Amelioration Of Flu-Like Symptoms At The Onset Of Interferon-ß-1b Therapy In Multiple Sclerosis By Low-Dose Oral Steroids Is Related To A Decrease In InterLeukin-6 Induction
Martinez-Caceres EM, Rio J, Barrau M, Duran I, Borras C, Tintoré M, Montalban X
Ann Neurol 1998 Oct;44(4):682-5
Unitat de NeuroImmunologia Clinica, Hospital General Universitari Vall d'Hebron, Barcelona, Spain
Low-dose oral Steroid use at the onset of Interferon-1b (IFN-ß-1b) therapy in Relapsing/Remitting Multiple Sclerosis (RR-MS) patients reduces Flu-Like symptoms.
To determine the mechanism by which Steroid treatment minimizes these side effects, we analyzed the percentage of InterLeukin-6 (IL-6), Interferon-gamma (IFN-), Tumor Necrosis Factor-alpha (TNF-), and IL-10-producing cells before and after 3 months of IFN-ß-1b therapy onset.
Our results support a relationship between IL-6 induction and fever. Such side effects can be ameliorated by Steroids.
Long-Term Steroid Therapy In Multiple Sclerosis
Domzal T, Zalewska B
Neurol Neurochir Pol 1992 Sep-Oct;26(5):621-5
Szaserow, Klinika Neurologiczna CSK WAM ul, Warszawa
PMID# 1291899; UI# 93180952
CorticoSteroids have a firm place in the treatment of MS, but as yet no generally accepted regimen of this therapy exists.
It is not known either, how to achieve the greatest effectiveness of these drugs and avoid side effects.
Many clinicians advocate high IntraVenous doses of MethylPrednisolone in a short time of 5-7 days. This method is more effective and leads to less adverse effects.
The studied patients received Prednisone (Encorton Polfa) in short course of 3 days every month. The dose of Encorton in each course depended on the clinical condition but never exceeded 200 mg.
The regimen was used in 18 patients who were followed up at least one year. Evident improvement or stabilization was obtained in 11 cases. No adverse effects were noted.
These results are comparable to those achieved with MethylPrednisolone. It may be supposed that every regimen of Corticoid treatment in MS is usefull if it causes no adverse effects.
The treatment by method of long-term pulse therapy with Corticoids is applicable in outpatients.
Expression Of Integrins On Activated T-Cells In Multiple Sclerosis
Effect Of IntraVenous MethylPrednisolone Treatment
Lujan S, Masjuan J, Roldan E, Villar LM, Gonzalez-Porque P, Alvarez-Cermeno
Mult Scler 1998 Jun;4(3):239-42
Ramon y Cajal Hospital, Dept of Immunology, Madrid, Spain
We studied the effect of IntraVenous MethylPrednisolone (MP) on the expression of the Integrins, LFA-1 and VLA-4, on activated blood T-Lymphocytes in 17 patients with relapses of Clinically Definite Relapsing/Remitting MS.
MP treatment did not induce changes in the expression of CD3+, CD4+, DR, LFA-1 or VLA-4 markers when measured in the total population of Lymphocytes in MS patients in relation to treatment.
Treatment influenced neither the LFA-1 nor VLA-4 positive cells within the CD3+ population. MP treatment clearly decreased the DR+ CD3+ cells (P < 0.01) and the percentage of DR+ CD3+ Lymphocytes bearing VLA-4 (P < 0.01).
However, this was not the case when we studied the percentage of Lymphocytes which expressed LFA-1.
GlucoCorticoids did not influence the mean intensity of the expression of the two Integrins quantified in either total or DR+ CD3+ Lymphocytes.
Although, further research seems warranted to investigate a possible effect of MP on Lymphocyte Integrin function, this work corroborates the idea that MP treatment may interfere with the mechanisms of T-Cell migration into CNS, thus modulating the activity of Multiple Sclerosis.
Sex-Specific Differences In Cortisol Production Rates In Humans
Vierhapper H, Nowotny P, Waldhausl W
Metabolism 1998 Aug;47(8):974-6
Univ of Vienna, Dept of Internal Medicine III, Austria
Production rates of Cortisol were determined in healthy men (n = 7) and in healthy women during the follicular phase of their menstrual cycle (n = 7).
Using the stable-isotope dilution technique and analysis by Gas Chromatography/Mass Spectrometry (GC/MS).
1Alpha,2alpha-D-Cortisol was infused for 10 hours (116 +/- 6 microg/h; 8 AM to 6 PM). Blood samples obtained at 20-minute intervals during the last 4 hours (2 PM to 6 PM) were pooled and used for analysis.
Estimated production rates of Cortisol were 0.94 +/- 0.15 mg/h and 0.38 +/- 0.14 mg/h in healthy men and women, respectively.
Even when corrected for body-surface area, production rates of Cortisol in men (0.48 +/- 0.09 mg/m2 x h) were higher (P < .001) than in women (0.22 +/- 0.08 mg/m2 x h).
An increased production rate of Cortisol was seen in 12 patients with Cushing's Syndrome, although in four of nine female patients, it was within the range considered normal for healthy men.
It is concluded that women have a lower production of Cortisol than men and that this sex-specific difference is of clinical relevance in patients with endogenous HyperCortisolism.
Role Of Th1 And Th2 Cells In AutoImmune DeMyelinating Disease
Braz J Med Biol Res 1998 Jan;31(1):55-60
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands
Evidence is accumulating that Th1 cells play an important role in the development of Multiple Sclerosis (MS) and Experimental Allergic EncephaloMyelitis (EAE), whereas Th2 cells contribute to recovery from disease.
A major determinant in the development of Th1 and Th2 cells is the type of Antigen-Presenting Cell (APC) involved and its functional characteristics, e.g., the production of InterLeukin-12.
Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE.
The potential of Cytokines, in particular InterLeukin-10, and GlucoCorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed.
Incidence Of Exacerbations In The First 90 Days Of Treatment With Interferon-ß-1b In Relapsing/Remitting Multiple
Khan OA, Hebel JR
Ann Neurol 1998 Jul;44(1):138-9
Univ of Maryland School of Medicine, and Veterans Affairs Medical Center, Dept of Neurology, Baltimore, MD 21201, USA
Interferon-beta-1b (IFN-ß-1b) is effective in reducing the frequency of exacerbations in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
Recently, a study suggested that treatment with IFN-ß-1b may place MS patients at risk of exacerbations by increasing Interferon-Gamma (IFN-)-secreting cells in the blood early after onset of treatment.
We conducted a retrospective study in 192 RRMS patients treated with IFN-ß-1b.
We did not observe an increase in the frequency of exacerbations early after the onset of treatment.
And suggest that the IFN--secreting cell surge linked to the onset of treatment with IFN-ß-1b may not be clinically significant.
Clues To The ImmunoPathogenesis Of Multiple Sclerosis By Investigating Untreated Patients During The Very Early Stage Of Disease
Neurol Sci 2001 Apr;22(2):145-9
Huddinge University Hospital, Department of Ophthalmology and NeuroImmunology Unit, Sweden
Plethora of abnormalities of the Immune system has been described in Multiple Sclerosis (MS).
They include a number of Myelin Antigens (e.g. MBP, MOG, PLP, MAG), the presence of reactive T-Cells in blood and, further enriched, in the CerebroSpinal Fluid (CSF).
Large numbers of B-Cells in the CSF secreting AntiBodies of multiple but unknown specificities, an increase of MonoNuclear Cells (MNC) expressing and secreting both pro- and anti-inflammatory Cytokines.
Including Th1 Cytokines Interferon-gamma (IFN-gamma) and InterLeukin (IL)-6, the Th2 related IL-4 and IL-10, and the Th3-driven TGF-beta.
Elevated numbers of MNC in both blood and CSF expressing a spectrum of MetalloProteinases and their inhibitors, as well as many other aberrations.
However, no consistent patterns have emerged that relate any, of these findings to clinical variables such as exacerbations, duration of disease, disability, or lesions in the Central Nervous System (CNS) detected at Magnetic Resonance Imaging.
In order to elucidate the relevance of these Immunological abnormalities in the PathoGenesis of MS, my colleagues and I studied patients with Acute Monosymptomatic Optic Neuritis (ON) and compared them with patients with clinically definite MS (CDMS).
The patients have not been treated and have not received CorticoSteroids or Interferon-beta. When comparing these two groups, we were unable to identify any differences in any of the variables mentioned.
Thus, very early MS, as represented by ON, shows the same full-blown pattern of Immunological abnormalities seen in CDMS.
Furthermore, a complete Epitope spread affecting MBP, MOG, PLP, MAG and other Myelin components is already present in ON. Whether any of these alterations play a PathoGenetic role is still unsettled.
Selective Depletion Of CD14+ CD16+ Monocytes By GlucoCorticoid Therapy
Fingerle-Rowson G, Angstwurm M, Andreesen R, Ziegler-Heitbrock HW
Clin Exp Immunol 1998 Jun;112(3):501-6
Univ of Munich, Dept of Internal Medicine I, Klinikum Grosshadern, Germany
GlucoCorticoids (GC) are potent Anti-Inflammatory and ImmunoSuppressive agents that act on many cells of the body, including Monocytes.
Here we show that a 5-day course of high dose GC therapy differentially affected the CD14++ and the CD14+ CD16+ Monocyte subpopulations in 10 patients treated for Multiple Sclerosis.
While the classical (CD14++) Monocytes exhibited a substantial increase from 495 +/- 132 to 755 +/- 337 cells/microl, the CD14+ CD16+ Monocytes responded with a pronounced decrease from 36 +/- 15 to 2 +/- 3 cells/microl (P < 0.001).
In 4/10 patients the CD14+ CD16+ Monocytes fell below detection limits (<0.2 cells/microl).
This observation was confirmed when the CD14+ CD16+ Monocytes were identified by virtue of their low CD33 expression as these cells decreased as well.
After discontinuation of GC therapy the CD14+ CD16+ Monocytes reappeared and reached normal levels after 1 week.
The profound depletion of CD14+ CD16+ Monocytes by GC as described here is a novel effect of GC action in Vivo and may contribute to GC-mediated ImmunoSuppression.
Determination of the number of this Monocyte subset may also serve to monitor the effectiveness of GC therapy in patients requiring ImmunoSuppressive treatment.
Multiple Sclerosis, The Great Masquerader: An Atypical Ocular Presentation
J Am Optom Assoc 1997 Dec;68(12):757-62
Asheville Eye Medical and Surgical Associates, P.L.L.C., North Carolina, USA
Multiple Sclerosis (MS) is the most common chronic disease of the Central Nervous System and is pleomorphic in it presentations.
The Optic pathways are frequently involved, and the classic Ocular abnormality is Optic Neuritis.
A case is presented of a 23-year-old woman in whom Optic Neuropathy developed and Multiple Sclerosis was diagnosed by NeuroRadioImaging, in spite of her lack of awareness of Vision loss.
The DeMyelinating lesions in MS may develop anywhere in the visual system and produce a variety of visual defects.
Magnetic Resonance Imaging (MRI) is the most sensitive method for demonstrating these lesions.
The cause of MS is unknown, but current opinion holds that AutoImmunity - perhaps induced by Viral Infection - is likely to be implicated in its EtioPathoGenesis. Currently, no method for prevention of MS is known.
- Comment in: J Am Optom Assoc 1997 Dec;68(12):745
Low-dose Steroids Reduce Flu-Like Symptoms At The Initiation Of IFN-ß-1b In Relapsing/Remitting MS
Rio J, Nos C, Marzo ME, Tintoré M, Montalban X
Neurology 1998 Jun;50(6):1910-2
Hospital General Universitari Vall d'Hebron, Unitat de NeuroImmunologia Clinica, Servei de Neurologia,
To determine whether low-dose Prednisone reduces flu-like symptoms at the initiation of Interferon-beta-1-b (IFN-ß-1b), we studied 71 patients with Clinically Definite, Relapsing/Remitting Multiple Sclerosis who were started on IFN-ß-1b.
Patients were randomized to receive Prednisone plus Paracetamol or only Paracetamol and were monitored for side effects.
Systemic side effects were minimal in the Steroid group compared with the NonSteroid group during the first 15 days of treatment (p=0.005).
At 3 months, both groups showed a similar frequency of flu-like symptoms. No differences in local reaction between the two groups were observed throughout the study.
Glucocorticoids increase IL-10 Expression In Multiple Sclerosis Acute Relapse
Gayo A, Mozo L, Suarez A, Tunon A, Lahoz C, Gutierrez C
J NeuroImmunol 1998 May 15;85(2):122-30
Universidad de Oviedo, Hospital Central de Asturias, Dept of Immunology, Spain
High doses of GlucoCorticoids (GCs) are widely employed to treat acute attacks in Relapsing/Remitting Multiple Sclerosis (MS) patients.
Their beneficial effects are partially due to their capacity to regulate the Cytokine network. In the present work, we have examined the effect of GCs on the production of the ImmunoSuppressor Cytokine IL-10.
Blood samples from MS patients suffering an acute relapse were obtained immediately before initiating therapy and after receiving a daily dose of 1 g IntraVenous MethylPrednisolone (MP) for four days.
Levels of IL-10 mRNA in PBMC were semiquantified by RT-PCR, whereas protein concentration in Serum and in cell culture supernatant was measured by ELISA.
Our results show that 7 out of the 9 patients studied displayed increased IL-10 mRNA expression as well as higher Serum IL-10 concentration following Steroid treatment.
In contrast, mRNA expression of two Inflammatory Cytokines, TNF and IFN, decreased following Steroid therapy.
In vitro experiments employing normal PBMC showed that MethylPrednisolone (MP) upregulated IL-10 expression as determined by measuring mRNA levels, flow cytometry of IntraCytoPlasmic protein concentration, and the amount of secreted protein.
Peak responses of secreted IL-10 by PBMC cultured cells treated with MP were obtained at 48 h.
The effect was Steroid-specific as IL-10 expression reversed to baseline levels in the presence of the GlucoCorticoid Receptor antagonist RU486. Contrary to the effect of MP on the spontaneous expression of IL-10, this drug downregulated LPS-induced IL-10 synthesis.
In fact, the concentration of IL-10 in LPS-induced IL-10 secretion from normal PBMC decreased upon addition of MP to cell cultures. Thus, it seems that MP exerts an opposite effect on the spontaneous and LPS-induced IL-10 production.
Our studies indicate that GCs may control inflammatory responses by upregulating production of the ImmunoSuppressor Cytokine IL-10.
Pathophysiologic And Somatic Investigations Of HypoThalamic-Pituitary-Adrenal Axis Activation In Depression
Michelson D, Gold PW
Ann N Y Acad Sci 1998 May 1;840:717-22
National Institutes of Mental Health, Bethesda, Maryland 20892, USA
Preclinical studies of Inflammatory and AutoImmune illnesses have demonstrated the importance of central components of the HPA Axis in disease Pathophysiology.
The implications of these data for human illness are poorly understood.
We have studied the Pathophysiology of the HyperCortisolism seen in two human illnesses involving the Central Nervous System, Multiple Sclerosis (MS) and Depression, and looked for demonstrable Somatic changes that may be associated with such HyperCortisolism.
Data from a study of medication-free patients with Multiple Sclerosis not in acute exacerbation suggest that compared with Depression, MS is associated with increased prominence of HypoThalamic VasoPressin secretion (p < 0.05).
Data from studies of Depressed patients with mild to moderate HyperCorticolism (assessed by 24-hour Urinary free Cortisol excretion) demonstrate marked reductions in Bone Mineral Density compared to healthy.
Carefully matched controls (p < 0.001), as well as changes in markers of bone metabolic activity similar to those seen in patients with Cushing's Disease or exogenous GlucoCorticoid treatment (p < 0.05).
Taken together, these studies suggest HPA axis dysregulations demonstrated in preclinical models of AutoImmune and Inflammatory illness also occur in human illness and may have important and lasting Somatic sequelae.
Current ImmunoTherapy In Multiple Sclerosis
Bashir K, Whitaker JN
Immunol Cell Biol 1998 Feb;76(1):55-64
Univ of Alabama at Birmingham, Dept of Neurology, Birmingham, Alabama 35233-7340, USA
The underlying Pathophysiology of Multiple Sclerosis is presumed to be AutoImmune in nature.
Attempts to find an effective treatment for this common disease of the Central Nervous System have primarily focused on Immune-Mediated therapies, both ImmunoSuppressive and ImmunoModulatory.
The wide variety of Immunological abnormalities detected in Multiple Sclerosis and its animal model, Experimental Allergic EncephaloMyelitis, has prompted the testing of a diverse array of drugs to be used for treatment.
Recent successes in the treatment of Relapsing/Remitting Multiple Sclerosis with Interferon-ß and Glatiramer Acetate (Copaxone) have renewed interest in and raised expectations for the effective control of this Neurological Disorder.
Improved methodology in clinical trials, the development of surrogate markers and the availability of novel therapies bode well for more rapid advances.