Anti-inflammatory effects of intravenous methotrexate associated with lipid nanoemulsions on antigen-induced arthritis

OBJECTIVE: To test the hypothesis that intravenous use of methotrexate associated with lipid nanoemulsions can achieve superior anti-inflammatory effects in the joints of rabbits with antigen-induced arthritis compared with commercial methotrexate. METHODS: Arthritis was induced in New Zealand rabbits sensitized with methylated bovine serum albumin and subsequently intra-articularly injected with the antigen. A nanoemulsion of methotrexate labeled with 3H-cholesteryl ether (4 mg/kg methotrexate) was then intravenously injected into four rabbits to determine the plasma decaying curves and the biodistribution of the methotrexate nanoemulsion by radioactive counting. Additionally, the pharmacokinetics of the methotrexate nanoemulsion were determined by high-pressure liquid chromatography. Twenty-four hours after arthritis induction, the animals were allocated into three groups, with intravenous injection with saline solution (n=9), methotrexate nanoemulsion (0.5 µmol/kg methotrexate, n=7), or commercial methotrexate (0.5 µmol/kg, n=4). The rabbits were sacrificed 24 h afterward. Synovial fluid was then collected for protein leakage and cell content analyses and synovial membranes were collected for histopathological analysis. RESULTS: The methotrexate nanoemulsion was taken up mainly by the liver and the uptake by arthritic joints was two-fold greater than that by control joints. The methotrexate nanoemulsion treatment reduced leukocyte influx into the synovial fluid by nearly 65%; in particular, mononuclear and polymorphonuclear cells were reduced by 47 and 72%, respectively. In contrast, cell influx was unaffected following treatment with commercial methotrexate. Protein leakage into the arthritic knees of the rabbits was also more limited following methotrexate nanoemulsion treatment than following commercial methotrexate treatment. CONCLUSIONS: The intravenous methotrexate nanoemulsion showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. This result is conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion

Decreased high-density lipoprotein cholesterol levels in polyarticular juvenile idiopathic arthritis

OBJECTIVES: To investigate the prevalence of dyslipoproteinemia in a homogeneous cohort of polyarticular juvenile idiopathic arthritis patients. METHODS: Based on the National Cholesterol Education Program, fasting lipoprotein levels and risk levels for coronary artery disease were determined in 28 patients with polyarticular juvenile idiopathic arthritis. The exclusion criteria included diabetes, thyroid dysfunction, smoking, proteinuria, lipid-lowering drugs, and hormone/diuretic therapy. Disease activity, disease duration, and therapy with corticosteroids and/or chloroquine were defined at the time of lipid measurements. RESULTS: Dyslipoproteinemia was identified in 20 of the 28 (71%) patients with polyarticular juvenile idiopathic arthritis. The primary lipoprotein risk factor was decreased high-density lipoprotein cholesterol (57%), followed by elevated levels of low-density lipoprotein cholesterol (18%), triglycerides (14%), and total cholesterol (7%). The male patients had decreased high-density lipoprotein cholesterol levels than the female patients (p<0.05). The incidence of decreased high-density lipoprotein cholesterol levels did not seem to be affected by disease activity or therapy because the incidence was similar in patients with active or inactive disease, with or without corticosteroid use and with or without chloroquine use. In addition, the frequency of decreased high-density lipoprotein cholesterol levels was similar in patients with short (&#8804;5 years) vs. long (>5 years) disease duration. CONCLUSIONS: Dyslipoproteinemia is highly prevalent in patients with polyarticular juvenile idiopathic arthritis and is primarily related to decreased high-density lipoprotein cholesterol levels; therefore, early intervention is essential

No deleterious effect of low dose methotrexate on titanium implant osseointegration in a rabbit model

OBJECTIVE: To evaluate the effect of low dose methotrexate alone or in combination with glucocorticoid treatment on titanium implant osseointegration. METHODS: Groups of 6-8 adult New Zealand White rabbits were treated for 18 weeks with saline (control), methotrexate, glucocorticoid, or methotrexate plus glucocorticoid. The animals received a titanium implant in the tibia at week 6. Lumbar spine and tibia bone mineral densities were analyzed before and after treatment. Histomorphometric analysis of bone cortical thickness, total bone area around the implant, and % of bone to implant contact was performed. RESULTS: After 18 weeks, the change in the bone mineral density in the lumbar spines and tibias in the methotrexate group was comparable to the control group (0.035 vs. 0.055 g/cm² and 0.021 vs. 0.041 g/cm², respectively). In contrast, both the glucocorticoid group and glucocorticoid plus methotrexate group had significant reductions at both sites. Histomorphometric analysis of the tibia in the control and methotrexate groups revealed no significant changes in cortical thickness (133 vs. 126 &#956;m), total bone area around the implant (33 vs. 30%), or bone to implant contact (40 vs. 38%). In contrast, glucocorticoid group had significant reductions compared to controls in tibia cortical thickness (99 vs. 133 &#956;m), total bone area around the implant (24 vs. 33%), and bone to implant contact (27 vs. 40%). Similar reductions were observed in the glucocorticoid plus methotrexate group. CONCLUSIONS: Our results demonstrate that low dose methotrexate treatment does not affect titanium implant osseointegration, suggesting that this therapy is safe for surgical procedures requiring a titanium implant

Gathering patients and rheumatologists' perceptions to improve outcomes in idiopathic inflammatory myopathies

Objective: Therapeutic targets in Idiopathic Inflammatory Myopathies (IIM) are based on the opinions of physicians/specialists, which may not reflect the main concerns of patients. The authors, therefore, assessed the outcome concerns of patients with IIM and compared them with the concerns of rheumatologists in order to develop an IIM outcome standard set. Methods: Ninety-three IIM patients, 51&nbsp;rheumatologists, and one&nbsp;physiotherapist were invited to participate. An open questionnaire was initially applied. The top&nbsp;10&nbsp;answers were selected and applied in a multiple-choice questionnaire, inquiring about the top&nbsp;3&nbsp;major concerns. Answers were compared, and the agreement rate was calculated. Concerns were gathered in an IIM outcome standard set with validated measures. Results: The top three outcome concerns raised by patients were medication side effects/muscle weakness/prevention functionality loss. The top three concerns among rheumatologists were to prevent loss of functionality/to ensure the quality of life/to achieve disease remission. Other's outcomes concerns only pointed out by patients were muscle pain/diffuse pain/skin lesions/fatigue. The agreement rate between both groups was&nbsp;41%. Assessment of these parameters guided the development of an IIM standard set which included Myositis Disease Activity Assessment Visual Analogue Scale/Manual Muscle Testing/fatigue and pain Global Visual Analogue Scale/Health Assessment Questionnaire/level of physical activity. Conclusion: The authors propose a novel standard set to be pursued in IIM routine follow-up, which includes not only the main patients/rheumatologist outcome concerns but also additional important outcomes only indicated by patients. Future studies are necessary to confirm if this comprehensive approach will result in improved adherence and ultimately in better assistance

Profile of cytokines and soluble TNF receptors in response to moderate and intense exercises in active and remission patients with systemic lupus erythematosus

Introduction: systemic lupus erythematosus (SLE) is a rheumatic autoimmune disease characterized by chronic inflammation that is associated with clinical symptoms and disease severity. Therefore, strategies to reduce inflammation, such as physical exercise, have a potential therapeutic role in SLE due to its anti-inflammatory effects. This study sought to compare cytokines and soluble TNF receptors response to: (1) moderate vs. intense aerobic exercise in active SLE (SLEACT) and remission SLE (SELREM) patients; (2) SLEACT vs. SLEREM patients undergoing moderate and intense aerobic exercises; and (3) SLE patients vs. healthy controls (HC) undergoing moderate and intense aerobic exercises. Methods: twelve SLEREM (age: 35.3±5.7 yrs; BMI: 25.6±3.4 kg/m2), 11 SLEACT (age: 30.4±4.5 yrs; BMI: 26.1±4.8 kg/m2) and 10 age-and BMI-matched HC (age: 30.6±5.2 yrs; BMI: 24.1±2.3 kg/m2) performed 30-min sessions of moderate (~50% of VO2max) and intense (~70% of VO2max) exercises. Serum cytokines (INF-γ, IL-10, IL-6, TNF-α) and soluble receptors (sTNFR1 and sTNFR2) were measured at rest, immediately after the exercise, every 30-min during three hours of recovery, and 24 h after the end of exercise session. Results: there were no differences for cytokines and sTNFRs responses between moderate and intense aerobic exercise for SLEACT and SLEREM patients (P\u3e0.05). Similar responses were found when SLEACT and SLEREM patients were compared for moderate and intense exercises, except for 1) serum TNF-α, which was lower in SLEACT than SLEREM patients after moderate exercise (P\u3c0.05); 2) serum sTNFR1, which was higher in SLEREM than SLEACT patients at 30th and 60th minutes of moderate exercise recovery (P=0.027 and P=0.036, respectively); and 3) serum sTNFR2, which remained higher during both sessions of exercise and recovery for SLEREM in comparison to SLEACT patients (P\u3c0.01). Also, a time-effect was observed for serum IL-6 and TNF-α (P\u3c0.05) after intense exercise with a posterior reduction under baseline values, reaching the values experienced by HC. Conclusion: cytokines and sTNFRs were not different in both exercise intensities for SLEACT and SLEREM, except for a few differences, which pointed out to a less inflammatory pattern in SLEACT patients, suggesting that exercise (even more intensive) can be safely performed by SLE patients with active disease. Finally, the reduction shown in serum IL-6 and TNF-α after intense exercise in SLEACT patients supports evidences for an anti-inflammatory effect of exercise and reinforces the importance of physical exercise to SLE treatment

Reproductive health aspects in men with idiopathic inflammatory myopathy: a multicenter study

OBJECTIVE: To evaluate reproductive health of males with idiopathic inflammatory myopathies (IIM), and comparing them with a control group. METHODS: Demographic data, urologic evaluation (including pubertal parameters and sexual/erectile function), testicular ultrasound, hormone profile, semen analysis, clinical features, and treatment of 25 IIM patients were evaluated. The control group was composed of 25 healthy males. RESULTS: Median age of IIM patients was similar to that of the control group (24 versus 27 years, P = 0.566). The frequency of sexual activity, number of partners with spontaneous pregnancies after the onset of the disease, and use of condom were significantly lower in IIM patients than in the control group (60% versus 96%, P = 0.004; 16% versus 60%, P = 0.0031; 40% versus 76%, P = 0.021, respectively). Moreover, the frequency of testicular atrophy (28% versus 4%, P = 0.049), elevated levels of FSH and/or LH (25% versus 0%, P = 0.05), and sperm abnormalities (40% versus 0%, P = 0.0006) were statistically higher in IIM patients than in the control group. Median age of onset of IIM and current age were significantly higher in IIM patients with sexual/erectile dysfunction than in patients without this dysfunction (41 versus 12.5 years, P = 0.014; 46 versus 21 years, P = 0.027, respectively). On the other hand, differences in the age of spermarche, parameters of gonadal function, disease activity, muscle enzymes, and treatment were not observed between IIM patients with or without sexual/erectile dysfunction. CONCLUSION: This is the first study to identify changes in reproductive health and gonadal dysfunction in male IIM patients. Rheumatologists should discuss sexual problems with their patients, counseling them on contraceptive methods.OBJETIVO: Avaliar a saúde reprodutiva de homens com miopatia inflamatória idiopática (MII) e compará-la com controles saudáveis. MÉTODOS: Vinte e cinco pacientes com MII (dermatomiosite ou polimiosite) foram avaliados com relação aos dados demográficos, exame urológico (incluindo parâmetros pubertários e função sexual/erétil), ultrassonografia testicular, perfil hormonal, análise seminal, características clínicas e tratamento. O grupo controle incluiu 25 homens saudáveis. RESULTADOS: A mediana da idade atual foi similar nos pacientes com MII e controles (24 versus 27 anos, P = 0,566). As frequências de atividade sexual, número de parceiras com gestações espontâneas após início da doença e uso de preservativo masculino foram significativamente menores nos pacientes com MII versus controles (60% versus 96%, P = 0,004; 16% versus 60%, P = 0,0031; 40% versus 76%, P = 0,021; respectivamente). Além disso, as frequências de atrofia testicular (28% versus 4%, P = 0,049), níveis elevados de FSH e/ou LH (25% versus 0%, P = 0,05) e alterações dos espermatozoides (40% versus 0%, P = 0,0006) foram estatisticamente maiores nos pacientes com MII quando comparados aos controles. As medianas das idades de início da doença e atual foram estatisticamente maiores nos pacientes com MII que apresentaram disfunção sexual/erétil versus sem disfunção (41 versus 12,5 anos, P = 0,014; 46 versus 21 anos, P = 0,027; respectivamente). Entretanto, comparando-se, pacientes com disfunção sexual/erétil e sem disfunção, nenhuma diferença foi evidenciada em relação à idade da espermarca, parâmetros de função gonadal, atividade da doença, enzimas musculares e tratamento. CONCLUSÃO: Este foi o primeiro estudo que identificou alterações da saúde reprodutiva e disfunção gonadal em homens com MII. Reumatologistas devem discutir problemas sexuais e orientar contracepção aos seus pacientes.FMUSP Departamento de PediatriaFaculdade de Medicina da Universidade de São Paulo Hospital das Clínicas Instituto da CriançaUniversidade Federal do Pará Departamento de PediatriaFMUSP HC ICrFMUSP HCUNIFESP Departamento de PediatriaUNIFESP Setor de Reumatologia PediátricaSanta Casa de São Paulo Setor de Reumatologia PediátricaFMUSP HC Departamento de RadiologiaUNIFESP, Depto. de PediatriaUNIFESP, Setor de Reumatologia PediátricaSciEL