RESUMO
OBJECTIVES: To explore the toxicity of low-dose methotrexate (MTX), an uncommon, but life-threatening event. METHODS: We analysed the presentation, course and risk factors of all patients admitted to the rheumatology ward with severe low-dose MTX toxicity. These patients were compared with patients without signs of relevant MTX toxicity. RESULTS: The 12 patients admitted for MTX toxicity included 7 patients with rheumatoid arthritis, 2 with psoriatic arthritis or psoriasis, 2 patients with giant cell arteritis and 1 with myositis. 1 patient died from infections, while 11 survived under folinic acid administration. All patients suffering from severe MTX toxicity were older than 70 years and were therefore compared with 400 patients who were also older than 70 years, but without MTX toxicity. Of these 400 control patients, the group of patients not on MTX (n=232) had more renal impairment than the group of patients on MTX (n=168). Compared with the 168 MTX-treated patients without toxicity, the 12 patients with life-threatening toxic events had a lower median estimated glomerular filtration rate (eGFR) at the routine visit preceding the acute event (64 (range 32-77) vs 69 (range 8 to >90) mL/min x 1.73, p=0.0251). A multivariate analysis found that patients with toxicity were more frequently treated with diuretics (6/12 vs 24/168), proton pump inhibitors (PPIs; 10/12 vs 70/168) and levetiracetam (2/12 vs 1/168). CONCLUSIONS: Patients older than 70 years with lower eGFR and being on diuretics, but also on PPIs and levetiracetam, have a significantly higher risk for MTX toxicity.
Assuntos
Artrite Reumatoide , Psoríase , Humanos , Idoso , Metotrexato/efeitos adversos , Diuréticos/efeitos adversos , Levetiracetam/uso terapêutico , Artrite Reumatoide/tratamento farmacológicoRESUMO
OBJECTIVES: We aimed to analyse the effects of real-life immunomodulatory therapy with cyclophosphamide and rituximab for interstitial lung disease (ILD) in patients with systemic sclerosis (SSc-ILD), anti-synthetase syndrome (ASS-ILD), or Sjögren's syndrome (SjS-ILD), in a single academic centre. METHODS: All inpatients with connective tissue diseases treated with intravenous bolus cyclophosphamide or rituximab were identified from the Medical Centre records. Information on patient characteristics, chest CT results, pulmonary function tests, therapies, and severe adverse events, were extracted from inpatient and outpatient records. RESULTS: Intravenous cyclophosphamide bolus therapy was used in 27 patients with SSc. Cyclophosphamide improved forced vital capacity (FVC) by more than 10% in 4 patients and stabilised it at -0.4% to +3.25% in 8. Rituximab constituted a rescue therapy in 14 SSc patients, and was used for treating 4 patients with ASS-ILD, 2 patients with SjS-ILD and one additional SSc-ILD patient. Rituximab led to FVC improvements of at least 5% in 8 patients and to stabilisation in another 6. 6 patients under cyclophosphamide and 8 patients under rituximab experienced severe adverse events. 8 of the 34 patients died, half of them from causes potentially related to therapy. CONCLUSIONS: In this subset of severely sick patients with connective tissue diseases, cyclophosphamide and/or rituximab led to improvement in 12 patients, and stabilisation was seen in 14. Despite the new options with nintedanib, immunomodulation remains a relevant therapeutic modality for ILD associated with connective tissue disease.
Assuntos
Doenças do Tecido Conjuntivo , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Humanos , Pulmão , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/etiologia , Estudos Retrospectivos , Rituximab/efeitos adversos , Escleroderma Sistêmico/complicações , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). METHODS: We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. RESULTS: Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. CONCLUSION: Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Granulomatose com Poliangiite/imunologia , Peroxidase/imunologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/epidemiologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Nefropatias/epidemiologia , Nefropatias/etiologia , Laringoestenose/epidemiologia , Laringoestenose/etiologia , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/epidemiologia , Otorrinolaringopatias/etiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/etiologia , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Rituximab/uso terapêutico , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS: We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS: Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION: MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.
Assuntos
Poliangiite Microscópica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto JovemRESUMO
Smoking is associated with increased incidence of chronic pain. However, the evidence is cross-sectional in nature, and underlying mechanisms remain unclear. In a longitudinal observational study, we examined the relationship between smoking, transition to chronic pain, and brain physiology. In 160 subjects with subacute back pain (SBP: back pain lasting 4-12 weeks, and no prior back pain [BP] for at least 1 year) pain characteristics, smoking status, and brain functional properties were measured repeatedly over 1 year. Sixty-eight completed the study, subdivided into recovering (SBPr, n = 31) and persisting (SBPp, n = 37), based on >20% decrease in BP over the year. Thirty-two chronic back pain (CBP: duration > 5 years) and 35 healthy controls were similarly monitored. Smoking prevalence was higher in SBP and CBP but not related to intensity of BP. In SBP, smoking status at baseline was predictive of persistence of BP 1 year from symptom onset (differentiating SBPp and SBPr with 0.62 accuracy). Smoking status combined with affective properties of pain and medication use improved prediction accuracy (0.82). Mediation analysis indicated the prediction of BP persistence by smoking was largely due to synchrony of fMRI activity between two brain areas (nucleus accumbens and medial prefrontal cortex, NAc-mPFC). In SBP or CBP who ceased smoking strength of NAc-mPFC decreased from precessation to postcessation of smoking. We conclude that smoking increases risk of transitioning to CBP, an effect mediated by corticostriatal circuitry involved in addictive behavior and motivated learning.
Assuntos
Dor nas Costas/fisiopatologia , Encéfalo/fisiopatologia , Dor Crônica/fisiopatologia , Fumar/fisiopatologia , Adulto , Dor nas Costas/complicações , Dor nas Costas/tratamento farmacológico , Mapeamento Encefálico , Dor Crônica/complicações , Dor Crônica/tratamento farmacológico , Progressão da Doença , Feminino , Seguimentos , Humanos , Modelos Logísticos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Fatores de Risco , Abandono do Hábito de Fumar , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: To assess the diagnostic performance of 11 commercial PR3- and MPO-ANCA ELISA systems (direct, capture and high sensitive [hs] ELISA). METHODS: Sera from 90 patients with AAV (GPA, MPA and CSS) and 20 disease controls (SLE; RA) and healthy individuals were tested for the presence of ANCA by IFT and by different ELISAs for the presence of PR3-and MPO-ANCA, respectively. Furthermore, the binding capacity of the IUIS-CDC reference sera for PR3-/MPO-ANCA in different commercial assays was analysed. RESULTS: Commercial ELISA kits for PR3-ANCA differed moderately in their sensitivity (from 45% to 62.5%). The highest sensitivity for PR3-ANCA was obtained with hs ELISA (kit A) and capture ELISA (kit N). Testing for MPO-ANCA the highest sensitivity (85%) was obtained with direct ELISA (kit D and I). Specificity was high in all kits. Only three PR3-ANCA commercial kits and three MPO-ANCA kits produced binding at the expected value for the IUIS-CDC reference sera (100 U/ml). In all of the kits, serial dilutions of the reference sera did not yield linearity. CONCLUSIONS: Second (capture) and third (high sensitivity) generation PR3-ANCA ELISA kits are superior to conventional ELISAs. Direct and capture MPO-ANCA ELISAs showed a good overall performance in all kits. Most of the kits have not been standardised to allow their results to be compared.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Ensaio de Imunoadsorção Enzimática , Mieloblastina/imunologia , Peroxidase/imunologia , Kit de Reagentes para Diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/normas , Alemanha , Humanos , Valor Preditivo dos Testes , Kit de Reagentes para Diagnóstico/normas , Padrões de Referência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: To report on the extended follow-up of relapsing/refractory CSS patients treated with mepolizumab with respect to relapse rates. METHODS: The follow-up consisted of regular clinic visits of patients who received nine infusions of mepolizumab (750mg IV) and switched to methotrexate 0.3mg/kg for maintenance of remission. Glucocorticoids were maintained as low as possible. Disease activity was measured using the Birmingham Vasculitis Activity Score (BVAS). Disease states as remission or relapse were defined according to the EULAR/EUVAS recommendations. The serum eosinophil cationic protein (ECP) was measured regularly and concentrations were correlated with BVAS. RESULTS: The follow-up of the study population under standard methotrexate maintenance therapy was extended to a median of 22 months. Three of nine patients were still in remission at the end of follow-up. During this time five major relapses in three and seven minor relapses in five out of the total nine patients were recognised. ECP levels were found to correlate stronger with the BVAS (r=0.38; p<0.0001) than other measures such as eosinophil counts. CONCLUSIONS: After induction of remission with mepolizumab the majority of patients suffered relapses when switched to methotrexate maintenance therapy. These data suggest that patients with CSS may require long term treatment with mepolizumab. Future trials in CSS should use other doses or dosing intervals for patients in remission. ECP is a promising marker of disease activity in CSS.