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Natalizumab treatment for multiple sclerosis inducing a toxic acute myocardial damage. Is there any relationship?
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Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon β-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability.
Multiple sclerosis is a chronic disease of the CNS that leads to substantial disability in most patients. The early phase is characterised by relapses and the later phase by progressive disability. Results from immunological, genetic, and histopathological studies and treatment trials have shown that the immune system plays a key part in the disease course. Findings from animal models and immunological studies of patients with multiple sclerosis suggest a change in the involvement of the immune system during disease initiation and progression. These findings suggest that a peripheral immune response targeting the CNS drives the disease process during the early phase, whereas immune reactions within the CNS dominate the progressive phase. These concepts for the differential involvement of immune responses in the early and progressive phase of this disease have important implications for future research in the pathogenesis and treatment of multiple sclerosis.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Objective:
The monoclonal antibody alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in multiple sclerosis (MS) patients when compared to β-interferon. The development of autoimmune diseases, including thyroid disease, has been reported in the literature with a frequency of 20 to 30%. In this article, we describe 4 cases of alemtuzumab-induced thyroid disease in patients with MS. We also performed a systematic review of the available literature.
Methods:
Four patients who had received alemtuzumab for MS and subsequently developed thyroid dysfunction are presented. We compared our patients' clinical courses and outcomes to established disease patterns. We also undertook a systematic review of the published literature.
Results:
All 4 patients presented with initial hyperthyroidism associated with elevated thyroid-stimulating hormone (TSH) receptor antibodies (TRAb). In 2 cases, hyperthyroidism did not remit after a total of 24 months of carbimazole therapy, and they subsequently underwent subtotal thyroidectomy. The third case subsequently developed biochemical hypothyroidism and required thyroxine replacement, despite having a markedly raised initial TRAb titer. Autoimmunity following alemtuzumab therapy in MS appears to occur as part of an immune reconstitution syndrome and is more likely in smokers who have a family history of autoimmune disease.
Conclusion:
Management of alemtuzumab-induced thyroid disease is similar to the management of "wild-type" Graves' disease. The use of alemtuzumab in this setting will necessitate close monitoring of thyroid function and early intervention when abnormalities are developing.
Background:
Clozapine is a unique anti-psychotic medication that is most effective in the treatment of refractory schizophrenia and reducing suicidality. Cardiomyopathy is among the side effects of this medication that limits its use. There are a number of case reports, case series and expert opinion papers discussing clozapine induced cardiomyopathy, but there is no evidence-based review of the subject to guide clinicians.
Methods:
We undertook a systematic review of the literature on cardiomyopathy associated with clozapine. The primary systemic search was in MEDLINE but EMBASE, PsycINFO, and Cochrane were searched and manufacturers of clozapine were contacted for cases. Articles were then individually reviewed to find additional reports.
Results:
We identified 17 articles detailing 26 individual cases and 11 additional articles without individual case data. The mean age at time of diagnosis was 33.5 years. The mean dose of clozapine on presentation was 360 mg. Symptoms developed at an average of 14.4 months after initiating clozapine. The clinical presentation was generally consistent with heart failure: including shortness of breath (60%) and palpitations (36%). Echocardiography at presentation showed dilated cardiomyopathy in 39% of cases and was not specified in other cases.
Conclusion:
There should be a low threshold in performing echocardiography in suspected cases of clozapine induced cardiomyopathy. Clozapine should be withheld in the setting of cardiomyopathy without other explanation. There is limited data on the safety of drug re-challenge in clozapine induced cardiomyopathy. Re-challenge may be considered in carefully selected cases but close monitoring and frequent echocardiography are required.
Context:
Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis.
Objective:
The objective of the study was a detailed description of thyroid dysfunction in CAMMS223.
Design:
Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist.
Results:
During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (P<.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year.
Conclusions:
Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves' hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism.
The existence of myocardial infarction despite angiographically normal coronary arteries was recognized more than 30 years ago. Since then, various series of such patients have been described, but the aetiology and pathogenesis of the condition are still a source of debate. Evidence exists for a role of coronary vasospasm, thrombosis, embolization and inflammation, per se or combined, in determining the occurrence of myocardial infarction in the presence of angiographically normal coronary arteries. Endothelial dysfunction, possibly superimposed to nonangiographically evident atherosclerosis, may be an underlying common feature predisposing to the acute event. Additionally, myocarditis may explain some of these occurrences. Myocardial infarction with normal coronary arteries is therefore likely the result of multiple pathogenetic mechanisms. Although most reports emphasize the good prognosis of this condition, in general much better than myocardial infarction with coronary artery disease, prognosis is likely variable according to the underlying mechanism. This review summarizes current knowledge on this condition and examines areas of recent progress.
In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.
In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
A 66-year-old woman presented with new-onset complete left bundle branch block and congestive heart failure. She had had chronic paranoid schizophrenia for 35 years and had been taking medications to control her psychiatric disorder for the past 10 years. A 2-dimensional echocardiogram performed at the onset of congestive heart failure showed dilated cardiomyopathy with global impairment of left ventricular function (ejection fraction <0.25). Despite withdrawal of the medications most likely responsible for the heart problems (perphenazine, 2 mg; and amitriptyline, 25 mg), the patient died of refractory congestive heart failure 2 years later. Histologic examination at autopsy showed evidence of persistent toxic myocarditis with fibrosis of the heart and persistent chronic hepatitis. These autopsy findings were considered to be drug related.
Echocardiographic image on apical four-chamber view shows akinesia of distal segments of anterior septal wall (white arrow)
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Fig. 1. Echocardiographic image on apical four-chamber view shows akinesia of distal segments of anterior septal wall (white arrow).
- Fama
Fama' et al. / International Journal of Cardiology 206 (2016) 127–128