Paola Frallonardo

Inflammatory osteoarthritis of the hand.

Inflammatory or erosive are terms used interchangeably to define a clinical subset of osteoarthritis of the hand (HOA), targeting interphalangeal joints and characterised by an abrupt onset, marked pain and functional impairment, inflammatory symptoms and signs, including stiffness, soft tissue swelling, erythema, paraesthesiae, mildly elevated C-reactive protein and a worse outcome than non-erosive HOA. This subset is defined radiographically by subchondral erosion, cortical destruction and subsequent reparative change, which may include bony ankylosis. Although the presence of both clinical and radiographic aspects are very suggestive for the diagnosis in most cases, doubts have been recently raised from some studies which, by means of sensitive imaging techniques such as magnetic resonance imaging (MRI) and sonography, had found erosive changes in most patients with HOA, including those without signs of erosions at conventional radiography. However, many findings suggest that subjects with erosive HOA exhibit more inflammatory features than those with non-erosive HOA in different ways, including clinical, laboratory and sonographic aspects. Thus, it is probably preferable to use the double term inflammatory/erosive to better define this particular subset of HOA.

Cytokine levels in human synovial fluid during the different stages of acute gout: role of transforming growth factor β1 in the resolution phase.

Objectives To determine the most relevant parameters in synovial fluid (SF) during the various stages of acute gout. Methods SFs from 38 gouty patients were analysed for white blood cell (WBC) count, percentage of polymorphonuclear cells (PMNs) and levels of interleukin 1β (IL-1β), IL-6, IL-8, tumour necrosis factorα (TNFα) and transforming growth factor β1 (TGFβ1). Patients were divided into three groups according to the length of time since onset of the attack: phase I (0–48 h), phase II (days 3–4) and phase III (days 5–7). Results Levels of WBCs were similar in SFs from phases I and II, while phase III showed the lowest WBC count. Percentages of PMNs were raised in all SFs. None of the cytokines analysed differed between phases I and II except for TGFβ1, which was higher in phase II. IL-1β, IL-6 and TNFα were higher in group 1 than in group 3. Levels of all the cytokines assessed, with the exception of TGFβ1, were significantly lower in phase III than in phase II IL-1β, p<0.05; IL-6, p<0.01; IL-8, p<0.001; TNFα, p<0.05).TGFβ1 levels were highest in SFs from phase III. Conclusion Cytokine levels in SFs may change depending on the different stages of acute gout, highlighting the role of TGFβ1 in the resolution of gout.

Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: A two-year prospective observational study

OBJECTIVE To evaluate the progression of subclinical atherosclerosis in Psoriatic Arthritis (PsA) patients treated with anti-tumor necrosis factor (TNF)-α agents. METHODS Thirty-two PsA patients classified according to the CASPAR criteria and attending the Rheumatology Unit of the University of Padua Medical Center were enrolled in a two-year prospective, observational study. In accordance with the ASAS/EULAR recommendations on the management of these patients, those studied were prescribed biological agents [etanercept (n=21), adalimumab (n=6), infliximab (n=5)]. Plasma lipids, inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), vessel endothelium growth factor (VEGF), osteoprotegerin (OPG), and TNF-α, as well as Disease Activity Score 28 calculated with CRP (DAS 28-CRP) were evaluated at baseline and after two years of treatment. Bilateral carotid B-mode ultrasound measurements [the mean-intima media thickness (mean-IMT), the mean maximum-IMT (M-Max)] of each carotid artery segment (common, bulb, and internal carotid artery) and the post-occlusion flow-mediated dilation (FMD) of the brachial artery were also assessed at baseline and after two years. RESULTS Despite an improvement in the DAS 28-CRP score (P<0.0005) and lower low-density lipoprotein cholesterol (P<0.013) and triglyceride (P<0.036) values, there was a significant progression in both the mean-IMT (P<0.0005) and M-Max (P<0.0005). Moreover, no recovery in FMD (P=ns) was observed after two years of anti TNF-α treatment. Serum TNF-α levels were increased (P=0.003) and OPG values were decreased (P=0.011) at the end of follow- up with respect to baseline values. CONCLUSIONS Despite improvement in clinical status, arterial remodelling was observed in the PsA patients who were treated with anti TNF-α agents for two years.

Coll2-1, Coll2-1NO2 and myeloperoxidase serum levels in erosive and non-erosive osteoarthritis of the hands

OBJECTIVE Erosive osteoarthritis of the hand (EHOA) is thought to be an aggressive variant of hand osteoarthritis (HOA) characterised by prominent local inflammation and radiographic aspects of bone erosions in interphalangeal (IP) joints. However, rare studies have until now investigated the value of biomarkers in these patients. Thus, we determined Coll2-1, a marker of type II collagen denaturation, its nitrated form (Coll2-1NO2) and myeloperoxidase (MPO) levels in serum of patients with EHOA vs non-EHOA and subsequently evaluated their relationships with disease indices of severity and activity. METHODS Coll2-1, Coll2-1NO2 and MPO were measured using specific immunoassays in 82 patients, 57 with EHOA, all females, median age 59 (41-74 yrs) and 20 with non-EHOA, all females, median age 55 (43-73 yrs), fulfilling the American College of Rheumatology (ACR) criteria for hand OA. EHOA was characterized by the presence of at least one central bone erosion on radiograph in the IP joints. Patients were also evaluated for disease duration, number of affected (swollen and painful or tender) joints, radiographic score (RS) by Kallman scale and high sensitivity C-reactive protein (hsCRP). RESULTS Serum levels of MPO were higher in EHOA (230.0 ± 152.1 ng/ml) than in non-EHOA (160.2 ± 111.5 ng/ml, P=0.037). Coll2-1NO2 levels trended towards an elevation in EHOA compared non-EHOA (0.40 ± 0.86 vs 0.22 ± 0.14 nmol/l, P=0.06), while Coll2-1 levels were not different. Correlations were found for disease duration and both MPO (R(2)=0.48, P=0.001) and Coll2-1NO2 (R(2)=0.73, P=0.01) after the splitting of the population in subgroups according to a cut off value above the 50th percentile. A correlation was found between hsCRP and MPO (R(2)=0.57, P=0.01). CONCLUSIONS This study clearly demonstrates an elevation of some serum biomarkers in EHOA, in comparison with non-EHOA. In particular, MPO, hsCRP and the ratio Coll2-1NO2/Coll2-1 discriminated the two subsets of hand osteoarthritis (HOA), and a trend was also observed for Coll2-1NO2. These data suggest that these biomarkers could be helpful for the diagnosis of EHOA.

Immunogenetic aspects of erosive osteoarthritis of the hand in patients from northern Italy.

Objectives: To compare the distribution of human leucocyte antigen (HLA) class I and II alleles in patients with erosive hand osteoarthritis (EHOA) to that of patients with non-erosive hand OA (non-EHOA) and in healthy Italian Bone Marrow Donors (IBMDs), in order to evaluate possible immunogenetic associations with EHOA. In the EHOA group we also sought possible associations between HLA alleles and disease severity. Methods: Ninety-four patients with EHOA (82 women, 12 men; mean age 61.4 ± 8.45 years) and 37 with non-EHOA (28 women, nine men; mean age 59.21 ± 9.07 years) were studied. Disease severity was measured by the number of clinically active joints (NCAJ) and by the radiographic score (RS) using the Kallman scale. HLA typing was undertaken for A, B, C, and DRB1 loci; HLA-DRB1* genotyping was determined using polymerase chain reaction (PCR) with sequence-specific primers. Frequencies were compared with those of the healthy IBMDs. Results: The alleles found more frequently in EHOA patients than in non-EHOA patients and healthy controls were: A23, A26, and A29; B38, B44, and HLA DRB1*01 and *07. The RS was more severe in the EHOA compared to the non-EHOA group (63.60 ± 23.14 vs. 34.34 ± 20.24, p < 0.001). Within the EHOA group, HLA-DRB1*07 was associated with a higher RS (67.36 ± 23 vs. 64.5 ± 18.5, p = 0.029). Conclusion: In this study of North Italian patients affected with EHOA, the HLA-DRB1*07 allele was found to be associated with both the development and greater severity of the disease.

Serological markers of erosive hand osteoarthritis

This review focuses on biomarkers in erosive hand osteoarthritis (EHOA), a subset of hand osteoarthritis (HOA), that primarily affects interphalangeal joints and is characterized by abrupt onset, severe pain and functional impairment, as well as signs of inflammation, in particular stiffness, swelling, erythema, paraesthesiae, and worse outcome. Inflammatory features and radiographic erosions are the main diagnostic hallmarks of this particular disease subset. As in other fields of OA, EHOA biomarkers can be classified as dry and soluble. Soluble biomarkers which are found in serum, synovial fluid and urine can be specific indicators of joint inflammation and degradation. With regard to inflammatory markers, C-reactive protein and myeloperoxidase have been found to be increased in EHOA, with respect to non-erosive HOA. All these markers have, moreover, been found to be correlated with disease activity. Another interesting marker linked to inflammation is hyaluronic acid, considered to be a marker of synovitis, which is frequently found in EHOA. The most useful cartilage markers in both erosive and non-erosive HOA, seems to be collagen (Coll) 2-1, Coll 2-1NO(2) and Col2-3/4C(short). Immunogenetic markers were also determined and an association between EHOA and a single nucleotide polymorphism on the gene encoding interleukin-1β was found in HLA and there was an increased frequency of HLA-B44 and HLA-DRB1*07 in EHOA.

Transcriptional network profile on synovial fluid T cells in psoriatic arthritis

The objective of the study was to quantify the transcriptional profile, as the main T cell lineage-transcription factors on synovial fluid (SF) T cells, in relation to SF cytokines and T cell frequencies (%) of psoriatic arthritis (PsA) patients. Reverse phase protein array was employed to identify interleukin (IL)-23Rp19-, FOXP3- and related orphan receptor gamma T (RORγt)- protein and Janus associated tyrosine kinases 1 (JAK1), signal transducer and activator and transcription 1 (STAT1), STAT3 and STAT5 phosphoproteins in total T cell lysates from SF of PsA patients. IL-1β, IL-2, IL-6, IL-21 and interferon (INF)-γ were measured using a multiplex bead immunoassay in SF from PsA patients and peripheral blood (PB) from healthy controls (HC). Frequencies of CD4+CD25−, CD4+CD25high FOXP3+ and CD4+CD25high CD127low Treg, and either mean fluorescence intensity (MFI) of FOXP3+ on CD4+ Treg or MFI of classic IL-6 receptor (IL-6R) α expression on CD4+CD25− helper/effector T cells (Th/eff) and Treg cells, were quantified in SF of PsA patients and in PB from HC by flow cytometry (FC). In PsA SF samples, IL-2, IL-21 and IFN-γ were not detectable, whereas IL-6 and IL-1β levels were higher than in SF of non-inflammatory osteoarthritis patients. Higher levels of IL-23R-, FOXP3- and RORγt proteins and JAK1, STAT1, STAT3 and STAT5 were found in total T cells from SF of PsA patients compared with PB from HC. Direct correlations between JAK1 Y1022/Y1023 and STAT5 Y694, and STAT3 Y705 and IL6, were found in SF of PsA patients. Increased proportion of CD4+CD25high FOXP3+ and CD4+CD25high CD127low Treg cells and brighter MFI of IL-6Rα were observed both on CD4+CD25high- and CD4+CD25− T cells in PsA SF. The study showed a distinctive JAK1/STAT3/STAT5 transcriptional network on T cells in the joint microenvironment, outlining the interplay of IL-6, IL-23, IL-1β and γC cytokines in the polarization and plasticity of Th17 and Treg cells, which might participate in the perpetuation of joint inflammation in PsA patients.

Anterior Chest Wall Involvement in Early Stages of Spondyloarthritis: Advanced Diagnostic Tools

Objective. Anterior chest wall (ACW) involvement is difficult to evaluate in patients with spondyloarthritis (SpA). Bone scan is sensitive to ACW involvement, while magnetic resonance imaging (MRI) detects early alterations in SpA. We compared the sensitivity and specificity of bone scans and MRI in assessing ACW in early SpA. Methods. Out of 110 patients with early SpA attending the Outpatient Rheumatology Unit Clinic of Padua University from January 2008 to December 2010, the 40 complaining of pain and/or tenderness [60% with psoriatic arthritis (PsA), 12.5% with ankylosing spondylitis, and 27.5% with undifferentiated SpA] underwent bone scans and MRI. Results. At clinical examination, sternocostoclavicular joints were involved in 87.5% on the right, 77.5% on the left, and 35% on the sternum. Bone scan was positive in 100% and MRI in 62.5% of these patients. Early MRI signs (bone edema, synovial hyperemia) were observed in 27.5%, swelling in 5%, capsular structure thickness in 37.5%, erosions in 15%, bone irregularities in 15%, osteoproductive processes in 12.5%, and osteophytes in 5%. A higher prevalence of Cw6, Cw7, B35, and B38 was found in 15%, 48%, 28%, and 12%, respectively, of the patients with PsA who had bone scans. Conclusion. Noted mainly in women, ACW involvement was frequent in early SpA. Both bone scans and MRI are useful in investigating ACW inflammation. Bone scans were found to have high sensitivity in revealing subclinical involvement, but a low specificity. MRI provides useful information for therapeutic decision making because it reveals the type and extent of the process. The significant associations of HLA-Cw6 and Cw7 with PsA could suggest that genetic factors influence ACW involvement.

Joint and bone assessment in hand osteoarthritis

Hand osteoarthritis (OA) is a common disease frequently affecting middle-aged women. Prevalence estimates for OA vary widely depending on the age and sex of the population studied, the assessment tools used, and the specific joint sites analyzed OA is characterized by the degradation of articular cartilage, subchondral bone changes and osteophyte formation at the joint margins leading to joint failure. The pathogenesis of the disease and its evolution are multifactorial involving biomechanical, metabolic, hormonal, and genetic factors. Moreover, the role of inflammation has recently been advanced as pivotal in OA onset and progression. In particular, an uncommon variant of hand OA, erosive hand OA, is characterized by inflammatory and degenerative interphalangeal proximal and distal joints. The diagnosis of different types of hand OA is centered on clinical and laboratory investigations which can distinguish the peculiar aspects of these forms. Joint and bone assessments in hand OA are widely studied but there is no agreement with regard to established parameters to make a definitive diagnosis. This report focuses on the laboratory and clinimetric assessments that can be used to distinguish hand OA subtypes and addresses the debatable association with low bone mineral density in osteoporosis.

Molecular mechanisms of pain in crystal-induced arthritis

Crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction triggered by the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals in articular and periarticular tissues. Severe, acute pain constitutes the most important clinical symptom in patients affected by these diseases. Pain along with redness, warmness, swelling, and stiffness in the affected joint arises abruptly in gout and disappears when the acute phase of the attack resolves. While an acute joint attack caused by calcium pyrophosphate crystals can mimic a gout flare, basic calcium phosphate crystal arthritis gives rise to a series of clinical manifestations, the most severe of which are calcific periarthritis, mostly asymptomatic, and a highly destructive arthritis known as Milwaukee shoulder syndrome, which is characterized by painful articular attacks. Pain development in CIA is mediated by several inflammatory substances that are formed after cell injury by crystals. The most important of these molecules, which exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord, are prostaglandins, bradykinin, cytokines (in particular, interleukin (IL)-1β), and substance P. The pharmacological treatment of pain in CIA is strictly associated with the treatment of acute phases and flares of the disease, during which crystals trigger the inflammatory response. According to international guidelines, colchicines, nonsteroidal anti-inflammatory drugs, and/or corticosteroids are first-line agents for the systemic treatment of acute CIA, while biologics, namely anti-IL-1β agents, should be used only in particularly refractory cases.