RESUMO
OBJECTIVES: Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how APR affects osteoclast formation in humans. METHODS: Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of APR. Effects of APR on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of APR on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients, as well as in healthy controls. RESULTS: APR significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, APR dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation and ex vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by APR. Finally, APR inhibited expression of the key osteoclast fusion protein dendritic cell-specific transmembrane protein. CONCLUSION: Phosphodiesterase 4 targeting by APR not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that APR has the potential to provide a direct bone protective effect in PsA.
Assuntos
Osteogênese/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Talidomida/análogos & derivados , Adulto , Idoso , Artrite Psoriásica/tratamento farmacológico , Estudos de Casos e Controles , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/uso terapêutico , Cultura Primária de Células , Talidomida/farmacologia , Talidomida/uso terapêuticoRESUMO
Gastrointestinal (GI) involvement is the leading cause of morbidity with great impact on health-related quality of life (HRQOL) in patients with systemic sclerosis (SSc). The UCLA-GIT 2.0 is a disease-specific HRQOL instrument for the assessment of GI symptoms severity in patients with SSc. We evaluated reliability and validity of the Serbian version of UCLA-GIT 2.0 by assessing association of GI involvement and other disease manifestations in patients with SSc. UCLA-GIT 2.0 was adapted into Serbian and administered to 104 patients with SSc who had previously completed the SF-36 questionnaire. We evaluated the internal consistency reliability and associations between the UCLA-GIT 2.0 and SF-36 scales. Data from patients' medical history were reviewed for other disease manifestations. UCLA-GIT 2.0 had acceptable reliability (defined as Cronbach's alpha >0 .69) and the majority of hypothesized correlations with SF-36 scale scores were of moderate magnitude (coefficient ≥ 0.30). Active disease and pulmonary fibrosis were associated with higher GIT Total scale score (p < 0.05). Distension mostly correlated with HRQOL impairment (r = 0.70, p < 0.001). The Serbian version of the UCLA-GIT 2.0 questionnaire has acceptable reliability and validity for the assessment of GI involvement in patients with SSc. GI impairment is very frequent in patients with active SSc, as well in those with pulmonary fibrosis.
Assuntos
Constipação Intestinal/diagnóstico , Diarreia/diagnóstico , Refluxo Gastroesofágico/diagnóstico , Escleroderma Sistêmico/diagnóstico , Idoso , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Reprodutibilidade dos Testes , Sérvia , Índice de Gravidade de Doença , Avaliação de SintomasRESUMO
OBJECTIVE: This study was performed to assess the impact of autologous conditioned serum (ACS) when added to preceding intra-articular glucocorticoid therapy on pain, function, and quality of life outcomes over 24 weeks. METHODS: In this single-center, randomized controlled trial involving 40 patients with advanced knee osteoarthritis (Kellgren-Lawrence grades III and IV), ACS or saline placebo was injected after 40 mg triamcinolone acetonide (TA) intra-articular injection. Numerical rating scale (NRS) pain scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) assessments were conducted at baseline and at weeks 3, 6, 12, and 24. The primary endpoint was the change in KOOS Pain at 24 weeks. Patient safety events were also monitored. RESULTS: At week 24, TA + ACS significantly improved KOOS Pain, Symptoms, Activities of Daily Living, Quality of Life, and KOOS Sport scores. TA + ACS also outperformed TA + placebo in NRS pain scores (average and maximum intensity) at week 24 and NRS pain score (at rest) at weeks 12 and 24. The TA injection followed by ACS or placebo was well-tolerated. CONCLUSION: ACS adds long-term pain relief and functional improvement to the short-term pain relief provided by glucocorticoids.
Assuntos
Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/tratamento farmacológico , Método Duplo-Cego , Qualidade de Vida , Atividades Cotidianas , Resultado do Tratamento , Triancinolona/uso terapêutico , Dor/tratamento farmacológico , Glucocorticoides/uso terapêutico , Injeções Intra-Articulares , Triancinolona Acetonida/uso terapêuticoRESUMO
OBJECTIVE: To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study of psoriasis patients without clinical evidence of musculoskeletal involvement who underwent baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intraarticular sites by high-resolution peripheral quantitative computed tomography. Adjusted relative risks of developing PsA associated with baseline vBMD and the presence of structural entheseal lesions were calculated using multivariable Cox regression models. RESULTS: The cohort included 114 psoriasis patients (72 men and 42 women) with a mean ± SD follow-up duration of 28.2 ± 17.7 months, during which 24 patients developed PsA (9.7 per 100 patient-years [95% confidence interval (95% CI) 6.2-14.5]). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4 per 100 patient-years [95% CI 12.5-34.3]; hazard ratio [HR] 5.10 [95% CI 1.53-16.99], P = 0.008). With respect to vBMD, a 1-SD increase in entheseal, but not intraarticular, vBMD was associated with an ~30% reduced risk of progression to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per 1 SD [95% CI 0.14-0.71]), and the association remained robust after multiple imputation of missing data (HR 0.64 [95% CI 0.42-0.98]). CONCLUSION: The presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.
Assuntos
Artrite Psoriásica/etiologia , Psoríase/complicações , Adulto , Densidade Óssea , Estudos de Coortes , Tecido Conjuntivo/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date. METHODS: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up. RESULTS: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed. CONCLUSIONS: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs. TRIAL REGISTRATION: NCT02483234 , registered 26 June 2015, retrospectively registered.
Assuntos
Artrite Psoriásica , Anticorpos Monoclonais Humanizados , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Estudos Transversais , Hotspot de Doença , Humanos , Estudos ProspectivosRESUMO
Genetic predisposition to systemic sclerosis (SSc) has still not been fully revealed. Interleukin-6 (IL-6) is a mediator of T cell proliferation and fibrotic events in SSc. Polymorphisms in the IL-6 are found to be important in susceptibility to development of SSc. We aimed to assess the frequency of -174 C/G of IL-6 gene polymorphism in SSc patients and healthy controls, as well as correlation with disease manifestations. In the case-control study, 102 patients with SSc and 93 controls were included. PCR-RFLP method was performed for genotyping promotor variants -174 C/G of IL-6 gene. The expression level of IL-6 was determined by qRT-PCR on subset of 50 patients and 13 healthy controls with different IL-6 genotypes. We used UCLA GIT 2.0 questionnaire to assess gastrointestinal involvement in SSc patients. The expression level of IL-6 gene was significantly higher in patients with SSc in comparison with healthy controls (p < 0.05). Carriers of C-allele of IL-6 gene compared to those with G allele, showed higher expression of IL-6 gene (95.8 vs. 41.2, p < 0.05), higher GIT total score (0.85 vs. 0.5, p < 0.05) and higher distension scale score (1.4 ± 0.9 vs. 0.78 ± 0.8, p = 0.05). No significant differences in genotype distribution and allele frequency were observed between patients and controls. The expression of IL6 gene varies significantly during the course of SSc. The IL-6 gene variant -174 C/G (presence of C-allele) is associated with higher IL-6 gene expression and greater GIT impairment in patients with SSc.
Assuntos
Gastroenteropatias/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , SérviaRESUMO
AIMS: Autologous conditioned serum (ACS; marketed as Orthokine®) is an autologous blood product that has previously shown efficacy in treatment of joint osteoarthritis, spinal radiculopathy, tendon and muscle injuries in randomized controlled trials. In this 24-week, randomized, double-blind study, we compared the efficacy and safety of ACS with glucocorticoid (betamethasone) injections in chronic supraspinatus tendinopathy patients. MATERIAL AND METHODS: Thirty-two patients with chronic supraspinatus tendinopathy were enrolled in the study. The ACS group received four ACS injections once weekly over four weeks and the glucocorticoid group received three betamethasone injections once weekly over three weeks with a placebo (saline) injection at week 4 into the enthesis and paratenon of the supraspinatus tendon. Study endpoints were pain intensity (VAS) and Constant Shoulder Score (CSS) assessed at weeks 0, 4 and 24. RESULTS: Shoulder pain intensity improved after 4 weeks and significantly improved after 24 weeks in patients treated with ACS compared with those treated with glucocorticoids (pain intensity week 4: ACS=22.0, glucocorticoid=32.0; week 24: ACS=15.0, glucocorticoid=40.0). CSS improved to a similar extent in both groups after 4 weeks. After 24 weeks, ACS patients exhibited significantly greater CSS improvements than glucocorticoid patients. Adverse events (n=8) were reported in betamethasone patients. CONCLUSIONS: Compared with betamethasone, ACS therapy improved joint function and reduced shoulder pain more effectively after 4 weeks of treatment; these improvements were sustained to week 24. Combined with its favorable safety profile, ACS appears to be a more effective treatment than glucocorticoids and could enhance the quality of life in patients with chronic rotator cuff tendinopathy.
Assuntos
Dexametasona/administração & dosagem , Segurança do Paciente , Plasma Rico em Plaquetas , Dor de Ombro/diagnóstico por imagem , Dor de Ombro/terapia , Tendinopatia/complicações , Adulto , Idoso , Autoenxertos , Dor Crônica , Método Duplo-Cego , Feminino , Hospitais Universitários , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Medição da Dor , Prognóstico , Estudos Prospectivos , Amplitude de Movimento Articular/efeitos dos fármacos , Amplitude de Movimento Articular/fisiologia , Dor de Ombro/etiologia , Dor de Ombro/fisiopatologia , Estatísticas não Paramétricas , Tendinopatia/diagnóstico por imagem , Resultado do Tratamento , Ultrassonografia Doppler/métodosRESUMO
The study aims to analyze the effects of induction treatment with cyclophosphamide (CYC) pulse therapy followed by maintenance treatment with other mild immunosuppressive agents on lung function in scleroderma (SSc) patients. Thirty patients with SSc (mean age 52 years, mean disease duration < 2 years) with forced vital capacity (FVC) ≤ 80% and/or diffusing capacity of carbon monoxide (DLco) ≤ 70% were included. Monthly CYC pulses were given for 6 months (induction treatment), followed by 3-monthly maintenance pulses for the next 18 months, and during the next 5 years patients received other mild immunosupressive therapy brought by the competent rheumatologist. The efficacy was evaluated by comparing FVC% and DLco% after 6, 24, and 84 months from the baseline. All patients completed induction and maintenance treatment with CYC. Three patients were lost to follow-up. The rest of 27 patients, during the next 5 years, received other immunosupressive agents (14 azathioprine, 9 methotrexate, and 4 mycophenolate mofetil). Three patients died in the 4 years of follow-up. By 6, 24, and 84 months, the mean FVC and DLco changes were + 0.47 and + 2.10, + 3.30 and - 2.49, and + 1.53 and - 3.76%, respectively. These changes were not significantly different from the baseline values. CYC does not appear to result in clinically significant improvement of pulmonary function but fulfilled criteria of stable disease. Maintenance treatment with other mild immunosupressive agents preserves the benefits achieved during CYC treatment.
Assuntos
Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Pulmão/fisiopatologia , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/fisiopatologia , Adulto , Monóxido de Carbono/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pulsoterapia/métodos , Fatores de Tempo , Resultado do Tratamento , Capacidade VitalRESUMO
Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease with unknown etiology. Numerous studies have indicated that the disease heterogeneity implies various genetic abnormalities. Considering that SSc is characterized by a strong sex bias and that the position of IRAK1 gene is on the X chromosome, we assume that variations in IRAK1 gene could explain female predominance of SSc. It was previously described that miR-146a has a role in 'fine-tuning' regulation of the TLR/NF-kB signaling pathway through down-regulation of IRAK1 gene. The aim of the present study was to analyze both variants and expression level of IRAK1 and miR-146a genes in terms of susceptibility to SSc and clinical presentation of SSc patients. We analyzed variants IRAK1 rs3027898 C > A and miR-146a rs2910164 C > G in 102 SSc patients and 66 healthy subjects. Genotyping was performed by Sanger sequencing. Expression level of IRAK1 mRNA and miR-146a in PBMCs was performed in subset of 50 patients and 13 healthy controls by RT-qPCR. Our results showed that there was no association between IRAK1 rs3027898 and the risk of SSc in women. However, the analysis of genotype distribution of the mir-146a rs2910164 C > G variant indicated that CC genotype shows strong association with lung fibrosis and active form of the disease. When expression level of IRAK1 gene was analyzed, we detected significant downregulation of IRAK1 mRNA in SSc patients compared to controls, as well as in male compared to female patients, in patients with ACAs autoantibodies and in patients with severe skin involvement. Regarding the expression level of miR-146a, we have found significantly reduced expression in SSc patients, in patients with skin involvement and in male SSc patients. The results from this study indicate that expression of IRAK1 gene could explain phenotypic heterogeneity of SSc and may be involved in the pathogenesis of SSc due to its differential expression in certain subgroups. Our results also suggested that miR-146a rs2910164 CC genotype may be predisposing factor for development lung fibrosis and more progressive form of SSc. Results from relative expression analysis of miR-146a demonstrated that changes in the level of this miRNA may have an impact on development and clinical course of SSc.
Assuntos
Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Quinases Associadas a Receptores de Interleucina-1/genética , MicroRNAs/genética , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/genética , Idoso , Alelos , Biomarcadores , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/metabolismoRESUMO
Systemic sclerosis (SSc) is a rare, chronic, multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. The basic mechanism appears to involve endothelial cell injury, overproduction of extracellular matrix proteins, and aberrant immune activation. So far, there have been a few attempts to find genetic biomarkers for monitoring disease activity or for correlation with certain symptoms. In order to reveal reliable biomarkers, we analyzed the expression of four genes representing three important signaling pathways, TLR7, TLR9, and JAK2-STAT3. Using RT-qPCR technique, we analyzed the expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells of 50 SSc patients and 13 healthy individuals. We detected significant upregulation of TLR7 gene expression in a group of SSc patients compared to non-SSc group. Receiver operating characteristic (ROC) analysis showed that TLR7 expression efficiently discriminates SSc cases from healthy individuals. High TLR7 expression positively correlated with the late form of disease, active SSc, and the presence of digital ulcers. Decreased levels of TLR9 and JAK2 mRNA were found in the patient's cohort in comparison to non-SSc individuals, but showed no correlation with specific clinical outcomes. The expression level of the STAT3 gene did not differ between the analyzed groups. This is the first study on the expression of TLR7, TLR9, and STAT3 genes in SSc patients. Our results show that TLR7, TLR9, and JAK2 genes are potential biomarkers for SSc. The results obtained in this study could contribute to better classification, monitoring, and outcome prediction of patients with SSc based on genetics.
Assuntos
Janus Quinase 2/genética , Fator de Transcrição STAT3/genética , Escleroderma Sistêmico/genética , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Transdução de SinaisRESUMO
Connective tissues diseases (CTDs) can also be diagnosed early by "external" and safe imaging methods beyond the visceral organ analysis. This study aims to explore various imaging techniques used in diagnosing CTDs. Skin impairment in systemic sclerosis (SSc) may be recognized and studied by the modified Rodnan skin score (mRSS), which has some drawbacks, whereas high-frequency ultrasound (US) seems advantageous for the early identification of skin involvement. Salivary gland involvement in Sjögren syndrome (SS) can be assessed using standard tests such as unstimulated salivary flow test, salivary gland scintigraphy or contrast sialography. However, US of the major salivary glands, as an alternative, seems a reliable method with good sensitivity and specificity for the diagnosis of SS. Both the qualitative and quantitative nailfold capillaroscopic (NVC) assessments in SSc patients affected by the Raynaud's phenomenon (RP) may assist in making a differential diagnosis between primary and secondary RP. Microcirculatory imaging by NVC, along with the laser Doppler analysis, seems useful in the prediction of complications and prognosis in CTDs (i.e. SSc) and in monitoring therapeutic trials.