Peter Joseph Jongen

Anti-Ro52 antibodies frequently co-occur with anti-Jo-1 antibodies in sera from patients with idiopathic inflammatory myopathy

We analysed 112 idiopathic inflammatory myopathy (IIM) sera for the presence of anti‐Ro, anti‐La and anti‐histidyl‐tRNA synthetase (Jo‐1) autoantibodies, and subsequently mapped B cell epitopes on the Ro52 protein recognized by anti‐Ro52+ IIM sera. Sera were characterized by immunoblotting, ELISA and RNA precipitation. Both anti‐Ro60 and anti‐La activity was found in 4% of IIM sera. Anti‐Ro52 antibodies were present in 20% of IIM sera. However, in anti‐Jo‐1+ IIM sera (21%), the frequency of the anti‐Ro52 antibodies was found to be much higher (58%). No cross‐reactivity between anti‐Ro52 and anti‐Jo‐1 antibodies could be detected in these sera. To learn more about the nature of anti‐Ro52 antibodies occurring in IIM sera, we analysed the major epitopes of the Ro52 protein targeted by anti‐Ro52+ IIM sera by immunoprecipitation of in vitro translated Ro52 deletion mutants. The major epitope was mapped in the region bordered by amino acids 126 and 252. This part of the protein includes a long α‐helical region which contains two potential coiled‐coil domains as well as a leucine zipper motif. Although no difference in Ro52 epitope recognition between anti‐Jo‐1+ and anti‐Jo‐1+IIM sera could be observed, our results suggest that the autoimmune response against Ro52 and Jo‐1 in IIM patients is coupled.

Fatigue in multiple sclerosis: interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability.

Although fatigue is a frequent complaint of patients with multiple sclerosis (MS), little is known about the origins of multiple-sclerosis-associated fatigue. Our primary focus was to study if the extent of cerebral abnormalities, as shown on magnetic resonance imaging (MRI), had any relation with the frequency and intensity of fatigue complaints of patients with a definite diagnosis of MS. Fatigue severity was rated by the patients with the use of a 2-week diary and a fatigue questionnaire, while conventional T1- and T2-weighted MRI provided several measures for cerebral abnormalities. In total, 72% of 45 patients reported to be seriously fatigued at least several times a week over the last 3-month period. Fatigue severity was not related to the total extent of cerebral abnormalities, or to MRI-based atrophy measures. Regional lesion load did not differ between fatigued and non-fatigued subjects. Although neurological disability, as measured by the Expanded Disability Status Scale (EDSS) and Neurological Rating Scale (NRS), did correlate significantly with most MRI measures, it showed no relation with fatigue severity. Neurological progression rates and number of exacerbations in the 2-year period prior to assessment were not significantly associated with the fatigue measures. Therefore, our findings suggest that differences in levels of self-reported fatigue in patients with multiple sclerosis cannot merely be explained by the degree of clinical disease activity, neurological disability or the extent of MRI abnormalities. These results are compared to other research findings and the possible role of alternative factors influencing fatigue in multiple sclerosis are discussed.

Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies.

Abstract The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the anti-Jo-1 autoantibody (20 %), followed by anti-tRNAHis (6 %), anti-Mi-2 (6 %), and anti-SRP (4 %). The presence of certain MSAs was clearly associated with specific clinical characteristics. Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.

Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial

BACKGROUND Interferon beta is commonly used to treat patients with relapsing-remitting multiple sclerosis; however, the treatment is only partially effective in reducing relapses and progression of disability. Corticosteroids are used to treat relapses in patients with multiple sclerosis. We therefore aimed to investigate the combination of cyclic methylprednisolone and interferon beta for the treatment of relapsing-remitting multiple sclerosis. METHODS In 2001, we designed a multicentre, double-blind, randomised, parallel-group trial, termed the methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN) study. Patients were recruited between October, 2002, and March, 2005 from 50 neurology departments in eight countries. We included treatment-naive patients with relapsing-remitting multiple sclerosis who had an expanded disability status scale (EDSS) score of 4 or less. Patients all started to receive interferon beta-1a and after 3 months were randomly assigned to add-on methylprednisolone or placebo 500 mg/day orally for 3 consecutive days per month for 3-4 years. Placebo tablets were identical to methylprednisolone tablets. Treating physicians, examining physicians, and patients were masked to treatment allocation. Patients were clinically assessed every 3 months and had brain MRI at baseline and 3 years later. The primary outcome was time to onset of disability progression, according to an increase in EDSS score sustained over 6 months. All patients who received at least one dose of study drug were included in all planned analyses. This trial is registered with ClinicalTrials.gov, NCT00168766. FINDINGS 341 patients were randomly assigned to methylprednisolone (n=172) or placebo (n=169); 171 patients in the methylprednisolone group and 167 in the placebo group received at least one dose of study drug. 90 patients had sustained disability progression: 44 of 167 in the methylprednisolone group and 46 of 171 in the placebo group. The time to sustained progression did not differ between groups (hazard ratio 0.879, 95% CI 0.566-1.365; p=0.57). There were 1436 adverse events, 24 of which were serious, in the methylprednisolone group and 1070 events, 35 of which were serious, in the placebo group. INTERPRETATION Monthly pulses of methylprednisolone in combination with interferon beta-1a do not seem to affect disability progression any more than interferon beta-1a treatment alone. More research is required to assess whether this treatment regimen might benefit particular subsets of patients. FUNDING Biogen Idec.

The heart in limb girdle muscular dystrophy

Objective To assess the frequency, nature, and severity of cardiac abnormalities in limb girdle muscular dystrophy, and its relation to age and weakness in various genotypes. Design In 26 autosomal dominant, 38 autosomal recessive, and 33 sporadic strictly defined patients with limb girdle muscular dystrophy, cardiac evaluation included history, physical examination, chest x ray, electrocardiography, 24 hour ECG Holter monitoring, and echocardiography. In 35 of the 71 autosomal recessive and sporadic cases muscle biopsies were available for sarcoglycan analysis. Main results Dilated cardiomyopathy was present in one autosomal dominant case and in three advanced autosomal recessive or sporadic patients, of whom two were found to have α sarcoglycan deficiency. Two of these three patients and three other cases showed ECG abnormalities known to be characteristic of the dystrophinopathies. A strong association between the absence of α sarcoglycan and the presence of dilated cardiomyopathy was found (p = 0.04). In six autosomal dominant cases there were atrioventricular (AV) conduction disturbances, increasing in severity with age and in concomitant presence of muscle weakness. Pacemaker implantation was necessary in four. Conclusions 10% of these patients had clinically relevant cardiac abnormalities. In autosomal dominant limb girdle muscular dystrophy one subtype characterised by muscle weakness and AV conduction disturbances is recognised. In the course of autosomal recessive/sporadic limb girdle muscular dystrophy, dilated cardiomyopathy may develop, probably related to deficiency of dystrophin associated proteins.

The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis:

The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.

Health-related quality of life in relapsing remitting multiple sclerosis patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study

BackgroundGlatiramer acetate (GA) and interferon-beta (INFb) are first-line disease modifying drugs for relapsing remitting multiple sclerosis (RRMS). Treatment with INFb is associated with a significant increase in health-related quality of life (HR-QoL) in the first 12 months. It is not known whether HR-QoL increases during treatment with GA.Methods197 RRMS patients, 106 without and 91 with prior immunomodulation/immunosuppression, were studied for HR-QoL (Leeds Multiple Sclerosis-QoL [LMS-QoL] scale, score range 0 - 32), fatigue (Fatigue Impact Scale [FIS]) and depressed mood (Beck Depression Inventory-Short Form [BDI-SF]) at baseline and 6 and 12 months after start of GA treatment.ResultsAt 6 and 12 months mean LMS-QoL scores were significantly increased in the treatment-naive patient group (p < 0.001), not in the pre-treated group. At month 12 43% of treatment-naïve patients had improved HR-QoL (increase LMS-QoL score 3 or more points) (p < 0.001). Likewise, mean FIS scores were decreased at months 6 and 12 in the treatment-naïve group (p < 0.01), not in the pre-treated group. In both groups mean BDI-SF scores did not change. No demographic or clinical baseline factor was predictive of HR-QoL increase. HR-QoL changes were zero to negative for patients who had discontinued GA before month 12 (28.4% of patients).ConclusionsIn RRMS patients without prior immunomodulation/immunosuppression treatment with GA was associated with an increase in HR-QoL in the first 6 months, that was sustained at 12 months. In 4 out of 10 patients HR-QoL improved. Increase in HR-QoL was associated with decrease in fatigue.

Cognitive performance in relapsing remitting multiple sclerosis: A longitudinal study in daily practice using a brief computerized cognitive battery

BackgroundThere is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS.MethodsForty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability.ResultsThe composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohens d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired.ConclusionsPreliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.

Polymyositis and dermatomyositis: no persistence of enterovirus or encephalomyocarditis virus RNA in muscle.

OBJECTIVES--A persistent infection of enteroviruses and cardioviruses has been implicated in polymyositis and dermatomyositis, but conventional hybridisation studies of the presence of enterovirus RNA and encephalomyocarditis (EMC) virus RNA in affected muscle have yielded conflicting results. To investigate further the possibility of viral persistence, the presence of viral RNA in muscle from patients with adult onset polymyositis and dermatomyositis was investigated using a polymerase chain reaction (PCR) technique. METHODS--Muscle tissue was obtained from 10 patients with polymyositis and five patients with dermatomyositis, all with adult onset active disease. A PCR was performed using primers with high specificity for enterovirus and EMC virus RNA, followed by Southern blot hybridisation with an oligonucleotide probe directed against the internal portion of the amplified product. A PCR directed against the Abelson tyrosine kinase mRNA served as an internal control for the presence and quality of RNA. RESULTS--A specific amplification for enterovirus or for EMC virus could not be seen in any of the muscle biopsy samples, despite a sensitivity of about 30 plaque forming units for enterovirus and of 100 plaque forming units for EMC virus. Southern blot hybridisation confirmed these results in that positive controls hybridised with the oligonucleotide probe, but no signal was obtained with the muscle specimens. CONCLUSION--A sensitive and specific PCR technique showed no evidence of the presence of enterovirus or EMC virus RNA in muscle samples from patients with polymyositis or dermatomyositis. These data do not support the proposal that viral RNA persistence plays a part in these idiopathic inflammatory myopathies.

Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis

OBJECTIVES To find whether CSF analysis may differentiate between relapsing-remitting and secondary progressive multiple sclerosis. METHODS In 17 patients with relapsing-remitting and 16 patients with secondary progressive multiple sclerosis, all without current or recent relapses, albumin CSF: peripheral blood ratio, mononuclear cell number, CD4+, CD8+, and B1+ subsets, CD4+:CD8+ ratio, IgG, IgG index, IgM, IgM index, complement components C3 and C4, and C3 and C4 indices, myelin basic protein, neuron specific enolase, S100, and lactate were determined. For each measure the statistical distance measure D2 was calculated. For computation of a discriminant score variables with a P value⩽0.15 were included (two sided univariate t test). These were albumin CSF: peripheral blood ratio, mononuclear cell number, IgM, IgM index, C3, C4, neuron specific enolase, S100, and lactate. Simultaneous distributions of the variables were compared between both groups (multivariate t test) and a discriminant score was computed (linear discriminant analysis). RESULTS The discriminant score allocated all 14 relapsing-remitting patients to the relapsing-remitting group (positive score) and 12 of 13 secondary progressive patients to the secondary progressive group (negative score). One secondary progressive patient was allocated to the relapsing-remitting group. CONCLUSIONS Patients with relapsing-remitting or secondary progressive multiple sclerosis differ in CSF profile and CSF analysis may help to differentiate between relapsing-remitting and secondary progressive multiple sclerosis.