Severe Relapse Research Articles

Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids.

Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.

Pro: Should all patients with anti-neutrophil cytoplasmic antibody-associated vasculitis be primarily treated with rituximab?

Randomized controlled trials have shown that rituximab is non-inferior to cyclophosphamide followed by azathioprine (CYC/AZA) for remission induction in severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The efficacy of rituximab is on par with CYC/AZA for 18 months, for patients with GPA and MPA alike, and for patients with any degree of renal impairment. The Rituximab in ANCA-associated Vasculitis (RAVE) trial also showed superiority of rituximab for patients presenting with a severe disease relapse. An exploratory analysis of the RAVE data further suggests that rituximab may be preferable for PR3-ANCA-positive patients as superiority was also achieved in that subset. When considering treatment options for patients with disease presentations for which only non-inferiority has been documented, safety concerns, compliance issues, the overall cost of each treatment approach to the patient, to society and to insurers, as well as individual patient preferences all should affect the decision-making process. The trials failed to uncover any difference in adverse events between rituximab and CYC/AZA. However, daily oral cyclophosphamide given for 3-6 months has measurable negative effects on fertility. Rituximab has certain compliance and convenience advantages. When assessing cost, the overall cost of a treatment, the societal context of the individual patient and not merely the sticker price of the drug should be considered. For all of these reasons, the author believes that CYC/AZA should be reserved for patients with newly diagnosed, MPO-ANCA-positive disease who raise no fertility, compliance or malignancy concerns.

Omega-3 fatty acids in first-episode schizophrenia - a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods.

BackgroundPolyunsaturated fatty acid (PUFA) metabolism abnormalities have been long implicated in the etiology of schizophrenia. Although several randomized clinical trials have been carried out to assess the efficacy of omega-3 PUFA as add-on therapy in reducing psychopathology in populations of chronic patients with schizophrenia, only a few concern first-episode schizophrenia. The majority of these studies used a 12-week intervention based on ethyl-eicosapentaenoic acid (ethyl-EPA), however, with conflicting results. An intervention based on docosahexaenoic acid plus EPA has not been used in first-episode schizophrenia studies so far. No add-on supplementation studies have been carried out in medicated first-episode schizophrenia patients to assess the efficacy of omega-3 PUFA in preventing relapses.MethodsA randomized placebo-controlled one-center trial will be used to compare the efficacy of 26-week intervention, composed of either 1320 mg/day of EPA and 880 mg/day of DHA, or olive oil placebo with regard to symptom severity and relapse rate in first-episode schizophrenia patients. Eighty-two patients (aged 16–35) will be recruited for the study. Eligible patients will be randomly allocated to one of two intervention arms: an active arm or a placebo arm (olive oil). The primary outcome measure of the clinical evaluation is schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Other outcomes include depressive symptoms, patient functioning and the level of insight. Correlates of change measured during the study will include structural brain changes, oxidative stress and defense, as well as neuroplasticity indicators. Metabolic syndrome components will also be assessed throughout the study.DiscussionBy comparing 26-week administration of EPA + DHA or (placebo) olive oil as add-on therapy in reducing symptom severity and one-year relapse rate in patients with first episode schizophrenia, it is intended to provide new insights into the efficacy of omega-3 PUFA and correlates of change, and contribute to the improvement of mental health care for individuals suffering from schizophrenia.Trial registrationThis study has been registered at Clinical Trials.gov with the following number: NCT02210962.

PND11 - Teriflunomide Shows Consistent Clinical Efficacy On Severe Relapses Across temso and tower: 2 Phase 3 trials

1Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 2Hannover Medical School, Hannover, Germany; 3Austin Health, Heidelberg, VIC, Australia; 4Caritas Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6Genzyme, a Sanofi company, Chilly-Mazarin, France; 7Sanofi, Chilly-Mazarin, France; 8University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada

Acute combined central and peripheral demyelination: a case report

Aim/Background: We report a case of Acute Combined Central and Peripheral Demyelination (ACCPD). This rare disease presents with features of both peripheral and central demyelination. Methods: Case Report Results: A 24 year-old Iraqi female presented with acute onset of ascending paralysis, numbness and areflexia over the course of a few days. Systemic examination was negative. She responded to IVIG. She suffered two severe relapses over the next three months, which resolved rapidly with PLEX/corticosteroid. CSF was normal after first and second relapses. Brain and cord MRI revealed multiple T2/FLAIR hyperintensities consistent with multiple sclerosis. There were no longitudinally extensive cord lesions. Aquaporin 4 antibody assay is pending. ANA was strongly positive; anti-DSDNA and SS antibodies were negative; complement4 was low and serum cyroglobulins were positive. Hepatitis C was negative. Ganglioside antibody assay was negative. Anti-neurofascin is pending. Neurophysiology confirmed features of an acquired demyelinating neuropathy with profound secondary axonal denervation. Conclusions: The underlying etiology of ACCPD is presumed autoimmune likely secondary to auto-antibody targeting of central and peripheral myelin epitopes. Low complement component 4 and cryoglobulinemia in this patient supports an autoimmune pathogenesis. Neurofascin has been previously reported as one such auto-antibody in ACCPD.

Teriflunomide Associated With Reductions in Severe MS Relapses

The TEMSO and TOWER trials demonstrate that both doses of teriflunomide (7 mg and 14 mg) each significantly reduce the annualized relapse rates in patients with relapsing multiple sclerosis. Post hoc analyses of both trials indicate that only teriflunomide 14 mg significantly reduces the rate of all 5 markers of severe relapse in both studies.

Celiac disease, collagenous sprue and microscopic colitis in IBD. Observations from a population-based cohort of IBD (ICURE)

Objective. Inflammatory bowel disease (IBD), microscopic colitis and celiac disease are all diseases with worldwide distribution and increased incidence has been reported from many areas. There is a shortage of studies investigating the occurrence of these diseases in the same individual and whether those affected demonstrate any particular phenotype. The aim of the study was to describe the concomitant incidence of microscopic colitis and celiac disease in a population-based IBD cohort. Methods. All 790 individuals in a prospective population-based cohort included 2005–09 from Uppsala region, Sweden, were reviewed regarding the appearance of microscopic or celiac disease before or after IBD diagnosis. Results. Fifty percent (396/790) of the patients had been examined for the possibility of celiac disease. Seventeen patients with celiac disease were found, representing 2.2% of the cohort. Patients with celiac disease were younger compared to the non-celiac patients and those with colitis had more often an extensive inflammation of the colon. Seventy-one percent (12/17) were women. The majority of the patients were diagnosed with celiac disease before IBD. Five patients with IBD had an earlier diagnosis of microscopic colitis or developed it after the IBD diagnosis. One teenager developed collagenous sprue, misinterpreted as a severe relapse of ulcerative colitis (UC) resulting in colectomy. Conclusions. The risk for celiac disease seems not to be increased in IBD, but those affected by both diseases seem to be predominantly women with extensive UC. There is a potential association between microscopic colitis and IBD.

Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: A functional imaging study in alcohol dependent subjects

The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene (OPRM1) is suggested to modulate alcohol-related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol-dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol-dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol׳s effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers׳ increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity.

Severe disease reactivation in four patients with relapsing-remitting multiple sclerosis after fingolimod cessation.

Fingolimod is a well-established, highly effective immunomodulatory treatment for patients with relapsing-remitting multiple sclerosis (RRMS). However, little is known about disease course after its discontinuation. This is a case series on four patients with RRMS who had a severe reactivation after fingolimod discontinuation. One patient had pretreatment with glatiramer acetate, interferon-β 1b and interferon-β 1a and another with interferon-β 1a, intravenous immunoglobulins and natalizumab whereas the other two were therapy naïve before fingolimod initiation. Patients were treated with fingolimod for two, thirty, forty-five and seventy-eight months, respectively. Fingolimod had to be discontinued because of persisting lymphopenia, severe varicella zoster virus infection, subarachnoid hemorrhage, and increased liver function enzymes, respectively. Between two to four months after fingolimod cessation these patients had a severe relapse. Cerebral magnetic resonance imaging (MRI) at this point revealed multiple new lesions, partially with contrast ring enhancement. Partial recovery was achieved after steroid pulse therapy followed by plasma exchange in two patients. Despite the limited evidence from our case series on potential disease reactivation exceeding pre-fingolimod activity in a subgroup of RRMS patients, particularly patients with previously high disease activity should undergo frequent clinical as well as radiological monitoring after fingolimod discontinuation.

Teriflunomide Shows Consistent Clinical Efficacy on Severe Relapses across Two Phase 3 Trials in Patients with Relapsing forms of Multiple Sclerosis, TEMSO and TOWER (P7.212)

Teriflunomide Shows Consistent Clinical Efficacy on Severe Relapses across Two Phase 3 Trials in Patients with Relapsing forms of Multiple Sclerosis, TEMSO and TOWER (P7.212)

Progressive Subacute Combined Degeneration: A Severe Relapse With Discontinuation of Vitamin B12 Treatment

Progressive Subacute Combined Degeneration: A Severe Relapse With Discontinuation of Vitamin B12 Treatment

Edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty in correction of unilateral cleft nasal deformity in secondary rhinoplasty.

Ala and nostril collapse are most raised complaints in secondary deformity of unilateral cleft patients. While a lot of techniques have been introduced so far, the purpose of this study was to evaluate the effectiveness of edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty to correct the collapse in lower lateral cartilage in the ala and nostril shaping. Fifty-seven patients with unilateral cleft nasal deformities were recruited. They all had primary surgery before and were left with nasal deformities. Based on the anatomic understanding, we operated on all the patients using edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty to correct the abnormal lateral collapse of nostril deformities. All the patients had an improvement in the shape of the ala and nostril immediately after the surgery. Follow-up at 6 months (or later) showed no severe relapse. The edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty is effective to correct ala and nostril deformities in unilateral cleft.

Joint assessment of dependent discrete disease state processes.

In multiple sclerosis, the primary clinical measure of disability level is an ordinal score, the expanded disability severity scale score. In relapsing-remitting multiple sclerosis, measures of relapse are additionally of interest. Multiple sclerosis patients are typically assessed with regard to both the expanded disability severity scale and relapse state at each follow-up visit. As both are discrete measures, the two can be viewed as jointly dependent Markov processes. One of the main goals of multiple sclerosis research is to accurately model, over time, both transitions between expanded disability severity scale states and change in relapse state. This objective requires a number of significant modeling decisions, including decisions about whether or not the combination of specific disease states is warranted and assessment of the dependence structure between the two disease processes. Historically, such decisions are often made in an ad hoc manner and are not formally justified. We propose novel use of Bayes factors and Bayesian variable selection in the assessment of jointly dependent Markovian processes in multiple sclerosis. Methods are assessed using both simulated data and data collected from the Partners Multiple Sclerosis Center in Boston, MA.

Predisposition to and effects of methamphetamine use on the adolescent brain.

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.

Consommation d’alcool après greffe de foie chez les patients transplantés pour cirrhose alcoolique

Liver transplantation is the gold standard treatment for terminal cirrhosis and liver cancer (if no surgical option is available). In France, the leading cause of liver transplantation is alcoholic cirrhosis. Severe alcohol relapse is often considered as a failure and concerns 11 to 26% of cases. The severe relapse causes a significant decrease in survival after 5 years of follow up, regardless of the origin of the transplantation. Predictors of relapse, like pretransplant abstinence duration, additional psychiatric co-morbidity, age, and level of social support have been assessed. However, alcohol addiction and liver transplantation are complex entities that cannot be reduced to a list of predictive factors. A multidisciplinary approach including an addiction specialist should identify and minimize the risk of severe relapse.

From immunomonitoring to immune intervention.

Host immune status is a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to prolonged immune defects, especially in the context of innovative stem cell sources such as umbilical cord blood transplantation (CBT) (1) or transplants from HLA haplo-identical family donors (Haplo-HSCT) (2, 3). This Frontiers Research Topic provides insights into mechanisms of immune reconstitution in an allogeneic environment, in order to improve monitoring and therapeutic intervention in allo-HSCT patients. Forcina et al. (4) critically review T and NK biomarkers, their threshold and clinical relevance. Many factors from the host, transplant conditioning, stem cell source, and genetic disparity may impact immune recovery. Few biomarkers have reached a clinical consensus: a rapid and potent CD4 T-cell recovery is associated with a favorable clinical outcome, CMV-specific CD8 T-cell counts measured by tetramers can predict a lower incidence of CMV disease. Other phenotypic or molecular markers, still based on small-sized studies, will need further validation in large scale-multicentric cohorts. This is the case of molecular markers of lymphocyte generation, such as T-cells evaluated by the quantification of T-cell rearrangement excision circles (TREC) as a surrogate marker of thymic activity. Clave et al. (3) indicate an impact of thymic function recovery on relapse following CBT as well as Haplo-HSCT in children treated for an hematological malignancy. In order to reach the routine medical practice, immunomonitoring tests need also to be simple and fast. This practical issue is well taken into account by Fuji et al. (5) reviewing T-cell monitoring of viral and fungal infections. CMV is still the most intensively studied virus in immunocompromised hosts. CMV shapes T and NK cell responses in many ways and may escape immune response. Among still unanswered questions, is the role of viral-specific (CMV and EBV) T-cell cross-reactivity against allogeneic targets in graft-versus-host and graft-versus-leukemia (6). Experimental models have proved their importance in allo-HSCT, especially deciphering mechanisms of allogeneicity in graft-versus-host disease (GVHD). Among rodents, rat models are relevant especially in some autoimmune conditions and solid organ transplantation, sometimes closer to the human disease than the “gold standard” murine models. Zinocker et al. (7) emphasize the interest of rat model in experimental GVHD, especially the rat skin explant assay as a tool for functional evaluation of GVHD. Experimental models are also required to provide the basis and for preclinical evaluation of immune-based therapies. This Frontiers Research Topic also reviews in some strategies already proposed in the clinics. Adoptive T-cell therapies have been conducted successfully by several groups to control life-threatening viral (EBV, CMV) reactivations. This leads to “off the shelf” strategies based on third party HLA-typed T-cell donors registries, which may have a major impact in transplant recipients (8). The development of therapeutic antibodies in cancer is one of the most active fields in clinical immunology. Many strategies are underway to improve their action, especially through their antibody-dependent cellular toxicity mediated by natural killer (NK) cells (9). One approach especially relevant in allo-HSCT would be to take advantage of the killer-immunoglobulin-like receptor (KIR) ligand incompatibility in addition to ADCC to boost NK functions. The impact of these different concepts, from basic knowledge to translational medicine, is integrated in state-of-the art reviews of two main “success stories” in allo-HSCT: CBT (1) and Haplo-HSCT (2).

P038 - Impact of stop β interferon on 20 cases of relapsing remitting multiple sclerosis in BMC Benghazi-Libya 2011

Background Multiple sclerosis is a common demylinating and inflamatory disease of the CNS with a presumed autoimmune etiology. Interferon β have been used for relapsing remitting multiple sclerosis through its regulatory properties on T-cell activation and cytokines production. Objectives During the war Benghazi-Libya (17 February 2011 revolution) multiple sclerosis patients have got stopped β interferon because unavailability of drugs which allow to evaluate the efficacy of β interferon on relapsing remitting multiple sclerosis regarding frequency and severity of relapses during months of stopping it. Methods Twenty cases of relapsing remitting multiple sclerosis aged 18–55 years of disease duration 1–11 years were on βinterferon none of them have a relapse studied in comparative retrospective prospective study disease relapse, none of the patients has relapse, no relapse, its severity, nature of relapse and respond to Rx in months of stoppage of β interferon and before stop it using frequency, percentage and P value. Results Fifteen cases of 20 got relapse (75% relapse rate) significant rate, 3 cases have more than 1 relapse, 12 got severe relapse, 11 cases admitted to hospital, all patients recieved Methylprednisolone 1 g (3–5 days), 13 got complete respond and 2 incomplete. Conclusion β Interferon is efficient in prevention of relapse and decreasing severity of relapse in relapsing remitting multiple sclerosis. Multiple sclerosis is a common demylinating and inflamatory disease of the CNS with a presumed autoimmune etiology. Interferon β have been used for relapsing remitting multiple sclerosis through its regulatory properties on T-cell activation and cytokines production. During the war Benghazi-Libya (17 February 2011 revolution) multiple sclerosis patients have got stopped β interferon because unavailability of drugs which allow to evaluate the efficacy of β interferon on relapsing remitting multiple sclerosis regarding frequency and severity of relapses during months of stopping it. Twenty cases of relapsing remitting multiple sclerosis aged 18–55 years of disease duration 1–11 years were on βinterferon none of them have a relapse studied in comparative retrospective prospective study disease relapse, none of the patients has relapse, no relapse, its severity, nature of relapse and respond to Rx in months of stoppage of β interferon and before stop it using frequency, percentage and P value. Fifteen cases of 20 got relapse (75% relapse rate) significant rate, 3 cases have more than 1 relapse, 12 got severe relapse, 11 cases admitted to hospital, all patients recieved Methylprednisolone 1 g (3–5 days), 13 got complete respond and 2 incomplete. β Interferon is efficient in prevention of relapse and decreasing severity of relapse in relapsing remitting multiple sclerosis.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

P.3.d.003 Cost-effectiveness study of long-acting injectable antipsychotics and functioning in psychosis with and without substance dependence

Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.

Other people's houses: how decades of bailouts, captive regulators, and toxic bankers made home mortgages a thrilling business

In the wake of the financial meltdown in 2008, many claimed that it had been inevitable, that no one saw it coming, and that subprime borrowers were to blame. This accessible, thoroughly researched book is Jennifer Taub's response to such unfounded claims. Drawing on wide-ranging experience as a corporate lawyer, investment firm counsel, and scholar of business law and financial market regulation, Taub chronicles how government officials helped bankers inflate the toxic-mortgage-backed housing bubble, then after the bubble burst ignored the plight of millions of homeowners suddenly facing foreclosure. Focusing new light on the similarities between the savings and loan debacle of the 1980s and the financial crisis in 2008, Taub reveals that in both cases the same reckless banks, operating under different names, received government bailouts, while the same lax regulators overlooked fraud and abuse. Furthermore, in 2013 the situation is essentially unchanged. The author asserts that the 2008 crisis was not just similar to the S&L scandal, it was a severe relapse of the same underlying disease. And despite modest regulatory reforms, the disease remains uncured: top banks remain too big to manage, too big to regulate, and too big to fail.