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Objectives Fibromyalgia symptoms have a significant impact on the quality of life and respond poorly to medications. It has been hypothesized that the use of low-energy pulsed electromagnetic field (PEMF) induces neuroprotective effects that may interfere with pain perception. We explored the efficacy of PEMF in patients affected by fibromyalgia. Methods Twenty-one females (median age 59 years, interquartile range [IQR] 16.5) affected by fibromyalgia were randomized to receive pulsed electromagnetic field-triple energy pain treatment (PEMF-TEPT) or placebo at T0 and at 4 weeks and 8 weeks. Fibromyalgia impact questionnaire (FIQ), widespread pain index (WPI), visual analog score (VAS) pain, symptom severity (SS) scale, and short form 36 (SF-36) health survey questionnaire have been evaluated. Results Patients in the PEMF-TEPT group had a significantly higher reduction of WPI compared to placebo (mean difference −12.90 ± standard deviation [SD] 5.32 vs. −1.91 ± 4.55, difference in difference [DD] of −10.99; P < 0.001), of SS score (−4.10 ± 4.85 vs. −2.00 ± 2.32; DD = −2.1; P < 0.05), of VAS pain (−48 ± 30.75 vs. −16.82 ± 23.69; DD = −31.18; P < 0.01). They also reported a higher improvement of FIQ and SF-36, albeit not reaching statistical significance. Conclusion In our pilot controlled study, PEMF-TEPT appeared to be safe and improved fibromyalgia symptoms.

Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.

Objectives To demonstrate that unsuccessful treatment optimization in early disease is associated with difficult-to-treat RA (D2T-RA). Methods In this retrospective multicentre cohort study conducted from 09/2021–03/2022, we enrolled individuals fulfilling the 2010 ACR/EULAR RA criteria diagnosed 2000–2019. The outcome was D2T-RA by the EULAR definition. We used robust regression to examine the associations with delay, dose, duration of methotrexate and discontinuation of glucocorticoids. We tested through multinomial regression which factors were associated with persistent inflammatory refractory RA (PIRRA) or non-inflammatory refractory RA (NIRRA). Sensitivity analysis included a case-control study matching the year of diagnosis. Results We enrolled 48 D2T-RA patients and 145 non-D2T-RA controls. Methotrexate was started within 3 months in 16.7% of D2T-RA vs 33.1% of non-D2T-RA (P = 0.011). Adequate duration of methotrexate was obtained in significantly fewer D2T-RA patients (70.8% vs 85.5%). Glucocorticoids were continued beyond 6 months in a higher proportion of D2T-RA patients (70.8% vs 33.8%, P Conclusion Failure to start methotrexate within 3 months and not being off glucocorticoids within 6 months are early predictive features of D2T-RA.

Olfactory dysfunction (OD) has been described in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but the underlying mechanisms are not completely understood. The causes of altered smell function can generally be divided into conductive, sensorineural or others. To date no specific treatment is available for AAV-related OD and the efficacy of currently available options has not been explored. The aim of this review is to provide an overview of the causes that may lead to OD in patients with AAV. Current available treatments for OD and possible options in patients with AAV presenting with smell impairment are also mentioned.

The revised Fibromyalgia Impact Questionnaire (FIQR) is a widely used fibromyalgia severity assessment tool that was introduced in 2009 prior to the publication of the American College of Rheumatology (ACR) preliminary fibromyalgia criteria in 2010 and its revision in 2016. In 2020, the modified Fibromyalgia Assessment Scale (FASmod) was published. The Polysymptomatic Distress scale (PSD) of the fibromyalgia criteria and FASmod include assessments of pain location severity and can be used for diagnosis as well as in non-fibromyalgia patients. The aim of this study is to provide equations for the conversion of the FIQR scores to PSD and FASmod as an aid to understanding and sharing fibromyalgia severity information.3089 patients with fibromyalgia, diagnosed according to the ACR 2010/2011 criteria and belonging to the Italian Fibromyalgia Registry completed FIQR, FASmod and PSD questionnaires. Pearson's correlation coefficient was used to test the correlations between indices. The least square regression approach was used to produce predictive equations for each scale based on the remaining scales.FIQR was correlated with PSD (r=0.714) and FASmod (r=0.801); PSD and FASmod showed the highest correlation (r=0.897), expected since they assess the same constructs. Predictive equations showing a linear model were effective in producing mean cohort values, but individual predictions deviated substantially, precluding prediction in the individual patient.Conversion equations that allow for interconversion of multiple scales fibromyalgia severity assessment scales are produced. These can be useful in obtaining mean values for cohorts but are not accurate enough for use in individual patients.

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Polymyalgia rheumatica is an inflammatory rheumatic disease of the elderly characterised by pain and stiffness in the neck and pelvic girdle, and is the second most common inflammatory rheumatic condition in this age group, after rheumatoid arthritis. Polymyalgia rheumatica can occur independently or in association with giant cell arteritis, which is the most common form of primary vasculitis. The diagnosis of polymyalgia rheumatica is usually based on clinical presentation and increase of inflammatory markers. There are no pathognomonic findings that can confirm the diagnosis. However, different imaging techniques, especially ultrasonography, can assist in the identification of polymyalgia rheumatica. Glucocorticoids are the cornerstone of the treatment of polymyalgia rheumatica, but they might be associated with different adverse events. A subgroup of patients presents with a refractory disease course and, in these cases, adding methotrexate as a steroid-sparing agent could be useful. In this review, we summarise the latest findings regarding the pathogenesis, diagnosis and management of polymyalgia rheumatica and try to highlight the possible pitfalls, especially in elderly patients.

In this paper, a study on the use of ICT support to help therapists and Systemic Sclerosis (SSc) patients in the recovery phase is described. The ReMoVES platform is conceived in the field of assistive computing technologies and delivers engaging exergames to be performed in conjunction with traditional rehabilitation both at home and at clinical centers, thus enabling the continuity of care. The present work refers to the implementation and integration in the ReMoVES platform of standard hand rehabilitative exercises for SSc that typically involves repetitive movements. Data related to game sessions are collected and analyzed for assessing the patients’ conditions.

A novel effervescent buffered solution of 70 mg alendronate (ALN-EX) was developed to improve upper gastrointestinal (GI) tolerability over alendronate tablets (ALN-T). Whether a better GI tolerability can improve persistence remains to be determined. This study evaluated persistence and reasons for discontinuation in patients treated with ALN-EX compared to a historical cohort on ALN-T. Post-menopausal women (PMW) from a standardized clinical database with BMD T-score

To investigate the effectiveness of the T-score values provided by Radiofrequency Echographic Multi Spectrometry (REMS) in the identification of patients at risk for incident osteoporotic fractures.A population of Caucasian women (30-90 years), enrolled from 2013 to 2016, underwent dual X-ray absorptiometry (DXA) and REMS scans at axial sites. The incidence of fragility fractures was assessed during a follow-up period up to 5 years. Afterwards, patients with and without incident fractures were stratified in two age-matched groups with a 1: 2 proportion (Group F' and Group NF', respectively). The performance of REMS T-score in discriminating between the two groups was quantitatively assessed and compared with DXA.1516 patients were enrolled and 1370 completed the follow-up (mean ± SD: 3.7 ± 0.8 years; range: 1.9-5.0 years). Fracture incidence was 14.0%. Age-matched groups included 175 fractured patients and 350 non-fractured ones, respectively (median age 70.2 [interquartile range: 61.0-73.3] and 67.3 [65.4-69.8] years, p-value ns). The groups resulted also balanced for height, weight and BMI (p-values ns). As expected, the differences in REMS T-score (for vertebral site, -2.9 [-3.6 to -1.9] in Group F', -2.2 [-2.9 to -1.2] in Group NF') and DXA T-score (-2.8 [-3.3 to -1.9] in Group F', -2.2 [-2.9 to -1.4] in Group NF') were statistically significant (p-value0.001). Analogous results were obtained for femoral neck. Considering the T-score cut-off of -2.5, REMS identified Group F' patients with a sensitivity of 65.1% and specificity of 57.7% of (OR = 2.6, 95%CI: 1.77-3.76, p 0.001), whereas DXA showed a sensitivity of 57.1% and a specificity of 56.3% (OR = 1.7, 95%CI: 1.20-2.51, p-value = 0.0032). For femoral neck, REMS sensitivity and specificity were 40.2% and 79.9%, respectively, with an OR of 2.81 (95%CI: 1.80-4.39, p 0.001). DXA, instead, showed a sensitivity and specificity of 42.3% and 79.3%, respectively, with an OR of 2.68 (95%CI: 1.71-4.21, p 0.001).REMS T-score resulted an effective predictor for the risk of incident fragility fractures in a population-based sample of female subjects, representing a promising parameter to enhance osteoporosis diagnosis in the clinical routine.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Background To date numerous quantitative methods to diagnose osteoporosis at peripheral sites have been developed. REMS (Radiofrequency Echographic Multi Spectrometry) is a non-ionizing instrument used to quantitatively evaluate bone mineral density at lumbar spine and femoral neck sites [1]. Objectives To assess the accuracy of REMS in osteoporosis diagnosis at axial sites (lumbar spine and hip) compared with the gold standard, Dual-energy X-ray absorptiometry (DXA). Methods We enrolled patients aged from 50 to 75 years and perfomed a total of 1,699 and 1,794 lumbar spine and proximal femur scans with REMS and DXA. A quality checks on DXA and REMS acquired data were performed through direct examination of scans by experienced operators. We investigated the agreement between the two techniques calculating: Pearson`s correlation coefficient (r), Standard Error of the Estimate (SEE) and efficiency (sensitivity and specificity) in identifying osteoporotic individuals (i.e. T-score ≤ -2.5). Results We found a good linear correlation between REMS and DXA BMD estimation, Pearson coefficient r=0.938 for lumbar spine and r=0.933 for proximal femur (p Conclusion REMS exhibited a high sensitivity and specificity in identifying osteoporotic patients at lumbar spine or proximal femur sites compared with gold-standard DXA. REMS accurately diagnosed osteoporotic patients in clinical routine, at both lumbar spine and proximal femur sites, without using ionizing radiation. References [1] Di Paola M, Gatti D, Viapiana O, et al. Osteoporos Int, 2018 Disclosure of Interests Giovanni Adami: None declared, Giovanni Arioli: None declared, Gerolamo Bianchi: None declared, Maria Luisa Brandi: None declared, Carla Caffarelli: None declared, Loredana Cavalli: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Luisella Cianferotti Speakers bureau: Abiogen Pharma, Bruno Farmaceutici, Shire, Francesco Conversano Shareholder of: Francesco Conversano own stocks of Echolight Spa, Marco Di Paola: None declared, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer, Giuseppe Girasole: None declared, Andrea Giusti: None declared, Stefano Gonnelli: None declared, Monica Manfedini: None declared, Maurizio Muratore: None declared, Ranuccio Nuti: None declared, Paola Pisani: None declared, Laura Quarta: None declared, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme

Background: Baricitinib is an oral selective JAK1/2 inhibitor recently approved in the EU for the treatment of rheumatoid arthritis (RA). No real-life data are available about its efficacy and safety. Objectives: To investigate the efficacy and safety profiles of baricitinib in a real-life setting. Methods: We performed a multicenter prospective observational study on adult RA patients starting JAK inhibitors between 12/2017 and 12/2018. Demographic and clinical data as well as laboratory values and adverse events were collected at baseline and after 12 and 24 weeks. Disease activity was measured by DAS28-CRP at baseline, after 12 and 24 weeks. Results: We obtained data from 150 patients with RA (women 116 – 77.3%; median age 60 years, inter-quartile range IQR 54-68; median disease duration 10 years, IQR 4-18) treated with baricitinib 2 or 4 mg QD, however only 2/150 (1.3%) at the reduced dosage. At the time of database lock 95/150 (63%) patients have completed the 12 weeks follow-up, 38/150 (25%) patients have completed the 24 weeks follow-up. Baricitinib was started after at least one conventional synthetic DMARD in all 148/150 cases (99%), being in all of cases methotrexate, while was started prior to a biologic DMARD in 57 (38%) patients. It was prescribed as a second line in 17/93 (18%) patients, third in 27 (29%), fourth or higher in 49 (53%). Baricitinib was prescribed as monotherapy in 57/150 (38%) patients, while combined with methotrexate in 65/150 (43%), at a median dosage of 15 mg/week. Oral corticosteroids were used by 105/150 (70%) patients, at a median dosage of 5 mg/day. Mean DAS28-CRP at baseline was 4.92 (standard deviation 1.22), with 65 (43.3%) patients having a DAS28-CRP>5.1. At both 12 and 24 weeks, a significant reduction of disease activity scores was observed (DAS28-CRP mean 3.07, SD 1.36, and 2.85, SD 1.35, respectively; p values Conclusion: In our real-world dataset, baricitinib is effective in reducing RA disease activity, after 12 weeks, being generally well-tolerated with few severe adverse events. Disclosure of Interests: Giacomo Maria Guidelli: None declared, Elena Generali: None declared, Chiara Bazzani: None declared, Roberto Gorla: None declared, Garifallia Sakellariou: None declared, Massimiliano Limonta: None declared, Maria Sole Chimenti: None declared, Roberto Perricone: None declared, Edoardo Conticini: None declared, Bruno Frediani: None declared, nicola boffini: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Marta Riva: None declared, Maria Rosa Pozzi: None declared, Rosa Daniela Grembiale Grant/research support from: BMS, Consultant for: JANSSEN, CELGENE, Speakers bureau: PFIZER, JANSSEN, BMS, NOVARTIS, Teodora Serban: None declared, Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Carlo Selmi Grant/research support from: Abbvie, Janssen, MSD, Novartis, Pfizer, Consultant for: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB, Speakers bureau: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB

Background: Still’s disease is a rare autoinflammatory disease, presenting in both pediatric [systemic juvenile idiopathic arthritis (SJIA)] and adult patients [adult-onset Still’s disease (AOSD]. Due to the rarity of the disease, clinical trials are limited and treatment guidelines are not available. In patients refractory to the classical therapy with NSAIDs, corticosteroids and DMARDs, the introduction of drugs targeting IL-1 has greatly expanded treatment options. Among these, canakinumab, a human monoclonal anti-IL-1β antibody, and anakinra, a human recombinant IL-1RA, have been recently approved for the treatment of refractory patients. Objectives: To produce recommendations, based on evidence and expert consensus, that can help clinicians in choosing the most appropriate treatment of AOSD, with particular attention to anti-IL-1 therapies, in order to achieve disease remission before the development of complications. Methods: The recommendations development process took place from April to October 2018 and consisted of three steps. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed: a) similarities and differences between SJIA and AOSD; b) efficacy and safety of IL-1 blockade in AOSD. The issue related to the treatment of AOSD with anti-IL1 therapies was specified into 4 questions: 1) efficacy and safety; 2) comparison among IL-1 inhibitors; 3) early versus late treatment; 4) systemic versus chronic articular pattern of the disease. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. At the third step of the consensus process, the voting results were analyzed, and the statements were finalized. Results: In the two literature searches, 332 and 358 publications were identified; 30 and 25 publications, respectively, were selected according to the inclusion criteria. Based on the review of the literature and personal clinical experience, 11 statements were developed. 48/67 rheumatologists (72%) participated to the Delphi process. Positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as first and as subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude a therapeutic response with another one. The lack of studies comparing early versus late treatment in AOSD patients did not allow to draw conclusions, however data from SJIA suggest a better response in early treated patients. Conclusion: The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies. Acknowledgement: Editorial support was provided by Springer Healthcare Communications and funded by Novartis Farma, Italy. Disclosure of Interests: Serena Colafrancesco: None declared, Maria Manara: None declared, Alessandra Bortoluzzi: None declared, Teodora Serban: None declared, Gerolamo Bianchi: None declared, Luca Cantarini: None declared, Francesco Ciccia Grant/research support from: CELGENE, PFIZER, Consultant for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, Paid instructor for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, Speakers bureau: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, MSD, ROCHE, AMGEN, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Marcello Govoni: None declared, Carlomaurizio Montecucco: None declared, Roberta Priori: None declared, Angelo Ravelli Grant/research support from: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Consultant for: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Speakers bureau: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Paolo Sfriso: None declared, Luigi Sinigaglia Speakers bureau: Yes, I,ve been invited speaker by Amgen, Ely Lilly, UCB, Abbvie, Roche and BMS.

Background:Low-intensity pulsed electromagnetic fields (PEMF) have been shown to improve gait parameters in frail older adults.1 Furthermore, the continuous exposure to PEMF (up to 1 year) have been demonstrated to produce progressive improvements in self-selected gait speed in older adults at risk of falling.2Objectives:To investigate the effects of two different treatment regimens of PEMF on physical performances in older adults presenting with rheumatoid arthritis (RA), osteoarthritis (OA) or severe osteoporosis (OP).Methods:Older adults presenting with RA, OA or OP, at increased risk of falls, evaluated in our Falls Prevention Clinic, were considered for a prospective observational study investigating the effects of PEMF on physical performances. PEMF were supplied by the THS 280 E device (THS-Therapeutic Solutions Srl, Milan, Italy). It provides a new therapeutic approach, named TEPS (Triple Energy Postural Stabilization), that represents an evolution of physical therapy.1,2 On the basis of the physician judgment, PEMF were administered following an intensive protocol, every 45 days (PEMF-45), or a standard validated protocol1,2, every 60 days (PEMF-60). All subjects were assessed at baseline and every 3 months with the following tests: 4 meters gait speed test [4MGS, seconds (sec)], timed up and go test (TUG, sec), chair stand test (CST, sec), short physical performance battery (SPPB, score), and hand grip strength (HGS) by hand dynamometer (Kg). Demographic, anthropometric and clinical characteristics, including pharmacological treatments and functional status were evaluated at baseline. Clinical and adverse events were assessed every 45 or 60 days after PEMF administration.Results:Overall, 94 patients were enrolled between January and December 2020. Of these, 43 subjects (N=33 PEMF-45, N=11 PEMF-60) with a valid 6-month follow-up assessment were considered for the current analysis. The two groups were comparable regarding the main baseline characteristics, and similar % of patients presented with RA, OA or OP. Mean age (±SE) was 78±7 in PEMF-45 and 77±7 in PEMF-60. As expected, all physical performance tests improved significantly from baseline to 6 months in both groups. Mean (±SE) 4MGS increased significantly more in PEMF-45 (from 3.24±0.12 sec to 2.83±0.18 sec) compared to PEMF-60 (from 3.22±0.21 sec to 3.02±0.30 sec, p=.018). Likewise, mean (±SE) CST improved more in PEMF-45 (from 12.4±0.9 sec to 8.7±0.4 sec) compared to PEMF-60 (from 11.1±1.5 sec to 9.8±0.7 sec, p=.002). No significant difference between groups was found for the other tests, although a trend toward better results in PEMF-45 was manifest: SPPB improved by 6.4% in PEMF-45 and by 3.0% in PEMF-60, and TUG decreased by 7.8% in PEMF-45 and by 6.1% in PEMF-60. During the 6 months observation period no adverse event was observed.Conclusion:Preliminary results of our ongoing prospective observational study suggest that a more frequent administration of PEMF produces greater improvements in some but not all physical performance parameters compared to a standard validated regimen1,2.References:[1]Giusti A et al., Geriatr Gerontol Int 2013. 2Giusti A et al., J Am Geriatr Soc 2014.Disclosure of Interests:Massimo Giovale: None declared, Giuseppina Tramontano: None declared, Rossana Galli: None declared, Simone Rando: None declared, Andrea Giusti Speakers bureau: UCB, Amgen, Kyowa Kirin, Abiogen Pharma, and Eli Lilly, outside the submitted work, Consultant of: EffRx and Abiogen Pharma, outside the submitted work, Lorenzo Bandi: None declared, Francesca Russo: None declared, Stefano Rampoldi Employee of: THS Therapeutic Solutions SRL, Luigi Carlo Bottaro: None declared, Gerolamo Bianchi Speakers bureau: Abbvie, Abiogen Pharma, Amgen, BMS, Celgene, Eli Lilly, GSK, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, Genzyme and Servier, outside the submitted work

Background:Fibromyalgia is a clinical condition characterized by diffuse chronic muscle-skeletal pain, fatigue, sleep/mood disorders and muscular stiffness. The pathogenesis of fibromyalgia remains poorly understood but numerous lines of evidence suggest a role for alterations of both the central and peripheral nervous systems leading to heightened pain sensitivity along with acorollariumof other symptoms1. Low-energy pulsed electromagnetic field (PEMF) has promising data in the prevention of falls in senior individuals and is believed to promote osteogenesis and angiogenesis thus proving promising to treat bone diseases with chronic pain2. No data is available in fibromyalgia.Objectives:To investigate the efficacy and safety of PEMF on fibromyalgia symptoms in a randomized single-blind pilot study.Methods:We enrolled 21 women (median age 59 years, IQR 16,5) affected by fibromyalgia according to the 2010 ACR classification criteria3not receiving chronic medical treatment for pain; patients were randomly allocated to receive PEMF TEPT (triple energy pain treatment) / New Sunrise 280 (THS - Therapeutic Solutions, Milan, Italy) on the selected points (10 agopuncture points) or scrambled points for 20 minutes at baseline (T0) and after 4 (T4) and 8 (T8) weeks. Outcome measures were recorded at T0, T4 and T8 and included FIQ (fibromyalgia impact questionnaire), WIP (widespread pain index), VAS pain, SS (symptom severity scale), and SF-36 (short form 36 health survey questionnaire).Results:Patients receiving the active treatment had a deep reduction of WIP from T0 to T8 (-76% vs -13% in placebo) with a statistically significant difference compared to the placebo group (p=0.0025) (Figure 1). In all endpoints, we observed a general reduction at T4 and T8 compared to T0 also for FIQ, VAS pain, SS, SF-36, regardless of the treatment arm and the decrease was higher in the active treatment arm compared to the placebo group, albeit not reaching statistical significance (Figure 2).Conclusion:The results of our pilot study show that PEMF is more effective than placebo in reducing widespread pain in fibromyalgia while confirming that a placebo effect is clear in this complex disease.References:[1]Targeting network hubs with noninvasive brain stimulation in patients with fibromyalgia Chelsea M. Kaplan, R.E. Harris, UnCheol Lee, Alexander F. DaSilva, George A. Mashour, Steven E. Harte. PAIN: January 2020 - Volume 161 - Issue 1 - p 43-46[2]Yuan J, Xin F, Jiang W. Underlying Signaling Pathways and Therapeutic Applications of Pulsed Electromagnetic Fields in Bone Repair.Cell Physiol Biochem. 2018;46(4):1581-1594[3]Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken).2010;62:600-61Disclosure of Interests:Massimo Giovale: None declared, Lucia Novelli: None declared, Stefano Rampoldi: None declared, Rossana Galli: None declared, Patrizia Monteforte: None declared, Marica Doveri: None declared, Gerolamo Bianchi Grant/research support from: Celgene, Consultant of: Amgen, Janssen, Merck Sharp & Dohme, Novartis, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Chiesi, Eli Lilly, GSK, Janssen, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Genzyme, Servier, UCB, Luigi Carlo Bottaro: None declared, Carlo Selmi Grant/research support from: AbbVie, Janssen, MSD, Novartis, Pfizer, Celgene, and Leo Pharma, Consultant of: Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and Sanofi-Regeneron, Speakers bureau: AbbVie, Aesku, Alfa-Wassermann, Bristol-Myers Squibb, Biogen, Celgene, Eli-Lilly, Grifols, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB Pharma

Background Acute phase response (APR) is a transient, flu-like reaction to first exposure to intravenous nitrogen-containing bisphosphonate (NBP). APR is characterised by a strong inflammatory response, associated with increases in circulating levels of IL-6 and TNF-, that is thought to be due to activation and increased proliferation of γδ T cells related to the molecular mechanism of action of NBP. Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), in both its soluble (s) and membrane-bound forms, is involved in the downregulation of T cell proliferation, cell cycle progression and cytokine production. High levels of serum sCTLA-4 have been reported in several autoimmune diseases, and its role as both inhibitor and enhancer of the immune response has been proposed. Objectives To evaluate the potential relationship between sCTLA-4 and the development of APR in patients treated with zoledronic acid (ZOL). Methods Included in the study were patients treated with a single intravenous ZOL infusion 5 mg. Exclusion criteria were previous treatment with ZOL, treatments interfering with CTLA-4, and estimated glomerular filtration rate Results Ten female patients (mean age 73-10 years) were included (2 had vertebral fractures and the remaining had osteoporosis), 5 of whom experienced APR (APR+) associated with the expected increases in serum CRP and IL-6. Baseline levels of sCTLA-4 did not differ between APR+ and APR- patients and decreased significantly in all from 32-9 ng/ml to 24-9 ng/ml (p=0.007) at 24 hr, 16-8 ng/ml (p=0.004) at 48 hr and 7-6 ng/ml (p Conclusion Contrary to our hypothesis, sCTLA-4 was not related to the occurrence of APR after ZOL. The significance of the substantial decrease of circulating levels of sCTLA-4 after ZOL in all studied patients warrants further investigation. Disclosure of Interests Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Daniele Saverino: None declared, Dario Camellino Consultant for: Janssen-Cilag, Novartis, AbbVie, Sanofi, Paid instructor for: Mylan, Andrea Giusti Grant/research support from: Abiogen Pharma, Consultant for: EffRx, Speakers bureau: Abiogen Pharma, Eli Lilly, AMGEN, Erika Iervasi: None declared, Giuseppe Girasole: None declared, Socrates Papapoulos Grant/research support from: No in the last 3 years, Consultant for: Amgen, Axsome, Gador, Radius Health, UCB, Speakers bureau: Amgen, UCB

The MARI study investigated the prescription patterns of methotrexate (MTX) in patients presenting with rheumatoid arthritis (RA) in Italy. The primary aims of this cross-sectional analysis from the MARI study were to investigate the effect of gender on the prescription patterns and safety of MTX therapy.The study enrolled 1336 patients with RA. Retrospective data included patients' clinical history, previous treatment with MTX and other DMARDs, and MTX modifications in the previous 12-month period. Cross-sectional data included information about current treatment with MTX (dose and route of administration, and adverse events), concomitant medications, disease activity, and modifications of MTX treatment at study entry. The prescription patterns of MTX, rates and causes of MTX modifications were analysed according to gender.There were no significant differences related to gender in the prescription patterns of MTX, either at 6 months after starting MTX or at the time of study entry. In the 12 months prior to study entry, women (4%) were more likely to undergo MTX modifications (dose or route of administration) compared to men (2%, p=0.032), due to subjective intolerance, but this difference was no longer significant after controlling for confounders. At study entry, a higher proportion of women (27%) reported tolerability issues (nausea and weakness) related to MTX compared to men (14%, p=0.001). Although a similar percentage of males and females changed dose or route of administration of MTX at the time of study entry, the reasons for such modifications were dissimilar between genders. Particularly, a higher proportion of women underwent MTX modification due to intolerance (women 6% vs. men 1%, p=0.002).In Italy, prescription patterns of MTX do not differ between genders. However, women seem to be at higher risk of adverse events leading to MTX modifications.

Background Positron emission tomography has shown the presence of large vessel vasculitis (LVV) in 30%–40% of patients with apparently isolated polymyalgia rheumatica (PMR)[1], but biomarkers associated with the presence of LVV in PMR patients are still lacking. Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and its soluble (s) form, resulting from alternative splicing, are well-known immune checkpoint receptor[2] and have shown to play a role both in neoplastic[3] and autoimmune diseases[4]. The rationale for studying the involvement of CTLA-4 in PMR is provided by the evidence of drug-induced PMR/giant cell arteritis (GCA) in patients treated with ipilimumab, an anti-CTLA-4 antibody[5]. Objectives To evaluate the concentration of sCTLA-4 in PMR patients and to correlate it with vascular and joint inflammation. Methods Forty consecutive patients with of PMR, of whom 9 also had also GCA, underwent a standardised clinical examination and a PET/CT scan. Arterial and joint uptake of FDG were scored relative to liver and then summed up to obtain a total vascular score (TVS) and a total joint score (TJS). Patients were further subdivided into three groups for the analysis of the correlation with joint and vascular uptake: “vasculitic patients” (with grade-3 uptake in at least one vascular district), patients with intermediate uptake (excluded from this set of analyses), and patients without vasculitis. sCTLA-4, was evaluated by ELISA. Patients without autoimmune diseases served as controls. Results sCTLA-4 serum levels were significantly higher in PMR patients than in controls (p Conclusions The present study provides the first evidence that serum sCTLA-4 concentration is elevated in PMR patients, and that it correlates with TVS. Although the exact mechanisms underlying the upregulation of sCTLA-4 remain elusive, we feel that aberrant production of cytokines, or abnormal activation of intercellular signalling pathways can be involved. References [1] Puppo C, Massollo M, Paparo F, Camellino D, et al. Giant Cell Arteritis: A Systematic Review of the Qualitative and Semiquantitative Methods to Assess Vasculitis with 18F-Fluorodeoxyglucose Positron Emission Tomography. Biomed Res Int2014;2014:574248. [2] Korhonen R, Moilanen E. Abatacept, a Novel CD80/86-CD28 T Cell Co-stimulation Modulator, in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol2009;104(4):276–84. [3] Cranmer LD, Hersh E. The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest2007;25(7):613–31. [4] Saverino D, Simone R, Bagnasco M, Pesce G. The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. Autoimmun Highlights 2010;1(2):73–81. [5] Goldstein BL, Gedmintas L, Todd DJ. Drug-Associated Polymyalgia Rheumatica/Giant Cell Arteritis Occurring in Two Patients After Treatment With Ipilimumab, an Antagonist of CTLA-4. Arthritis Rheumatol2014;66(3):768–9. Disclosure of Interest None declared

Introduction Clodronic acid is a non-nitrogen-containing bisphosphonate largely used from some decades in the prevention and treatment of postmenopausal and secondary osteoporosis. In addition to antiresorptive activity, clodronate has shown anti-inflammatory and analgesic properties, and modulatory effects on bone and cartilage metabolism. Evidence acquisition A literature review has been conducted to characterize the mechanism of action of clodronate and to retrieve available evidence about the use of clodronate in primary and secondary osteoporosis, and its potential role in other musculoskeletal conditions and orthopedic surgery. Evidence synthesis The efficacy and safety of the available clodronate formulations (oral, intravenous and intramuscular) in the prevention and treatment of postmenopausal and secondary osteoporosis, including corticosteroid-induced osteoporosis and bone mass loss secondary to endocrine, gastrointestinal and neoplastic diseases, have been demonstrated in a variety of clinical trials. The analgesic, anti-inflammatory, bone- and chondro-modulating properties of clodronate have allowed to expand its use in other musculoskeletal conditions to those currently approved. Clodronate has proven to be beneficial in the treatment of osteoarthritis of the knee and of the hand, in the management of complex regional pain syndrome, and in the peri- and postoperative phase in subjects undergoing arthroplasty. Conclusions The analysis of the available literature has shown that clodronate has relevant musculoskeletal effects beyond the antiresorptive activity. Further research is needed to better position clodronate therapy in the management of these conditions and to define the optimal formulation and dose regimen in any of the tested new indications.

Background Osteoporotic vertebral fractures (VFs) are often misdiagnosed because asymptomatic and occurring in the absence of specific trauma. Further, diagnostic assessment of VFs may be suboptimal. Aim of the study To assess the misdiagnosis of vertebral fractures on local radiographic readings in the cohort of patients enrolled in the POINT study. Methods We enrolled hospitalised patients, admitted for any cause to the Internal Medicine Units of 37 hospitals participating to the cross-sectional previously published POINT study. The assessment of VFs was performed both by local radiologists and by two expert skeletal radiologists, by using semiquantitative method (SQ). To better evaluate mild vertebral deformities, the two central radiologists also used the algorithm-based qualitative assessment (ABQ). Results The radiographs of 661 patients (401 females; mean age 75.8 ± 8.0) were evaluated. The inter-reader percent agreement between two central expert radiologists per-vertebra assessment was excellent (99.78%; k = 0.984; 95% CI, 0.977–0.991). Central reading identified 318/661 (48.1%) patients with at least one VF. Local and central readings agreed in 502/661 (75.9%) patients, resulting in a fair reproducibility (k = 0.52; 95% confidence interval 0.44–0.59). Diagnostic performance parameters of local readings were: sensitivity 76.1%; specificity 75.8%; PPV 74.46%; NPV 77.38%). By examining 9254 vertebrae, central and local readers diagnosed 665 (7.2%) and 562 (6.1%) VFs respectively. Misdiagnosis (102 false positives and 205 false negatives) mainly occurred for mild VFs. Local readings identified correctly 460 out 665 VFs diagnosed by central readings, resulting in sensitivity of 69.2% and PPV of 81.8%. Conclusions Following a standardized protocol of acquisition techniques and of interpretation criteria, an excellent agreement between local and central readings for moderate and severe vertebral fractures resulted. However a significant amount of mild vertebral fractures, that are the most of VFs, were misdiagnosed by local radiologists. In order to improve VFs assessment, the radiologists should be trained and sensitized in relation to the relevant clinical significance of osteoporotic VFs identification.

The aim of this study was to establish consensus for potential early symptomatic knee osteoarthritis (ESKOA) clinical definition and referral criteria from primary care to rheumatologists, based on available data from literature and a qualitative approach, in order to perform studies on patients fulfilling such criteria and to validate the obtained ESKOA definition. A complex methodological approach was followed including: (1) three focus groups (FG), including expert clinicians, researchers and patients; (2) a systematic literature review (SLR); (3) two discussion groups followed by a Delphi survey. FG and SLR were performed in parallel to inform discussion groups in order to identify relevant constructs to be included in the modified Delphi survey. ESKOA is defined in the presence of: (a) two mandatory symptoms (knee pain in the absence of any recent trauma or injury and very short joint stiffness, lasting for less than 10min, when starting movement) even in the absence of risk factors, or (b) knee pain, and 1 or 2 risk factors or (c) three or more risk factors in the presence of at least one mandatory symptom, with symptoms lasting less than 6 months. These criteria are applicable in the absence of active inflammatory arthritis, generalized pain, Kellgren-Lawrence grade >0, any recent knee trauma or injury, and age lower than 40years. Knee pain in the absence of any recent trauma lasting for less than 6months was considered as the referral criterion to the rheumatologist for the suspicion of ESKOA. This consensus process has identified provisional clinical definition of ESKOA and defined potential referral criterion to rheumatologist, in order to test ESKOA obtained definition in prospective validation studies.

Aim: To evaluate the short-term effects of a 10-min exposure to low-intensity, pulsed, electromagnetic fields (PEF) on gait characteristics in older adults with low bone mineral density. Methods: In a single-center, double-blind, randomized-controlled trial, community-dwelling older adults aged ≥70 years were randomized (3:2 ratio) to receive a 10-min treatment with PEF (mean intensity 1.5 mW) or placebo. The following gait parameters were assessed at baseline and just after the intervention/placebo with the GAITRite Portable Walkway system: self-selected gait speed (cm/s), stride length (cm), support base (cm) and double support phase (s). Results: In the intervention group (25 patients), both self-selected gait speed and stride length increased significantly from baseline, whereas the double support phase decreased. In the placebo group, all gait parameters except for support base remained unchanged. The mean percent increase (±standard deviation) of self-selected gait speed was significantly (P = 0.010) greater in the intervention group (20.1 ± 15.6) compared with the placebo group (10.5 ± 13.1), whereas no significant difference in the mean percent variation of the other parameters was found between the two groups. During the intervention, no adverse event was observed. A similar proportion of patients in the two groups reported one fall in the 30 days after the intervention/placebo. Conclusions: This is the first randomized-controlled trial showing the potential beneficial effects of PEF on gait characteristics in older adults. Further phase III randomized trials are warranted to establish their potential benefits (e.g. fall prevention) on fall-related health outcomes in elderly patients. Geriatr Gerontol Int 2013; 13: 393–397.

OBJECTIVES: To compare the effects on parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol. DESIGN: Randomized-controlled trial with 6-month follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Sixty community-dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism. INTERVENTION: Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D3 group) or cholecalciferol 1,000 IU/day (daily D3 group). MEASUREMENTS: Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, β-C-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion. RESULTS: The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)D

Objective. Bisphosphonates may have a chondroprotective effect in patients with knee OA (KOA), but the results of clinical trials with oral bisphosphonates have been contradictory. In this Phase 2 randomized, partially blind clinical trial, we tested the efficacy of IA clodronate vs HA in patients with primary KOA. Methods. One hundred and fifty men or women aged 50–75 years suffering from KOA were randomized to one of five IA therapies: (i) clodronate 0.5 mg one IA injection/week for 4 weeks; (ii) clodronate 1 mg one IA injection/week for 4 weeks; (iii) clodronate 2 mg one IA injection/week for 4 weeks; (iv) clodronate 1 mg two IA injections/week for 2 weeks (clodronate 1 þ 1 mg); and (v) HA 20 mg one IA injection/week for 4 weeks. Results. Visual analogue scores (VASs) for different types of pain and the Lequesne index significantly improved in all treatment groups after the first injection and continued to improve even 2–4 weeks after the last injection without significant difference among the groups. A significant (P ¼ 0.03) linear trend for a dose–response (0.5–2 mg clodronate) relationship was found for active movement VAS pain. Both joint extension and mobility scores improved significantly at all time points in all treatment groups without statistical differences among them. Conclusions. This study indicates that IA clodronate provides symptomatic and functional improvements at least as good as those obtained with HA. Trial Registration. Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali - Agenzia Italiana del Farmaco. Comitato Etico Azienda Ospedaliera Universitaria Senese number CLIO 22/02 http://oss-sper-clin.agenziafarmaco.it

With the aging of the population worldwide, osteoporotic fractures are becoming a serious problem in the Western world. Male osteoporosis is associated with a significant burden in terms of morbidity, mortality and economic cost. Although less frequent in men than women, osteoporosis is a relatively common problem. The increasing prevalence and awareness of osteoporosis and fractures in men, together with the development of easy-to-measure tools and risk indicators to optimize case-finding strategies, has increased the demand for a better understanding of the pathogenesis of this condition and, in turn, for appropriate and effective treatments. This article reports recent findings regarding the pathophysiology and treatment of male osteoporosis that have been discussed by some of the most outstanding scientists in this field at a meeting held in Santa Margherita, Italy, on 6–8 November 2008.

BACKGROUND The role of bisphosphonates (BPs) in the management of patients with hypercalciuria (HC) associated with osteoporosis is still uncertain. The aim of the study was to evaluate the effect of alendronate and indapamide alone or in combination on bone mineral density (BMD) and 24-h urinary calcium excretion (24-CaU) in post-menopausal women with HC and low BMD. METHODS A total of 77 post-menopausal women with HC (24-CaU > 4 mg/kg/day) and low BMD [T-score < -2.0 at lumbar spine (LS), femoral neck (FN) or total hip (TH)] from two centres of Northern Italy were randomized to receive indapamide 2.5 mg daily alone (24 patients, IND group), alendronate 70 mg weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN + IND group). Throughout the study, all subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1000 mg. Patients were instructed to increase water intake up to 2000 mL daily. The percentage and absolute changes of BMD at LS, FN and TH, and the variation of 24-CaU from baseline at 1 year were the primary outcomes. Serum calcium, phosphate, parathyroid hormone and bone alkaline phosphatase were also measured. RESULTS Overall 67 women completed the study and were included in the final analysis. Patients in the three groups were similar with regard to baseline characteristics. BMD did not significantly change from baseline after 1 year of treatment with indapamide (LS: +1 +/- 3.1%; FN: -0.3 +/- 3.5%; TH: -0.4 +/- 3.1%), while it showed a significant increase from baseline in the other two groups (ALN; LS: +5.8 +/- 4.2%, P < 0.001; FN: +3.9 +/- 7.9%, P = 0.018; TH: +2 +/- 3.6%, P = 0.006) (ALN + IND; LS: +8.2 +/- 5.3%, P < 0.001; FN: +4.9 +/- 6.7%, P = 0.007; TH: +2.9 +/- 4.2%, P = 0.004). Patients in the combination group showed a significantly higher increase of BMD at LS compared to ALN (P = 0.04). After 1 year, 24-CaU values significantly decreased from baseline in all groups (IND, 239 +/- 78 versus 364 +/- 44, P < 0.001) (ALN, 279 +/- 68 versus 379 +/- 79, P < 0.001) (ALN + IND, 191 +/- 68 versus 390 +/- 55, P < 0.001). The mean percentage decrease of 24-CaU in ALN + IND group (-50%) was significantly greater compared to ALN (-24%, P < 0.001) and IND (-35%, P = 0.012). CONCLUSIONS These results show a benefit, in terms of BMD improvement and 24-CaU reduction, associated with BPs' therapy in combination with indapamide in HC associated with osteoporosis. The combination therapy demonstrated a reduction of 24-CaU and an increase in LS BMD superior to that observed with alendronate alone. Our results support a new potential approach with BPs associated with thiazide diuretics or indapamide in the management of post-menopausal women with HC and associated bone loss. Studies on the larger sample size are needed to demonstrate the efficacy on the fracture outcome.

Bone turnover markers (BTMs) are widely used for the management of osteoporosis, and the premenopausal reference range is the target value for the treatment of postmenopausal osteoporosis with antiresorbing agents. Three serum BTMs (serum C-telopeptide of type I collagen [CTX], osteocalcin [OC], and N-terminal propeptide of type I procollagen [P1NP]), serum calcium, creatinine, phosphate, magnesium, and follicle-stimulating hormone (FSH) were measured in 638 healthy premenopausal women aged 20-50 years. In 83 women on the contraceptive pill (CP), the levels of the three BTMs adjusted for all confounding factors were 14-26% lower (P0.005) than in non-CP users. In 18 women considered perimenopausal for serum FSH levels30 IU/mL despite having regular menses, BTM levels were significantly higher than in age-matched women. This group of subjects and the women on the CP were excluded from further analysis. The three BTMs significantly decreased with advancing age and were negatively and independently correlated with body mass index (P0.001) and serum phosphate. In conclusion, we confirm that CP use is associated with significantly lower BTM values. An increase in BTM concentrations can be observed in perimenopausal women, i.e., women with normal menses but FSH levels30 IU/mL. BTMs decrease substantially with advancing age, and this appears to be associated with changes in body weight and serum phosphate. New normative ranges for serum OC, CTX, and P1NP were identified; and our findings in general impose a redefinition of the criteria for establishing the normal ranges for BTMs.

OBJECTIVES: To determine whether secondary hyperparathyroidism (HPTH) due to hypovitaminosis D affects bone mineral density (BMD) response to alendronate (ALN) in elderly women with osteoporosis. DESIGN: Randomized, controlled trial with 1-year follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Community-dwelling women aged 60 and older with a BMD T-score below -2.5 and secondary HPTH with vitamin D insufficiency. INTERVENTION: One hundred twenty subjects were randomly assigned to receive ALN 70 mg once a week alone or ALN 70 mg once a week plus calcitriol (1,25D3) 0.5 microg daily. MEASUREMENTS: BMD measured using dual-energy x-ray absorptiometry at the lumbar spine (L1-L4), femoral neck, and total hip and serum levels of intact PTH at baseline and 12 months. RESULTS: After 1 year, BMD of the lumbar spine, femoral neck, and total hip significantly increased from baseline in both groups (P

The aim of this study was to assess how the management of rheumatoid arthritis (RA) with methotrexate (MTX) in Italy is adherent to current national recommendations.We performed a cross-sectional and retrospective analysis of data collected from the MARI study, a multicentre survey on Italian patients with RA on treatment with MTX for at least 12 months. Retrospective data included patient's clinical history, previous treatment with MTX, screening tests performed before MTX prescription. Cross-sectional data were collected about current treatment with MTX, concomitant medications, and disease activity. Each proposition of the 2013 Italian recommendations on the use of MTX in RA was reformulated in terms of audit criteria, and adherence to provided indications was evaluated for every patient.Among the 1336 included patients, less than 40% had started treatment with MTX within 3-6 months from the diagnosis and nearly 30% of them were prescribed with an initial dose of MTX between 12.5 and 15 mg/week. Screening for HBV and HCV infection as well as chest x-ray was performed in a proportion of patients around 60% and more than 90% of them underwent lab tests before MTX prescription and regularly throughout the treatment. Folic acid supplementation was given at recommended dosages in a high proportion of patients.Our survey showed a good adherence of Italian rheumatologists to recommendations regarding safety issues with MTX in RA, but a suboptimal approach in terms of time and dosage of the treatment in the early phases of the disease.

Much work has been directed at establishing the impact of osteoporosis and related fragility fractures in rheumatic diseases. Several cross-sectional studies reported that disability and reduced motility that are due to functional impairment are among the most important determinants of bone loss in different rheumatic diseases. At the same time, longitudinal studies have confirmed the detrimental effect of uncontrolled disease activity on bone density. In this perspective, the suppression of inflammation probably remains the main concern when considering treatment options. Besides these variables, pharmacologic agents that are used commonly in the treatment of these conditions probably have an adjunctive effect on bone loss in rheumatic patients. Large epidemiologic studies have demonstrated clearly that patients who have RA, SLE, or AS are at an increased risk for fragility fractures. Further studies are required to investigate the effective impact of osteoporosis and fragility fractures in other rheumatic diseases, and to define the relationship between OA and osteoporosis. A better appreciation of the impact and mechanisms of osteoporosis in rheumatic diseases by rheumatologists represents a clinical challenge; however, a greater understanding of this frequent complication will improve the quality of health care and the lives of patients who have rheumatic diseases.

Background. Fracture is a disabling clinical outcome after transplantation, but there is little histopathological information on long-term renal recipients with severe osteopenia. Methods. Twenty kidney recipients (8.3±1.9 years after transplantation), 13 males and 7 females (five postmenopausal) with nearly normal renal function, affected by severe osteopenia (T-score: males= -4.9±0.28; females= -5.08±0.47) underwent bone biopsy and morphometric X-ray absorptiometry to evaluate vertebral fractures. Results. Histopathological diagnosis was osteoporosis-osteopenia in seven patients, osteitis fibrosa in six, prevalent osteomalacic lesion in six, and "normal" bone in one patient. Significant increases in osteoid volume (OV/BV), osteoid surface, osteoblastic surface (ObS/BS) and osteoid thickness were observed. OV/BV and Obs/BS ratios were inversely correlated to cumulative doses of MPRED (r 2 = 0.85 P