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The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA. [ABSTRACT FROM AUTHOR]

Introduction: So far no clinical or experimental evidences clearly explain how and which systemic sclerosis (SSc) patients will experience a functional and radiological progression of interstitial lung disease (ILD). Objectives: The aim of the study was to investigate whether any bronchoalveolar lavage fluid (BALF) characteristic, compared with clinical, functional and radiological parameters, is associated with the risk of progression of ILD and worse survival in SSc patients. Methods: Lung involvement was evaluated in 110 consecutively examined SSc patients with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT); 73 patients with evidence of ILD on HRCT underwent BAL. The progression of ILD was evaluated with PFTs and HRCT after 1-year follow-up. A 36-month survival analysis was assessed. Results: ILD patients with alveolitis had a higher risk to have restrictive lung disease and honeycombing, to experience a worsening in honeycombing score or to develop honeycombing. ILD progression was associated with the evidence of honeycombing on HRCT, with the presence of eosinophils, with an inverted CD4/CD8 ratio and with a higher CD19 percentage count in the BALF or with a positive BALF microbiological culture. The patients with ILD had a worse overall survival. The diffuse disease was the only independent risk factor of overall mortality, and the extent of honeycombing on HRCT was the only independent risk factor of lung disease-related mortality. Conclusion: Our study suggests the importance of evaluating ILD with HRCT and BAL in order to characterize the risk factors of SSc lung involvement progression. Please cite this paper as: De Santis M, Bosello SL, Peluso G, Pinnelli M, Alivernini S, Zizzo G, Bocci M, Capacci A, La Torre G, Mannocci A, Pagliari G, Varone F, Pistelli R, Danza FM and Ferraccioli G. Bronchoalveolar lavage fluid and progression of scleroderma interstitial lung disease. Clin Respir J 2012; 6; 9-17. [ABSTRACT FROM AUTHOR]

Abstract: Sjögren''s syndrome (SS) is a chronic, inflammatory, autoimmune disease characterized by lymphocytic infiltration of the exocrine glands leading to qualitatively altered and diminished or absent salivary and lachrymal secretion, and by marked B-cell hyperreactivity. Many efforts have been made to define a panel of salivary and lachrymal markers helpful to design diagnostic tests able to replace blood tests and tissue biopsies for the diagnosis of primary and secondary SS. Several proteomic-based studies have indicated that a number of proteins and peptides can be considered SS biomarkers, being 2–3-fold up- or down-regulated compared to normal subject or having an exclusive presence in the saliva or tears of SS patients. Unfortunately, several factors make it difficult to define a comprehensive salivary and lachrymal panel of markers of SS, as the lack of a comprehensive proteomic analysis of human tears and saliva of healthy subjects, the lack of uniform protocols to collect and treat these samples, and the high grade of posttranslational modification of the proteins in these fluids. [Copyright &y& Elsevier]

Objective. To obtain the simplest definition of minimal disease activity (MDA) and to compare it with published proposed definitions of MDA in patients with RA.Methods. Two hundred and fourteen patients with long-standing RA (LSRA) were evaluated for clinical and laboratory parameters. Factor analysis was performed to remove redundant variables included in the core set measure for MDA definition stated by the OMERACT. Receiver operating characteristic (ROC) curves analysis allowed to obtain optimal cut-off predictors of a 28-joint disease activity score (DAS28) ⩽2.85. These were tested in 112 LSRA and 95 early-onset RA (ERA) patients.Results. Factor and ROC curve analysis showed that the best predictors of a DAS28 ⩽ 2.85 in LSRA cohort were: (i) ESR <20 mm/h (sensitivity: 80%, specificity: 54%); (ii) swollen joint count (out of 28) ⩽2 (sensitivity: 95%, specificity: 74%); (iii) patient global assessment (0–100) ⩽15 (sensitivity: 78%, specificity: 78%); and (iv) HAQ (0–3) ⩽0.5 (sensitivity: 91%, specificity: 61%). To each of these four criteria we assigned a value of 1 when it was satisfied (score ranging: 0–4). The cut-off with the highest overall accuracy for identifying RA patients with DAS28 ⩽ 2.85 was a score &geqslant;3. We adopted these four parameters in order to define the residual MDA (RMDA). Comparing RMDA criteria, in distinct 112 LSRA and 95 ERA patients, with OMERACT, Simplified Disease Activity Index and Clinical Disease Activity Index definitions of MDA, we found a good agreement in the LSRA cohort and moderate agreement in the ERA cohort.Conclusions. HAQ, PaGA, SJC28 and ESR allow identification of RA patients with an RMDA. The RMDA criteria behaves similarly to OMERACT definitions, but appears more simple and feasible. [ABSTRACT FROM PUBLISHER]

Objective: This study applied a synovitis score obtained during routine care from ultrasound (US)–guided biopsies of synovial tissue (ST) in patients with rheumatoid arthritis (RA) and patients with other inflammatory and noninflammatory joint diseases to identify pretreatment synovial biomarkers associated with disease characteristics, and to integrate the findings into a multiparameter nomogram for use in baseline prediction of diagnosis and treatment response in treatment‐naive rheumatoid arthritis (RA) patients. Methods: The study enrolled a total of 1,015 patients with various autoimmune diseases (545 patients with RA, 167 patients with psoriatic arthritis [PsA], 199 patients with undifferentiated peripheral inflammatory arthritis [UPIA], 18 patients with crystal‐induced arthritis, 26 patients with connective tissue diseases, and 60 patients with osteoarthritis [OA] [as part of the SYNGem cohort]). All patients underwent a US‐guided ST biopsy at baseline, and patients were then stratified according to disease phase. The KSS, along with disease characteristics and clinical outcomes, were incorporated into a nomogram for prediction of achievement of clinical remission in RA patients who were previously naive to treatment. In patients in whom a treat‐to‐target strategy was applied, remission was defined as change in the Disease Activity Score in 28 joints (DAS28) at 6 months after treatment initiation. Results: The KSS significantly differed among RA patients, as well as PsA patients and UPIA patients, when compared to OA patients. In RA, the KSS directly correlated with the DAS28 and was related to autoantibody positivity in treatment‐naive RA patients. Moreover, at baseline, treatment‐naive RA patients achieving 6‐month remission according to DAS28 had a lower KSS, shorter duration of symptoms (very early RA [VERA]), and lower disease activity than treatment‐naive RA patients not achieving remission according to DAS28. Results of logistic regression analysis identified the following synergistic predictive factors of achievement of DAS28‐based disease remission at 6 months: having a short disease duration (VERA), not having high disease activity, and having a KSS of <5 at baseline. A nomogram integrating these baseline clinical and histologic characteristics in treatment‐naive RA patients yielded an up to 81.7% probability of achieving 6‐month remission according to the DAS28. Conclusion: The KSS is a reliable tool for synovitis assessment on US‐guided ST biopsy, contingent on the phase of the disease and the autoimmune profile of each patient. This tool could be integrated within a therapeutic response–predictive nomogram for the prediction of treatment response in RA patients who were previously naive to treatment. [ABSTRACT FROM AUTHOR]

Objectives: Depression is commonly associated with psoriatic arthritis (PsA), but its risk factors in these patients are largely unrecognized. Pro-inflammatory cytokines involved in the pathogenesis of PsA have been associated with depression in patients without autoimmune diseases. The aim of this study was to establish whether PsA patients with and without depressive symptoms differed for general or clinical variables and serum cytokines milieu. Methods: One hundred and fifty consecutive patients with PsA were screened for depressive symptoms with Hospital Anxiety and Depression Scale (HADS-D). Patients with and without depressive symptoms were compared according to the prevalence of general risk factors for depression, comorbidities, PsA features and serum IL-6, TNF-α, and IL-17A. Results: Fifty-eight patient (38.7%) had a depressive mood. Depressive symptoms were associated with female sex (p = 0.03) and current smoking (p = 0.05). Patients with and without depressive symptoms did not differ for general risk factors for depression and comorbidities. Depressed patients had more frequently psoriatic nail disease (p = 0.02) and significant physical disability (HAQ-DI ≥ 0.5) (p < 0.01) and were more frequently in moderate or high disease activity according to DAPSA score (p = 0.01). Depressed patients had higher serum IL-6 (p < 0.01) and comparable serum IL-17A and TNF-α. A cutoff of 2.27 pg/ml of serum IL-6 had the best ability to predict an HADS-D ≥ 8 (AUC 0.666 ± 0.044; p < 0.01). Multivariate logistic regression analysis confirmed that serum IL-6 ≥ 2.27 pg/ml was independently associated with depressive symptoms (OR 3.5; CI 1.6–7.8; p < 0.01). Conclusions: Higher serum Il-6 is associated with depressive symptoms. This association suggests a direct role of systemic inflammation in the modulation of mood in PsA patients. Key Points • High PsA disease activity and physical disability are associated with depression. • Higher serum levels of IL-6 are independently associated with depression in PsA. • IL-6 might play a direct role in the development of depression in PsA patients. [ABSTRACT FROM AUTHOR]

The article presents a case of a 42-year-old female who was presented to a clinic for routine visit for her 15-year long psoriatic disease with skin, nail and joint involvement to discuss silent acro-osteolysis in psoriatic disease and recurrent micro-trauma.

Objective. The objective of this study was to determine whether BMI and gender could lead to a different response rate to anti-TNF agents in patients affected by axial SpA. Methods. One hundred and seventy patients with active axial SpA (defined as a BASDAI ≥4) treated with an anti-TNF agent [adalimumab (ADA), etanercept (ETA), infliximab (IFX)] were retrospectively evaluated. Patients were divided according to the baseline BMI as normal weight (BMI < 25), overweight (BMI 25–30) and obese (BMI ≥ 30). After 12 months of treatment a 50% improvement of the initial BASDAI (BASDAI50) was the primary end point and BASDAI ≤1 was the secondary end point. Results. After 12 months of anti-TNF treatment, 67.8% of men and 46.2% of women reached the BASDAI50 ( P = 0.01). According to BMI categories, the rate of BASDAI50 achievement decreased from 72.8% in normal weight subjects to 54.5% in overweight and 30.4% in obese subjects ( P < 0.001). In the logistic regression analysis, the best independent predictors of failure to obtain a BASDAI50 response at the 12th month of therapy in axial SpA patients were female gender [odds ratio (OR) 3.23 (95% CI 1.52, 7.14)] and a BMI ≥30 [OR 3.57 (95% CI 1.15, 11.11)]. Analysing outcomes based on IFX therapy (the larger subgroup), the BASDAI50 response rate fell from 79.0% in normal weight subjects to 56.7% in overweight and 16.7% in obese subjects ( P < 0.001). No significant differences were observed with ADA and ETA. Conclusion. Data suggest that being female, overweight and mostly obese is associated with a lower rate of success in obtaining response status in axial SpA patients treated with anti-TNF drugs. Body weight could represent a modifiable factor to reach the best outcome in axial SpA patients treated with TNF blockers. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine whether different subsets of B cells characterize synovial fluid (SF) or synovial tissue (ST) of seropositive or seronegative rheumatoid arthritis (RA) with respect to the peripheral blood (PB). PB, SF and ST of 14 autoantibody (AB)-positive (rheumatoid factor [RF]-IgM, RF-IgA, anti-citrullinated peptide [CCP]), 13 negative RA and 13 no-RA chronic arthritides were examined for B-cell subsets (Bm1-Bm5 and IgD-CD27 classifications), zeta-associated protein kinase-70 (ZAP70) expression on B cells and cytokine levels (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8 and monocyte chemotactic protein [MCP]-1). Synovial tissues were classified as aggregate and diffuse patterns. No differences were found in B-cell percentages or in subsets in PB and SF between AB+ and AB- RA and no-RA. In both AB+ and AB- RA (and no-RA), the percentage of CD19+/ZAP70+ was higher in SF than in PB (AB+: P = 0.03; AB-: P = 0.01; no-RA: P = 0.01). Moreover, SF of both AB+ and AB- RA (and no-RA) patients was characterized by a higher percentage of IgD-CD27+ and IgD-CD27- B cells and lower percentage of IgD+CD27- (P < 0.05) B cells compared to PB. In SF, ZAP70 positivity is more represented in B cell CD27+/IgD-/CD38-. The aggregate synovitis pattern was characterized by higher percentages of Bm5 cells in SF compared with the diffuse pattern (P = 0.05). These data suggest that no difference exists between AB+ and AB- in B-cell subset compartmentalization. CD27+/IgD-/ZAP70+ memory B cells accumulate preferentially in the joints of RA, suggesting a dynamic maturation of the B cells in this compartment. [ABSTRACT FROM AUTHOR]

Background: β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β4, β4 sulfoxide, and β10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. Methods: β-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. Results: Thymosin β4, β4 sulfoxide, and β10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β4 levels seem to have a protective role against lung tissue damage. Thymosin β4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. Conclusions: We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status. [ABSTRACT FROM AUTHOR]

Background: b-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β4, β4 sulfoxide, and β10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. Methods: β-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. Results: Thymosin β4, β4 sulfoxide, and β10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β4 levels seem to have a protective role against lung tissue damage. Thymosin β4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. Conclusions: We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status. [ABSTRACT FROM AUTHOR]

Abstract: We analyzed peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 16 rheumatoid arthritis (RA), 9 spondyloarthritis (SpA), 3 microcrystal arthritis patients, to define the presence of Th17 and Th1 and their relationship with inflammatory activity, and TCR-zeta chain and ZAP-70 levels. Th17 were significantly higher in SF than in PB and more abundant in microcrystal arthritis patients compared to the other groups. Irrespectively of the diagnosis, SF Th17 percentages correlated with joint (SF total leukocyte count, neutrophil percentage) and systemic (C reactive protein [CRP], fibrinogen, erythrocyte sedimentation rate) inflammation markers. SF Th1 percentages directly correlated with inflammation and disease activity (CRP, swollen joint count [SJC]) indices in SpA, but not in RA patients. These observations support the role of Th17 in the pathogenesis of inflammatory arthritides. The TCR-zetadim lymphocytes in SF were found to produce the highest amounts of cytokines including IL-17, whereas no ZAP-70 impairment was associated to Th17. [ABSTRACT FROM AUTHOR]

Background: The goal of our study was to evaluate the diagnostic performance of the anti-cyclic citrullinated peptide 2 (anti-CCP2) assay in patients with autoimmune and inflammatory disorders. Methods: We tested the specificity and sensitivity of anti-CCP2 antibodies measured by ELISA in 787 patients with rheumatoid arthritis (RA), 1024 patients with other autoimmune/inflammatory rheumatic disease and 401 subjects without autoimmune rheumatic disease. The optimal cut-off value was defined as the value with the highest diagnostic accuracy (receiver operating characteristic curve analysis). Interval-specific likelihood ratios (LRs) were calculated for each range bounded by defined anti-CCP2 values. Results: To distinguish between patients with RA and controls, the cut-off value with the highest diagnostic accuracy for anti-CCP2 was 2.8 U/mL. Comparing the optimal cut-off value for anti-CCP2 to that recommended by the manufacturer (5.0 U/mL), an increase in prevalence between the proportions of test-positive patients was found for RA, undifferentiated connective tissue disease and undifferentiated arthritis. Evaluating interval-specific LRs for the selected ranges bound by two anti-CCP2 values, in RA and diseased controls, the LRs were 0.40 for values <5.0 U/mL, 6.66 for 5.0–15.0 U/mL, 27.01 for 15.1–30.0 U/mL and 28.89 for >30.0 U/mL. Conclusions: The cut-off value of 2.8 U/mL for anti-CCP2 has the highest diagnostic accuracy. A value of anti-CCP2 >15 U/mL is associated with an increase in the likelihood of RA disease. Clin Chem Lab Med 2010;48:829–34. [ABSTRACT FROM AUTHOR]

Background: β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β4, β4 sulfoxide, and β10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters.Methods: β-thymosins concentrations were determined by reverse phase-high performance liquid chromatography-electrospray-mass spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls.Results: Thymosin β4, β4 sulfoxide, and β10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β4 levels seem to have a protective role against lung tissue damage. Thymosin β4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis.Conclusions: We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status. [ABSTRACT FROM AUTHOR]