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Concept: Relapse

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Background B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. Methods In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. Results The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. Conclusions Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Concepts: Immune system, Monoclonal antibodies, Magnetic resonance imaging, Multiple sclerosis, Relapse, Rituximab, Hoffmann–La Roche

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OBJECTIVE To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN Retrospective case series. SETTING Neurology department at a tertiary referral center. PATIENTS Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. MAIN OUTCOME MEASURES Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Concepts: Immune system, Population, Effectiveness, Multiple sclerosis, Relapse, Interleukin, Interleukin 6, Neuromyelitis optica

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Abstract Background: Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) has been proposed to be associated with Multiple Sclerosis (MS). Zamboni et al reported significant improvement in neurological outcomes in MS patients who underwent Percutaneous Transluminal Angioplasty (PTA). Objectives: To retrospectively evaluate the neurological outcomes in MS patients who underwent PTA. Method: Relapsing remitting MS patients who underwent PTA and completed at least one year post PTA were assessed. Patients with clinically isolated syndrome or progressive forms of MS were excluded. Primary endpoint was the proportion of relapse-free patients at one year. Secondary endpoints were change in mean EDSS score and proportion of patients with new MRI activity (defined as either Gadolinium-enhancing or new T2 lesions) at one year. Results: 45 patients satisfied the inclusion criteria. Females constituted 71.1%. The mean age and mean disease duration were 33.76 and 7.16 years respectively. At one-year post-PTA, the proportion of relapse-free patients decreased from 84.44% to 66.67% (p = 0.085) whereas the mean EDSS score increased (p = 0.017). The proportion of patients with new MRI activity increased significantly from 17.78% to 44.44% (p = 0.012). 35.6% of patients stopped their DMTs. There was no difference among the patients who stopped their DMTs with respect to relapses, EDSS score or new MRI activity. Conclusion: The study revealed that PTA in relapsing remitting MS patients was not associated with any neurological improvement. However, there was an increase in disease activity irrespective of the adherence to DMTs. Further evidence of the association between CCSVI and MS is required.

Concepts: Retrospective, Magnetic resonance imaging, Multiple sclerosis, Clinically isolated syndrome, Relapse, Radiology, Angioplasty, Chronic cerebrospinal venous insufficiency

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INTRODUCTION: Fasting during the Ramadan month is a cornerstone of Islam. Several disorders of the chronobiological rhythms occur during this month and impact on mood. Through this paper the authors provide a literature review of the impact of fasting on patients with bipolar disorders. MATERIALS AND SUBJECTS: A literature review using Mesh keywords through Medline database. From 1970 to 2011, articles in French and English were selected. RESULTS: Circadian rhythm refers to the approximately 24-hour cycles that are generated by an organism. Most physiological systems demonstrate circadian variations. Many hormones and other metabolisms, such as gastric pH, insulin, glucose, calcium and plasmatic gastrine, have been shown to exhibit circadian oscillation. The role of social rhythm in behaviors and its influence on circadian rhythms in humans is now obvious. It has been shown that the lack of concentration and irritability increased continuously during Ramadan month and reached its peak at the end of the month. Mood and vigilance are significantly decreased during the fasting month. Several authors have stated that the course of bipolar illness may be affected by the changes in social rhythm that occur during Ramadan (fasting month). Studies which have been devoted to this topic are sparse. Kadri et al., in 2000, studied 20 bipolar patients during the fasting month of Ramadan of 1417 (Hegirian calendar, corresponding to January 1997). Diagnosis of bipolar disorder was made according to ICD-10 criteria. Patients were assessed during the week before Ramadan, the second and the fourth weeks of the fasting month and the first week after its end, with the Hamilton Depression and Bech-Rafaelsen scales. The plasma concentration of lithium was also assessed. The main finding of the study was that 45% of the patients relapsed, 70% during the second week, and the remaining patients at the end of Ramadan. These relapses were not related to plasma concentration of lithium. Most of the relapses were manic (71,4%). Patients who did not relapse had more insomnia and anxiety during the second and third weeks of the study. The side effects of lithium increased and were seen in 48% of the sample, mostly dryness of the mouth with thirst and tremor. However, Farooq et al. in 2006 studied 62 bipolar patients during the fasting month of Ramadan 1427 (from 25 September to 24 October 2006). Serum lithium, electrolytes, Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were assessed, one week before Ramadan, mid Ramadan and one week after Ramadan. The side effects and toxicity were measured by symptoms and signs checklist. There was no significant difference in mean serum lithium levels at three time points. The scores on HDRS and YMRS showed significant decrease during Ramadan (F=34,12, P=0,00, for HDRS and F=15,6, P=0,000 for YMRS). Also the side effects and toxicity did not differ significantly at the three point’s assessment. CONCLUSION: All physiologic parameters are influenced by the circadian rhythm, which is influenced in its turn by the food rhythm. So far, the results of these two main studies, with opposite results, do not help us advise bipolar patients to fast or not to fast. Other studies in this field are badly needed.

Concepts: Sleep, Relapse, Bipolar disorder, Mania, Insomnia, Melatonin, Ramadan, Ultradian

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A case of rapidly relapsing pyoderma gangrenosum (PG) of the left preauricular area with no undermined borders is described. This might be considered a case of malignant pyoderma (PM), a rare variety of PG. Five months after complete healing obtained with systemic corticosteroids, the preauricular lesion of PG relapsed. As retreatment with oral methylprednisolone induced glucose intolerance and high arterial pressure, sulfa drugs were initially employed with a transitory recovery of the skin lesion. A successive prolonged course with minocycline induced a new complete resolution. To date, at six months' follow-up, the patient is relapse-free. This case confirms that sulfa drugs and minocycline may also be considered alternative therapies in PM. PM is a variety of PG characterized by specific morphological features, a higher tendency to relapse, and poor responsiveness to treatment.

Concepts: Rheumatoid arthritis, Artery, Corticosteroid, Relapse, Systemic lupus erythematosus, Pharmaceutical drug, Pyoderma gangrenosum, Methylprednisolone

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The standard treatment for patients with metastatic GCT relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing 3-drug regimen, which usually yields a complete response (CR) rate <50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study.

Concepts: Clinical trial, Cancer, Oncology, Lung cancer, Chemotherapy, Relapse, Chemotherapy regimens, Carboplatin

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The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI on-study, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study was: 11 ITI successes (78.6 %); one partial success; one failure; and one relapse. Thus, the ITI follow-up study was helpful in providing a long-term prognostic determination of inhibitors.

Concepts: Statistical significance, Relapse, Failure, Success, Immune tolerance

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Peginterferon beta-1a (Plegridy™), an interferon beta-1a conjugated to a methoxy polyethylene glycol (PEG) molecule, is available in the EU and the USA for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS). In a 96-week multinational, phase III study in this patient population (ADVANCE), subcutaneous peginterferon beta-1a 125 µg every 2 weeks significantly reduced the adjusted annualized relapse rate over 48 weeks, compared with placebo, corresponding to 36 % fewer relapses per patient-year. Significant reductions versus placebo were also observed in the risk of relapse and disability progression, the number of new or newly enlarging T2-weighted hyperintense lesions, and various other magnetic resonance imaging endpoints. The efficacy of peginterferon beta-1a was sustained over 96 weeks, with preliminary data from the first year of an ongoing 2-year extension of ADVANCE indicating continued benefit longer-term. In ADVANCE, peginterferon beta-1a had an acceptable tolerability profile that was consistent with that of established interferon beta treatments. Adverse events were generally mild or moderate in severity, with injection-site erythema and influenza-like illness reported most commonly. Amongst other adverse events of special interest, peginterferon beta-1a was not associated with an increased risk of autoimmune disorders, depression/suicidal ideation, infections or seizures. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of peginterferon beta-1a versus existing therapies are not yet possible. Although final data from the extension of ADVANCE are awaited, current evidence suggests subcutaneous peginterferon beta-1a every 2 weeks extends the treatment options currently available for adults with RRMS, with the dosing regimen imparting potential compliance advantages over non-PEGylated interferon beta formulations that require more frequent administration.

Concepts: Cytokines, Magnetic resonance imaging, Interferon, Multiple sclerosis, Relapse, Interferon beta-1a, Interferon beta-1b, Interferon type I

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Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested.

Concepts: Scientific method, Medicine, Disease, Medical terms, Greek loanwords, Symptom, Multiple sclerosis, Relapse

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Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the absence of validated biomarkers to guide drug selection. Methods such as stratifying patients on the basis of estimated risk for future disability, weighing patient specific factors and preferences, and using objective outcomes to adjudicate treatment success are discussed. Emerging drug therapies and strategies are also reviewed.

Concepts: Pharmacology, Medicine, Brain, Randomized controlled trial, Nuclear magnetic resonance, Magnetic resonance imaging, Multiple sclerosis, Relapse