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1.
Clin Exp Immunol ; 188(1): 174-181, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28076879

RESUMO

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.


Assuntos
Autoanticorpos/imunologia , Granulomatose com Poliangiite/imunologia , Imunoglobulina M/imunologia , Poliangiite Microscópica/imunologia , Mieloblastina/imunologia , Adulto , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Biomarcadores , Feminino , Granulomatose com Poliangiite/diagnóstico , Humanos , Imunoglobulina G/imunologia , Masculino , Poliangiite Microscópica/diagnóstico , Pessoa de Meia-Idade , Índice de Gravidade de Doença
2.
Genes Immun ; 16(7): 470-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26291516

RESUMO

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.


Assuntos
Alelos , Antígenos HLA/genética , Miosite/genética , Adolescente , Adulto , Autoanticorpos/imunologia , Estudos de Casos e Controles , Dermatomiosite/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Polimiosite/genética , Fatores de Risco , População Branca
3.
Clin Exp Rheumatol ; 33(2 Suppl 89): S-77-83, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26016754

RESUMO

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.


Assuntos
Granulomatose com Poliangiite/epidemiologia , Poliangiite Microscópica/epidemiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Distribuição por Idade , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Estudos de Coortes , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/imunologia , Humanos , Nefropatias/etiologia , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/etiologia , Seleção de Pacientes , Peroxidase/imunologia , Índice de Gravidade de Doença
4.
Arthritis Rheum ; 65(9): 2441-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23754238

RESUMO

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Poliangiite Microscópica/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Azatioprina/administração & dosagem , Azatioprina/uso terapêutico , Estudos Cross-Over , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Rituximab , Resultado do Tratamento
5.
Clin Exp Rheumatol ; 27(1 Suppl 52): S45-52, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19646346

RESUMO

OBJECTIVE: The glycosylation status of autoantigens appears to be crucial for the pathogenesis of some autoimmune diseases, since carbohydrates play a crucial role in the distinction of self from non-self. Proteinase 3 (PR3), the main target antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG), contains two Asn-linked glycosylation sites. The present study explores the influence of the glycosylation status of PR3 on the PR3 recognition by ANCA in a well characterized population of patients with WG. METHODS: Forty-four patients with WG (459 serum samples) who participated in a multicenter randomized trial, were tested by capture ELISA for ANCA against PR3 and deglycosylated recombinant variants of PR3. RESULTS: The patients were followed for a median of 27 months, and the median number of serum samples per patient was 10. At baseline, the correlation between the levels of ANCA against PR3 and against all the deglycosylated recombinant variants of PR3 were greater than 0.94 (?<0.001 for all the comparisons). Longitudinal analyses comparing the levels of ANCA against PR3 versus all the deglycosylated recombinant variants of PR3, using linear mixed models, showed no significant statistical differences (rho >or=0.90 in all cases). CONCLUSION: The glycosylation status of PR3 has no impact on its recognition by ANCA in WG.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Granulomatose com Poliangiite/imunologia , Mieloblastina/imunologia , Adulto , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Reações Antígeno-Anticorpo , Linhagem Celular Transformada , Feminino , Glicosilação , Granulomatose com Poliangiite/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mieloblastina/metabolismo
6.
J Clin Invest ; 80(2): 499-506, 1987 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-3038960

RESUMO

Chronic inflammatory myositis similar to human polymyositis occurs in mice after infection with a strain of Coxsackievirus B 1 (CVB 1). To investigate the role of T cells in the pathogenesis of this disorder, we compared disease expression in T cell-deficient athymic nude (nu/nu) mice and heterozygotes (nu/+) with normal T cell function. Acute infectious myositis occurred in nu/nu and nu/+ mice. Chronic (greater than 21 d postinfection) weakness and myositis, however, developed only in nu/+. Resistance to disease in nu/nu mice was not explained by insusceptibility to infection; the amount of virus lethal for 50% of mice and virus replication were comparable in both groups. Additionally, anti-CVB 1 antibody production was similar in both groups. Reconstitution of infected nu/nu mice with spleen cells from normal mice resulted in disease. These results demonstrate that chronic weakness after infection with this virus is not simply a sequela of acute myonecrosis and suggest that T cells play a pivotal role in the pathogenesis of chronic myositis.


Assuntos
Infecções por Coxsackievirus/imunologia , Enterovirus Humano B/imunologia , Miosite/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Antivirais/imunologia , Enterovirus Humano B/crescimento & desenvolvimento , Enterovirus Humano B/patogenicidade , Imunidade Celular , Camundongos , Camundongos Nus/imunologia , Miosite/patologia , Baço/imunologia , Replicação Viral
7.
Rheum Dis Clin North Am ; 20(4): 995-1015, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7855333

RESUMO

Several infectious agents have been linked to chronic inflammatory myositis. The mechanisms proposed usually involve presumed persistent infection or induction of an autoimmune response following infection. Agents most often implicated are the enteroviruses (especially coxsackieviruses), echoviruses in patients with agammaglobulinemia, retroviruses including HIV-type 1 and human T-cell lymphotropic virus type 1, and the protozoan Toxoplasma gondii. In the majority of cases, however, no specific infectious agent can be identified.


Assuntos
Miosite/etiologia , Viroses/complicações , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Parasitárias/complicações , Toxoplasmose/complicações
8.
Arthritis Care Res ; 9(3): 197-205, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8971229

RESUMO

OBJECTIVE: To investigate the effect of 3 commercial wrist orthoses on finger dexterity and hand function of patients with rheumatoid arthritis (RA). METHODS: Forty-two patients with definite RA participated in the cross-over study comparing 3 styles of commercial wrist orthoses. Finger dexterity and hand function of the dominant hand were assessed while splinted and unsplinted, at the initial session and after 1 week of intermittent orthosis use. Finger dexterity was assessed using two subtests from the Purdue Pegboard Test (Purdue) and hand function was assessed using the Jebsen-Taylor Hand Function Test (Jebsen-Taylor). RESULTS: Both finger dexterity and hand function were reduced by splinting; men and women were affected similarly. There was no difference in finger dexterity or hand function afforded by the 3 orthoses. Results on both the Purdue and Jebsen-Taylor tests showed a significant learning effect across time. CONCLUSIONS: The 3 commercial wrist orthoses studied reduce dexterity similarly and significantly. When commercial wrist orthoses are to be used during tasks that require maximum dexterity, this reduction should be weighed against the known benefits of splinting.


Assuntos
Artrite Reumatoide/reabilitação , Força da Mão , Mãos/fisiopatologia , Contenções/normas , Atividades Cotidianas , Artrite Reumatoide/fisiopatologia , Estudos Cross-Over , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Contenções/provisão & distribuição
9.
Arthritis Care Res ; 9(1): 42-50, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8945112

RESUMO

OBJECTIVE: To investigate the immediate and short-term effects of 3 commercial wrist orthoses on grip strength and function. METHODS: Thirty-six patients with definite rheumatoid arthritis participated in the randomized, controlled, cross-over design study of 3 commercial wrist extensor orthoses. Dominant-hand dynamometric grip strength was assessed at both initial and followup sessions while splinted and nonsplinted. Functional impact was assessed using a written questionnaire. RESULTS: All 3 commercial orthoses reduced grip strength when first donned. After a 1-week adjustment period, one orthosis, the Smith and Nephew Roylan D-Ring (Roylan), afforded splinted grip strength equal to that of the nonsplinted grip strength. The other 2 orthoses continued to reduce grip strength, and afforded splinted grip strength significantly below that of the Roylan. The Roylan was deemed comfortable by more subjects than the other orthoses. CONCLUSIONS: The belief that commercial orthotic use increases grip strength, either immediately or after 1 week, is not supported by this study's data. Different styles of commercial wrist orthoses appear to have differing influence on splinted grip strength.


Assuntos
Atividades Cotidianas , Artrite Reumatoide/reabilitação , Força da Mão , Aparelhos Ortopédicos/normas , Punho/fisiopatologia , Artrite Reumatoide/fisiopatologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
10.
Arthritis Care Res ; 10(1): 27-35, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9313387

RESUMO

OBJECTIVE: To describe patients' functional uses of 3 commercial wrist orthoses, to describe patients' preference patterns for the orthoses, and to clarify orthotic attributes that are viewed positively and negatively. METHODS: Using a cross-over design, 42 patients with definite rheumatoid arthritis used each of 3 commercial orthoses for one week. There was a one-week wash-out between each week of use. At the end of the study, private semi-structured interviews were conducted with each participant. Data from close-ended questions were tabulated. Open-ended data were analyzed using qualitative methods. RESULTS: Patients reported that the 3 commercial wrist orthoses reduced wrist pain similarly, but that comfort and a sense of security during functional tasks were only found if the orthoses were comfortable and well-fitting. Most subjects preferred the padded, short forearm orthosis, though a small number found it uncomfortably warm, and many complained that it was difficult to use when wearing long-sleeved garments. Common complaints about the two elastic orthoses included chafing at the thumb webspace and chafing at the proximal closures. Longer forearm length was often perceived as providing unnecessarily high levels of wrist support. CONCLUSIONS: No single orthosis suited all subjects. Satisfaction with an orthosis appears to be based not only on its therapeutic effect, but also the comfort and ease of its use. To maximize patient satisfaction and improve the likelihood of appropriate fit and comfort, several styles of commercial orthoses should be available. The current trend toward restricted clinic stocks appears contrary to both therapeutic goals and patient satisfaction.


Assuntos
Atividades Cotidianas , Artrite Reumatoide/reabilitação , Satisfação do Paciente , Contenções/normas , Articulação do Punho , Adulto , Idoso , Artrite Reumatoide/psicologia , Estudos Cross-Over , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Metodológica em Enfermagem
11.
Patient Educ Couns ; 11(3): 235-41, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10288063

RESUMO

Based on a needs assessment of our ambulatory patients and review of available arthritis education programs, we developed an innovative education and exercise program, the Minnesota Arthritis Training Program (MATP). Patients are taught self-management skills including how to: (1) interpret changing physical symptoms and limitations caused by joint inflammation and apply modifications to their individualized exercise program; (2) recognize common drug toxicites and use a decision analysis schema to manage side effects to decrease the risk of serious toxicity and decrease dependency on professionals safely; (3) develop strategies to modify activity schedules to make the most of limited stamina; (4) recognize and understand psychological problems produced by rheumatoid arthritis (RA) including sexual dysfunction, depression and breakdown of communication; and (5) reconstitute social support systems.


Assuntos
Artrite Reumatoide/terapia , Terapia por Exercício , Educação de Pacientes como Assunto , Autocuidado , Tomada de Decisões , Humanos , Minnesota
12.
Am J Occup Ther ; 52(7): 573-8, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9693703

RESUMO

Occupational therapists are expanding their use of custom and commercial soft splints fabricated from neoprene (polychloroprene), but little has been written regarding dermatological issues associated with this material. Skin contact with neoprene poses two dermatological risks: allergic contact dermatitis (ACD) and miliaria rubra (i.e., prickly heat). Allergic reaction to neoprene is generally ascribed to the accelerants used to manufacture the man-made rubber, specifically thiourea compounds and mercaptobenzothiazole (MBT). Symptoms of neoprene-related ACD include itching, skin eruptions, swelling, and hemorrhages into the skin. Miliaria rubra creates small, red, elevated, inflammatory papules and a tingling, burning sensation. Although neoprene hypersensitivity is rare, its incidence may grow as neoprene becomes a more commonly used material. It is recommended that therapists screen patients for a history of dermatological reactions to neoprene or other materials containing thiourea compounds or MBT and educate patients to discontinue splint use if dermatological symptoms develop. Therapists are also encouraged to notify splint manufacturers regarding all ACD reactions.


Assuntos
Dermatite Alérgica de Contato/etiologia , Miliária/etiologia , Neopreno/efeitos adversos , Contenções/efeitos adversos , Adulto , Dermatite Alérgica de Contato/fisiopatologia , Humanos , Masculino , Miliária/fisiopatologia , Prognóstico , Fatores de Risco
13.
Arthritis Rheumatol ; 66(11): 3151-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25047592

RESUMO

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/prevenção & controle , Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Prevenção Secundária/métodos , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Prednisona/uso terapêutico , Estudos Prospectivos , Recidiva , Indução de Remissão/métodos , Rituximab , Fatores de Tempo , Resultado do Tratamento
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