The effect of large-dose prednisone therapy on IgG subclasses in multiple sclerosis

The effect of large-dose prednisone therapy (3960 mg over 56 days) on IgG subclasses in the cerebrospinal fluid and sera, as well as on their intrathecal synthesis, was studied in 15 patients with clinically definite multiple sclerosis. The concentration of IgG subclasses was measured using ELISA with monoclonal antibodies against human IgG subclasses, secondary biotinylated antibody and avidin-biotin-peroxidase complex. There was a decrease of IgG1, IgG3 and IgG4 in the CSF of MS patients after the treatment, but the differences did not reach statistical significance. The IgG index was decreased about 34% (p<0.01) after the therapy. This was mainly due to diminished synthesis of IgG1 and IgG3. The significance of IgG subclasses in the pathogenesis of MS is discussed.     

Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis

Beta-interferon (beta-IFN) has a proven treatment effect on relapsing-remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN combined with a low daily dose of prednisone (n = 33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis factor-alpha (TNFalpha) and intracellular adhesion molecule-1 (ICAM-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFalpha, interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS.     

Serum immunologic markers in multiple sclerosis patients on continuous combined therapy with beta-interferon 1a, prednisone and azathioprine

Break-through symptoms (BTS) in multiple sclerosis (MS) patients on beta-interferon (beta-IFN) monotherapy are most frequently treated with a brief administration of steroids. Here, we report the results of monitoring serum immunologic markers recorded at three-month intervals for 1.5 years in responders to beta-INF 1a (Avonex) monotherapy (n =21) and MS patients placed on Avonex with prednisone (n =83) and Avonex, prednisone and azathioprine (AZA) (n =21) because of BTS. Compared to 23 healthy controls, patients on Avonex monotherapy and Avonex with prednisone, in individuals on Avonex, prednisone and AZA, a significant decrease in serum concentration of soluble intercellular adhesion molecule-1 (sICAM-1) (P=0.001) was established. Combined therapy with Avonex, prednisone and AZA was associated with a significant increase in the serum level of interleukin (IL)10 (P <0.001). Compared to Avonex monotherapy, combined therapy suppressed the serum level of IL12p40, antagonized elevation in the serum concentration of soluble IL2 receptor (sIL2R) and inhibited an increase in the serum soluble CD95 (sCD95) molecule. In patients studied, no significant differences in the serum level of IL18 and tumor necrosis factor-alpha (TNF-alpha) were established. These findings are important in understanding some of the immunoregulatory mechanisms induced by combined therapy in MS.     

The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis

Oral prednisone (1)might be a convenient, inexpensive alternative to IV methylprednisolone (IVMP) if the bioequivalent dose was known. We compared the total amount of steroid absorbed after 1250 mg oral prednisone vs 1 gram IVMP in 16 patients with multiple sclerosis (MS). At 24 hours, the mean area under the concentration-time curve (AUC), the main component of bioavailability, did not differ between groups (p = 0.122). This suggests that the amount of absorbed corticosteroid is similar after either steroid at these doses.     

Biological markers in multiple sclerosis

Advances in treatments for MS and the prospect of more (and increasingly effective) therapies make the search for disease-related biomarkers essential and urgent. Markers are needed for subtyping the disease itself, and for detecting disease-specific inflammation, axonal damage, remyelination and individual responses to therapies. The current dearth of reliable markers reflects our lack of knowledge of MS aetiology and pathogenesis. New technologies promise to boost understanding of MS and help identify biological markers for different aspects of the disease. The study of cerebrospinal fluid is of primary importance, as this bodily fluid is most likely to contain traces of products of the pathological/reparative processes occurring at the lesional level.     

Immunological markers in multiple sclerosis

Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing, among others, autoreactive T cells and activated macrophages. These observations indicate that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that, along with chemokines, adhesion molecules and metalloproteases, modulate at different levels the pathogenic process underlying MS. Due to their central role in MS pathogenesis, “inflammatory” molecules might represent suitable peripheral markers of disease (disease-trail) and/or disease activity (state-trait). However, reliable disease-trait or state-trait immunological markers for MS have not yet been identified. The intrinsic characteristics of these molecules (i. e. autocrine/paracrine activity, short half-life, redundancy) may in part explain their inconsistency as disease markers. Additionally, the unreliability of methodologies and the lack of careful patient stratification can also, at least in part, account for the unsatisfactory results so far obtained.     

Cell-mediated immunological status in multiple sclerosis patients

In vitro lymphocyte proliferation in response to allogeneic pooled cells, mitogens (PHA, Con A and PWM), and PPD was measured in 67 patients with clinically definite MS and in 67 age and sex-matched controls. Overall, dose-response curves in the two groups were similar, but response to PHA and PWM was significantly greater among patients, and a greater percentage of patients failed to respond to peak and suboptimal PPD concentrations. There was a reduced response to allogeneic pooled cells in Dw2 positive controls, and, in both patients and controls, a tendency towards a higher PPD response in Dw2 positive males. The results suggest that there is some alteration of balance of immune regulation in MS, which is slightly affected by Dw2 status.     

The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis

The effects of magnesium glycerophosphate oral therapy on spasticity was studied in a 35-year-old woman with severe spastic paraplegia resulting from multiple sclerosis (MS). We found a significant improvement in the spasticity after only 1 week from the onset of the treatment on the modified Ashworth scale, an improvement in the range of motion and in the measures of angles at resting position in lower limbs. No side-effects were reported and there was no weakness in the arms during the treatment.     

Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis

BACKGROUND: Prednisone and methylprednisolone are well absorbed orally and have lower treatment costs than IV methylprednisolone, but concern that low-dose corticosteroid may cause increased disease activity and that high oral doses may cause gastric ulceration inhibits use of oral therapy for MS attacks. METHODS: Gastric mucosal injury, detected by measurement of gastric permeability, was examined after five alternate day doses of IV methylprednisolone (1 g) or oral prednisone (1,250 mg) in 21 patients with MS. A triple sugar test solution was consumed at bedtime, and urine was collected overnight. Urine sugar concentrations were determined by high-pressure liquid chromatography. Gastric permeability was expressed as total mg of sucrose excreted. RESULTS: Seventeen patients completed the protocol (12 oral, 5 IV). Baseline sucrose excretion was normal in all. Both groups demonstrated an increase in gastric permeability after steroid treatment, but there was no difference between the two groups (95% CI 95 to 91 mg, p = 0.96). After treatment, three (25%) patients in the oral group, and two (40%) patients the IV group, had modestly abnormal gastric permeability (95% CI 34 to 64%, P = 0.6). CONCLUSIONS: Short-term high-dose oral prednisone is not associated with greater gastric damage, as measured with permeability tests, than IV methylprednisolone. High-dose oral prednisone should be considered a first-line treatment option for MS attacks.     

The effect of Dantrium on spasticity in multiple sclerosis

The effect of a new peripherally acting muscle relaxant drug, Dantrium®, on spasticity was tested on 8 patients with a clear multiple sclerosis or with a long-standing spastic paraparesis suggestive of multiple sclerosis. The effect was evaluated both with regular clinical examination and with clectromyographic technique. The latter concerned a quantitative analysis of the patient's ability to voluntarily control fine neuromuscular activity both with and without the drug. The results indicated that the spasticity was markedly reduced in 5 patients out of 8. In 3 cases the spasticity was slightly reduced or there was no effect at all. In most cases the patients were tired and dizzy during the first days of medication. No other side effects whatsoever were noted. Electromyographically it was found that the ability of the patients to control fine neuromuscular activity was increased with Dantrium, indicating that the reduction of the spasticity increased the ability for fine control of the muscles. It is suggested that the EMG test used in this study for the ability to voluntarily control neuromuscular inhibition and activity could be used as an objective experimental procedure for evaluating anti-spastic drugs.     

The effect of lymphocytapheresis on multiple sclerosis]

We studied the effect of lymphocytapheresis (LCP) on the expanded disability status scale (EDSS) clinical score, lymphocyte subsets and Interleukin-2 (IL-2) production by peripheral blood mononuclear cell (PBM) in 5 patients with multiple sclerosis (MS). The EDSS clinical score significantly decreased after LCPs (p < 0.05). PBM IL-2 production and CD 4/8 ratio significantly decreased (p < 0.05, p < 0.05), and the number of neutrocytes and CD 11 b+CD 8+ (%) significantly increased immediately after LCP (p < 0.05, p < 0.05). Down-regulation of PBM IL-2 production and CD 4/8 ratio and up-regulation of CD 11 b+CD 8+ may account for therapeutic effect of LCP on MS. However, similar changes were observed in patients with CIDP and MG during immunoadsorbent therapy (IAT). It is possible that down-regulation of PBM IL-2 production and CD 4/8 ratio and up regulation of CD 11 b+CD 8+ and the number of neutrocytes may commonly result from apheresis therapy using extra-corporeal circulation.     

Relevance of immunological variables in neuroborreliosis and multiple sclerosis

OBJECTIVES: The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities. METHODS: Three cohorts of patients were investigated: MS (n = 42), NB (n = 27) and other neurological diseases (OND) (n = 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Q(alb) (CSF/serum albumin ratio) as a marker of blood-CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining. RESULTS: Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually anti-measles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Q(alb) in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Q(alb) in 81.5% and normal cell count in 7.4%. CONCLUSION: MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.     

Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells

Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-beta therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.     

Effect of hyperbaric oxygen treatment on immunological parameters in multiple sclerosis

Hyperbaric oxygen (HBO) treatment has been reported to cause amelioration of clinical symptoms in patients with multiple sclerosis (MS). We have treated 10 MS patients with hyperbaric oxygen (100% O2 at 2 atmospheres absolute for 90 min daily for a total of 20 exposures), and performed immunological studies on peripheral blood and cerebrospinal fluid (CSF). After treatment there was a significant increase in total and helper T lymphocyte counts in peripheral blood, as well as an increase in both E, Fc gamma and C3b receptor-bearing lymphocytes. The responses to the mitogens PHA, con A and PWM were unchanged. Granulocytes showed an increased proportion of Fc gamma receptor and C3b receptor positive cells after treatment. The O2 consumption of granulocytes also increased, but phagocytosis, as measured by chemiluminescence, was unchanged. Serum IgA levels were slightly increased, while IgG and IgM concentrations remained unchanged after treatment. Cerebrospinal fluid cell counts, protein and IgG concentrations, as well as IgG indexes remained unchanged.     

Immunomodulatory therapy in multiple sclerosis

During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon beta1b, two preparations of interferon beta1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon beta1a slowed the progression of disability in relapsing multiple sclerosis. One interferon beta1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.