Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in Rheumatoid Arthritis patients.

OBJECTIVES: 1) To assess the association of NETosis and NETosis-derived products with the activity of the disease and the development of cardiovascular disease in RA; 2) To evaluate the involvement of NETosis on the effects of biologic therapies such as anti-TNF alpha (Infliximab) and anti-IL6R drugs (Tocilizumab). METHODS: One hundred and six RA patients and 40 healthy donors were evaluated for the occurrence of NETosis. Carotid-intimae media thickness was analyzed as early atherosclerosis marker. Inflammatory and oxidative stress mediators were quantified in plasma and neutrophils. Two additional cohorts of 75 RA patients, treated either with Infliximab (n = 55) or Tocilizumab (n = 20) for six months, were evaluated. RESULTS: NETosis was found increased in RA patients, beside myeloperoxidase and neutrophil elastase protein levels. Cell-free nucleosomes plasma levels were elevated, and strongly correlated with the activity of the disease and the positivity for autoantibodies, alongside inflammatory and oxidative profiles in plasma and neutrophils. Moreover, ROC analyses showed that cell-free nucleosomes levels could identify RA patients showing early atherosclerosis with high specificity. RA patients treated either with IFX or TCZ for six months exhibited decreased generation of NETs. Concomitantly, clinical parameters and serum markers of inflammation were found reduced. Mechanistic in vitro analyses showed that inhibition of NETs extrusion by either DNase, IFX or TCZ, further abridged the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system. CONCLUSIONS: NETosis-derived products may have diagnostic potential for disease activity and atherosclerosis, as well as for the assessment of therapeutic effectiveness in RA.

Validity of the ankylosing spondylitis disease activity score (ASDAS) in patients with early spondyloarthritis from the Esperanza programme.

OBJECTIVES: To evaluate the validity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) in early spondyloarthritis (SpA) in comparison with conventional clinical measures of disease activity. METHODS: Six hundred and seventy-six incident cases of early SpA from the Esperanza programme were included. Patients were categorised into high and low disease activity states based on patient and physician global assessment scores and on the physician's decision to start treatment with a disease-modifying antirheumatic drug or tumour necrosis factor blocker. The discriminant ability of ASDAS-C-reactive protein (CRP) and ASDAS-erythrocyte sedimentation rate (ESR) was tested using standardised mean differences between patients with high and low disease activity. Convergent validity was tested by Pearson correlation between ASDAS versions and other measures of disease activity. RESULTS: ASDAS-ESR and ASDAS-CRP showed good correlation with BASDAI (r=0.79 and 0.74, respectively). Both indices correlated well with the patient global assessment (r=0.70 in both indices) and moderately with the physician global score (r=0.46 and 0.47, respectively). CRP and ESR showed poor correlation with patient- and physician-derived measures. ASDAS performed similarly across the global SpA sample, ankylosing spondylitis (AS), non-radiographic axial SpA and peripheral SpA. CONCLUSIONS: ASDAS performed as a valid activity score even being slightly better than the Bath Ankylosing Spondylitis Disease Activity Index in its ability to discriminate between high and low disease activity in early SpA. ASDAS performed similarly in AS, early forms of SpA, non-radiographic axial SpA and peripheral SpA.

2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis.

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS).

OBJECTIVE: Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. METHODS: Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). RESULTS: Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset <40 years (OR 9.9); and (5) no improvement with rest (OR 7.7). If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 91.7% in the patients participating in the workshop, and 79.6% and 72.4%, respectively, in the validation cohort. CONCLUSION: This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts' criteria are robust, easy to apply and have good face validity.

Effectiveness of reducing infliximab dose interval in non-responder patients with refractory spondyloarthropathies. An open extension of a multicentre study.

OBJECTIVE: To evaluate the therapeutic effectiveness of reducing the infliximab dose interval to 6 weeks in spondyloarthropathy patients not responding to 5 mg/kg every 8 weeks. METHODS: After 30 weeks of infliximab therapy, 25 patients were classified as responders [Bath Ankylosing Spondylitis Activity Index (BASDAI) <4 cm or ESR <30 mm/h and CRP <5 mg/l, n = 15; group A] or non-responders (patients who did not achieve the response established for group A; n = 10; group B). Responders continued on 5 mg/kg every 8 weeks and non-responders decreased the dose interval to 6 weeks. BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), ESR, CRP and ankylosing spondylitis assessment (ASAS) criteria were used to assess response. RESULTS: At 62 weeks, 11 of 15 patients (73.3%, 95% confidence interval = 44.9-92.2%) from group A and three of 10 patients (30%, 95% confidence interval = 6.7-65.2) from group B were responders (P = 0.049). Eighty per cent (eight of 10 patients from group A) and 22.2% (two of 9 patients from group B) achieved 50% BASDAI improvement (P = 0.023), and nine of 11 patients (81.8%) and four of 10 (40%) from groups A and B, respectively, reached ASAS20 at 62 weeks (P = 0.08). CONCLUSION: Patients on infliximab 5 mg/kg every 8 weeks with persistent disease activity may benefit from reducing the dose interval to 6 weeks.

Anti-tumour necrosis factor alpha therapy for ankylosing spondylitis: international experience.

The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these rheumatic disorders. Tumour necrosis factor alpha (TNFalpha) is a cytokine that has been shown to mediate inflammatory and regulatory activities in SpA and other immune mediated diseases, including other arthritides and inflammatory bowel disease. Positive results have been reported in several international open label and randomised controlled trials of infliximab and etanercept, the two main biological agents targeting TNFalpha, which have included approximately 300 patients with SpA. Specifically, TNFalpha-directed therapy resulted in significant improvements in disease activity, function, and quality of life in these patients, most of whom had AS and received infliximab. Preliminary evidence from open label, long term extension trials suggests clinical benefit with continued use. Serious side effects were rare and consistent with experience from patient groups receiving infliximab or etanercept treatment for inflammatory bowel disease or rheumatoid arthritis. Together, these findings herald an age of more effective treatment of patients with AS with anti-TNFalpha and other emerging biological agents.

Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis.

OBJECTIVE: To study the local and systemic behavior of the tumor necrosis factor-alpha (TNF-alpha) in patients with active uveitis. METHODS: TNF-alpha levels were measured in aqueous humor and peripheral blood samples using an enzyme-linked immunosorbent assay from 23 patients with uveitis and 16 control patients who had been operated on for uncomplicated cataracts. RESULTS: Aqueous humor and sera of patients with uveitis showed higher levels of TNF-alpha than those of controls (p < 0.001). A comparison of cytokine levels between aqueous humor and sera showed significantly higher levels of TNF-alpha in serum than aqueous humor (p < 0.001). Correlation studies using the regression test for successive steps showed that serum TNF-alpha levels correlated with recurrent uveitis (r = 0.4150; p = 0.0489). CONCLUSIONS: TNF-alpha is a cytokine that participates actively in the pathogenesis of clinical uveitis. Our data emphasize the greater systemic than local participation of TNF-alpha. Finally, an elevated serum TNF-alpha seems to be associated with a recurrent pattern of uveitis.

[Aqueous humor and serum interleukin-6 in patients with uveitis]. / Interleucina-6 en humor acuoso y suero de pacientes con uveítis.

PURPOSE: A study on local and systemic behavior of interleukin-6 in patients with active uveitis. METHODS: IL-6 levels were measured in aqueous humor and peripheral blood samples using an enzyme-linked immunosorbent assay (ELISA) from 23 patients with uveitis and 16 control patients who had been operated for uncomplicated cataracts. RESULTS: Aqueous humor of patients with uveitis showed higher levels of interleukin-6 than those of controls (p<0.001). A comparison of cytokine levels between aqueous humor and serum from patients with uveitis showed significantly higher levels of interleukin-6 in aqueous than serum (p<0.001). Correlation studies using regression test for successive steps failed to demonstrate any association between interleukin-6 levels and the different clinical characteristics of uveitis patients (laterality, onset, patterns, visual damage, localization, inflammatory activity, etiology, and association with the B27 + histocompatibility antigen). CONCLUSIONS: IL-6 is a cytokine that actively participates in the pathogenesis of clinical uveitis. Our data emphasize the greater local than systemic participation of this cytokine.

Joint hypermobility in patients with fibromyalgia syndrome.

OBJECTIVE: To test the hypothesis that joint hyperlaxity can play some role in the pathogenesis of pain in primary fibromyalgia. METHODS: A total of 66 women with fibromyalgia (according to the 1990 American College of Rheumatology criteria) and 70 women with other rheumatic diseases were examined for joint laxity based on 5 criteria (The Non-Dominant Spanish modification). Individuals meeting 4 or 5 criteria were considered to be hyperlax. RESULTS: Joint hyperlaxity was detected in 18 (27.3%) of the patients with fibromyalgia and 8 (11.4%) of those with another rheumatic disorder. The statistical analysis revealed significant differences (P < 0.05) between both groups. CONCLUSION: The results of this study suggest that joint hypermobility and fibromyalgia are associated. Joint hyperlaxity may play a prominent role in the pathogenesis of pain in fibromyalgia.

Stereological analysis of the synovial membrane in rheumatic disorders: diagnostic value of volume-weighted mean nuclear volume estimation.

Quantitative evaluation of nuclear size of synoviocytes was performed on 48 synovial biopsies in various rheumatic disorders: osteoarthritis (n = 10), rheumatoid arthritis (11), and chronic non-specific synovitis (14). Thirteen tissue specimens from non-inflammatory synovial membrane were included as a control group. Using the point-sampled intercepts method, unbiased stereological estimates of volume-weighted mean nuclear volume (nuclear upsilon v) were obtained. A slight increase in nuclear volume was observed in osteoarthritis in comparison with the control group with an overlap in 90% of cases. However, in rheumatoid arthritis there was a significant increase of nuclear upsilon v. Significant differences were found between rheumatoid arthritis and the control and osteoarthritis groups (P < or = 0.001). In biopsies from patients diagnosed as chronic non-specific synovitis the averaged nuclear upsilon v values were between those in osteoarthritis and rheumatoid arthritis with a wide range of data. Similar, but less significant differences were demonstrated between rheumatic disorders when using mean nuclear area. Further analysis of chronic non-specific synovitis patients in combination with nuclear upsilon v estimates as a simple, unbiased, complementary tool are required to better establish the diagnostic value of nuclear stereology in the diagnosis of rheumatic disorders.

[The vascular risk factors in patients with adult ischemic necrosis of the femur head]. / Factores de riesgo vascular en pacientes con necrosis isquémica de cabeza femoral del adulto.

The authors studied 23 patients affected by ischemic necrosis of the femoral head, following a common standardised protocol, highlighting the habit (smoking and alcohol intake), lipids and biochemist parameters, as vascular risk factors to sufferers of this disease. They found that with the smoking habit, the high intake of lipids and the excess of alcohol ingestion were significant in the studied group. Neither obesity nor blood hypertension were significant. This supports the vascular etiology of ischemic necrosis of femoral head in adults.