Algirdas Venalis

Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study

Objective To compare the efficacy and safety of treatment with infliximab plus methotrexate with methotrexate alone in methotrexate-naive patients with active psoriatic arthritis (PsA). Methods In this open-label study, patients 18 years and older with active PsA who were naive to methotrexate and not receiving disease-modifying therapy (N=115) were randomly assigned (1:1) to receive either infliximab (5 mg/kg) at weeks 0, 2, 6 and 14 plus methotrexate (15 mg/week); or methotrexate (15 mg/week) alone. The primary assessment was American College of Rheumatology (ACR) 20 response at week 16. Secondary outcome measures included psoriasis area and severity index (PASI), disease activity score in 28 joints (DAS28) and dactylitis and enthesitis assessments. Results At week 16, 86.3% of patients receiving infliximab plus methotrexate and 66.7% of those receiving methotrexate alone achieved an ACR20 response (p<0.02). Of patients whose baseline PASI was 2.5 or greater, 97.1% receiving infliximab plus methotrexate compared with 54.3% receiving methotrexate alone experienced a 75% or greater improvement in PASI (p<0.0001). Improvements in C-reactive protein levels, DAS28 response and remission rates, dactylitis, fatigue and morning stiffness duration were also significantly greater in the group receiving infliximab. In the infliximab plus methotrexate group, 46% (26/57) had treatment-related adverse events (AE) and two patients had serious AE, compared with 24% with AE (13/54) and no serious AE in the methotrexate-alone group. Conclusions Treatment with infliximab plus methotrexate in methotrexate-naive patients with active PsA demonstrated significantly greater ACR20 response rates and PASI75 improvement compared with methotrexate alone and was generally well tolerated. This trial is registered in the US National Institutes of Health clinicaltrials.gov database, identifier NCT00367237.

The impact of systemic sclerosis on arterial wall stiffness parameters and endothelial function

Systemic sclerosis (SSc) is characterized by thickening and fibrosis of skin and internal organs that is associated with vascular damage. SSc may lead to arterial dysfunction and premature aging of the arteries. However, its relationship with parameters of arterial wall dysfunction has not been fully explored. To determine if carotid–radial pulse wave velocity (PWV), aortic augmentation index (AIx) and endothelial function are altered in SSc patients, 17 consecutive patients with SSc and 34 age- and gender-matched controls were included in our study. PWV and AIx were assessed non-invasively by applanation tonometry. The endothelium-dependent flow-mediated dilatation (FMD) test in a brachial artery was performed by the ultrasound system. The blood investigations included serum lipid profile, glucose, and high-sensitivity CRP (hsCRP) measurements. As compared to controls, SSc patients had significantly higher medians of the AIx (p = 0.002) and the PWV (p = 0.04) and the median of the FMD was significantly lower (p = 0.001). Stepwise linear regression including comorbid factors showed that SSc was a significant independent predictor of all arterial wall parameters measures. SSc patients have increased AIx and PWV and lower FMD as compared to control subjects. The relationship between SSc and measures of arterial wall parameters still remains unclear. Though replication of the results presented here is required, we conclude that SSc has a great impact on large and conduit arteries damage.

Disease activity and health status in rheumatoid arthritis: a case-control comparison between Norway and Lithuania.

Objective: To compare disease characteristics and health status in patients with rheumatoid arthritis (RA) from two countries, Norway and Lithuania. Methods: Patients were recruited from the RA registers in Vilnius (Lithuania) and Oslo (Norway). For each patient from Vilnius, a patient matched for age and sex from the Oslo register was selected. Sociodemographic characteristics, disease process, and health status were compared between the patient groups. Results: 201 Lithuanian patients and 201 Norwegian patients were included. Mean (SD) age in both groups was 55.9 (10.0) years, and 83% were women. Patients from Lithuania were less often employed (27% v 42%; p=0.001), had higher disease activity expressed by the disease activity score (DAS28; mean (SD) 5.3 (1.0) v 4.4 (1.4); p<0.001), had worse physical function by the modified Health Assessment Questionnaire (MHAQ; mean (SD) 2.3 (0.8) v 1.6 (0.5); p<0.001), had more often comorbidity (73% v 53%; p<0.001) and they reported worse general health measured by Short Form-36 Health Survey (SF-36; mean (SD) 23.2 (13.5) v 44.5 (21.3); p<0.001). The proportions of patients who had used disease modifying drugs were similar, but the pattern of use differed. Conclusion: Important differences in employment, disease activity, physical function, and self reported health status were observed in patients with RA from two northern European countries. Socioeconomic inequalities, differences in disease management, and access to specialised health care, as well as methodological issues regarding instruments and data collection are likely explanations. These data support the view that management of RA should be adapted to country-specific needs.

Relationship between serum levels of TGF-β1 and clinical parameters in patients with rheumatoid arthritis and Sjögren's syndrome secondary to rheumatoid arthritis

TGF-β1 is a pleiotropic cytokine, which prevents inappropriate autoimmune responses and balances the requirements of proper immune cell levels during pathologic states that trigger the immune response. We assessed the serum levels of TGF-β1 and determined the relationship between TGF-β1 and clinical parameters in patients with rheumatoid arthritis (RA) and Sjögrens syndrome (SS) secondary to RA (SS + RA). Comparison of the serum levels of TGF-β1 in patients with RA, SS + RA and NHD differed significantly (51.7 ± 12.4 ng/ml (RA); 33.0 ± 3.1 ng/ml (SS + RA) and versus 31.6 ± 2.0 ng/ml (NHD)). We further found correlations between TGF-β1 levels and radiologically defined joint damage determined by the Steinbrocker scoring system, symptoms and signs of SS. We conclude that serum levels of TGF-β1 may reflect ongoing autoimmune inflammation and correlate with joint damage in RA.

Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNF α Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients

Objective. To analyze the clinical relevance of the levels of TNFα blockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time. Methods. Clinical characteristics (disease activity, and adverse events), serum TNFα blockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFα blockers for a median of 28 months. Results. Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and nonresponders (P > 0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08–120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64–52.52)). Conclusion. Patients not responding to treatment had higher serum anti-ADA and anti-INF Ab concentrations. Anti-INF Ab formation is related to increased risk of infusion related reactions, changing to another biologic drug, and treatment discontinuation.

Prevalence of paraneoplastic rheumatic syndromes and their antibody profile among patients with solid tumours

The aims of this study were to assess the prevalence of paraneoplastic rheumatic syndromes in a cohort of patients with newly diagnosed solid tumours and to describe their autoimmune profile, comparing it to the controls. Screening questionnaires (3,770) were distributed, and during a three-step study, 94 patients were confirmed to have both paraneoplastic syndrome and oncology diagnoses. Three control groups–patients with undifferentiated arthritis, Raynauds phenomenon for non-malignant causes and solid tumours only–were designed to compare with the paraneoplastic cases and their immunology profile. The prevalence of paraneoplastic rheumatic syndromes was 2.65% (95% CI 0.21–3.20). The group of patients with arthritis and the group of patients with Raynauds syndrome were found to prevail among other clinical presentations of paraneoplastic rheumatic syndromes. Both paraneoplastic syndromes were linked to malignancies of the urogenital system. Antinuclear antibodies were found to be similarly frequent in the paraneoplastic arthritis, paraneoplastic Raynauds phenomenon and the solid tumour groups. No differences were observed when comparing paraneoplastic arthritis and undifferentiated arthritis, except that the patients with paraneoplastic arthritis were older. Comparing paraneoplastic Raynauds to Raynauds phenomenon, male preponderance in the paraneoplastic Raynauds phenomenon group was observed, and the patients were obviously older. Paraneoplastic rheumatic syndromes are rare and more often occur in older patients. Among them, paraneoplastic arthritis and Raynauds syndrome were the most frequent. The immunology profile does not help in discriminating between arthritis and paraneoplastic arthritis patients and is of limited use in Raynauds differential diagnosis.

The impact of high-dose narrowband ultraviolet A1 on dermal thickness, collagen and matrix-metalloproteinases in animal model of scleroderma

OBJECTIVE The main purpose of the present study was to define the impact of high-dose of 365±5nm ultraviolet A1 (UVA1) on dermal fibrosis in the pre-established, bleomycin-induced mouse model of scleroderma. METHODS DBA/2 strain mice with the pre-established, bleomycin-induced scleroderma were irradiated with cumulative UVA1 dose of 1200J/cm2 and in parallel were challenged with prolonged administration of bleomycin. Non-treated groups served as the control. Light source emitting a narrow band UVA1 light of 365±5nm and 21mW/cm2 power density was used in the study. Histological analysis was performed for the evaluation of dermal thickness. The expressions of matrix-metalloproteinase-1 (MMP-1), matrix-metalloproteinase-3 (MMP-3), collagen types I and III were evaluated by immunohistochemical analyses. The Mann - Whitney U test was used for statistical analysis. RESULTS Dermal thickness in mice injected with bleomycin during all the experiment (8weeks) and irradiated with UVA1 for the last 5weeks was significantly lower than that in mice challenged only with bleomycin for 8weeks (253.96±31.83μm and 497.43±57.83μm, respectively; P=0.002). The dermal thickness after phototherapy was lower as compared with the pre-existing fibrotic changes observed after 3weeks of bleomycin injections (253.96±31.83μm and 443.87±41.76μm, respectively; P=0.002). High-dose of UVA1 induced the 5.8- and 5.2-fold increase in MMP-1 and MMP-3 expressions, respectively, and the 1.2- and 1.4-fold decrease in collagen type I and collagen type III expressions in the pre-established, bleomycin-induced scleroderma model as compared to that in the control non-irradiated mice (P=0.002). CONCLUSIONS Our study has demonstrated that a cumulative 365±5nm UVA1 radiation dosage of 1200J/cm2 not only prevents the progression of dermal fibrosis, but also induces a regression of pre-existing fibrotic changes.

Human mesenchymal adipose stromal cells from mature adipocyte fraction

More effective techniques should be employed for isolation of human mesenchymal stromal cells derived from adipose tissue (ADSC), seeking to make adipose tissue biopsies smaller in volume and thus less invasive. In this study, we compared properties of ADSC isolated by several different methods from the same samples of adipose tissue in order to enhance yields of potential ADSC. The mature adipocyte fraction was investigated using the ceiling culture method, including both ceiling and bottom cell fractions, and the control culture method with standard amount of medium. The results were also compared using the stromal vascular fraction from the same samples. The most efficient was the bottom cell population isolated from the mature adipocyte fraction by ceiling culture method. These cells readily differentiated into osteogenic, adipogenic and chondrogenic lineages and, similar to stromal vascular fraction cells, displayed high proliferation potential. Cultures of mature adipocyte fractions with standard amount of medium were considerably less effective. Mature adipocyte fractions yields large quantities of adipose-derived stem cells that have properties comparable with stromal vascular fraction cells suitable for tissue regeneration, especially when only small biopsies can be taken.

The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice

PURPOSE To define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. MATERIALS AND METHODS 42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365±5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. RESULTS Skin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9±113.2μm and 394±125.9μm, respectively) in comparison to the dermal thickness of non-treated animals (599±55.7μm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11±1.7 and 13±2.2, respectively, as compared to that in non-treated mice (23±3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. CONCLUSIONS The results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment.

Paracrine Potential of the Human Adipose Tissue-Derived Stem Cells to Modulate Balance between Matrix Metalloproteinases and Their Inhibitors in the Osteoarthritic Cartilage In Vitro

Adipose tissue represents an abundant source of stem cells. Along with anti-inflammatory effects, ASC secrete various factors that may modulate metabolism of extracellular matrix in osteoarthritic (OA) cartilage, suggesting that the presence of ASC could be advantageous for OA cartilage due to the recovery of homeostasis between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs). To evaluate these effects, cartilage explants (CE) were cocultured with ASC for 3 and 7 days under stimulation with or without IL-1β. The pattern of gene expression in CE was modified by ASC, including the upregulation of COL1A1 and COL3A1 and the downregulation of MMP13 and COL10A1. The production of MMP-1, MMP-3, and MMP-13 by ASC was not significant; moreover, cocultures with ASC reduced MMP-13 production in CE. In conclusion, active production of TIMP-1, TIMP-2, TIMP-3, IL-6, IL-8, and gelatinases MMP-2 and MMP-9 by ASC may be involved in the extracellular matrix remodelling, as indicated by the altered expression of collagens, the downregulated production of MMP-13, and the reduced chondrocyte apoptosis in the cocultured CE. These data suggest that ASC modulated homeostasis of MMPs/TIMPs in degenerated OA cartilage in vitro and might be favourable in case of the intra-articular application of ASC therapy for the treatment of OA.