Nicola Pappone

Extraspinal manifestations of diffuse idiopathic skeletal hyperostosis

DISH is a condition characterized by calcification and/or ossification of soft tissues, mainly entheses, ligaments and joint capsules. Its prevalence increases with age and, therefore, DISH is a relatively common entity in the elderly. The classical site of involvement is the spinal column with right anterolateral soft tissue ossification being the most characteristic feature. However, DISH is not limited to the spine, and may affect multiple peripheral sites independently. Extraspinal entheseal ossifications are common and observing their isolated presence may lead to the diagnosis of DISH. Furthermore, hypertrophic or atypical OA observed in joints usually not affected by primary OA has frequently been reported in DISH. Several metabolic derangements and concomitant diseases have been suggested to be associated with DISH including obesity, increased waist circumference, hypertension, dyslipidaemia, diabetes mellitus (DM), hyperuricaemia, metabolic syndrome and an increased risk for cardiovascular diseases. Witnessing the present increase in lifespan, obesity, DM and metabolic syndrome in the Western population, the prevalence of DISH should be expected to rise. In order to increase the awareness for DISH, this review focuses on the extraspinal features of the condition.

The psoriatic arthritis cost evaluation study: a cost-of-illness study on tumour necrosis factor inhibitors in psoriatic arthritis patients with inadequate response to conventional therapy

Objective. To evaluate costs, benefits and cost–effectiveness of anti-TNF agents in PsA patients with inadequate response to conventional treatment. Methods. A total of 107 patients, from nine Italian rheumatology centres, with different forms of PsA were given anti-TNF treatment, mainly etanercept (87%). Information on resource use, health-related quality of life, disease activity, function and laboratory values were collected at baseline and through out the 12 months of therapy. Cost (expressed in euro 2007) and utility (measured by EuroQol) before and after anti-TNF therapy initiation were compared in order to estimate the incremental cost per quality-adjusted life year (QALY) gained, and cost–effectiveness acceptability curve was calculated. Results. At the end of 12 months, there was a significant increase in direct cost due to an increase of drug cost caused by TNF inhibitors that was only partially offset by the decrease in indirect cost. In the last 6 months of therapy, the direct cost increased by €5052, the cost for the National Health System (NHS) by €5044 and the social cost by €4638. However, a gain of 0.12 QALY resulted in a cost per QALY gained of €40 876 for the NHS and of €37 591 for the society. The acceptability curve showed that there would be a 97% likelihood that anti-TNF therapy would be considered cost-effective at willingness-to-pay threshold of €60 000 per QALY gained. Conclusion. Cost–effectiveness ratios are within the commonly accepted willingness-to-pay threshold. These results need to be confirmed in larger samples of patients.

Obesity and psoriatic arthritis: from pathogenesis to clinical outcome and management

PsA is an axial and/or peripheral inflammatory arthritis associated with psoriasis, included in the group of spondylarthritides. It has been suggested that PsA could be a systemic disease, involving even coronary arteries and the heart. An increased prevalence of vascular risk factors has been found in PsA subjects as compared with the general population and psoriatic subjects. Moreover, PsA patients exhibit an increased prevalence of liver steatosis, a marker of metabolic syndrome, and of obesity. Interestingly, many reports demonstrate that adipose tissue is metabolically active, representing a source of inflammatory mediators, known as adipokines. The latter include TNF-α, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1 (PAI-1), IL-6, leptin and adiponectin, leading to a pro-inflammatory status in obese subjects. This evidence supports the idea of obesity as a low-grade inflammatory disease. Accordingly, obesity might be associated with some rheumatic diseases. In particular, it seems to affect several features of PsA, such as its development, cardiovascular risk and clinical outcome. Recent data suggest that increased BMI in early adulthood increases the risk of PsA development in psoriatic patients, supporting a link between fat-mediated inflammation and joint involvement. Obesity may represent an additive cardio-metabolic risk factor in PsA subjects. Abdominal obesity may also determine an increased risk of not achieving minimal disease activity in PsA patients, highlighting the role of abdominal fat accumulation as a negative predictor of good clinical response to biologic agents. This review assesses the relationship between obesity and PsA according to the available literature.

Diffuse Idiopathic Skeletal Hyperostosis Prevalence in Subjects With Severe Atherosclerotic Cardiovascular Diseases

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of different entheseal sites. Several metabolic factors have been suggested to be involved in DISH development. We assessed the prevalence of DISH and its relationship to traditional vascular risk factors in a cohort of patients diagnosed with cardiovascular diseases.

Cardiovascular effects of Etanercept in patients with psoriatic arthritis: evidence from the cardiovascular risk in rheumatic diseases database.

Introduction: Many literature data support the possibility of an increased cardiovascular (CV) risk in psoriatic arthritis (PsA) patients compared with the general population. This cannot be entirely explained by the presence of traditional vascular risk factors. It has been suggested that inflammation may act synergistically with traditional vascular risk factors, thus contributing to the atherosclerotic process and to the increased CV risk. Areas covered: In order to evaluate the CV effects of the control of systemic inflammation by Etanercept, in the present study we analyze data recorded in the Cardiovascular Risk in Rheumatic Diseases study group database to perform a further analysis on the effects of Etanercept on primary hemostasis, secondary hemostasis and carotid subclinical atherosclerosis. Platelet reactivity is increased in patients with poorly controlled PsA. Among patients receiving Etanercept, those achieving minimal disease activity show a platelet reactivity comparable to healthy controls. Similarly, the anti-inflammatory effect of Etanercept is associated with a significant improvement of hemostatic and fibrinolytic parameters in PsA subjects, maximal changes being documented in patients achieving minimal disease activity. In addition, the treatment with Etanercept seems to be associated with a carotid intima-media thickness significantly lower as compared with matched patients receiving traditional disease-modifying anti-rheumatic drugs. Expert opinion: Our data can be suggestive of the reduction of the CV risk in patients with PsA treated with Etanercept.

Subclinical carotid atherosclerosis in patients with chronic obstructive pulmonary disease: a meta-analysis of literature studies

Abstract Background: Chronic obstructive pulmonary disease (COPD) patients have an increased cardiovascular (CV) morbidity and mortality. Common carotid intima-media thickness (CCA-IMT) and carotid plaques are surrogate markers of subclinical atherosclerosis and predictors of CV events. Methods and results: We performed a meta-analysis to evaluate the association between COPD and subclinical atherosclerosis. Studies evaluating the impact of COPD on CCA-IMT and on the prevalence of carotid plaques were systematically searched. Results: Twenty studies (2082 COPD patients and 4844 controls) were included, 12 studies with data on CCA-IMT (13 data-sets on 1180 COPD patients and 2312 controls) and 12 studies reporting on the prevalence of carotid plaques (1231 COPD patients and 4222 controls). Compared to controls, COPD patients showed a significantly higher CCA-IMT (mean difference [MD]: 0.201 mm; 95%CI: 0.142, 0.260; p < .001), and an increased prevalence of carotid plaques (Odds Ratio [OR]: 2.503; 95%CI: 1.333, 2.175; p < .0001). Meta-regression models showed a direct association between disease severity [as expressed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) class] and the difference in the risk of carotid plaques presence between COPD patients and controls. Conclusions: COPD is significantly associated with subclinical atherosclerosis. These findings may be useful to plan adequate CV prevention strategies. Key messages COPD patients show a higher CCA-IMT and an increased prevalence of carotid plaques compared with controls. A more severe pulmonary disease is associated with a higher prevalence of carotid plaques in COPD patients. Screening for subclinical atherosclerosis may be worthy in COPD patients to plan specific prevention strategies.

EMG Patterns in Robot Assisted Reaching Movements of Upper Arm

Variations in muscle activation, underlying improvements in muscle strength and muscle function, in response to training of patients with congenital or acquired brain injuries, are still poorly understood. Much better results in sensorimotor and cognitive processes are promised by the emerging robot-mediated therapy. One of the most interesting features of a robot-mediated therapy is the ability to quantify the performance of the rehabilitation tasks proposed to the patient. Although the shoulder is the most complex joint in the body, both as to freedom range and for the muscular-tendon structure, not so many commercial or research devices have been proposed to study its movements and no study has proposed a standardized, quantitative electromyographic assessment during robot-assisted reaching movements of the upper arm. This study aimed to develop a quantitative assessment of the electromyographic pattern of the arm’s muscles involved in reaching movements robot-assisted by means of indices used to describe effectively the main features of the pattern in four normal subjects and to implement rehabilitation strategies patients oriented. Each subject underwent the proposed motor task and EMG recording, repeating the trial three times; for a total of twelve reaching movements for each sequence. Number of EMG activations and deactivations recorded for each of the eight studied muscles are gathered. The proposed method effectively described the main pattern’s features in normal subjects.

Long Term Costs and Outcomes in Psoriatic Arthritis Patients Not Responding to Conventional Therapy Treated with Tumor Necrosis Factor Inhibitors: The Extension of Psoriatic Arthritis Cost Evaluation (PACE) Study

OBJECTIVES Poor information on long-term outcomes and costs on tumour necrosis factor (TNF) inhibitors in psoriatic arthritis (PsA) are available. Our aim was to evaluate long-term costs and benefits of TNF- inhibitors in PsA patients with inadequate response to conventional treatment with traditional disease-modifying anti-rheumatic drugs (tDMARDs). METHODS Fifty-five out of 107 enrolled patients included in the study at one year, completed the 5-year follow-up period. These patients were enrolled in 8 of 9 centres included in the study at one year. Patients aged older than 18 years, with different forms of PsA and failure or intolerance to tDMARDs therapy were treated with anti-TNF agents. Information on resource use, health-related quality of life (HRQoL), disease activity, function and laboratory values were collected at baseline and through the 5 years of therapy. Costs (expressed in Euro 2011) and utility (measured by EQ-5D instrument) before TNF inhibitor therapy and after 1 and 5 years were compared. RESULTS The majority of patients (46 out of 55; 83.6%) had a predominant or exclusive peripheral arthritis and 16.4% had predominant or exclusive axial involvement. There was a statistically significant improvement of the most important clinical variables after 1 year of follow-up. These improvements were maintained also after 5 years. The direct costs increased by approximately €800 per patient-month after 1 year, the indirect costs decreased by €100 and the overall costs increased by more than €700 per patient-month due to the cost of TNF inhibitor therapy. Costs at 5 year were similar to the costs at 1 year. The HRQoL parameters showed the same trends of the clinical variables. EQ-5D VAS, EQ-5D utility and SF-36 PCS score showed a significant improvement after 1 year, maintained at 5 years. SF-36 MCS showed an improvement only at 5 years. CONCLUSIONS The results of our study suggest that TNF blockers have long-term efficacy. The higher cost of TNF inhibitor therapy was balanced by a significant improvement of HRQoL, stable at 5 years of follow-up. Our results need to be confirmed in larger samples of patients.

Is diffuse idiopathic skeletal hyperostosis a disease or a syndrome? Need for studies on angiogenesis-stimulating activity

DISH is a common but often unrecognized systemic disorder mainly observed in the elderly. This condition is characterized by calcification and ossification of entheseal sites. At present, ossification and calcification of the antero-lateral aspect of the thoracic spine is considered to be the epidemiological hallmark of this condition. However, DISH is not limited to the spine and has been reported to involve also peripheral sites [1]. The clinical relevance of DISH is slowly being acknowledged as several symptoms have been shown to be related to this condition. DISH can be entirely asymptomatic or produce incarceration syndromes, spinal immobility, radiculopathy and myelopathy with the possibility of paraand tetraparesis, dysphagia and dysphonia, rhinolalia by irritation of the recurrent laryngeal nerve, reduced lung capacity and airway obstruction [2]. Furthermore, individuals with DISH have a significantly higher risk of spinal fractures after low impact trauma compared with individuals with a non-ankylotic spine [3]. The exact mechanisms that contribute to the new bone growth in patients with DISH, particularly in entheseal sites, are still under discussion. The high prevalence of DISH among medieval clergymen suggested the hypothesis that a monastic way of life could be a predisposition to DISH. Several recent studies have revealed a significant association between DISH and metabolic disorders, such as diabetes mellitus, hyperinsulinaemia, obesity, dyslipidaemia and hyperuricaemia [4], further supporting the hypothesis that the lifestyle of medioeval clergymen (large amounts of food, sedentary life) may have predisposed them to develop DISH. Although the pathogenesis of DISH is poorly understood, many authors have described the possible contributing role of mechanical stress, toxic factors and genetic factors. Moreover, changes in the Wnt, nuclear factor kappa B, bone morphogenetic protein 2, PGI2 and endothelin-1 signalling pathways have been also suggested to play a role in the development of DISH [5]. Overall, literature studies support the hypothesis that DISH is the result of an active process of new bone formation involving specific mediators and cells (heterotopic ossification), rather than a passive process in degenerating connective tissues (dystrophic calcification). In line with this theory, we believe that the process of new bone formation in entheseal regions of patients with DISH is determined by abnormal growth and activity of osteoblasts, with active bone remodelling, osteoblastic bone formation and osteoclastic bone resorption. The process of osteogenesis is induced and maintained by several growth factors that are not restricted to bone, such as insulin, insulin-like growth factor-1 and growth hormone [6]. However, if there is a systemic increase of these mediators, the open question is why the ossification process starts in certain sites and not in others. Literature evidence supports the hypothesis that angiogenesis is the key location factor of the ossification process in patients with DISH. Angiogenesis is important for osteoblast proliferation, thus playing a pivotal role in skeletal development and bone repair [7]. The intercellular signalling between vascular endothelium and bone cells is an essential part of the process of new bone formation. Endothelium is able to direct osteoclast and osteoblast precursors to specific areas through a complex intercellular signalling pathway, involving a plethora of mediators such as VEGF, basic fibroblast growth factor, TGF-b and PDGF. In addition, bone endothelial cells could be considered to display their own distinctive characteristics, with a capacity to respond to bone regulators such as cytokines, oestrogen and PTH [7]. Thus, an active process of heterotopic ossification with specific endothelial differentiation and subsequent bone cell migration could at least in part explain the process of new bone formation in patients with DISH. The high prevalence of DISH among patients with metabolic disorders may further support the crucial pathogenic role of angiogenesis. Growing evidence is emerging regarding the involvement of angiogenesis in metabolic syndrome-associated disorders, including visceral obesity, dyslipidaemia, diabetes and subclinical atherosclerosis [8]. Atherosclerosis is a systemic dysfunctional endothelial disease with chronic inflammation and fibroproliferation. Angiogenesis is the natural protective response to the ischaemic injury of the vessel wall, providing oxygen and metabolic support as the intima undergoes thickening, but at the same time contributing to plaque growth [8]. The important pathogenic role of angiogenesis in the atherosclerotic process of patients with metabolic disorders is established and could be considered the link between these disorders and DISH. Angiogenesis might be the common pathogenic background of several conditions included in the metabolic syndrome (e.g. carotid atherosclerosis, visceral obesity) and DISH could be identified as part of this syndrome. In keeping with this, high prevalence of aortic valve sclerosis, a recognized marker of atherosclerosis and an independent predictor of

Ankylosing Spondylitis and Posture Control: The Role of Visual Input

Objectives. To assess the motor control during quiet stance in patients with established ankylosing spondylitis (AS) and to evaluate the effect of visual input on the maintenance of a quiet posture. Methods. 12 male AS patients (mean age 50.1 ± 13.2 years) and 12 matched healthy subjects performed 2 sessions of 3 trials in quiet stance, with eyes open (EO) and with eyes closed (EC) on a baropodometric platform. The oscillation of the centre of feet pressure (CoP) was acquired. Indices of stability and balance control were assessed by the sway path (SP) of the CoP, the frequency bandwidth (FB1) that includes the 80% of the area under the amplitude spectrum, the mean amplitude of the peaks (MP) of the sway density curve (SDC), and the mean distance (MD) between 2 peaks of the SDC. Results. In severe AS patients, the MD between two peaks of the SDC and the SP of the center of feet pressure were significantly higher than controls during both EO and EC conditions. The MP was significantly reduced just on EC. Conclusions. Ankylosing spondylitis exerts negative effect on postural stability, not compensable by visual inputs. Our findings may be useful in the rehabilitative management of the increased risk of falling in AS.