Plasma pentraxin 3 in idiopathic inflammatory myopathies: a possible new biomarker of disease activity.

Pentraxin-3 (PTX3) is a component of humoral innate immunity with essential functions both in promotion and resolution of inflammation. We aimed to study the PTX3 in the plasma and in the muscle of patients with idiopathic inflammatory myopathies (IIM) and whether PTX3 may correlate with disease activity. Plasma PTX3 levels were assessed in 20 patients with IIMs, 10 dermatomyositis (DM), and 10 polymyositis (PM), compared to 10 patients with rheumatoid arthritis (RA) and 10 healthy donors (HDs) aged, sex, and body mass index matched. Disease activity in IIMs was assessed by Myositis Disease Activity Assessment Visual Analog Scale (MYOACT), while disease activity score on 28 joints (DAS28) was used for RA patients. Muscle histopathology and immunohistochemical (IHC) analyses were also performed. Mean plasma PTX3 levels were significantly higher in IIM patients than HDs (518 ± 260 pg/ml vs. 275 ± 114 pg/ml, P = 0.009). Linear regression analysis adjusted for age, sex, and disease duration showed a direct correlation between PTX3 and CPK levels (ß: 0.590), MYOACT (ß: 0.759), and physician global assessment of disease activity (ß: 0.832) in IIMs. No association between PTX3 levels and DAS28 was found in RA. Global PTX3 pixel fraction was higher in IIM than HDs muscle, but a lower PTX3 expression was found in perifascicular areas of DM and in myofibers with sarcolemmal staining for membrane attack complement. PTX3 plasma levels were increased in IIMs and correlated with disease activity suggesting a possible role as biomarker of disease activity. PTX3 showed a different distribution in DM or PM muscle.

Evidence-based algorithm for diagnosis and assessment in psoriatic arthritis: results by Italian DElphi in psoriatic Arthritis (IDEA).

Psoriatic arthritis (PsA) is a chronic inflammatory disease involving skin, peripheral joints, entheses, and axial skeleton. The disease is frequently associated with extrarticular manifestations (EAMs) and comorbidities. In order to create a protocol for PsA diagnosis and global assessment of patients with an algorithm based on anamnestic, clinical, laboratory and imaging procedures, we established a DElphi study on a national scale, named Italian DElphi in psoriatic Arthritis (IDEA). After a literature search, a Delphi poll, involving 52 rheumatologists, was performed. On the basis of the literature search, 202 potential items were identified. The steering committee planned at least two Delphi rounds. In the first Delphi round, the experts judged each of the 202 items using a score ranging from 1 to 9 based on its increasing clinical relevance. The questions posed to experts were How relevant is this procedure/observation/sign/symptom for assessment of a psoriatic arthritis patient? Proposals of additional items, not included in the questionnaire, were also encouraged. The results of the poll were discussed by the Steering Committee, which evaluated the necessity for removing selected procedures or adding additional ones, according to criteria of clinical appropriateness and sustainability. A total of 43 recommended diagnosis and assessment procedures, recognized as items, were derived by combination of the Delphi survey and two National Expert Meetings, and grouped in different areas. Favourable opinion was reached in 100% of cases for several aspects covering the following areas: medical (familial and personal) history, physical evaluation, imaging tool, second level laboratory tests, disease activity measurement and extrarticular manifestations. After performing PsA diagnosis, identification of specific disease activity scores and clinimetric approaches were suggested for assessing the different clinical subsets. Further, results showed the need for investigation on the presence of several EAMs and risk factors. In the context of any area, a rank was assigned for each item by Expert Committee members, in order to create the logical sequence of the algorithm. The final list of recommended diagnosis and assessment procedures, by the Delphi survey and the two National Expert Meetings, was also reported as an algorithm. This study shows results obtained by the combination of a DElphi survey of a group of Italian rheumatologists and two National Expert Meetings, created with the aim of establishing a clinical procedure and algorithm for the diagnosis and the assessment of PsA patients. In order to find accurate and practical diagnostic and assessment items in clinical practice, we have focused our attention on evaluating the different PsA domains. Hence, we conceived the IDEA algorithm in order to address PsA diagnosis and assessment in the context of daily clinical practice. The IDEA algorithm might eventually lead to a multidimensional approach and could represent a useful and practical tool for addressing diagnosis and for assessing the disease appropriately. However, the elaborated algorithm needs to be further investigated in daily practice, for evidencing and proving its eventual efficacy in detecting and staging PsA and its heterogeneous spectrum appropriately.

Two-year survival rates of anti-TNF-α therapy in psoriatic arthritis (PsA) patients with either polyarticular or oligoarticular PsA.

OBJECTIVES: To evaluate the 2-year drug survival rates of the tumour necrosis factor (TNF)-α blockers adalimumab, etanercept, and infliximab in psoriatic arthritis (PsA) patients with either oligoarticular (oligo-PsA) or polyarticular PsA (poly-PsA). METHOD: We studied a prospective cohort of 328 PsA patients with peripheral arthritis (213 with poly-PsA and 115 with oligo-PsA), beginning their first ever anti-TNF-α treatment with adalimumab, etanercept, or infliximab. The aim of the study was to evaluate the drug survival rates and possible baseline predictors at 2 years. RESULTS: After 24 months, persistence in therapy with the first anti-TNF-α blocker was not statistically different in the oligo-PsA (70.4%) and poly-PsA (65.7%) subsets. Predictors of drug discontinuation were female sex [hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.00-2.68, p = 0.04] and starting the therapy in years 2003-8 (HR 0.51, 95% CI 0.33-0.80, p = 0.003). In poly-PsA, the persistence of etanercept (68.3%) was significantly higher than that of adalimumab (51.9%, p = 0.01), whereas in oligo-PsA no significant difference was detected. In poly-PsA, the period 2003-8 was a negative predictor (HR 0.36, 95% CI 0.21-0.62, p = 0.0001) whereas in oligo-PsA female gender was a positive predictor of drug discontinuation (HR 2.08, 95% CI 1.02-4.24, p = 0.04). With regard to clinical outcomes, the best responses in terms of European League Against Rheumatism (EULAR) 'good' response or Disease Activity Score (DAS28) remission, crude or adjusted according to the LUND Efficacy indeX (LUNDEX), were seen in patients on etanercept or infliximab. CONCLUSIONS: Our study provides some evidence that anti-TNF-α drugs may perform differently in PsA, and that the analysis of clinical disease subsets may improve our knowledge and promote better management of PsA.

Influence of TNF-α inhibition on oxidative stress of rheumatoid arthritis patients.

The aim of this study was to assess circulating levels of reactive oxygen metabolites (ROMs) as a marker of oxidative stress in rheumatoid arthritis (RA) patients during an anti-tumor necrosis factor alpha (TNF-α) treatment. We enrolled 40 patients with RA (36 females; age 53 ± 13 yrs) treated with different subcutaneously administered TNF-α inhibitors. The oxidative status was determined on the basis of plasma samples taken before, at 24 and 52 weeks of the anti-TNF-α treatment. Hydroperoxide levels were measured using the d-ROMs test, a useful clinically proven oxidative stress marker. During the anti-TNF-α therapy, we observed a significant reduction in serum ROMs levels in RA patients from 33.2 ± 10 mg H2O2/L at baseline to 29.5 ± 7 and 29.3 ± 9 mg H2O2/L, at 24 and 52 weeks, respectively (p<0.05). We also identified a significant correlation between the oxidative stress status and the disease activity score on 28 joints/C-reactive protein and health assessment questionnaire disability index. The results of our study demonstrate that a good control of the disease with anti-TNF-α agents can reduce oxidative stress in RA patients. However, further studies of larger patient cohorts are needed to confirm these preliminary data.

Body mass does not affect the remission of psoriatic arthritis patients on anti-TNF-α therapy.

OBJECTIVES: There is evidence that fat tissue may influence the response to therapy in patients with arthritis. The aim of this study was to assess whether the body mass index (BMI) affects rates of clinical remission in patients with psoriatic arthritis (PsA) treated with anti-tumour necrosis factor (TNF)-α biological drugs. METHOD: We retrospectively studied 135 patients with active peripheral PsA (45 obese, 47 overweight, and 43 normal-weight). Baseline BMI was correlated with the clinical response to adalimumab, etanercept, or infliximab. After 36 months (median, range 6-79) of treatment, disease remission rates were assessed using the Disease Activity Score in 28 joints (DAS28) or the Simplified Disease Activity Index (SDAI). Possible predictors of clinical outcomes were assessed by multivariate analysis. RESULTS: At baseline, BMI was significantly correlated only with the Health Assessment Questionnaire (HAQ) score (r = 0.21, p = 0.02) and not with disease activity. BMI did not predict disease remission or changes in HAQ score following anti-TNF-α therapy. Obese patients showed a significantly higher HAQ score and took significantly lower doses of prednisone than normal-weight or overweight patients, but their disease remission rates on the DAS28 (37%) or the SDAI (21%) were not significantly different from those of the other two groups (44% and 21%, respectively), regardless of the TNF-α inhibitor prescribed. CONCLUSIONS: In our retrospective analysis, disease activity and clinical response to anti-TNF-α therapy in PsA do not seem to be affected by BMI. Further prospective studies are needed to confirm these preliminary results.

Repeated infusions of low-dose infliximab plus methotrexate in psoriatic arthritis: immediate benefits are not maintained after discontinuation of infliximab.

OBJECTIVE: To assess the long-term efficacy and tolerability of a therapy consisting of infliximab at low dosage plus methotrexate in patients with psoriatic arthritis (PsA). As a second objective, we assessed whether the improvement obtained after 54 weeks of infliximab could be maintained with methotrexate alone. METHODS: A group of 26 patients with peripheral PsA resistant to various DMARDs were treated with infliximab + methotrexate for 54 weeks. RESULTS: The clinical response after the induction period was constant and progressive, with a high percentage of patients achieving an ACR50 response. The ESR and CRP values also declined continuously and gradually, but only CRP returned to normal values. During the follow-up period after 54 weeks, infliximab was stopped and the improvement obtained lasted for 2-6 months. The secondary end point was not achieved, and an extension period was designed. Results at 78 weeks are presented. CONCLUSIONS: Open questions for treating patients with infliximab and methotrexate are the schedule and the length of the administration and how to preserve the improvement obtained after the drug discontinuation.

Increased Bcl-2/p53 ratio in human osteoarthritic cartilage: a possible role in regulation of chondrocyte metabolism.

OBJECTIVE: To determine whether Bcl-2, p53, and Fas/CD95 help to control cartilage metabolism. METHODS: Six normal and 14 osteoarthritic (OA) cartilage samples were examined, and two zones from each sample showing the least (Min) and most (Max) anatomical damage were selected. Chondrocytes were isolated by sequential enzymatic digestion and freshly processed. Bcl-2, p53, and Fas/CD95 expression was evaluated by immunofluorescence and FACS analysis; the cell cycle was analysed using propidium iodide, and chondrocyte proliferation assessed by [(3)H]thymidine incorporation. RESULTS: Intracellular levels of Bcl-2 were significantly higher in Max (27.5%) than in Min (21%, p<0.01) OA or normal chondrocytes (18.5%, p<0.01). Intracellular p53 expression was significantly decreased in Max (25.5%) compared with Min (37%, p<0.01) OA or normal cartilage (41.5%, p<0.05). Fas/CD95 receptor expression on surface chondrocytes did not significantly differ between OA and normal cartilage. Cell cycle analysis showed that the proportion of activated chondrocytes in the S phase was significantly higher in Max (69%) than in Min (49%) OA or normal cartilage (43%). The prevalence of proliferating chondrocytes progressively increased according to the degree of OA damage (mean (SEM) Min 1247 (260), Max 2423 (460), p<0.05). Chondrocyte [(3)H]thymidine uptake correlated positively with Bcl-2 (r(s) = 0.62, p = 0.009) and correlated inversely with p53 levels (r(s) = -0.55, p = 0.02). CONCLUSIONS: Bcl-2 and p53 play a part in apoptosis, but also help to regulate chondrocyte growth and differentiation. Whereas Bcl-2 promotes cell survival, p53 can arrest cell cycle. The data confirm that chondrocyte activity is enhanced in OA and suggest that the increased Bcl-2/p53 ratio sustains the metabolic boost of chondrocytes.

[The treatment of recurrent uveitis with TNF-alpha inhibitors]. / Il trattamento delle uveiti recidivanti con inibitori del TNFalfa.

OBJECTIVE: Uveitis is a severe manifestation of rheumatic diseases since it can lead to visual impairment and even blindness. Ocular involvement is frequently a clinical challenge because its occurrence often requires changes of the therapeutic strategy. There are growing evidence that tumor necrosis factor alpha (TNFalpha) inhibitors may be an effective treatment of refractory uveitis. Purpose of this study was to evaluate the efficacy and safety of TNFalpha blocking agents in patients with seronegative spondylo-arthropathies (SNSA) and Behcet disease (BD) associated relapsing uveitis. METHODS: Five consecutive patients with chronic or relapsing uveitis were prospectively studied. Two patients with SNSA had recurrent anterior uveitis and three patients had BD associated uveitis (one anterior, two posterior uveitis). All of the patients were taking systemic and topical corticosteroids and three of them were also treated with DMARDs (methotrexate, cyclosporine, sulphasalazine) without clinical benefit. Four patients received infliximab, an anti-TNFalpha monoclonal antibody, at a dosage of 5 mg/kg body weight and one patient was treated with etanercept, a TNFalpha receptor p75-Fc fusion protein, at a dosage of 25 mg twice weekly. RESULTS: Both infliximab and etanercept induced a marked improvement in uveitis and none relapse was observed throughout all the study. Systemic corticosteroids were progressively tapered and stopped in all patients. Also methotrexate and sulphasalazine were discontinued, while cyclosporine dose has been reduced by 30%. No side effects were observed. CONCLUSIONS: Therapy with TNFalpha blockers, infliximab and etanercept, was effective and safe in the treatment of rheumatic disease associated uveitis. A complete remission was achieved even in patients with severe steroid resistant uveitis. Further controlled studies on larger number of patients are needed to better define the different forms of ocular involvement that can benefit from the therapy with TNFalpha inhibitors.