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1.
Ann Rheum Dis ; 78(2): 192-200, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30396903

RESUMO

OBJECTIVES: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. METHODS: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). RESULTS: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. CONCLUSION: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos/métodos , Etanercepte/administração & dosagem , Adulto , Antirreumáticos/normas , Artrite Psoriásica/tratamento farmacológico , Medicamentos Biossimilares/normas , Dinamarca , Substituição de Medicamentos/normas , Etanercepte/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espondilartrite/tratamento farmacológico , Resultado do Tratamento
2.
Ann Rheum Dis ; 76(8): 1426-1431, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28473425

RESUMO

OBJECTIVES: According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry. METHODS: Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients. RESULTS: Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention. CONCLUSION: In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Substituição de Medicamentos , Infliximab , Sistema de Registros , Espondiloartropatias/tratamento farmacológico , Adulto , Idoso , Medicamentos Biossimilares , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Respir Res ; 18(1): 141, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720095

RESUMO

BACKGROUND: Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). METHOD: CD45+ CD34+ CD11b+ (7-AAD- CD3- CD19- CD294-) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. RESULTS: 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCOc (r = -0.61 an r = -0.58 both p < 0.05). CONCLUSIONS: We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCOc was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.


Assuntos
Artrite Reumatoide/complicações , Diferenciação Celular , Separação Celular/métodos , Citometria de Fluxo , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Monócitos/patologia , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Asma/sangue , Asma/patologia , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Colágeno Tipo I/metabolismo , Estudos Transversais , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Fenótipo , Valor Preditivo dos Testes , Pró-Colágeno/metabolismo , Capacidade de Difusão Pulmonar , Índice de Gravidade de Doença , Fatores de Tempo
6.
Rheumatology (Oxford) ; 54(12): 2156-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26175471

RESUMO

OBJECTIVES: To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy. METHODS: All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated. RESULTS: Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years. CONCLUSION: Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Adalimumab/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/epidemiologia , Dinamarca/epidemiologia , Etanercepte/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Indução de Remissão , Índice de Gravidade de Doença , Resultado do Tratamento
7.
BMJ Open ; 7(7): e015536, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698330

RESUMO

INTRODUCTION: Spondyloarthritis (SpA) is a heterogeneous spectrum of rheumatic diseases with either predominantly axial inflammatory symptoms of the spine and sacroiliac joints or predominantly peripheral arthritis. The two main entities of axial SpA (axSpA) are ankylosing spondylitis or non-radiographic axSpA (nr-axSpA). Tumour necrosis factor-α inhibitors have revolutionised the treatment of patients with axSpA who failed to respond to non-steroidal anti-inflammatory drugs and physical therapy. Chronic pain is common in patients with SpA and may still persist despite the lack of signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in SpA. The painDETECT Questionnaire (PDQ) is a screening tool developed to detect neuropathic pain components. The primary objective is to explore the prognostic value of the PDQ regarding treatment response in patients with axSpA 3 months after initiating a biological agent. Secondary aim is to evaluate the impact of extra-articular manifestations, comorbidities and patient-reported outcomes and elucidate if these factors influence treatment response. METHOD AND ANALYSIS: We will include 60 participants (≥18 years of age) diagnosed with axSpA independent of main entity, who initiate or switch treatment of a biologic. Data will be collected at baseline and at endpoint following Danish clinical practice (≥3 months) of treatment with biologics. We will explore whether the PDQ and other phenotypical patient characteristics are prognostically important for response to biological therapy according to established response criteria like 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (50%) and Ankylosing Spondylitis Disease Activity Score. ETHICS AND DISSEMINATION: The study is approved by the Region of Southern Denmark's Ethics committee (S-20160094) and has been designed in cooperation with patient representatives. The study is registered at clinicaltrials.gov (NCT02948608, pre-results). Dissemination will occur through publication(s) in international peer-reviewed journal(s).


Assuntos
Fatores Biológicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Espondilartrite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/uso terapêutico , Dinamarca , Feminino , Humanos , Masculino , Manejo da Dor , Medição da Dor , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Análise de Regressão , Projetos de Pesquisa , Índice de Gravidade de Doença
8.
Medicine (Baltimore) ; 96(26): e7297, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28658131

RESUMO

INTRODUCTION: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis. METHODS AND ANALYSIS: All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup (ie, chest X-ray/abdominal ultrasound); and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences.


Assuntos
Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/tratamento farmacológico , Polimialgia Reumática/diagnóstico , Polimialgia Reumática/tratamento farmacológico , Prednisolona/uso terapêutico , Esteroides/uso terapêutico , Biópsia , Dinamarca , Fluordesoxiglucose F18 , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/fisiopatologia , Humanos , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Osteoporose/induzido quimicamente , Osteoporose/fisiopatologia , Seleção de Pacientes , Polimialgia Reumática/complicações , Polimialgia Reumática/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prednisolona/efeitos adversos , Prevalência , Compostos Radiofarmacêuticos , Método Simples-Cego , Esteroides/efeitos adversos , Artérias Temporais/patologia , Vasculite/fisiopatologia
9.
Am J Case Rep ; 17: 883-886, 2016 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-27881835

RESUMO

BACKGROUND Leptospirosis is a zoonosis transmitted through urine of infected animals. Symptoms range from mild influenza-like symptoms to severe pulmonary hemorrhagic syndrome (SPHS); the latter are often fatal. The serogroup distribution in Denmark has changed from 1988 to 2012, with Icterohaemorrhagiae and Sejroe now being predominant. CASE REPORT A 45-year-old Danish woman living in an area endemic for Hanta virus, without prior medical history, was admitted because of lower back pain radiating to the left hip, fever, headache, nausea, and malaise. Two weeks before admission she had been bitten by a mouse or a rat. Blood tests revealed raised white cells and CRP, electrolyte imbalances, raised creatinine, low thrombocytes, and a slightly decreased clotting factor (II, VII, and X). Treatment with broad-spectrum intravenous antibiotics and supporting therapy was initiated very quickly. Eight hours after admission she died from respiratory failure where severe hemoptysis was observed. Leptospiral DNA was later detected in a urine sample. CONCLUSIONS This case represents leptospirosis with severe pulmonary hemorrhagic syndrome. In spite of immediate treatment with broad-spectrum antibiotics, the patient died a few hours after hospital admission.


Assuntos
Hemoptise/etiologia , Leptospirose/complicações , Dor Lombar/etiologia , DNA Bacteriano/análise , Diagnóstico Diferencial , Feminino , Hemoptise/diagnóstico , Humanos , Leptospira/genética , Leptospirose/microbiologia , Dor Lombar/diagnóstico , Pessoa de Meia-Idade , Radiografia Torácica , Índice de Gravidade de Doença , Síndrome
10.
Am J Case Rep ; 17: 494-8, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27418121

RESUMO

BACKGROUND Gout is characterized by deposition of uric acid crystals (monosodium urate) in tissues and fluids. This can cause acute inflammatory arthritis. The 2015 ACR/EULAR criteria for the diagnosis of gout include dual energy computed tomography (DECT)-demonstrated monosodium urate crystals as a new criterion. DECT is a spectral decomposition that permits recognition of different types of tissues based on their characteristic energy-dependent photon attenuation. A positive scan is defined as the presence of urate at articular or periarticular sites. CASE REPORT We describe a 51-year-old woman known to have anorexia nervosa. During our clinical examination, we detected plenty of tophi on both hands, but no swollen joints. The diagnosis of gout was made by visualizing crystals in a biopsy from a tophus. The first line of treatment was allopurinol, the second line was rasburicase, and the current treatment is febuxostat 80 mg/day, allopurinol 300 mg twice a day, and colchicine 0.5 mg twice a day. The patient has unchanged arthralgia and the size and number of tophi remain the same as before treatment in spite of active treatment for 3 years. Previously the patient had problems with adherence, but now she claims that she follows the proposed treatment. The last plasma urate (P-urate) was 0.57 mmol/L. Following two years of treatment, DECT of hands visualized monosodium urate crystal deposits in the tophi, as seen on the clinical photos, but also crystals in relation to the tendons and soft tissue.  CONCLUSIONS DECT is an imaging modality useful to assess urate crystal deposits at diagnosis of gout and could be considered during treatment evaluation. Lack of adherence to treatment should be considered when P-urate values vary significantly and when DECT scans over years persistently visualize monosodium urate crystals.


Assuntos
Absorciometria de Fóton , Anorexia Nervosa/complicações , Gota/diagnóstico , Gota/tratamento farmacológico , Absorciometria de Fóton/métodos , Alopurinol/uso terapêutico , Biomarcadores/sangue , Biópsia , Colchicina/uso terapêutico , Quimioterapia Combinada , Febuxostat/uso terapêutico , Feminino , Gota/sangue , Gota/complicações , Supressores da Gota/uso terapêutico , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Urato Oxidase/uso terapêutico , Ácido Úrico/sangue
11.
BMJ Open ; 6(4): e009134, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27098820

RESUMO

INTRODUCTION: Cardiovascular morbidity is a major burden in patients with rheumatoid arthritis (RA). In this study, we compare the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for cardiovascular disease (CVD) in patients with early RA fulfilling the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) criteria. METHODS AND ANALYSIS: The study is a prospective, randomised, open label trial with blinded end point assessment and balanced randomisation (1:1) conducted in 10 outpatient clinics in Denmark. The primary end point after 5 years of follow-up is a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularisation. Secondary outcomes are: the proportion of patients achieving low-density lipoprotein cholesterol <2.5 mmol/L, glycated haemoglobin <48 mmol/mol, blood pressure <140/90 mm  Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes and normoalbuminuria (urinary albumin creatinine ratio <30 mg/g) after 1 year of follow-up and the proportion of patients in each treatment group achieving low RA disease activity after 1 year, defined as a disease activity score C-reactive protein (DAS28-CRP) <3.2 and a DAS28-CRP score <2.6 after 12, 24 and 60 months. Furthermore, all hospitalisations for acute and elective reasons will be adjudicated by the event committee after 12, 24 and 60 months. Three hundred treatment-naive patients with early RA will be randomly assigned (1:1) to receive either conventional treatment administered and monitored by their general practitioner according to national guidelines (control group) or a stepwise implementation administered and monitored in a quarterly rheumatological nurse-administered set-up of behaviour modification and pharmacological therapy targeting (1) hyperlipidaemia, (2) hypertension, (3) hyperglycaemia and (4) microalbuminuria (intervention group). ETHICS AND DISSEMINATION: This protocol is approved by the local ethics committee (DK-S-2014007) and The Danish Health and Medicines Authority. Dissemination will occur through presentations at National and International conferences and publications in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02246257.


Assuntos
Artrite Reumatoide/complicações , Doenças Cardiovasculares/prevenção & controle , Hipolipemiantes/administração & dosagem , Projetos de Pesquisa , Sinvastatina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/prevenção & controle , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Proteína C-Reativa/análise , Dinamarca , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hiperlipidemias/prevenção & controle , Hipertensão/prevenção & controle , Lipoproteínas LDL , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
12.
Ugeskr Laeger ; 176(25A)2014 Dec 15.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25497616

RESUMO

A 63-year-old woman consulted the Department of Rheuma-tology for hip pain. X-rays were normal. No signs of arthritis. Four days after she was hospitalized with abdominal pain. CT-urography revealed three enlarged lymph nodes. A biopsy revealed a double-hit lymphoma, an aggressive B-cell lymphoma with translocation of both MYC and BCL2. After starting chemotherapy the hip pain disappeared. A brief complete remission was followed by CNS relapse and death 11 months after diagnosis.


Assuntos
Artralgia/etiologia , Linfoma de Células B/complicações , Síndromes Paraneoplásicas/etiologia , Doenças Reumáticas/etiologia , Antineoplásicos/uso terapêutico , Diagnóstico Diferencial , Evolução Fatal , Feminino , Articulação do Quadril/patologia , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Pessoa de Meia-Idade , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/tratamento farmacológico , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/tratamento farmacológico
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