Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review.

BACKGROUND: So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population. OBJECTIVE: The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared. RESULTS: Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately. CONCLUSION: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

Fluctuations of MS births and UV-light exposure.

BACKGROUND: Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. AIM: To assess the correlation between fluctuation of sunlight and birth season in persons with MS. METHODS: For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. RESULTS: Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P < 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). CONCLUSION: Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.

Therapeutic immunoadsorption increases the level of circulating soluble HLA molecules.

BACKGROUND AND OBJECTIVES: Immunoadsorption (IA) is an established procedure to remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind to human leucocyte antigen (HLA) molecules, we were interested to know whether removal of Ig will also influence the plasma concentration of soluble HLA (sHLA). PATIENTS AND METHODS: Nine patients suffering from severe autoimmune disease and undergoing 17 single courses of IA treatment were monitored for their sHLA class I (sHLA-I) and sHLA-DR plasma levels. Plasma was separated by a hollow-fiber-type separator. Plasma samples were taken before therapy, after 15 min of recirculation (without operating the adsorber), after 1 and 2 liters of plasma adsorption, and 24 and 48 h after the end of IA. RESULTS: Before treatment the mean levels of sHLA-I and sHLA-DR were 0.37 (+/-0.06 SEM) and 0. 32+/-0.05 microg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA-DR (0.80+/-0.10 microg/ml) was observed (p<0.001), whereas sHLA-I was only slightly affected (mean: 0.45+/-0.06 microg/ml). sHLA concentrations returned to initial levels after 24 h. CONCLUSION: The significant increase in sHLA-DR may contribute to the immunomodulatory effect of IA.

Treatment of chronic progressive multiple sclerosis with intravenous immunoglobulins--interim results on drug safety of an ongoing study. IVIG study group.

In a blinded administrative look we analyzed the safety profile of intravenous immunoglobulin (IVIG) treatment in an ongoing randomized, placebo controlled double blind study on the treatment of multiple sclerosis (MS) patients with primary or secondary chronic progressive MS. Up to October 1999 131 patients were included in the study. Collectively, these patients received approximately 1,200 infusions either with IVIG (400 mg/kg bodyweight every 4 weeks) or with placebo; approximately 600 IVIG infusions were administered. All reported serious adverse events (SAE), including reports on adverse events submitted directly to the drug safety department of the sponsor, were closely analyzed A total of 25 SAE's (in 25 patients) have been reported up until 15th October 1999, whereby the main criterion for 'serious' in all of these cases was hospitalization. None of these 25 SAE were regarded as drug related. No side effects relating to liver functions, kidney functions or rheological problems have been reported. Since the mean score on the EDSS-scale of the patients at the point of inclusion in the study was 5.6 (median EDSS: 6.0) we conclude that IVIG treatment, at a dose of 400 mg/kg bodyweight every 4 weeks, is a relatively safe therapy even for severely disabled multiple sclerosis patients.

Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis -- outline of a double-blind randomized, placebo-controlled trial.

We present the design of a double-blind, randomised placebo-controlled phase III study to evaluate safety and efficacy of IVIG in the treatment of patients suffering from primary or secondary chronic progressive multiple sclerosis. The primary endpoint is disability. Two measures of disability were chosen in order to assess the primary end point (a) sustained improvement (assessed at month 6, confirmed at month 9) and (b) progression to increasing disability of the disease (sustained for 3 months) at any time during the course of this 2 years study. The disability is measured by the Extended Disability Status Scale (EDSS). Secondary end points include the assessment of visual function, functions of the upper extremity, cognitive functions, depression and quality of life.

Genetic predisposition to multiple sclerosis as revealed by immunoprinting.

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty-eight clinically well-characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA-DRB1*, T-cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes. Altogether, approximately 17,000 genetic analyses were performed. Patients were grouped according to the course of MS-relapsing-remitting or chronic progressive. Most of the genetic markers were not associated with increased risk or their exact contribution was not clear (e.g., tumor necrosis factor). The relative risks for HLA-DRB1*15+ and DRB1*03+ individuals were 3.64 and 1.42, respectively. In both groups of patients, certain TCRB gene polymorphisms were risk factors. In DRB1*03+ individuals the relative risk was increased (> 22) when a specific TCRBV6S3 allele was also inherited. Furthermore, distinct linkage disequilibria of TCRBV6S1/TCRBV6S3 elements in patients and control subjects strongly suggested an additional risk factor in the TCRBV region for DRB1*15+ individuals. These findings are discussed with respect to the pathogenesis and rational approaches to the therapy of MS.

The neuroimmune hypothesis in Parkinson's disease.

The role of immune mechanisms in the pathogenesis of Parkinson's disease is still a matter of controversy. Immunological abnormalities have been reported in various brain areas and in peripheral immune parameters. Beside antigen specific findings which might indicate an autoimmune process directed against dopaminergic neurons, non-antigen specific abnormalities have been found, which could be caused either by a disease specific process and/or by immunological properties of various anti-parkinsonian drugs, e.g. bromocriptine. Immune reactions may imitate or maintain the degenerative process. In this case possible neuroprotective strategies interfering with immune functions could be developed. Further investigations are necessary to elucidate the impact of immune mechanisms on the degenerative process in Parkinson's disease.

[Mechanisms of action of intravenous immunoglobulins]. / Wirkmechanismen intravenöser Immunglobuline.

Intravenous immunoglobulins (IVIG) are now used to treat various diseases, including autoimmune diseases, systemic inflammatory diseases, allografts and for replacement therapy in the case of IgG deficiency. Only in some of the indications has the efficacy of this treatment been confirmed in large-scale studies. Also, in many cases the modes of action remain unclear. Principally, the following therapeutic strategies can be differentiated: Replacement treatment, blocking of the effector molecules, influencing of the cellular and humoral limbs of the immune defence system and interaction with cytokines. In certain CNS diseases, displacement of pathological immunoglobulins may be involved. It would be desirable to acquire more detailed knowledge about modes of action with the aim of using IVIG with greater specificity in the future.

Is alpha-methyldopa-type autoimmune hemolytic anemia mediated by interferon-gamma?

Drug-related autoimmune hemolytic anemia appearing with warm-reacting antibodies can be classified according to the offending substances. One of the subtypes can be induced by alpha-methyldopa. However, the pathophysiology of the underlying mechanism is not yet known. In parallel, patients with Parkinson's disease and other extrapyramidal disorders, who are under administration of dopaminergic drugs, often present with abnormal findings with respect to immune parameters. In order to reveal further mechanisms within the immune response, the capability of patients under dopaminergic medication to release cytokines after a stimulatory signal was examined. Therefore, 18 patients who were treated with the dopamine analogue lisuride were compared with an aged-matched control group of 21 healthy volunteers. After stimulation with phytohemagglutinin (PHA), mitogen-induced concentrations of interferon-gamma were significantly higher in the patients treated with lisuride than in the control group. Interferon-gamma leads to an upregulation of MHC class-I and especially class-II molecules on antigen-presenting cells and to an induction of antibody production in B cells. This condition can result in the induction of an autoimmune process. It might be supposed that alpha-methyldopa-type autoimmune hemolytic anemia is mediated by elevated levels of interferon-gamma produced in T cells after a stimulatory signal.

[Is dopaminergic therapy immunologically rejuvinating? Increased interferon-gamma production with the dopaminergic agent lisuride]. / Macht dopaminerge Therapie immunologisch jung? Erhöhte Interferon-gamma-Produktion unter dem Dopaminergikum Lisurid.

Eighteen patients with advanced Parkinson's disease (n = 13) or dopamine-sensitive dystonia (n = 5) were treated with the dopaminergic agent, lisuride, applied as a long-term subcutaneous infusion. The results were compared with those obtained in a group of younger, and a group of older, healthy volunteers. The liberation of gamma-interferon (gamma-IFN) following mitogenic stimulation of whole blood with phytohemagglutinin (PHA) was highly significantly elevated in comparison with the group of older healthy volunteers, and clearly, but not significantly, elevated in comparison with the younger group. There was no difference between patients with dystonia and those with Parkinson's disease. The effect observed is thus probably due to lisuride. This effect might explain the longer life expectancy and reduced proclivity for infection shown by patients with Parkinson's disease. It needs to be determined whether, on the basis of these initial data, a therapeutic principle for the treatment of diseases that can be directly influenced by gamma-IFN can be derived.

Neurophysiological findings and MRI in anterior spinal artery syndrome of the lower cervical cord: the value of F-waves.

Ten hours after onset of an anterior spinal artery syndrome (ASAS) F-waves could not be obtained from the paralysed left hand muscles. F-waves in the right hand were present and motor nerve conduction studies were normal on both sides. One week later paralysis of the right hand together with paraparesis occurred. Two days later F-waves from the right hand had disappeared. Three weeks later MRI confirmed the diagnosis of ischaemic spinal cord infarction.