Francesca Bartoli

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study

Objective To evaluate the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy. Methods 20 patients with SSc with refractory polyarthritis and seven with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept. All patients with SSc-myopathy received abatacept. Clinical and biological assessments were made at the start of treatment and at the last infusion. Results After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response. Treatment was stopped in two patients because of inefficacy. After 11 months’ treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria. Abatacept did not improve muscle outcome measures in SSc-myopathy. No significant change was seen for skin or lung fibrosis in the different groups. Both treatments were well tolerated. Conclusions In this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc. No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria. Larger studies with longer follow-up are warranted to further determine the safety and effectiveness of these drugs in SSc.

Flow‐Mediated Vasodilation and Carotid Intima‐Media Thickness in Systemic Sclerosis

Abstract:  Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow‐mediated vasodilation (FMD) and carotid intima‐media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high‐resolution B‐mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41%± 4.56% versus 7.66%± 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 ± 0.29 mm versus 0.77 ± 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.

Early Atherosclerosis and Autoantibodies to Heat‐Shock Proteins and Oxidized LDL in Systemic Sclerosis

Abstract:  Autoimmune diseases are characterized by enhanced atherosclerosis. Humoral immune responses to mycobacterial HSP‐65, human HSP‐60, and to oxLDL have been established in a number of human autoimmune diseases and are considered to be associated with atherosclerosis. The aim of this study was to evaluate carotid artery intima‐media thickness (IMT) in patients having systemic sclerosis (SSc) and to find out whether early atherosclerosis is associated with these autoantibodies. Forty‐four patients having SSc underwent clinical evaluation and carotid artery IMT measurement. Several autoantibodies were tested among patients and a control group. The antibodies against human HSP‐60 were measured by antihuman (IgG/IgM) HSP‐60 ELISA kit. IgGs and IgMs antimycobacterial HSP‐65 were determined using an ELISA with mycobacterial recombinant HSP‐65 antigens. Similarly, anti‐oxLDL antibodies were measured by an ELISA kit. Abnormal IMT levels were significantly more common in SSc patients compared with control subjects. Age was found as the sole most significant clinical parameter associated with carotid artery IMT in SSc. Disease duration, type of SSc, lung function tests, and cardiovascular risk factors were not associated with IMT in these patients. Levels of HSP‐60, HSP‐65, and oxLDL autoantibodies were similar among patients compared with controls, and in patients having “positive” IgM anti‐HSP‐65, higher IMT values were found. Abnormal carotid IMT is more prevalent in SSc than in normal subjects. Age rather than other clinical parameters is associated with early atherosclerotic changes in SSc. Autoantibodies to oxLDL, HSP‐60, and HSP‐65 are not elevated in SSc and there is only a borderline association with carotid artery IMT.

Digital ulcers as a sentinel sign for early internal organ involvement in very early systemic sclerosis

OBJECTIVE The aim of this study was to evaluate the presence of digital lesions in very early diagnosis of SSc (VEDOSS) patients and its possible association with internal organ involvement. METHODS One hundred and ten VEDOSS patients were investigated for the presence of digital ulcers (DUs), digital pitting scars, calcinosis, necrosis or gangrene, nailfold videocapillaroscopic abnormalities, disease-specific autoantibodies (ACA and anti-topo I) and internal organ involvement. RESULTS Four patients reported a history of digital pitting scars, while 25 patients presented an active DU or reported a history of DUs. In particular, 16 patients presented with active DUs (14/16 also reporting a history of previous DUs), while the other 9 patients reported a history of DUs only. A statistically significant association between DUs and oesophageal manometry alteration was found in the whole DU population, as well as in the history of DU and the presence of active DU with/without a history of DU subgroups (P < 0.01, P = 0.01 and P < 0.05, respectively). DUs were observed in VEDOSS patients with internal organ involvement but not in those without organ involvement. CONCLUSION DUs are already present in VEDOSS patients characterized by internal organ involvement, significantly correlating and associating with gastrointestinal involvement. DUs may be a sentinel sign for early organ involvement in VEDOSS patients.

Reduced circulating levels of angiotensin-(1–7) in systemic sclerosis: a new pathway in the dysregulation of endothelial-dependent vascular tone control

Objective: Systemic sclerosis (SSc) impairs endothelium-dependent vasodilatation. Among angiotensin I (Ang I)-derived compounds, vasoconstrictor angiotensin II (Ang II) and vasodilator angiotensin-(1–7) (Ang-(1–7)), cleaved from ACE and neutral endopeptidase (NEP) 24.11, respectively, play an important role in vascular tone regulation. Ang-(1–7) may act independently or by activating other vasodilating molecules, such as nitric oxide (NO) or prostaglandin I2 (PGI2). Our aim was to assess, in patients with SSc, circulating levels of Ang I, Ang II and Ang-(1–7), with their metabolising enzymes ACE and NEP, and levels of NO and PGI2, and to correlate them to the main characteristics of SSc. Methods: Levels of Ang I, Ang II, Ang-(1–7), NEP, ACE, NO and PGI2 were measured in 32 patients with SSc, who were also assessed for humoral and clinical characteristics, and 55 controls. Results: Plasma Ang I, Ang II and Ang-(1–7) levels were lower in patients with SSc than in controls (p<0.001in all cases). When Ang II and Ang-(1–7) levels were expressed as a function of the available Ang I, lower Ang-(1–7) levels in patients with SSc than in controls were confirmed (p<0.001), while no difference was found for Ang II levels. In patients with SSc, the Ang II/Ang-(1–7) ratio indicated a prevalence of Ang II over Ang-(1–7), while in controls Ang-(1–7) was prevalent (p<0.001). Levels of ACE, NEP, NO and PGI2 were lower in patients with SSc than in controls (p<0.05 in all cases). Conclusion: In patients with SSc, prevalence of the vasoconstricting Ang II over the vasodilator Ang-(1–7) suggests a dysfunction of the angiotensin-derived cascade that may contribute to dysregulation of vascular tone.

Therapeutic challenges for systemic sclerosis: facts and future targets.

Abstract:  Pulmonary arterial hypertension (PAH) is an important cause of death in systemic sclerosis (SSc), despite the improvement of therapies. An early diagnosis and the use of drugs interfering with the main pathogenic pathways of PAH is pivotal for the improvement of prognosis in primary PAH and PAH secondary to autoimmune rheumatic diseases, mainly SSc. Lately, new specific therapies have been developed targeting prostacyclin, endothelin, and nitric oxide pathways, the major pathogenic pathways leading to endothelial dysfunction in PAH. Epoprostenol improved life expectancy of patients with primary and secondary PAH, but its continuous intravenous administration requires experienced centers. More stable analogues of prostacyclin, administrated by intravenous (iloprost, treprostinil), subcutaneous, inhalatory (treprostinil, iloprost), and oral route (Beraprost) have shown efficacy in PAH. Bosentan, the first oral endothelin receptor antagonist (with affinity for endothelin A and B receptors) improves exercise function and survival in PAH, both primary and secondary to autoimmune rheumatic diseases. This is confirmed also for Sitaxsentan and Ambrisentan, selective A receptor antagonists. Because of its short half‐life and systemic side effects, short‐term NO inhalation is used only in short‐term management of PAH in critically ill adults. Inhibitors of NO degradation, such as sildenafil, a phosphodiesterase (PDE) type 5 inhibitor, improved functional and hemodynamic parameters without significant side effects. Vardenafil and taladafil, longer‐acting PDE inhibitors, also have vascular pulmonary selectivity. All these drugs may be used in combination, to maximize their clinical benefit not only in patients unresponsive to single drugs, but also potentially as initial therapy of PAH.

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist

Objective. To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice. Methods. Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected. Results. The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75–259.28; p < 0.001). Conclusion. Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.

Calcinosis in systemic sclerosis: subsets, distribution and complications

OBJECTIVE To retrospectively analyse the features of calcinosis in a cohort of SSc patients. METHODS Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded. RESULTS In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal. CONCLUSION Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications.

A large rheumatoid nodule mimicking hepatic malignancy

Approximately 40% of patients with rheumatoid arthritis (RA) suffer from extra-articular manifestations [1], including appearance of rheumatoid nodules. These are found predominantly along the extensor surfaces of the forearm and the elbow, and less often, in visceral organs [2]. This article is protected by copyright. All rights reserved.

THU0641-HPR The Challenge of Pet Therapy in Rheumatology: Evidence for The Improvement of Patients Compliance in Systemic Sclerosis

Background “Pet Therapy”, better defined as Animal-assisted Intervention (AAI), is based on the interaction between animal and human being and is a tool which may complement and support traditional therapies. It can be used on patients affected by different diseases, improving their quality of life from behavioral, physical and psychosocial point of view. Objectives The aim of our study was to evaluate the effect of AAI in improving quality of life and compliance to standard pharmacological treatment in a cohort of Systemic Sclerosis (SSc) patients. Methods 42 SSc patients attending at Scleroderma Unit and undergoing iloprost intravenous infusion were divided in three groups: 1) 14 SSc patients (mean age 60.4±8.6 yrs) submitted to 20 AAI sessions with a professional team (doctor, nurse, couple of animal-handler); 2)control (C1) 14 SSc patients (mean age 63.4±5.3 yrs) engaged in alternative social activity as create a cookbook; 3)control (C0) 14 SSc patients (mean age 62.3±6.8 yrs) without any alternative activity. All patients underwent psychological evaluation at baseline (t0) and at the end of project of AAI (t1); moreover the following test (italian standardized version) was performed at the beginning (s0) and at the end (s1) of each single session: General Anxiety State-Trait Anxiety Inventory (STAI-T), Beck Depression Inventory (BDI), Social Interaction Anxiety Scale (SIAS), Eysenck Personality Questionnaire-Revised (EPQ-R), the Social Phobia Scale (SPS), the Toronto Alexythymia Scale (TAS-20), the Thought Control Questionnaire (TCQ), the Visual Analog Scale (VAS), the State-anxiety (STAI-S). Results At the end of each session, AAI group showed a decrease of the anxiety state level while it was higher in the two control groups (ps<0.001). VAS scale resulted lower both in AAI group (p<0.001) and in C1 group (p<0.01). Moreover, STAI-T and TAS scores were significantly reduced in AAI group at t1 compared to t0 and to both control groups (ps<0.001). No significant differences were found for depression in the BDI scores at the end of all sessions. TCQ scale showed that patients treated with AAI, compared to control group C0, had greater capacity to avoid unpleasant and unwanted thoughts by using positive distraction strategies (p<0.05).The EPQ-R test (used for analyze personality traits, such as extraversion/introversion) revealed in AAI group an enhancement of extroversion trait compared to both C1 and C0 (p<0.05). Conclusions In agreement with literature [1], our work showed that AAI might be a crucial tool to support the traditional therapies thanks to the creation of a different relationship between patient and doctor. This may allow a better compliance to the therapy in a chronic disease like SSc, where patients compliance is usually low. References Matuszek S. Animal-facilitated therapy in various patient populations: systematic literature review. Holist Nurs Pract. 2010 Jul-Aug;24(4):187–203. Disclosure of Interest None declared