Ondansetron hypersensitivity: a clinical diagnosis protocol and cross-reactivity study

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Anaphylaxis to intravenous methylprednisolone hemisuccinate in a patient with immune thrombocytopenia

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Glutathione PEGylated liposomal methylprednisolone (2B3-201) attenuates CNS inflammation and degeneration in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis.

Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS. After disease onset, mice were randomized to receive either saline, three injections of free MP (high dose MP, 100mg/kg i.v.), two injections of free MP (low dose MP, 10mg/kg; i.v.), or two injections of 2B3-201 (10mg/kg i.v.). Treatment with a low dose of 2B3-201 significantly reduced the severity of EAE as compared to saline control, similar to treatment with high dose free MP, while a low dose of free MP was not effective. In a histological analysis of the spinal cord, treatment with 2B3-201 significantly decreased T cell as well as macrophage/microglia infiltration in the CNS by about 50%. Moreover, application of a low dose of 2B3-201 or a high dose of free MP reduced the amount of astrocyte activation as well as the extent of axonal loss and also demyelination in spinal cord lesions as compared to low dose MP or sham treatment. In summary, in the murine MOG-EAE model of MS, a glutathione PEGylated liposomal formulation of MP (2B3-201) is clinically and histologically as effective as free MP at one tenth of the dosage as well as at a lower application frequency and clearly more effective than the same dosage of free MP. These positive proof-of-concept efficacy studies warrant further development of 2B3-201 for the treatment of neuroinflammatory conditions such as MS.

Intra-articular corticoid injection induces circulating glucocorticoid bioactivity and systemic immune activation in juvenile idiopathic arthritis.

OBJECTIVE: To study the systemic effects of intra-articular (IA) glucocorticoid (GC) injections in juvenile idiopathic arthritis (JIA). METHODS: The study group comprised 21 JIA patients being treated with IA methylprednisolone [MP (n = 15) or MP plus triamcinolone hexacetonide (THA) (n = 6)] prescribed on clinical indications. The systemic effect of MP was assessed by measuring circulating glucocorticoid bioactivity (GBA) with a recombinant cell transactivation assay 7 and 24 h after the IA injections, and after 2 months. The systemic immunological responses were studied with a novel assay for testing patient serum-induced changes in the secretion of interferon (IFN)-γ and interleukin (IL)-5 from target cells. RESULTS: Administration of IA GC induced serum GBA (p = 0.001) and suppressed circulating cortisol levels (p = 0.002) 7 h after the injection. Serum withdrawn 24 h after the IA injection induced less IL-5 secretion from mitogen-activated target cells when compared with pre-treatment sera (p = 0.036). This decrease in target cell T helper (Th)2 response (IL-5) was MP dose related (r = -0.550, p = 0.018). High IL-5 secretion from target cells prior to the IA injections was associated with good clinical outcome at 2 months, seen as a low number of active (p = 0.044) and restricted joints (p = 0.049). CONCLUSION: IA GC injections have systemic effects that are reflected in the serum as an immediate elevation of GBA, a decrease of endogenous cortisol as well as a suppressive effect of patient serum on target cell IL-5 secretion. These systemic effects may play a role in the attenuation of disease activity.

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

OBJECTIVE: To clarify the association of clinical and prognostic features with dermatomyositis (DM)-specific autoantibodies (Abs) in adult Japanese patients with DM. DESIGN: Retrospective study. SETTING: Kanazawa University Graduate School of Medical Science Department of Dermatology and collaborating medical centers. Patients A total of 376 consecutive adult Japanese patients with DM who visited our hospital or collaborating medical centers between 2003 and 2008. MAIN OUTCOME MEASURES: Clinical and laboratory characteristics of adult Japanese patients with DM and DM-specific Abs that include Abs against Mi-2, 155/140, and CADM-140. RESULTS: In patients with DM, anti-Mi-2, anti-155/140, and anti-CADM-140 were detected in 9 (2%), 25 (7%), and 43 (11%), respectively. These DM-specific Abs were mutually exclusive and were detected in none of 34 patients with polymyositis, 326 with systemic sclerosis, and 97 with systemic lupus erythematosus. Anti-Mi-2 was associated with classical DM without interstitial lung disease or malignancy, whereas anti-155/140 was associated with malignancy. Patients with anti-CADM-140 frequently had clinically amyopathic DM and rapidly progressive interstitial lung disease. Cumulative survival rates were more favorable in patients with anti-Mi-2 compared with those with anti-155/140 or anti-CADM-140 (P < .01 for both comparisons). Nearly all deaths occurred within 1 year after diagnosis in patients with anti-CADM-140. Conclusion Dermatomyositis-specific Abs define clinically distinct subsets and are useful for predicting clinical outcomes in patients with DM.

IgE-mediated hypersensitivity reactions to methylprednisolone.

BACKGROUND: Allergic reactions to systemically administered corticosteroids seem to be infrequent considering their extensive use. The aim of the study was to evaluate the IgE response in patients with immediate allergic reactions to methylprednisolone (MP). METHODS: Four subjects who developed immediate reactions after MP administration and ten controls with good tolerance to MP administration were evaluated. Skin prick and intradermal testing were done using MP, hydrocortisone (HC), and dexamethasone (DX). If negative, a drug provocation test (DPT) was done to confirm the diagnosis and assess cross-reactivity. The in vitro IgE response was evaluated by the basophil activation test (BAT) and ImmunoCAP. RESULTS: Three patients were diagnosed by the presence of a positive skin test in the immediate reading with MP, two by prick and one by intradermal testing, and one patient was skin test negative and diagnosed by DPT. All four patients had good tolerance to HC and DX. The BAT was positive for just MP in those patients with positive skin tests, with all patients being negative for HC and DX. Two patients were also ImmunoCAP positive to MP. CONCLUSIONS: This study confirms the existence of immediate allergic reactions to MP and that some are mediated by specific IgE antibodies. Skin testing, ImmunoCAP and the BAT are useful to confirm the diagnosis.

Expansion of regulatory CD8+ T-lymphocytes and fall of activated CD8+ T-lymphocytes after i.v. methyl-prednisolone for multiple sclerosis relapse.

INTRODUCTION: Multiple sclerosis (MS) is a multifocal chronic inflammatory demyelinating disease of the central nervous system. Axonal damage correlates with the presence of macrophages and CD8+ T-lymphocytes at brain lesions. The gold standard of therapy at MS relapse are iv glucocorticoids (GC). The aim of the study was to assess the changes on the different subsets of circulating CD8+ T-lymphocytes at relapse and after iv GC therapy. PATIENTS AND METHODS: We consecutively studied 20 patients at MS relapse before and at day 5 after initiation of i.v. methyl-prednisolone (MP) therapy (1 g/day for 3-5 days). CD4+ and CD8+ T-lymphocytes subsets were studied by multiparametric flow-cytometry. As control group, 18 healthy subjects were studied. RESULTS: Treatment with i.v. MP suppressed activated (CD8+CD38+HLA-DR+, p=0.05) and effector memory (CD8+CD27-CD45RO+) T-lymphocytes (p=0.07). By contrast, an increase of naïve (CD8+CD27+CD45RO-) (p=0.07) and regulatory CD8+CD25+ T-lymphocytes was observed (p<0.002). At MS relapse, there was an inverse correlation between regulatory CD8+CD25+CD28- T-lymphocytes and activated CD4+ (r = -0.6; p=0.012) and CD8+ (r = -0.66; p=0.004) T-lymphocytes. After i.v. MP treatment, positive correlation between regulatory CD4+CD25+high T-lymphocytes and CD8+CD25+ T-lymphocytes was observed (r=0.74; p<0.0001). CONCLUSIONS: Our data suggest that i.v. MP may contribute to changes observed on the differentiation of CD8+ T-lymphocytes, namely blocking their complete maturation, and expansion of regulatory CD8+ T-lymphocytes. We hypothesize an additional effect of i.v. MP in inhibiting axonal damage which may add a neuroprotective effect on MS relapse.

Comparison of megadose methylprednisolone versus conventional dose prednisolone in hematologic disorders.

Glucocorticoids (GCs) are known for their clinically useful effects in immunologic and inflammatory disorders. Although there is a huge volume of knowledge concerning the cellular and molecular effects of GCs, statements regarding their effects in multiple diseases at variable doses are not clear-cut owing to pharmacogenetic differences. The main actions of GCs in hematologic disorders have been related to their differentiation-inducing and apoptosis-inducing effects, but modification of several steps of the hematopoietic and/or immune pathway has also been reported. In our clinic, mega-dose methylprednisolone (MDMP) has been successfully used for treatment of different hematologic diseases, such as leukemias, bone marrow failure in aplastic anemia, hypoplastic anemia, myelodysplastic syndrome, neutropenia, autoimmune diseases, and in some congenital hereditary diseases. Both clinical and experimental studies in our department revealed that MDMP was more effective than conventional dose steroids. It is interesting that MDMP can be curative in some congenital hereditary diseases such as Diamond-Blackfan syndrome. However, more research is required to clarify their roles in biology, physiology, and molecular genetics.

The corticosteroid-induced inhibitory effect on NK cell function reflects down-regulation and/or dysfunction of triggering receptors involved in natural cytotoxicity.

Corticosteroids are known to inhibit NK cell functions. However no information is available on whether such inhibition may affect the expression and/or the function of receptors involved in NK cell activation. In an attempt to analyze this point, we studied peripheral blood NK cells isolated from pediatric patients undergoing allogeneic BM transplantation. NK cells were analyzed before, during and after methylprednisolone administration to treat acute graft-versus-host disease. In NK cells freshly isolated from peripheral blood during methylprednisolone treatment, the surface expression of activating receptors, particularly NKp46 and NKp30, was consistently reduced. Such impaired expression could also be detected after 5 days of culture in IL-2. Such cultured NK cells also failed to express the IL-2-inducible NKp44 receptor. Accordingly, cytotoxicity against different tumor target cell lines was sharply reduced. The effect on NK cells isolated from healthy individuals and cultured in the presence of methylprednisolone was also analyzed. A similar inhibitory effect occurred in the expression of activating NK receptors. In addition, a sharp impairment of NK cytotoxicity against different tumor target cell lines or immature DC was detected.

Allergic contact dermatitis to methylprednisolone aceponate in a topical corticosteroid.

A 42-year-old registered nurse presented with a recurrent history of multifactorial hand dermatitis, which had ceased to respond to the topical corticosteroid that she was using. Patch testing revealed strong reactions to both Advantan Fatty Ointment (Commonwealth Serum Laboratories, Melbourne, Australia), and its active ingredient, methylprednisolone aceponate. Methylprednisolone aceponate is one of the more sensitizing topical corticosteroids and is becoming increasingly recognized as a significant allergen.

Serum levels of soluble TNFalpha receptors (sTNFR1 and sTNFR2) during corticosteroid treatment in patients with Graves' ophthalmopathy.

UNLABELLED: TNFalpha was shown to play an important role in the autoimmune inflammatory process of Graves' ophthalmopathy (GO). In our previous study we found no significant changes in serum TNFalpha levels in GO patients. The aim of the present study was to estimate an influence of corticosteroids on serum levels of TNFalpha receptors (sTNFR1 and sTNFR2) in GO patients and to assess their potential as a guideline of immunosuppressive therapy. We detected serum sTNFRI and sTNFR2 in three groups of subjects: 18 patients with clinical symptoms of ophthalmopathy [Clinical Activity Score (CAS) > or = 4, anamnesis of GO > or = 1 yr], 16 patients with Graves' disease without ophthalmopathy (Gd) and 14 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) and subsequent treatment with oral prednisone (P). The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and after the end of the corticosteroid therapy. The levels of serum sTNFR1 and sTNFR2 were determined by ELISA. Serum levels of sTNFR1 were significantly higher in GO individuals as compared to the control group (p < 0.01). We have found a significant decrease in sTNFR1 concentration in corticosteroid-respondent patients (satisfactory clinical effect, decrease of CAS > or = 1) as compared to the pretreatment values after MP treatment (p < 0.05) and after 14 days of prednisone (p < 0.01). There were significant differences in sTNFR2 level after MP treatment (p < 0.02) and after corticosteroid administration (p < 0.05) between responders and non-responders. Baseline values of sTNFRI in GO individuals were positively correlated with CAS (r = 0.6, p < 0.02). CONCLUSIONS: TNFalpha acting through its receptors plays an important role in the pathogenesis of Graves' ophthalmopathy. Moreover, the beneficial influence of corticosteroids on the course of GO may be explained, at least in part, by an inhibition of sTNFR1 and sTNFR2. Measurement of soluble TNFalpha receptors might potentially serve as an indicator in prognostic estimation of corticosteroids' efficacy.