RESUMO
Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions.
Assuntos
Povo Asiático/genética , Toxidermias/genética , Toxidermias/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Alopurinol/efeitos adversos , Alopurinol/imunologia , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/imunologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/imunologia , Biomarcadores , Carbamazepina/efeitos adversos , Carbamazepina/imunologia , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/imunologia , Estudos de Casos e Controles , Cefalosporinas/efeitos adversos , China/etnologia , Citocinas/imunologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Supressores da Gota/efeitos adversos , Supressores da Gota/imunologia , Humanos , Metazolamida/efeitos adversos , Metazolamida/imunologia , Polimorfismo de Nucleotídeo Único , Sulfassalazina/efeitos adversos , Sulfassalazina/imunologiaAssuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Sulfassalazina/uso terapêutico , Administração Tópica , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/imunologia , Doença Crônica , Resistência a Medicamentos/imunologia , Feminino , Seguimentos , Humanos , Rinite/imunologia , Sinusite/imunologia , Sulfassalazina/administração & dosagem , Sulfassalazina/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Mucous membrane pemphigoid (MMP) still represents a potentially life- and sight-threatening disease. In a subset of patients with severe MMP, conventional immunosuppressants are ineffective or contraindicated. OBSERVATIONS: Twenty-five patients with severe refractory MMP, including 5 with mucous membrane-dominant epidermolysis bullosa acquisita, received 1 or 2 cycles of rituximab (375 mg/m(2) weekly for 4 weeks). Twenty-one of the patients were receiving concomitant therapy with dapsone and/or sulfasalazine therapy, which was maintained during rituximab cycles. Complete responses in all affected sites (ocular and/or extraocular) were obtained in 17 patients (68%) by a median time of 12 weeks after the first cycle, and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. In all but 1 of the 10 patients with ocular lesions, their eyes became noninflammatory within a mean of 10 weeks. Among the 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids and were hypogammaglobulinemic. Treatment with immunosuppressants was discontinued for all other patients, and no other infection was observed. Ten patients experienced relapse after a mean of 4 (range, 1-16) months after achieving complete responses. CONCLUSIONS: Rituximab appears to have rapid and dramatic efficacy in patients with severe, refractory MMP. The occurrence of severe infections in patients receiving concomitant conventional immunosuppressants supports using rituximab without other immunosuppressants. Controlled prospective studies are warranted to define an optimal treatment protocol.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Penfigoide Mucomembranoso Benigno/tratamento farmacológico , Adolescente , Adulto , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/imunologia , Autoanticorpos/imunologia , Estudos de Coortes , Doenças Transmissíveis/induzido quimicamente , Doenças Transmissíveis/imunologia , Dapsona/imunologia , Dapsona/uso terapêutico , Fármacos Dermatológicos/imunologia , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Fatores Imunológicos/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Penfigoide Mucomembranoso Benigno/imunologia , Rituximab , Índice de Gravidade de Doença , Sulfassalazina/imunologia , Sulfassalazina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Sulfonamides are generally classified into 2 groups: antibiotics and non-antibiotics. Recent studies showed that patients allergic to sulfonamide antibiotics do not have a specific risk for an allergy to sulfonamide non-antibiotic. However, the anti-inflammatory drug sulfasalazine represents an important exception. Used in rheumatic diseases, it is classified as a non-antibiotic sulfonamide, but is structurally related to antibiotic sulfonamides. Therefore, we aimed to analyze in vitro the cross-reactivity between the antimicrobial sulfamethoxazole and the anti-inflammatory drug sulfasalazine. METHODS: PBMC from 2 patients with severe hypersensitivity syndrome to sulfasalazine, 3 patients with sulfamethoxazole allergy and 5 healthy donors were isolated and incubated with medium only (negative control), 2 concentrations (10, 100 µg/ml) of sulfapyridine, 2 concentrations (100, 200 µg/ml) of sulfamethoxazole, and tetanus toxoid (10 µg/ml) as a positive control. After 6 days of culture, (3)H-thymidine was added and cell proliferation was measured. RESULTS: In all patients tested, the lymphocyte transformation tests were positive for both sulfapyridine and sulfamethoxazole, suggesting a strong cross-reactivity to these drugs. None of the healthy donors reacted to any of the drugs tested. We refrained from provoking our patients with either sulfasalazine or sulfamethoxazole, as they had a clear, typical history, severe symptoms and were positive on in vitro tests to both compounds. CONCLUSIONS: We demonstrate that in the case of sulfamethoxazole and sulfasalazine, cross-reactivity is dependent on chemical features rather than the indication of the drugs. Therefore, patients with hypersensitivity to sulfasalazine or sulfamethoxazole should be specifically advised to avoid both drugs.
Assuntos
Anti-Infecciosos/imunologia , Hipersensibilidade a Drogas/etiologia , Sulfametoxazol/imunologia , Sulfassalazina/imunologia , Adulto , Idoso , Reações Cruzadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sulfametoxazol/efeitos adversos , Sulfassalazina/efeitos adversosRESUMO
Sulfasalazine is an antibiotic used in the treatment of inflammatory bowel diseases. For the assessment of sulfasalazine in several biological matrices, an Enzyme-Linked Immunosorbent Assay (ELISA) method based on polyclonal antibodies was developed and characterized. The immunoassay showed a high sensitivity (IC50=0.51 ng mL(-1)) and specificity, a detection limit of 0.02 ng mL(-1) and a dynamic range of 0.06-3.75 ng mL(-1) (80-20% inhibition). The immunoassay performed well when it was applied to spiked plasma samples (from 0.5 to 2.0 ng mL(-1)) previously cleaned up by protein precipitation with methanol. Recoveries ranged from 83 to 119%, with a mean value of 99% (CV=13%). Since sulfasalazine remaining of a treatment reaches the systemic circulation in unchanged form, the immunoassay can be applied to the determination of this pharmaceutical in human plasma in order to facilitate the control of the patients through the application of personal doses.
Assuntos
Sulfassalazina/sangue , Sulfassalazina/química , Animais , Bovinos , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Coelhos , Sulfassalazina/análise , Sulfassalazina/imunologiaAssuntos
Antibacterianos/administração & dosagem , Anticorpos Antibacterianos/sangue , Infecções por Clostridium/imunologia , Clostridium perfringens/imunologia , Sulfassalazina/administração & dosagem , Antibacterianos/imunologia , Artrite Reumatoide/tratamento farmacológico , Humanos , Sulfassalazina/imunologiaRESUMO
Sulphasalazine a drug used for the treatment of rheumatoid arthritis (RA) shows a wide range of biological activities all of which might contribute to the beneficial clinical effect seen during treatment of RA. This review summarizes some of the biological activities and discusses these in context of possible modes of action of the drug. Sulphasalazine has been described as an antibacterial drug, an anti-inflammatory drug or as an immunomodulator. From the reviewed data it is concluded that the effects of sulphasalazine on various immunological processes, are of outstanding importance for its mode of action.
Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Sulfassalazina/farmacologia , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Antirreumáticos/imunologia , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Humanos , Sulfassalazina/imunologia , Sulfassalazina/farmacocinéticaRESUMO
Sulphasalazine is an effective drug for the treatment of rheumatoid arthritis in adults. In paediatric patients, the drug has been used to treat inflammatory bowel disease and is currently under investigation for the treatment of juvenile chronic arthritis. Although sulphasalazine has a rather low incidence of serious side effects, one of the most common is skin rash, thought to be an allergic reaction. In adults, sulphasalazine desensitization programmes have proven to be effective for the treatment of this side effect. We present the case of a 7-year-old boy suffering from HLA-B 27 positive juvenile chronic arthritis. After initiation of treatment with sulphasalazine he developed an allergic skin rash, but tolerated the drug well after completion of a desensitization programme. To our knowledge, this is the first report of a paediatric patient with juvenile chronic arthritis successfully desensitized with sulphasalazine.
Assuntos
Antirreumáticos/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Dessensibilização Imunológica , Toxidermias/terapia , Sulfassalazina/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/imunologia , Artrite Juvenil/imunologia , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Toxidermias/imunologia , Humanos , Masculino , Sulfassalazina/administração & dosagem , Sulfassalazina/imunologiaRESUMO
OBJECTIVE: To analyze whether the intestinal mucosa in rheumatoid arthritis (RA) is immunologically abnormal and whether sulfasalazine (SSZ) possesses any local intestinal immunoregulatory effect. METHODS: Lymphocyte subpopulations and HLA-DR expression were evaluated in biopsy specimens from the duodenal-jejunal mucosa and in peripheral blood samples obtained from 17 patients with RA, both before and after 16 weeks of SSZ treatment. The same mucosal assays were also performed in 7 controls. RESULTS: The mucosa of the small intestine in RA patients showed no differences in morphology, HLA-DR expression, or the amounts and distribution of CD3+, CD4+, CD8+, and gamma/delta + lymphocytes compared with the control group. However, there was a reduction in mucosal CD3+ and gamma/delta + lymphocyte numbers after SSZ therapy, which did not correspond to a change in peripheral blood CD3+ lymphocyte number. SSZ treatment also tended to diminish the peripheral blood CD4+:CD8+ cell ratio (P = 0.05). CONCLUSION: No signs of inflammation or immunologic abnormalities were seen in RA duodenal-jejunal mucosa. In this part of the intestine, however, SSZ exerted immunoregulatory effects that were not encountered in the peripheral blood.
Assuntos
Adjuvantes Imunológicos/farmacologia , Artrite Reumatoide/imunologia , Mucosa Intestinal/imunologia , Sulfassalazina/imunologia , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Biópsia , Complexo CD3/análise , Antígenos CD4/análise , Antígenos CD8/análise , Duodeno , Feminino , Antígenos HLA-DR/análise , Humanos , Imuno-Histoquímica , Mucosa Intestinal/química , Mucosa Intestinal/patologia , Jejuno , Contagem de Leucócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/análise , Sulfassalazina/uso terapêuticoRESUMO
Skin rash is a common side effect of sulphasalazine. Desensitisation, with a gradual introduction of the drug, may prevent rash. This study reports a 33% (3/9 patients) success rate of desensitisation in patients with arthritis. Desensitisation should only be attempted if sulphasalazine has been efficacious in treating the joint symptoms.
Assuntos
Artrite Juvenil/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Dessensibilização Imunológica , Toxidermias/etiologia , Sulfassalazina/efeitos adversos , Adulto , Idoso , Toxidermias/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sulfassalazina/imunologia , Sulfassalazina/uso terapêuticoAssuntos
Dessensibilização Imunológica , Glucosamina/análogos & derivados , Sulfassalazina/imunologia , Combinação de Medicamentos , Glucosamina/administração & dosagem , Glucosamina/imunologia , Humanos , Imunoglobulina A/análise , Doença Mista do Tecido Conjuntivo/tratamento farmacológico , Doença Mista do Tecido Conjuntivo/imunologia , Sulfassalazina/administração & dosagem , Vasculite/tratamento farmacológico , Vasculite/imunologiaRESUMO
Desensitization to sulphasalazine was successful in 16 of 21 (76%) arthritic patients who previously had skin rash from sulphasalazine (success rate: 8 of 13, or 62%) or sulphonamide (success rate: 8 out of 8 patients). Desensitization to sulphasalazine is a simple outpatient procedure which allows many subjects who develop a skin rash to sulphonamide or sulphasalazine to start or continue sulphasalazine treatment.
Assuntos
Artrite/tratamento farmacológico , Dessensibilização Imunológica , Sulfassalazina/imunologia , Sulfassalazina/uso terapêutico , Adulto , Idoso , Artrite/imunologia , Toxidermias/etiologia , Toxidermias/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/tratamento farmacológico , Sulfassalazina/efeitos adversos , Sulfonamidas/efeitos adversos , Sulfonamidas/imunologia , Sulfonamidas/uso terapêuticoRESUMO
Salazopyrin is effective in the management of connective tissue diseases, it is safe and useful for long-term management. However, it's use may be complicated by a skin rash which may necessitate withdrawal of therapy. Four patients with connective tissue diseases were treated with salazopyrin in desensitisation doses, as management with full dosage had previously been followed by a skin rash. In two patients, we were able to achieve a daily dosage of 2 g salazopyrin, in one case therapy was continued with a lower dosage, and withdrawal of the drug proved necessary in one patient. Desensitisation of salazopyrin induced rash is an easy procedure and is, possible in most cases. It may be worthwhile for many patients.
Assuntos
Doenças do Tecido Conjuntivo/tratamento farmacológico , Dessensibilização Imunológica , Sulfassalazina/administração & dosagem , Doenças do Tecido Conjuntivo/imunologia , Exantema/induzido quimicamente , Exantema/imunologia , Feminino , Humanos , Masculino , Sulfassalazina/efeitos adversos , Sulfassalazina/imunologiaRESUMO
Sulfasalazine is an important therapeutic agent in the management of chronic inflammatory bowel disease (CIBD). Unfortunately, adverse reactions to this drug have been reported in 5-55% of treated patients. These include dose-related side effects like nausea, malaise, and headache or hypersensitivity reactions such as rash, fever, hives, arthralgia, hepatitis, etc. Studies in adults with successful reintroduction of sulfasalazine after a desensitization program have been reported; however, with regard to children, no such data are available. Fourteen children and adolescents (5-16 yr old) diagnosed to have CIBD manifested hypersensitivity to sulfasalazine within 2 months of onset of treatment. All had pancolitis--secondary to Crohn's disease (CD) in four and to ulcerative colitis (UC) in 10. All of them were on steroids. Sulfasalazine was discontinued in all after symptoms of hypersensitivity developed. Three patients with severe reaction were diagnosed prior to desensitization experience. Desensitization, beginning with 5-50 mg of sulfasalazine/day, was attempted in the other 11 children. The dose was gradually increased by 5-50 mg increments every 3 days. Desensitization was successful in only five children, who were ultimately able to tolerate 1.5-3.0 g of sulfasalazine daily again. In the rest (six of 11 patients), oral 5-ASA (Asacol) was administered, and three could not tolerate it. One of these three with intolerance to Asacol required colectomy. One did not tolerate Asacol or Dipentum. Our findings suggest that sulfasalazine desensitization should be attempted in all patients developing hypersensitivity reactions before trying alternative therapy.
Assuntos
Dessensibilização Imunológica , Hipersensibilidade a Drogas/prevenção & controle , Doenças Inflamatórias Intestinais/tratamento farmacológico , Sulfassalazina/administração & dosagem , Sulfassalazina/efeitos adversos , Adolescente , Ácidos Aminossalicílicos/efeitos adversos , Criança , Doença Crônica , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Toxidermias/etiologia , Toxidermias/prevenção & controle , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Masculino , Mesalamina , Síndrome de Stevens-Johnson/induzido quimicamente , Síndrome de Stevens-Johnson/prevenção & controle , Sulfassalazina/imunologiaRESUMO
Numbers of IgA producing cells in peripheral blood were determined by the enzyme linked immunospot (ELISPOT) technique in 15 patients with inflammatory arthritides receiving sulphasalazine treatment. The numbers of IgA producing cells decreased significantly after the first three weeks of treatment. In 11 of the patients this decrease persisted, whereas a subsequent increase was seen in the four others; in two of these latter patients this increase coincided with a temporary withdrawal of the sulphasalazine treatment. A reduction of serum concentrations of IgA and haptoglobin was seen after three months' treatment. Eleven of the patients had a subjective improvement in their joint disease during the first three months of treatment. Analysis of circulating cells committed for IgA secretion may constitute one way of assessing gut associated immunity indirectly, and the present data suggest that sulphasalazine has a rapid effect on lymphocytes possibly originating from the gut and that such an effect precedes improvement in laboratory parameters and clinical symptoms in arthritic diseases.
Assuntos
Células Produtoras de Anticorpos/imunologia , Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Imunoglobulina A/imunologia , Espondilite Anquilosante/imunologia , Sulfassalazina/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Humanos , Espondilite Anquilosante/tratamento farmacológico , Sulfassalazina/imunologiaRESUMO
Two patients with ulcerative colitis and a past history of allergic reactions to sulfasalazine had similar reactions when treated with 5-aminosalicylic acid. This suggests that, at least in some patients, the adverse effects of sulfasalazine are due to 5-aminosalicylic acid rather than sulfapyridine. Desensitization to sulfasalazine was successfully carried out in one patient but was not attempted in a second.
Assuntos
Ácidos Aminossalicílicos/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Adulto , Dessensibilização Imunológica , Hipersensibilidade a Drogas , Tolerância a Medicamentos , Humanos , Masculino , Mesalamina , Pessoa de Meia-Idade , Sulfapiridina/efeitos adversos , Sulfassalazina/efeitos adversos , Sulfassalazina/imunologiaRESUMO
Sulfasalazine has proven to be an effective agent in the therapy of inflammatory bowel disease (IBD). Despite long and widespread usage, the mechanism of action of this drug is still not understood. Several investigators have suggested that the drug might act as an immunosuppressant. To examine this possibility, an in vivo study was undertaken to ascertain any quantitative change in the circulating T cells, Ig-bearing B cells, and complement receptor-bearing lymphocytes (CRL) of patients before and during therapy with sulfaslazine. Concomitant responses to skin test antigens were also evaluated. In vitro studies with control cells were performed to determine the influence of sulfasalazine and its components (sulfapyridine or 5-aminosalicylic acid) on the extent of antibody-dependent cellular cytotoxicity (ADCC), as well as on the number of T cells and CRL. Results indicate that neither sulfasalazine nor either of its components quantitatively alters those subpopulations of circulating mononuclear cells studied in vivo or in vitro--nor are these compounds responsible for any functional inhibition of ADCC.