RESUMO
BACKGROUND: Dutch newborn screening (NBS) for Cystic Fibrosis (CF) introduced in 2011 showed a sensitivity of 90% and a positive predictive value (PPV) of 63%. We describe a study including an optimization phase and evaluation of the modified protocol. METHODS: Dutch protocol consists of four steps: determination of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP), DNA analysis by INNO-LiPA and extended gene analysis (EGA). For the optimization phase we used results of 556,952 newborns screened between April 2011 and June 2014 to calculate effects of 13 alternative protocols on sensitivity, specificity, PPV, ratios of CF to other diagnoses, and costs. One alternative protocol was selected based on calculated sensitivity, PPV and costs and was implemented on 1st July 2016. In this modified protocol DNA analysis is performed in samples with a combination of IRT ≥60 µg/l and PAP ≥3.0 µg/l, IRT ≥100 µg/l and PAP ≥1.2 µg/l or IRT ≥124 µg/l and PAP not relevant. Results of 599,137 newborns screened between 1st July 2016 and 31st December 2019 were similarly evaluated as in the optimization phase. RESULTS: The modified protocol showed a sensitivity of 95%, PPV of 76%, CF to CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnoses (CRMS/CFSPID) ratio 12/1, CF/CF carrier ratio 4/1. Costs per screened newborn were slightly higher. Eleven children, of whom five with classic CF, would not have been referred with the previous protocol. CONCLUSIONS: The modified protocol results in acceptable sensitivity (95%) and good PPV of 76% with minimal increase in costs.
Assuntos
Fibrose Cística , Criança , Recém-Nascido , Humanos , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Triagem Neonatal/métodos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Proteínas Associadas a Pancreatite , Tripsinogênio , DNARESUMO
BACKGROUND: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. METHODS: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. RESULTS: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. CONCLUSION: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. ONE-SENTENCE SUMMARY: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.
Assuntos
Fibrose Cística , Inibidores da Fosfodiesterase 4 , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Reposicionamento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Inibidores da Fosfodiesterase 4/uso terapêutico , Mutação , Colforsina , Genótipo , OrganoidesAssuntos
Antirreumáticos/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Hemólise/efeitos dos fármacos , Sulfassalazina/efeitos adversos , Adulto , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , HumanosRESUMO
AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.
Assuntos
Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Cloretos/análise , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Quinolonas/farmacologia , Suor/química , Suor/efeitos dos fármacos , Adolescente , Adulto , Índice de Massa Corporal , Criança , Correlação de Dados , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVE: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. METHODS: In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. RESULTS: We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. CONCLUSION: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.
Assuntos
Aminofenóis , Aminopiridinas , Benzodioxóis , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística , Estado Nutricional/efeitos dos fármacos , Quinolonas , Suor/química , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Benzodioxóis/administração & dosagem , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/efeitos adversos , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Homozigoto , Humanos , Masculino , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Lupus nephritis (LN) is the most frequent and one of the most severe organ manifestations of systemic lupus erythematosus. The central pathogenetic mechanism is characterized by the loss of immune tolerance against autoantigens of the cell nucleus, which can lead to renal inflammation via the formation of nuclear autoantibodies. The clinical manifestations of LN encompass nephritic syndrome with the special form of rapidly progressive glomerulonephritis, nephrotic syndrome and thrombotic microangiopathy. The diagnostic procedures consist of renal function and urine analysis as well as the determination of serum autoantibody profiles and complement components. An early renal biopsy enables a differentiation between the prognostically different forms of LN. In addition to supportive measures, a differentiated immunosuppressive treatment is the main approach for prognostically unfavorable forms. Important components are corticosteroids, cyclophosphamide and mycophenolate mofetil for induction treatment. Currently investigated treatment principles include next generation calcineurin inhibitors and anti-B cell treatment.
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Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Microangiopatias Trombóticas/patologia , HumanosRESUMO
Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.
Assuntos
Códon sem Sentido/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Fibrose Cística/tratamento farmacológico , Gentamicinas/uso terapêutico , Organoides/citologia , Oxidiazóis/uso terapêutico , Células Cultivadas , Coccidiostáticos/uso terapêutico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , RNA/genéticaRESUMO
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 DoençaRESUMO
BACKGROUND: Hyperuricemia is not only associated with gout but also with hypertension, atherosclerosis and chronic kidney disease (CKD); however, in cases of disproportionally high serum uric acid levels without symptoms of gout and slowly progressive chronic kidney failure especially in young people, a genetic cause of hyperuricemia needs to be considered. PATHOGENETIC ASSOCIATIONS: The results of experimental studies suggest that hyperuricemia can be a pathophysiologically relevant cardiovascular risk factor. In animal studies hyperuricemia leads to oxidative stress and vascular dysfunction and chronically elevated uric acid levels can result in structural changes of the vessel wall. Epidemiological data show a connection between hyperuricemia and hypertension and uric acid lowering therapy has been shown to lower arterial blood pressure. In CKD, uric acid increases in parallel with the decline in GFR and an increase in proteinuria. Several ongoing prospective clinical trials will clarify if pharmacological lowering of uric acid will translate into reduction of relevant cardiovascular and renal endpoints. THERAPY: The treatment of gout and the medicinal prophylaxis of further gout attacks depend on the comorbidities and especially CKD.
Assuntos
Doenças Cardiovasculares/epidemiologia , Gota/epidemiologia , Gota/terapia , Hiperuricemia/epidemiologia , Hiperuricemia/terapia , Nefropatias/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Causalidade , Comorbidade , Humanos , Incidência , Nefropatias/prevenção & controle , Fatores de RiscoRESUMO
Biomimetic calcium phosphate coatings have been developed for bone regeneration and repair because of their biocompatibility, osteoconductivity, and easy preparation. They can be rendered osteoinductive by incorporating an osteogenic agent, such as bone morphogenetic protein 2 (BMP-2), into the crystalline lattice work in physiological situations. The biomimetic calcium phosphate coating enables a controlled, slow and local release of BMP-2 when it undergoes cell mediated coating degradation induced by multinuclear cells, such as osteoclasts and foreign body giant cells, which mimics a physiologically similar release mode, to achieve sustained ectopic or orthotopic bone formation. Therefore, biomimetic calcium phosphate coatings are considered to be a promising delivery vehicle for osteogenic agents. In this review, we present an overview of biomimetic calcium phosphate coatings including their preparation techniques, physico-chemical properties, potential as drug carrier, and their pre-clinical application both in ectopic and orthotopic animal models. We briefly review some features of hydroxyapatite coatings and their clinical applications to gain insight into the clinical applications of biomimetic calcium phosphate coatings in the near future.
RESUMO
Treatment efficacies of drugs depend on patient-specific pharmacokinetic and pharmacodynamic properties. Here, we developed an assay to measure functional levels of the CFTR potentiator VX-770 in human plasma and observed that VX-770 in plasma from different donors induced variable CFTR function in intestinal organoids. This assay can help to understand variability in treatment response to CFTR potentiators by functionally modeling individual pharmacokinetics.
Assuntos
Aminofenóis/farmacocinética , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Mucosa Intestinal , Intestinos , Organoides , Quinolonas/farmacocinética , Antimutagênicos/farmacocinética , Bioensaio , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Monitoramento de Medicamentos/métodos , Humanos , Mucosa Intestinal/metabolismo , Intestinos/patologia , Mutação/efeitos dos fármacos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Resultado do TratamentoAssuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Granulomatose com Poliangiite/tratamento farmacológico , Poliangiite Microscópica/tratamento farmacológico , Terapia Combinada , Comorbidade , Granulomatose com Poliangiite/diagnóstico , Humanos , Poliangiite Microscópica/diagnóstico , Plasmaferese , Recidiva , RituximabRESUMO
OBJECTIVES: To investigate the nature of the relationship between proteinase 3 anti-neutrophil cytoplasm autoantibody (PR3-ANCA) and relapse in patients with early systemic granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: Clinical data from 16 relapsing and 12 non-relapsing patients with early systemic GPA from a randomised clinical trial were correlated to monthly PR3-ANCA values over 18 months. Each sample was examined using 9 different enzyme-linked immunosorbent assays (ELISAs) to ensure reliability of ANCA results. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays in samples after remission. RESULTS: A PR3-ANCA peak was identified in all relapsing and non-relapsing patients and coincided with relapse in all 14 evaluable relapsing patients. The monthly increment before the peak, however, was similar in relapsing and non-relapsing patients in all assays. Increments from remission to peak were higher in relapsing patients in 2/9 assays. PR3-ANCA values at entry and peak PR3-ANCA values were higher in relapsing patients in 3/9 and 2/9 assays, respectively. However, large overlaps of PR3-ANCA values prevented a distinction between relapsing and non-relapsing patients. The median time to reach peak values was 14 months in relapsing and 12 months in non-relapsing patients with scheduled termination of treatment at 12 months. CONCLUSIONS: The predictive value for relapses of PR3-ANCA determinations confirm and extend previous reports. Although all relapses were related to PR3-ANCA increases, reduction or withdrawal of immunosuppression without relapse was also related to increases and may explain the lack of predictive value of sequential PR3-ANCA determinations.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Mieloblastina/imunologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Secondary vasculitis is a form of vasculitis for which an underlying disease is known. Diseases associated with secondary vasculitis include infections, drug hypersensitivity, malignancy, rheumatoid arthritis, collagen vascular disease and sarcoidosis. Moreover, there are numerous conditions that can mimic vasculitis clinically, in laboratory testing, radiographically and in histopathology. It is evident that distinguishing primary vasculitis from secondary vasculitis and also vascular inflammation from non-vasculitic disorders (vasculitis mimics) has significant therapeutic implications.
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Artrite Reumatoide/diagnóstico , Infecções Bacterianas/diagnóstico , Toxidermias/diagnóstico , Neoplasias/diagnóstico , Sarcoidose/diagnóstico , Vasculite/diagnóstico , Diagnóstico Diferencial , HumanosRESUMO
Methotrexate (MTX) in low-doses is an important component of anti-inflammatory therapy of rheumatoid arthritis and other inflammatory joint diseases. In contrast to high-dose administration of MTX in oncology, which can lead to direct tubulus toxicity and subsequent renal failure, renal side-effects are a rare exception for low-dose MTX. The biggest problem under low-dose MTX is that an already limited renal function due to comorbidities or an increasing, sometimes clinically insufficiently monitored renal insufficiency due to comedications, such as non-steroidal antirheumatics (NSAR) and antibiotics, leads to a reduced excretion of MTX and therefore to an accumulation in serum. This is primarily accompanied by gastrointestinal mucositis and bone marrow depression. For this reason low-dose MTX should never be administered once the glomerular filtration rate (GFR) is less than <30 ml/min and only 50% of the original dosage should be administered if the GFR is between 30 and 60 ml/min.
Assuntos
Antirreumáticos/toxicidade , Artrite Reumatoide/tratamento farmacológico , Metotrexato/toxicidade , Insuficiência Renal/induzido quimicamente , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/toxicidade , Antirreumáticos/administração & dosagem , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Comorbidade , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Insuficiência Renal/sangue , Fatores de RiscoRESUMO
BACKGROUND: Understanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases. METHODS: Formalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n=39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n=46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n=48). RESULTS: All samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P=0.003), significantly fewer mutations in the PI(3)K signalling pathway (P=0.003) and fewer CIMP high tumours (P=0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations. CONCLUSION: The development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3)K signalling pathway.
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Carcinoma/patologia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Aberrações Cromossômicas , Estudos de Coortes , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Progressão da Doença , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologiaRESUMO
Patients with inflammatory rheumatic diseases often suffer from considerable comorbidities that can arise due to the chronic systemic inflammatory activity of the rheumatic disease itself, disorders of immune defense, or as a result of antirheumatic treatment; they can also occur independently. For example, almost 50% of patients with rheumatoid arthritis already exhibit two further chronic diseases at the time of initial manifestation. With regard to the elevated mortality observed in patients with rheumatism, particularly cardiovascular morbidity and increased predisposition to infections are of note. In addition, this article addresses further important possible concomitant diseases, i.e., osteoporosis and tumor diseases. A ground rule is to identify comorbidities and treat them just as diligently as the underlying rheumatic disease so that the patient with rheumatism should be accompanied by an interdisciplinary team of internists during each phase of the disease. Effective control of the systemic inflammatory activity may serve to reduce the risk of certain cardiovascular and neoplastic comorbidities.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Difosfonatos/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , HumanosRESUMO
Since the introduction of combined immunosuppressive therapy consisting of oral cyclophosphamide (CYC) and glucocorticosteroids (GC) in the 1970s, the outcome of antineutrophil cystoplasmic antibodies (ANCA)-associated vasculitides has improved dramatically over the last decades. However, the long-term follow-up of patients treated with CYC plus GC has revealed a high treatment-related morbidity and mortality and a high proportion of patients suffering from relapses (up to 50%), requiring CYC and GC again. Methotrexate (MTX) can replace CYC for induction of remission in patients with a non life-threatening disease course of ANCA associated vasculitides ('early systemic'). Furthermore, MTX can be used as a maintenance medication after induction of remission with CYC (plus GC), provided there is a decent renal function with a GFR >50 ml /min. As with any maintenance regimen, we do not know exactly for how long to continue MTX maintenance therapy. When using MTX as remission induction or maintenance regimen a tight control of urinary sediment and kidney function is mandatory in order to detect a potential renal relapse or de novo manifestation.