Inger Nennesmo

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies

Objective: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. Methods: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1α, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon γ (IFNγ), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. Results: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by ⩾20% in three or more variables of the disease activity core set, four were unchanged and two worsened ⩾30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. Conclusions: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis

BACKGROUND Primary hemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disorder with very high mortality rates, mainly affecting infants and young children, which is characterized by fever, hepatosplenomegaly, and cytopenias. Of great clinical importance are the neurologic symptoms, which are common and may even dominate the clinical picture and precede the systemic presentation. These symptoms are extremely variable, ranging from irritability, bulging fontanelle, and neck stiffness, to convulsions, cranial nerve palsies, ataxia, hemiplegia/tetraplegia, and unconsciousness. METHODS To elucidate this neurologic involvement further, we reviewed the neuropathologic postmortem findings from 23 children and their neurologic symptoms. RESULTS Macroscopically, edema was present in many cases, and in some with advanced disease, softening and destruction of the tissue were conspicuous. The microscopic picture was exceedingly variable, ranging from almost normal to very advanced changes. In the mildest form of HLH, only the meninges were involved with infiltration of lymphocytes and macrophages (stage I), whereas more advanced cases in addition also showed perivascular infiltrates (stage II). In even more advanced disease there was also a diffuse infiltration in the tissue (stage III), as well as a multifocal necrosis. A prominent astrogliosis was present in such cases. Hemophagocytosis was seen in most patients, most commonly in the leptomeninges. CONCLUSIONS HLH affecting the central nervous system imitates several neurologic disorders and may be misdiagnosed. A staging system for the neuropathologic findings is presented. In children with obscure central nervous systems symptoms and a progressive encephalopathy, the diagnosis of HLH may be considered, in particular because treatments are available.

Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with the death of motor neurons in the spinal cord and brainstem. The cause of ALS is unknown and there is no cure. This study demonstrates, for the first time, that vascular endothelial growth factor (VEGF) delays progression of symptoms and prolongs survival in a Cu/Zn superoxide dismutase (SOD1) transgenic mouse model of ALS. These observations suggest that VEGF or related compounds, might be of value in the treatment of ALS patients. Ann Neurol 2004

Neuron to neuron transmission of herpes simplex virus ☆: Transport of virus from skin to brainstem nuclei

Herpes simplex virus (HSV) injection into the snout of mice was followed by the appearance of HSV antigen in neurons in trigeminal ganglia, main sensory and spinal tract trigeminal nuclei, reticular formation including raphe nuclei and locus ceruleus on both sides. The findings indicate that HSV spreads via axons, passes through a series of neurons and in this way can reach vital nuclei in the brainstem including monoaminergic neurons from the primary replication area in the lip.

Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease

The accumulation of β-amyloid in the brain is an early event in Alzheimer’s disease. This study presents the first patient with Alzheimer’s disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer’s disease brain. The patient underwent positron emission tomography studies with 18F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of 3H-nicotine and 125I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.

Skeletal Muscle Fibers Express Major Histocompatibility Complex Class II Antigens Independently of Inflammatory Infiltrates in Inflammatory Myopathies

The aim of our study was to address the question of whether muscle fibers express major histocompatibility complex (MHC) class II in inflammatory myopathies. For this purpose we performed a systematic study of MHC class II antigen expression on muscle fiber membranes in muscle tissue from polymyositis and dermatomyositis patients in various stages of disease activity. Thirty-two patients with classical clinical signs of myositis were divided into subgroups depending on duration of clinical signs of myositis and presence or absence of inflammatory infiltrates in muscle tissue. Immunohistochemistry as well as double-immunofluorescence stainings were used to identify the presence of MHC class II in muscle tissue. MHC class I was included for comparison. Quantification of positive staining was performed using an image analysis system in addition to evaluation by manual microscopic scoring and laser confocal microscopy. It was demonstrated that a significant proportion of skeletal muscle fibers in inflammatory myopathies express MHC class II as well as MHC class I and that MHC antigen expression is independent of the inflammatory cell infiltration. Furthermore, there were no differences in staining pattern between polymyositis and dermatomyositis patients. Our results indicate that MHC class II and MHC class I molecules may be involved in initiating and maintaining the pathological condition in myositis rather than only being a consequence of a preceding local inflammation.

Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue

The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man. In previous studies, we reported that Linomide suppressed the clinical EAN and myelin antigen-reactive T and B cell responses. Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180-199 and Freunds complete adjuvant was strongly suppressed by ABR-215062 administered daily subcutaneously from the day of inoculation. ABR-215062 dose-dependently reduced the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves. The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines IFN-gamma and TNF-alpha, as well as the enhancement of anti-inflammatory cytokine IL-4 in lymph node cells and periphery nerve tissues, respectively, in a dose-dependent manner. These effects indicate that ABR-215062 may mediate its effects by regulation of Th1/Th2 cytokine balance and suggest that ABR-215062 is potentially a new chemical entity for effective treatment of autoimmune diseases.

T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells

Dermatomyositis and polymyositis are disabling rheumatic diseases characterized by an appreciable number of T cells infiltrating muscle tissue. The precise phenotype, function and specificity of these cells remain elusive. In this study, we aimed to characterize T cells in muscle tissue and circulation and to investigate their association to clinical phenotype. Twenty-four patients with dermatomyositis and 42 with polymyositis were screened for frequency of CD4+CD28null and CD8+CD28null T cells in peripheral blood by flow cytometry. Presence of these cells in inflamed muscle tissue from 13 of these patients was analyzed by three-color immunofluorescence microscopy. Effector functions, proliferation and Ag specificity were analyzed by flow cytometry after in vitro stimulation. The clinical relevance of CD28null T cells was analyzed by multiple regression analyses including six separate and combined disease variables. We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28null and CD8+CD28null T cells in patients with dermatomyositis and polymyositis. Muscle-infiltrating CD28null T cells were found already at time of diagnosis. Disease activity correlated with the frequency of CD8+ T cells in the inflamed muscles of polymyositis patients. Circulating CD4+CD28null and CD8+CD28null T cells were significantly more frequent in human CMV (HCMV) seropositive individuals, responded to HCMV Ag stimulation, and correlated with disease duration. These cells also display a proinflammatory cytokine profile, contain perforin and lack the costimulatory molecule CD28. Our observations imply that CD28null T cells represent clinically important effector cells in dermatomyositis and polymyositis, and that HCMV might play a role in propagating disease in a subset of patients.

Resolution of inflammation is altered in Alzheimer's disease.

Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimers disease (AD).

POLG1 Mutations Associated With Progressive Encephalopathy in Childhood

Abstract We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol &ggr;), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.