RESUMO
The management of acute gout in the hospital setting may be challenging since most patients are elderly with multiple unstable comorbidities. However, there are no prospective clinical trials for hospitalized patients with gout to guide optimal management. Evidence indicates that steroids or adrenocorticotropic hormone (ACTH) may be effective and safe therapeutic options for these patients. This study aimed at directly comparing the efficacy and safety of ACTH vs betamethasone for the treatment of gout in hospitalized patients. This is the first prospective clinical trial for hospitalized patients with gout. We designed a randomized, open label study to assess the efficacy and safety of a single intramuscular injection of either ACTH or betamethasone in hospitalized patients with acute gout. Primary efficacy endpoints were the change in intensity of pain as recorded using a Visual Analogue Scale (VAS) at baseline compared to 24 h (ΔVAS24h), and 48 h. Moreover, we assessed safety and effects on the hypothalamic-pituitary-adrenal (HPA) axis, glucose and lipid homeostasis, bone metabolism, electrolytes and renal function. 38 patients were recruited. Both treatments were highly effective. The mean ± SE ΔVAS24h and ΔVAS48h for ACTH was 4.48 ± 0.29 and 5.58 ± 0.26, respectively. The mean ± SE ΔVAS24h and ΔVAS48h for betamethasone was 4.67 ± 0.32 and 5.67 ± 0.28, respectively. Direct comparison between the two groups at 24 h and 48 h did not show statistically significant differences. Both treatments were well tolerated and safe. The effects on all metabolic parameters were mostly minimal and transient for both treatments. However, ACTH may affect less the HPA axis and bone metabolism compared to betamethasone, thus leading to the conclusion that. ACTH and betamethasone are effective and safe for the management of acute gout in hospitalized patients but that ACTH may associate with less disturbance of the HPA axis and bone metabolism. Our data support the use of both drugs as first line treatments for hospitalized patients with gout.Clinical trial registration: ClinicalTrials.gov NCT04306653.
Assuntos
Artrite Gotosa , Gota , Hormônio Adrenocorticotrópico/efeitos adversos , Idoso , Artrite Gotosa/tratamento farmacológico , Betametasona , Gota/tratamento farmacológico , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Estudos Prospectivos , Esteroides/uso terapêuticoRESUMO
Treatment of acute gout consists of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and steroids. However, the typical patient with gout has multiple comorbidities such as cardiovascular disease, hypertension, renal dysfunction or diabetes/metabolic syndrome that represent contraindications to these therapeutic options. The aim of this study is to review the available evidence regarding the use of ACTH as an alternative therapeutic option for acute gout and explore potential mechanisms of action. We performed an electronic search (MEDLINE, Scopus and Web of Science) using the keywords ACTH or adrenocorticotropic hormone combined with gout or crystal-induced arthritis. ACTH appears suitable for patients with many comorbidities due to its good safety profile. Clinical evidence shows that ACTH is at least as effective as classic agents. The mechanism of action of ACTH in gout is not entirely known. Robust experimental evidence points to the direction that ACTH does not act solely by triggering the release of endogenous steroids but also appears to downregulate inflammatory responses by activating melanocortin receptors on innate immune cells, such as macrophages. Moreover, indirect evidence indicates that ACTH may have an IL-1 antagonistic effect. We propose that ACTH may be an alternative therapeutic option for gout in patients with multiple comorbidities. Large-scale studies assessing the efficacy and safety of ACTH compared to classic therapeutic options are needed.
Assuntos
Hormônio Adrenocorticotrópico/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Hormônios/uso terapêutico , Hormônio Adrenocorticotrópico/farmacologia , Animais , Terapia Biológica/métodos , Humanos , Interleucina-1/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , CamundongosRESUMO
Recent data suggests that rituximab may favorably affect skin fibrosis and lung function in patients with systemic sclerosis. Based on experimental data suggesting a key role of B and T cells in scleroderma we aimed to explore the effect(s) of rituximab treatment on T cell subpopulations. Fifteen patients with scleroderma who received rituximab treatment and six who received standard treatment alone were recruited. Peripheral CD4+IL4+, CD4+INFγ+, CD4+IL17+ and CD4+CD40L+ T cells were assessed using flow cytometry. Using ELISA, serum levels of IL4 were assessed. Skin CD4+IL4+ T cells were assessed with confocal microscopy from skin biopsies. Following rituximab treatment skin CD4+IL4+ T cells obviously decreased as seen with confocal microscopy. Moreover, peripheral CD4+IL4+ T cells decreased significantly compared to those from patients who received standard treatment alone: median (IQR): 14.9 (22.63-12.88) vs 7.87 (12.81-4.9)%, p = 0.005 and 9.43 (19.53-7.50)% vs 14.86 (21.96-6.75)%, p = NS at baseline and 6 months later respectively, whereas there was no difference in serum IL4 levels. Peripheral CD4+CD40L+ T cells also decreased significantly following rituximab treatment compared to those from patients who received standard treatment alone: median (IQR): 17.78 (25.64-14.44)% vs 8.15 (22.85-3.08)%, p = 0.04 and 22.13 (58.77-8.20)% vs 72.11 (73.05-20.45)%, p = NS at baseline and 6 months later respectively. Furthermore, peripheral CD4+INFγ+ and CD4+IL17+ T cells revealed no differences following rituximab treatment. Our study demonstrates a link between rituximab treatment and CD4+IL4+ T cell decrease both in the skin and peripheral blood of patients with SSc.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Fatores Imunológicos/uso terapêutico , Interleucina-4/sangue , Rituximab/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ligante de CD40 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Resultado do TratamentoRESUMO
OBJECTIVES: The activity of the Wnt pathway, a critical mediator of fibrosis, is regulated by Dickkopf-1 (Dkk-1). Dkk-1 is absent from scleroderma skin in contrast to skin from healthy subjects where it is clearly expressed. There are no data on circulating levels and function of Dkk-1 in patients with systemic sclerosis (SSc). Our objectives are to assess: i) circulating and functional levels of Dkk-1 in patients with SSc and ii) whether the striking lack of Dkk-1 skin expression is also evident in a) clinically uninvolved skin from patients with SSc and b) very early disease prior to skin thickening. METHODS: Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 controls. Skin biopsies were obtained from SSc patients from a) clinically involved skin b) clinically uninvolved skin, c) oedematous skin prior to skin thickening. RESULTS: Circulating and functional Dkk-1 levels were similar in patients with SSc and controls. Healthy skin displayed a high Dkk-1 immuno-expression in the epidermis and dermal fibroblasts in contrast to clinically involved scleroderma skin where Dkk-1 was totally absent. In all biopsies of clinically uninvolved skin Dkk-1 was only moderately expressed whereas skin from very early disease displayed only a weak Dkk-1 immunoreactivity. CONCLUSIONS: The downregulation of Dkk-1 at the oedematous phase of the disease indicates that the Wnt pathway is involved early in the disease process and may play a role in driving fibrosis. The decrease in Dkk-1 expression in clinically uninvolved scleroderma skin indicates that skin in SSc is universally affected.
Assuntos
Fibroblastos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Regulação para Baixo , Feminino , Fibroblastos/patologia , Fibrose , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Pele/patologia , Via de Sinalização WntRESUMO
Objectives: Several aquaporins (AQPs) are present in the salivary glands, likely contributing to their secretions. AQP dysfunction may contribute to the salivary gland dysfunction in SS. Antibodies to AQP4 and AQP1 are detected in neuromyelitis optica and are believed to play a pathogenic role. We aimed to search for antibodies to several AQPs in the sera from SS patients in an effort to shed light on the pathogenic mechanisms of SS. Methods: We searched for antibodies to six AQPs in the sera of 34 SS patients without neurological findings using ELISAs with synthetic peptides corresponding to the three extracellular domains of each AQP, radioimmunoassays with AQPs, Western blots and competition experiments with cell-embedded AQPs. Results: Thirteen (38.2%) SS patients had antibodies to extracellular domains of AQP1 (two), AQP3 (one), AQP8 (six) or AQP9 (four); none had AQP4 or AQP5 antibodies. Each patient had antibodies to only one extracellular domain. AQP binding was further verified by radioimmunoassay with intact AQPs, western blots and AQP-transfected cells. In contrast, none of the 106 healthy controls or 68 patients with other autoimmune diseases had antibodies to intact AQPs. Expression of AQP8 (the major antibody target) on human salivary glands was shown by immunohistochemistry. Patients with anti-AQP antibodies had more severe xeropthalmia compared with anti-AQP-negative patients, suggesting a potential pathogenic role of these antibodies. Conclusion: Antibodies to AQPs (especially to AQP8 and AQP9) are frequent in SS patients. The likely important role of AQPs in salivary gland secretions justifies further research.
Assuntos
Anticorpos/sangue , Aquaporinas/imunologia , Síndrome de Sjogren/imunologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Saliva/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/sangueRESUMO
BACKGROUND: Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis. METHODS: Thirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured. RESULTS: ADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study. CONCLUSION: Clopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc. CLINICAL TRIAL REGISTRATION: ISRCTN63206606 . Registered 02/Dec/2014.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Escleroderma Sistêmico/tratamento farmacológico , Úlcera Cutânea/induzido quimicamente , Ticlopidina/análogos & derivados , Difosfato de Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Clopidogrel , Endotélio Vascular/metabolismo , Feminino , Dedos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Estudo de Prova de Conceito , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Escleroderma Sistêmico/sangue , Serotonina/sangue , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
OBJECTIVES: Undifferentiated arthritis (UA) is an inflammatory oligo/polyarthritis where no definite diagnosis can be reached. Patients with UA may progress towards a chronic inflammatory disease, however, in some cases arthritis may completely resolve. To date, a universally accepted diagnostic and therapeutic algorithm for UA is not available. METHODS: We retrospectively studied 192 patients with UA followed by us over the last 10 years in the early arthritis clinic of our institution. RESULTS: A total of 192 patients, 91 men (47.4%) and 101 women (52.6%), with mean age 57.9±17.8 years, were included in the study. Eighty-four patients (43.7%) presented with acute/subacute mono-/pauci-arthritis, 56 patients (29.2%) with chronic mono-/pauci arthritis, 42 patients (21.9%) with acute polyarthritis and 10 (5.2%) with chronic polyarthritis. From the total of 192 patients, 102 are currently followed. Current diagnosis at the time of this report included: rheumatoid arthritis in 18 (17.6%) patients, self-limiting arthritis in 35 (34.4%), undifferentiated/unclassified arthritis in 45 (44.1%), spondyloarthropathy in 3 (2.9%), and crystal-induced arthritis in one (1%). The time between the initial evaluation and the definitive diagnosis of RA ranged between 6 and 15 months. Seropositivity (RF and/or ACPA) and disease duration were strong predictors of developing RA in our cohort. CONCLUSIONS: Our data indicate that seropositive patients with chronic symptoms carry an increased risk of developing RA, and that these patients may be candidates for a more aggressive treatment.
Assuntos
Artrite/diagnóstico , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite/sangue , Artrite/classificação , Artrite/tratamento farmacológico , Artrite/imunologia , Biomarcadores/sangue , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Testes Sorológicos , Centros de Atenção Terciária , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the safety and efficacy of long-term treatment with rituximab (RTX) in patients with systemic sclerosis (SSc). METHODS: Eight patients with SSc-associated interstitial lung disease (ILD) received 4 cycles of RTX and had a follow-up of 2 years. Lung involvement was assessed by pulmonary function tests and chest HRCT. Skin involvement was assessed both clinically and histologically. RESULTS: We found a linear improvement of lung function and skin thickening over the 2 years of RTX treatment. There was a significant increase of FVC at 2 years compared to baseline (mean ± SEM: 77.13±7.13 vs. 68.13±6.96, respectively, p<0.0001). Similarly, DLco increased significantly at 2 years compared to baseline (mean ± SEM: 63.13±7.65 vs. 52.25±7.32, respectively, p<0.001). Skin thickening, assessed with the MRSS, improved significantly at 2 years compared to baseline (mean ± SEM: 4.87±0.83 vs. 13.5±2.42, respectively, p<0.0001). A reduction in myofibroblast score was seen histologically following RTX treatment. CONCLUSIONS: Our results indicate that long-term treatment with RTX may favourably affect lung function and skin fibrosis in patients with SSc. Larger scale, multicentre, randomised, controlled studies are needed to further explore the efficacy of RTX in SSc.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Esclerodermia Difusa/tratamento farmacológico , Pele/efeitos dos fármacos , Adulto , Idoso , Análise de Variância , Anticorpos Monoclonais Murinos/efeitos adversos , Biópsia , Esquema de Medicação , Feminino , Fibrose , Grécia , Humanos , Fatores Imunológicos/efeitos adversos , Modelos Lineares , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Valor Preditivo dos Testes , Testes de Função Respiratória , Rituximab , Esclerodermia Difusa/complicações , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/fisiopatologia , Pele/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
To dissect the mechanisms of anti-TNFα-induced autoimmunity we examined the phenotype and function of B cells from anti-TNFα-treated patients. Levels of Lyn, Syk, SHP-1, tyrosine 348 phospho-Syk (Y348-Syk) and tyrosine phosphorylated (P-Y) proteins were evaluated and B-cell-surface CD20, CD21 and CD5 were also assessed in 29 patients treated with TNF-α blockers. Following treatment, Lyn, but not Syk or SHP-1, significantly increased particularly in patients with spondyloarthropathies. Increased Lyn levels following treatment correlated with increased Lyn activity as evidenced by a 2.9-fold increase of Y348-Syk (a Lyn target). Peripheral B-cells from 56.3% of the patients displayed a tendency towards increased P-Y levels without any BCR-initiated activation during treatment. CD20, but not CD21, significantly increased in patients with rheumatoid arthritis. Circulating CD5+ B-cells were also significantly expanded during treatment. Our findings suggest that B cells in anti-TNFα-treated patients display functional and phenotypical aberrations that may enhance our understanding of TNF-α blocker-induced autoimmunity.
Assuntos
Antirreumáticos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígenos CD20/biossíntese , Doenças Autoimunes/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Western Blotting , Antígenos CD5/biossíntese , Separação Celular , Etanercepte , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Fenótipo , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 6/biossíntese , Proteínas Tirosina Quinases/biossíntese , Receptores de Complemento 3d/biossíntese , Receptores do Fator de Necrose Tumoral/uso terapêutico , Quinase Syk , Quinases da Família src/biossínteseRESUMO
Several lines of evidence from basic research indicate that B cells may contribute to the pathogenesis of systemic sclerosis. Clinical studies as well have provided preliminary data pointing to the direction that B-cell depletion with rituximab might be a therapeutic option for patients with this debilitating disease.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Humanos , Doenças Pulmonares Intersticiais/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab , Escleroderma Sistêmico/complicaçõesRESUMO
OBJECTIVE: To assess the efficacy of rituximab (RTX) in SSc. METHODS: Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m(2))] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically. RESULTS: There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean +/- s.d.: 68.13 +/- 19.69 vs 75.63 +/- 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DL(CO)) increased significantly in the RTX group compared with baseline (mean +/- s.d.: 52.25 +/- 20.71 vs 62 +/- 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DL(CO) in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean +/- s.d.: 13.5 +/- 6.84 vs 8.37 +/- 6.45 at baseline vs 1-year, respectively, P < 0.001). CONCLUSION: Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Linfócitos B/efeitos dos fármacos , Biópsia , Moléculas de Adesão Celular/metabolismo , Colágeno/metabolismo , Esquema de Medicação , Humanos , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Depleção Linfocítica/métodos , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Rituximab , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Tomografia Computadorizada por Raios X , Capacidade Vital/efeitos dos fármacosRESUMO
OBJECTIVES: Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. METHODS: A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). RESULTS: Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. CONCLUSIONS: Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.
Assuntos
Linfócitos B/efeitos dos fármacos , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Rituximab/administração & dosagem , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Linfócitos B/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/complicações , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/efeitos adversos , Escleroderma Sistêmico/complicações , Pele/efeitos dos fármacos , Pele/patologia , Fatores de TempoRESUMO
Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFα blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean ± SEM ng/mL 122.9 ± 11.6 versus 177.4 ± 24.58, p = 0.038) and patients with RA (mean ± SEM ng/mL 244.8 ± 37.5, p = 0.0004). Patients with AS receiving TNFα blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean ± SEM ng/mL 95.8 ± 14.9 versus 149.2 ± 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFα treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS.
Assuntos
Osteoblastos/metabolismo , Serotonina/sangue , Transdução de Sinais , Espondilite Anquilosante/sangue , Espondilite Anquilosante/metabolismo , Adulto , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença de Crohn/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Demografia , Duodeno/efeitos dos fármacos , Duodeno/metabolismo , Duodeno/patologia , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Fosforilação/efeitos dos fármacos , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Triptofano Hidroxilase/metabolismo , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway. METHODS: Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration. RESULTS: In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFß expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFß in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFß was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022). CONCLUSIONS: This is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFß-Dkk-1 axis in improving skin fibrosis.
Assuntos
Fatores Imunológicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Rituximab/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Adulto , Feminino , Fibroblastos/metabolismo , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Humanos , Imunoensaio , Imuno-Histoquímica , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta , Regulação para CimaRESUMO
OBJECTIVE: Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation. METHODS: Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model. RESULTS: Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment. CONCLUSIONS: Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.
Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Regulação da Expressão Gênica , Proteínas Hedgehog/sangue , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Linhagem Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos , Osteogênese/genética , Transdução de Sinais , Espondilite Anquilosante/sangue , Resultado do TratamentoRESUMO
BACKGROUND: ACTH, a member of the melanocortin group of proteins, has long been used in the treatment of gout and is considered as an alternative therapeutic option, especially in difficult-to-treat patients. METHODS: We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout. We identified 5 studies assessing the efficacy of ACTH in acute crystal-induced arthritis. RESULTS: In the studies for acute gout, a total of 266 patients have been treated with ACTH; treatment was highly efficacious with a response rate of 77.9-100%. Only few side effects, such as hyperglycemia, hypokalemia, and edema, were reported, all of which were mild. The available evidence for acute CPP crystal arthritis is limited. A total of 19 patients have been assessed in retrospective studies; the response rate was 90-100%, whereas no significant side effects were recorded. The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands; ACTH is able to stimulate melanocortin receptors on macrophages and downregulate gouty inflammation. CONCLUSIONS: Data suggests that ACTH is effective in acute crystal-induced arthritis and may be a first-line therapy in patients with multiple medical problems. We propose that further evaluation of ACTH should be performed, with a large-scale, randomized controlled study focusing on safety issues in patients with multiple comorbidities.
Assuntos
Hormônio Adrenocorticotrópico/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Condrocalcinose/tratamento farmacológico , Gota/tratamento farmacológico , Humanos , Resultado do TratamentoRESUMO
We present a case of an elderly man, who initially presented with right facial nerve palsy, ipsilateral headache, elevated erythrocyte sedimentation rate (ESR) and no fever. A presumptive diagnosis of giant cell arteritis was made and the patient was treated with high-dose steroids. A temporal artery biopsy was negative. Several months later, while on 16 mg of methylprednisolone daily, he presented with severe sensorimotor peripheral symmetric neuropathy, muscle wasting and inability to walk, uncontrolled blood sugar and psychosis. A work-up for malignancy was initiated with the suspicion of a paraneoplastic process. At the same time a biopsy of the macular skin lesions that had appeared on the skin of the left elbow and right knee almost simultaneously was inconclusive, whereas a repeat biopsy from the same area of the lesions that had become nodular, a month later, was indicative of Kaposi's sarcoma. Finally, a third biopsy of a similar lesion, after spreading of the skin process, confirmed the diagnosis of Kaposi's sarcoma. He was treated with interferon α and later was seen in very satisfactory condition, with no clinical evidence of neuropathy, normal muscle strength, no headache, normal electrophysiologic nerve studies, involution of Kaposi's lesions and a normal ESR.
RESUMO
OBJECTIVE: We aimed at assessing the efficacy and safety of adrenocorticotropic hormone (ACTH) for the treatment of acute gout in hospitalized patients. METHODS: We retrospectively reviewed our inpatient consultation records and identified 181 cases of gout where ACTH was used as first line treatment. The hospital medical records of these patients were fully reviewed. A total of 181 patients were treated with 1mg of synthetic ACTH intramuscularly. RESULTS: A response was seen in 77.90% of patients and was evident the day following ACTH injection. The majority of non-responders (87.50%) were treated once more with ACTH the day following the first injection; 82.85% of these patients responded. A relatively small percentage of responders suffered a second gouty attack (11.34%) at a median of four days from the initial attack. They were retreated with a single ACTH course and all responded. Blood pressure and potassium levels remained stable 24 and 48 hours following ACTH administration. Diabetic patients showed an increase in fasting glucose levels 24 hours following the injection compared to baseline but this increase was not evident at 48 hours. CONCLUSIONS: Our data indicate that ACTH is effective and safe for the treatment of gout in hospitalized patients. ACTH is an attractive therapeutic option for hospitalized patients since the use of non-steroidal anti-inflammatory drugs, steroids or colchicine in this patient population may be problematic.
Assuntos
Hormônio Adrenocorticotrópico/administração & dosagem , Hormônio Adrenocorticotrópico/efeitos adversos , Artrite Gotosa/tratamento farmacológico , Gota/tratamento farmacológico , Doença Aguda , Idoso , Artrite Gotosa/epidemiologia , Comorbidade , Feminino , Gota/epidemiologia , Hormônios/administração & dosagem , Hormônios/efeitos adversos , Hospitalização , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: Calcinosis is frequently encountered in patients with systemic sclerosis (SSc) and may be associated with significant morbidity. No treatment has shown so far an unequivocal beneficial effect. METHODS: We performed an extensive internet search (MEDLINE) using the keywords calcinosis, calcification, scleroderma, systemic sclerosis, and treatment. RESULTS: Our patient had extensive Calcinosis, Raynaud, Esophagitis, Sclerodactyly, telangiectasia (CREST)-related calcinosis, frequently ulcerating and painful. Following 2 rituximab courses (consisting of 4 weekly infusions, 375 mg/m(2) each), calcinosis significantly improved and pain disappeared. Pharmacologic agents used in the treatment of SSc-associated calcinosis include diltiazem, minocycline, warfarin, biphosphonates, and intravenous immunoglobulin. Other therapeutic approaches include surgical excision, laser vaporization, and extracorporeal shock wave lithotripsy. CONCLUSIONS: Evidence for all existing therapies is weak and therefore larger scale controlled studies are needed. Rituximab appears as a promising treatment especially in view of recent evidence that this therapy may be also effective in the underlying disease.