTs.

Modified Delphi study of decision-making around treatment sequencing in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Existing effectiveness models of disease-modifying drugs (DMDs) for relapsing-remitting multiple sclerosis (RRMS) evaluate a single line of treatment; however, RRMS patients often receive more than one lifetime DMD. To develop treatment sequencing models grounded in clinical reality, a detailed understanding of the decision-making process regarding DMD switching is required. Using a modified Delphi approach, this study attempted to reach consensus on modelling assumptions. METHODS: A modified Delphi technique was conducted based on three rounds of discussion amongst an international group of 10 physicians with expertise in RRMS. RESULTS: The panel agreed that the expected time from disease onset to Expanded Disability Status Scale 6.0 is a proxy for disease severity as well as suitable for classifying severity into three groups. A modelled clinical decision rule regarding the timing of switching should contain at least the time between relapses, magnetic resonance imaging outcomes and the occurrence/risk of adverse events. The experts agreed that the assessment of adverse event risk for a DMD is dependent on disease severity, with more risks accepted when the patient's disease is more severe. The effectiveness of DMDs conditional on their position in a sequence and/or disease duration was discussed: there was consensus on some statements regarding this topic but these were accompanied by a high degree of uncertainty due to considerable knowledge gaps. CONCLUSION: Useful insights into the medical decision-making process regarding treatment sequencing in RRMS were obtained. The knowledge gained has been used to validate the main modelling concepts and to further generate clinically meaningful results.

Management of pancreaticoduodenal artery aneurysm associated with coeliac artery stenosis.

Pancreaticoduodenal and gastroduodenal artery aneurysms are rare but require early radiological or surgical intervention due to a high risk (61%) of rupture. A 71-year-old woman presented with an incidental 30-mm aneurysm arising from the inferior pancreaticoduodenal artery associated with coeliac axis stenosis. She underwent embolisation of the pancreaticoduodenal aneurysm, but the coeliac axis stenosis was not amenable to radiological intervention. She remained well at six months of follow-up and a repeat computed tomography angiogram six months later reported stable appearances. The management of pancreaticoduodenal aneurysms is discussed.

Infrainguinal Vein Graft Stenoses: Long-Term Outcomes of Graft Angioplasty.

OBJECTIVE: Graft angioplasty combines the durability and ability of surgical bypasses to treat long arterial occlusions with the minimally invasive nature of endovascular procedures. The purpose of this study was to evaluate the efficacy of single and repeated graft angioplasty in revising failing infrainguinal vein bypass grafts and to determine predictors of medium- and long-term freedom from revision after graft angioplasty. METHOD: This was a retrospective analysis from a prospectively maintained database. Consecutive endovascular revisions of graft-threatening lesions identified by duplex ultrasound surveillance were reviewed from 2003 to 2010. Patients were followed up until death, major amputation, or the end of follow-up, with the data last updated on January 1, 2013. RESULTS: 178 graft angioplasty procedures performed in 114 bypass grafts in 103 limbs from 98 patients were studied. At 5 years, freedom from revision was 22.6%, graft survival was 45.8%, amputation-free survival was 57.9%, and patient survival was 64.9%. Analysis of repeated angioplasties found no evidence that effectiveness diminishes significantly with the number of previous angioplasties performed (p=.892). Higher Rutherford Grade of ischemia and longer time interval from index surgery to first angioplasty were significant positive predictors of medium- and long-term patency. CONCLUSION: Percutaneous transluminal angioplasty of infrainguinal vein grafts is safe and effective in the treatment of failing grafts identified by duplex surveillance. Graft angioplasties do not lose effectiveness when repeated and have shown cumulative benefit in prolonging graft survival. Treatment of claudicants and time interval from graft implantation of more than 6 months at the time of first angioplasty are positive predictors of at least medium-term patency after graft angioplasty.

Stenting as a bail-out option after failed percutaneous transluminal angioplasty in infrainguinal vein bypass grafts.

OBJECTIVES: To study the safety and efficacy of bare and covered stents in infrainguinal vein grafts after failure of PTA for treating graft stenoses. METHODS: An analysis of a prospective database of all patients who underwent stenting of infrainguinal vein bypass grafts at this institution between 1 January 2008 and 31 December 2012 was carried out. The main outcome considered was primary patency, which was reported at 1, 6 and 12 months. RESULTS: A total of 18 patients with a mean age of 73 years (range: 56 to 86) were included. The indications for stent placement were significant recoil (7, 39%), graft rupture (6, 33%), residual vein cusps (3, 17%) and aneurysmal degeneration (2, 11%). There was a high overall technical success rate of 94% (17/18) and arrest of haemorrhage was achieved in all cases of graft rupture. The primary patency at 1, 6 and 12 months was 89%, 71% and 59%, respectively. CONCLUSION: The use of bare and covered stents in infrainguinal vein grafts appears safe and effective. They are an excellent bail-out option for the treatment of graft rupture and give acceptable short-term results.

Factors Affecting Medium-Term Outcomes After Crural Angioplasty in Critically Ischemic Legs.

OBJECTIVES: To study factors affecting patency and medium-term outcomes after crural angioplasty. MATERIALS AND METHODS: All crural angioplasties between March 2003 and September 2010 were reviewed from a prospective database to analyze primary patency, amputation-free survival, and limb salvage. RESULTS: Five hundred and twenty-seven limbs in 478 patients (58.7% male, mean age 73.9 ± 0.53 years) were treated. In all, 49.1% were diabetic patients and 7.4% were dialysis dependent. Primary patency was 65.5%, 57.8%, 48.5%, and 32.9% at 1, 6, 12, and 36 months, respectively. Amputation-free survival was 75.2% at 1 year and 59.0% at 3 years. Limb salvage at 3 years was 92.7%. Rutherford categories 5 and 6 had a consistent adverse effect on patency. This led to an adverse amputation-free survival and limb salvage at 3 years. CONCLUSION: Crural angioplasty is an effective treatment for limb salvage. Its outcomes are adversely affected by diabetes, renal disease, coronary disease, and worsening Rutherford grade.

Cranial ultrasound for the diagnosis of giant cell arteritis. A retrospective cohort study.

BACKGROUND: Establishing a diagnosis of giant cell arteritis, or indeed ruling it out, may be difficult. We describe an evaluation of temporal artery colour duplex ultrasound as first line investigation in patients with suspected giant cell arteritis. METHODS: A retrospective cohort study of all patients undergoing colour duplex ultrasound for suspected giant cell arteritis between January 2005 and January 2014 was undertaken at a teaching hospital. A minimum clinical follow-up of three months was required. Patients were classified on the basis of ultrasound reports, using described features such as a halo sign or arterial wall thickening and clinical diagnosis of giant cell arteritis after at least 3 months follow-up, determined by the treating physician. The relationship of colour duplex ultrasound to a final clinical diagnosis of giant cell arteritis was analysed. RESULTS: A total of 87 patients underwent colour duplex ultrasound: 36 (41%) had clinically confirmed giant cell arteritis at 3-month follow-up. The positive predictive value of colour duplex ultrasound for a clinical diagnosis at 3 months was 97% (95% confidence interval (CI) 93 to 99%) and negative predictive value 88% (95% CI 76 to 95%). Sensitivity was 81% (95% CI 64 to 92%) and specificity 98% (95% CI 90 to 100%). CONCLUSIONS: A high positive and negative predictive value of arteritis on colour duplex ultrasound indicates that temporal artery biopsy may be unnecessary in suspected giant cell arteritis, particularly where clinical suspicion of giant cell arteritis is high or low.

Lower limb ischaemic symptoms in the young patient: popliteal artery entrapment.

This case report describes a case of Popliteal Entrapment Syndrome causing unilateral ischaemic claudication symptoms in an otherwise healthy soldier. The condition is rare but is an important cause of exercise related leg pain; untreated it can progress to structural arterial damage requiring reconstruction. Early identification of such cases may allow less invasive treatment.

Below-the-ankle angioplasty is a feasible and effective intervention for critical leg ischaemia.

AIM: Occlusion or severe stenosis of pedal and plantar arteries limits surgical options for critical limb ischaemia (CLI). Below-the-ankle (BTA) angioplasty is potentially useful as an adjunct to proximal angioplasty. In this study, the feasibility and outcome of this procedure were explored, as they have not been evaluated previously. METHODS: Patients' demographics, indications, procedures and outcomes were recorded. Outcomes were determined by technical success, primary patency, limb salvage and amputation-free survival (AFS) rates. RESULTS: Between 2004 and 2008, 42 cases of BTA angioplasty were performed for 39 patients. Forty cases (95.2%) had CLI. Technical success was achieved in 88% of cases. At 6, 12 and 24 months, AFS was 70.7%, 60.9% and 57.1%, limb salvage was 84.9%, 81.9% and 81.9% and patient survival was 83.3%, 73.8% and 67.3, respectively. Seven major amputations (16.6%) were performed, four of which had failed angioplasty. Two patients required re-intervention. Univariate analysis showed insulin-dependent diabetics, occlusive lesions, failure of angioplasty and state of the run off to be the predictors of limb loss. CONCLUSIONS: BTA angioplasty for pedal and plantar arterial occlusive disease is technically feasible. It has good medium-term clinical outcome and limb salvage in a group of patients with poor surgical options.

B-cells in multiple sclerosis.

B-cells may be involved at many levels in the pathogenesis of MS, starting from the earliest stage of antigen capture, continuing through the processes of tissue damage and even extending through to remyelination and repair. Recent advances in our understanding of normal B-cell biology and abnormal regulation of their functions in relation to the pathology of MS are discussed in this review. Current treatments already target B-cell responses; consequently, this effect may be one explanation for the efficacy of these treatments in some types of MS. The results of specific anti-B-cell therapies are awaited. Even if success is limited, it is possible that targeting this important group of cells, whether as antigen-presenting cells, as regulators of immune responses or as antibody-secreting cells, will form at least part of more successful treatment strategies in the future.

Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy believed to be caused by the bovine spongiform encephalopathy agent, an abnormal isoform of the prion protein (PrP(sc)). At present there is no specific or effective treatment available for any form of CJD. Pentosan polysulphate (PPS), a large polyglycoside molecule with weak heparin-like activity, has been shown to prolong the incubation period of the intracerebral infection when administered to the cerebral ventricles in a rodent scrapie model. PPS also prevents the production of further PrP(sc) in cell culture models. These properties of PPS prompted its cerebroventricular administration in a young man with vCJD. Long-term continuous infusion of PPS at a dose of 11 microg/kg/day for 18 months did not cause drug-related side effects. Follow-up CT scans demonstrated progressive brain atrophy during PPS administration. Further basic and clinical research is needed in order to address the issue of efficacy of PPS in vCJD and in other prion diseases.

Central pontine myelinolysis complicating treatment of multicentric Castleman's disease and Kaposi's sarcoma in a patient with AIDS.

An HIV positive black African woman presented with widespread lymphadenopathy and pancytopenia that had been ascribed to tuberculosis. Lymph node biopsy showed both Kaposi's sarcoma and multicentric Castleman's disease. Despite antiretroviral therapy and chemotherapy the patient deteriorated, developing confusion and dysphasia. A cranial magnetic resonance scan showed central pontine myelinolysis. Despite supportive therapy the patient died.

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Progressive intrathoracic lymphadenopathy: EBV associated non-Hodgkin's lymphoma.

A 30 year old man presented with late stage HIV disease and intrathoracic lymphadenopathy. Histology of a mediastinal biopsy suggested infective follicular hyperplasia or a peripheral T cell lymphoma. Subsequently, Epstein-Barr virus (EBV) infection was demonstrated in lymphocytes in the biopsy. Later, hepatosplenomegaly and peripheral lymphadenopathy developed. Histology of a cervical lymph node biopsy showed EBV associated diffuse large B cell (non-Hodgkin's) lymphoma.

Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state.

Traditionally, emphasis has been placed on the roles of Th cells in generating and amplifying both cellular and humoral memory responses. Little is known about the potential contributions of B cell subsets to immunological memory. Resting memory B cells have generally been regarded as poor APC, attributed in part to the relative paucity of costimulatory molecules identified on their surface. We describe a novel subpopulation of human memory B cells that express CD80 in their resting state, are poised to secrete particularly large amounts of class switched Igs, and can efficiently present Ag to and activate T cells. This functionally distinct B cell subset may represent an important mechanism by which quiescent human B cells can initiate and propagate rapid and vigorous immune memory responses. Finally, these studies extend recent observations in the murine system and highlight the phenotypic and functional diversity that exists within the human B cell memory compartment.

Worsening lipid profile is associated with progression of carotid artery stenosis.

BACKGROUND: To determine if uncontrolled hypercholesterolaemia predisposes to progression of carotid artery stenosis. METHODS: Fasting blood samples were collected from 76 patients referred for carotid duplex ultrasound for investigation of transient ischaemic attacks or recent stroke. Patients were grouped depending on the severity of the stenosis found. Patients on lipid lowering agents were excluded. The data were analysed using one way analysis of variance and the c2 test as appropriate. RESULTS: There were more men in the 70-99% group (15 vs 6, c2 = 10.6, p < 0.001, Table I). The total cholesterol was raised in all three groups. Patients with carotid stenosis of 70-99% had significantly elevated triglycerides (2.4 mmol vs 1.47 mmol and 1.37 mmol, p < 0.003), low HDL (1.14 mmol vs 1.45 mmol and 1.18 mmol, p < 0.003) and a higher cholesterol/HDL ratio (5.56 vs 4.29 and 4.71, p < 0.014) compared with the other two groups. There was no difference in lipoprotein(a) in the three groups. CONCLUSIONS: Increased triglycerides and low HDL cholesterol seen in the 70-99% group suggest that a worsening lipid profile is associated with progression of carotid artery stenosis.

Monocyte-derived dendritic cells: a potential target for therapy in multiple sclerosis (MS).

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.

Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation.

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.