L. Carli

Thyroid Cancer in Systemic Lupus Erythematosus: A Case-Control Study

CONTEXT Although advances in treatment have permitted patients with systemic lupus erythematosus (SLE) to live longer, the rates of several types of cancers in these patients appear to be increasing. OBJECTIVE We used a prospective study to investigate the prevalence and features of thyroid cancer in SLE patients. DESIGN AND PATIENTS The prevalence of thyroid cancer in 153 unselected SLE patients was compared with that in two population-based, gender- and age-matched control groups: 1) 459 subjects from an iodine-deficient area (iodine-deficient control) and 2) 459 subjects from an iodine-sufficient area (iodine-sufficient control). Thyroid function was assessed by measuring circulating thyroid hormones and autoantibodies, thyroid ultrasonography, and where necessary, fine-needle aspiration cytology. MAIN OUTCOME AND RESULTS The levels of circulating TSH, and anti-thyroglobulin and anti-thyroperoxidase antibodies were significantly higher in SLE patients (P < 0.001 for all). In addition, patients with SLE also exhibited a higher prevalence of hypothyroidism (P < 0.001). Five cases of papillary thyroid cancer were detected among SLE patients, whereas no cases were observed among iodine-deficient controls (P = 0.001), and only one case was observed among iodine-sufficient controls (P = 0.001). Among SLE patients with confirmed thyroid cancer, 80% showed evidence of thyroid autoimmunity, whereas only 31% of SLE patients without thyroid cancer exhibited evidence of thyroid autoimmunity (P = 0.02). CONCLUSIONS These data suggest that the prevalence of papillary thyroid cancer in SLE patients is higher than in age-matched controls, particularly in patients with thyroid autoimmunity. Consequently, careful thyroid surveillance is recommended during the follow-up of these patients.

Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus

Osteoporosis (OP) and fragility fractures (FFx) are a known comorbidity in patients with systemic lupus erythematosus (SLE). This work aimed at evaluating (1) the prevalence of OP and FFx in a cohort of SLE and (2) the risk factors associated with both OP and FFx. The following data were collected from clinical charts: age, sex, menopausal status (MP), body mass index, smoking habits, disease duration, daily dose and cumulative glucocorticoids (GCs), type of organ involvement, comorbidities and medications. Data on bone metabolism, calcium and vitamin D supplementation and treatment with bisphosphonates, teriparatide or denosumab were collected, together with bone mineral density (BMD) values (measured by dual-energy X-ray absorptiometry (DXA)) and history of FFx (occurred after the onset of SLE and unrelated to trauma). OP and reduced BMD were defined according to the WHO. 186 patients were included (women 175, men 11; mean age 46.4±13 years, mean disease duration 14.9±9 years). At their last visit, 97 patients (52.2%) had a reduced BMD and 52 (27.9%) had OP. 22 patients (11.8%), all women, had at least one FFx; six patients (27.3%) were pre-menopausal. On univariate analysis, age, cumulative dose of GC, MP, therapy with antiepileptics and chronic renal failure (CRF) were correlated with OP (p<0.03); age, total amount of GC, MP, CRF, anticoagulants (AC) and antiepileptic therapy were correlated with FFx (p<0.05). The multivariate logistic model confirmed a direct association of OP and age, MP and antiepileptic therapy (p≤0.01) and of FFx and age, chronic therapy with AC and antiepileptics (p<0.03). In conclusion, low BMD is frequently observed in SLE, and FFx are observed also in premenopausal patients. Together with traditional risk factors (age, MP and GC), CRF and chronic treatments with AC or antiepileptics seem to be associated with a higher risk profile for OP and FFx occurrence.

Sleep disorders and systemic lupus erythematosus.

Objective Sleep disturbances are often seen in rheumatic diseases, including systemic lupus erythematosus (SLE). However, the prevalence of sleep disorders in SLE as well as the contributing factors to their occurrence remain poorly understood. The aim of this paper is to review the clinical and psychobiological data on the relationship between sleep disturbances and SLE. Method We performed a systematic search of MEDLINE, EMBASE and PsychINFO, using MeSH headings and keywords for “sleep disorders” and “SLE.” Results Nine studies reporting the relationship between sleep disorders and SLE were found. Prevalence rates of sleep disorders ranged between 55% and 85%; differences in assessment techniques appeared to be a major source of this variability. In the majority of the studies an association between sleep disorders and disease activity, pain and fatigue has been reported. Psychosocial variables, depression, steroid use, and the role that sleep disruption has on pain, inflammation and cytokines, have been hypothesized as possible psychobiological factors. Conclusions Sleep disorders appear to occur in more than half of patients with SLE and appear to be associated with disease activity. Pain and fatigue are also related to sleep disorders. Among the hypotheses on the possible mechanisms underlining the association between sleep disorders and SLE, psychosocial/psychological factors, especially depression, were the most frequently reported.

The role of imaging in the evaluation of joint involvement in 102 consecutive patients with systemic lupus erythematosus

OBJECTIVE To assess the prevalence of joint involvement in consecutive patients with systemic lupus erythematosus (SLE) by means of clinical assessment, joint US and MRI and to evaluate the sensitivity and specificity of physician evaluation of joint involvement. METHODS At enrollment, patients underwent a complete physical examination including a 44-joint count, and hand deformities were scored. On the day of enrollment, each patient underwent a non-dominant hand-wrist ultrasound (US) examination and a non-dominant hand-wrist MRI study without contrast injection. RESULTS One hundred and two patients (F 95, M 7) were enrolled. By physician examination hand or wrist involvement was diagnosed in 23.5%. At least one pathological finding was revealed by US examination at wrist and/or hand joints in 55%. We found a low sensitivity (46.5%) with high specificity (93.2%) of the physician assessment for the evaluation of joint involvement. The MRI imaging showed at least one erosion in 47.3% patients at the hand and in 98.9% at the wrist; in healthy subjects erosions were found in 19.6% and 97.8% at the hand and wrist, respectively. CONCLUSIONS In conclusion, (i) physicians tend to underestimate the severity of joint involvement in SLE; (ii) US assessment shows a high prevalence of joint and tendon involvement; and (iii) the MRI evaluation shows a high prevalence of damage, suggesting that joint involvement in SLE could be more severe than expected.

TNF-alpha inhibitors in Systemic Lupus Erythematosus. A case report and a systematic literature review

Abstract Joint involvement is a common manifestation of systemic lupus erythematosus (SLE) and is described as a non-erosive mild synovitis. However some SLE patients may present a more severe joint involvement requiring aggressive therapy. We describe the case of a SLE patient with a severe arthritis unresponsive to methotrexate, successfully treated with anti-TNF-alpha drug as induction therapy and we report the results of a systematic literature review on the use of TNF-alpha inhibitors in SLE.

Occurrence of organ-specific and systemic autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases: report of data obtained through direct patient interviews.

Studies have demonstrated a familial aggregation of systemic and organ-specific autoimmune diseases. The aim of the present survey was to obtain, by patient interviews, a preliminary estimate of the prevalence of systemic and organ-specific autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases (CTD) or inflammatory arthritis followed at our unit. Between June 2007 and January 2008, 626 patients and 85 controls (patients with osteoarthritis, osteoporosis, or fibromyalgia) were interviewed. Three hundred ten patients (50%) versus 21 controls (25%) were found to have at least one relative affected with an autoimmune condition (p < 0.0001). The most common conditions were organ-specific autoimmune diseases: 160 (34%) autoimmune thyroid (AT) disease, 112 (24%) psoriasis, 21 vitiligo, and 19 insulin-dependent diabetes mellitus. Systemic autoimmune diseases were reported in 126 relatives: rheumatoid arthritis (66 cases, 14%), 16 sacroileitis, and CTD (43 cases). A significant difference was observed in the prevalence of AT disease between the relatives of the patients and controls (3% versus 0.5%). In conclusion, these data confirm the high prevalence of autoimmune conditions, particularly of AT disease, among the relatives of patients.

The promising role of lung ultrasound in systemic sclerosis

Ultrasound (US) has an emergent and relevant role in the assessment of systemic sclerosis (SSc) even if there are many fields and applications that still have not been sufficiently explored. In this review, we will report an update of the available data regarding the use of US in lung involvement that might cause disability and mortality in SSc patients. Lung US does not employ ionizing radiation and is more rapid and less expensive than traditional high-resolution tomography (HRCT). Furthermore, recent initial studies have demonstrated that US scores correlated to HRCT and functional respiratory test results in SSc interstitial lung disease. The research agenda for the future should include a more profound investigation of its specificity (comparison with healthy subjects and other diseases) and sensitivity to change at follow-up, to adequately disseminate its use in daily practice and clinical trials.

Treatment with Allogenic Mesenchymal Stromal Cells in a Murine Model of Systemic Lupus Erythematosus

Objective Pre-clinical and uncontrolled studies in patients with systemic lupus erythematosus (SLE) showed that mesenchymal stromal cells (MSCs) have a potential therapeutic role in refractory cases. The optimal therapeutic strategy in these patients remain to be elucidated. Our aim was to test the hypothesis that repeated administrations of 1×106/kg body weight of allogenic MSCs, that is a significantly lower dosage with respect to the fixed 1×106 MSC used in animal models, can be effective in improving the clinical course of a murine SLE model. Methods Bone marrow derived MSCs were obtained from 12-week-old C57BL/6J mice. Seventy-five 8 weeks old female NZ mice were randomly assigned to receive via caudal vein the following alternative treatments: 1) single infusion of 106 MSCs/kg body weight at 18 weeks of age (NZs18) or at at 22 weeks of age (NZs22); 2) multiple monthly infusions of 106 MSCs/kg body weight starting at 18 weeks of age (NZM18) or at 22 weeks of age (NZM22); 3) saline infusions (NZc) Fifteen 8 weeks old C57BL/6J mice (Envigo, Huntingdon, UK) were used as untreated controls (C). Weekly, body weight was recorded and twenty-four hour urines were collected by metabolic cages for each animal; proteinuria was detected by dipstick analysis. At sacrifice, peripheral blood samples were collected from mice and anti-dsDNA antibodies were detected by enzyme immunoassorbent assay (ELISA) method using commercial kits. At sacrifice, kidneys were analyzed for histopathology and immunohistochemical analysis for B220, CD4, MPO, CD4+Foxp3, F40/80 infiltration was performed. Results Proteinuria occurrence was delayed NZS and NZM mice, no differences were observed in anti-dsDNA autoantibody titer among the groups at the different time-points; at 36 weeks, no significant differences were observed in term of nephritis scores. Inflammatory cells deposition (MPO and F4/80 positive cells) in NZM was significantly higher than in NZ and NZS. An overexpression of B lymphocytes (B220) was found in NZM while T regulatory cells (CD4+ Foxp3+ cells) were reduced in both NZS and NZM with respect to NZc. Conclusions Overall, our study failed to show a positive effect of a treatment with murine MSCs in this model and, for some aspects, even deleterious results seem to be observed.

AB0190 Treatment with Bone Marrow Mesenchymal Stromal Cells in a Murine Model of Systemic Lupus Erythematosus

Background In recent decades, cell-based therapies have emerged as a new therapeutic option for refractory and severe systemic lupus erythematosus (SLE) (1). Mesenchymal stromal cells (MSCs) could represent an excellent candidate but several aspects remain to be extensively investigated such as the most efficient treatment timing and dosage. Objectives The present research is aimed at comparing the effect of different protocols of allogenic MSCs infusions on clinical and serological parameters in a mouse model of SLE. Methods 35 female New Zealand Black/New Zealand White F1 (NZB/W) mice have been used as model of SLE and 10 C57BL/6J mice have been used as donors of allogenic bone marrow derived MSCs (BMMSCs). NZB/W mouse were divided into the following experimental groups:– 5 NZB/W treated with a single MSCs infusion at 20 weeks of age (NZB/W20)– 5 NZB/W treated with a single MSCs infusion at 24 weeks of age (NZB/W24)– 5 NZB/W treated with a single MSCs infusion at 32 weeks of age (NZB/W32)– 5 NZB/W treated with multiple MSCs infusions started at 20 weeks of age (NZB/WM20)– 5 NZB/W treated with multiple MSCs infusions started at 24 weeks of age (NZB/WM24)– 10 NZB/W mouse not treated as Controls (C) Proteinuria was recorded weekly and peripheral blood serum samples were collected at sacrifice to test for anti-dsDNA antibodies (Alpha Diagnostics International). At sacrifice, kidneys were harvested and sections were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). H&E and PAS stained sections were evaluated for glomerular, interstitial and vascular lesions according to a modified score described by Tao X et al (2). Results In untreated mice (C) proteinuria was detectable at 17 weeks of age (3.5±2.7 mg/day) and further increased until 35 weeks of age (12.5±3.5 mg/day). At 24 weeks, proteinuria was 1.8±2.3 mg/day in C group, 0.9±0.4 mg/day in NZB/W20, 0.7±0.5 mg/day in NZB/WM20. At 30 weeks proteinuria was 4.9±2 mg/day in untreated mice, 4.6±5 mg/day in NZB/W20, 3.2±0.2 mg/day in NZB/W24, 0.7±0.5 mg/day in NZB/WM20 and 0.8±0.4 mg/day in NZB/WM24. At 36 weeks proteinuria was 12.5±3.5 mg/day in C group, 8.5+6.1 mg/day in NZB/W20, 3.7+3.4 mg/day in NZB/W24, 9.4+5.1 mg/day in NZB/W32, 6.5±5 mg/day in NZB/WM20 (p=0.006 vs C group) and 4.5+2.5 mg/day in NZB/WM24 (P<0.0001 vs C group). The titers of the anti-dsDNA antibody did not change between groups. No significant differences in histological kidney scores were observed between single and multiple treatments. Conclusions Our results showed that multiple MSCs infusion are associated with a decrease of proteinuria; on the contrary both single and multiple treatments had no effect on autoantibodies production as well as on histological progression of the kidney disease. References Hugle T et al. stem cell transplantation for rheumatic autoimmune diseases. Arthritis Res Ther, 2008. Tao X et al. Therapeutic impact of the ethyl acetate extract of Tripterygium wilfordii Hook F on nephritis in NZB/W F1 mice. Arthritis ResTher, 2006. Disclosure of Interest None declared

Antiphospholipid syndrome: state of the art on clinical practice guidelines

Antiphospholipid syndrome (APS) is a rare disease characterised by venous and/or arterial thrombosis, pregnancy complications and the presence of specific autoantibodies called antiphospholipid antibodies. This review aims to identify existing clinical practice guidelines (CPG) as part of the ERN ReCONNET project, aimed at evaluating existing CPGs or recommendations in rare and complex diseases. Seventeen papers providing important data were identified; however, the literature search highlighted the scarceness of reliable clinical data to develop CPGs. With no formal clinical guidelines in place, diagnosis and treatment of APS is largely based on consensus and expert opinion. Patients’ unmet need refers to the understanding of the disease and its clinical picture and implications, the need of education for patients, family members and healthcare providers, as well as to the development of monitoring pathways involving multiple healthcare providers.