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The concern about the offspring’s health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

To assess, in a setting close to real life, the efficacy and safety of weekly subcutaneous tocilizumab (TCZ-SC) 162 mg, alone or with a conventional synthetic DMARD (csDMARD), in moderate-to-severe RA patients with inadequate response to DMARDs or anti-TNFα drugs. This national, multicenter, open-label, phase IIIb trial is part of an umbrella study (TOZURA). Patients were treated for 52 weeks followed by 8 weeks drug-free to evaluate immunogenicity. The primary end point was the Clinical Disease Activity Index (CDAI) change from baseline at weeks 2 and 24. Other efficacy parameters, including sleep quality, and the safety and immunogenicity were also assessed up to week 52. Of 288 patients enrolled in 43 Italian centers, 78.8% received TCZ-SC (86.8% females; mean age 54.7 ± 12.1 years; mean disease duration 7.8 ± 7.5 years; DMARD-IRs 94.7%). Of these, 78.0% completed the 52-week period and 52.0% received concomitant methotrexate. TCZ-SC yielded a significant reduction in median CDAI from baseline already at week 2, which progressed up to week 24 and remained stable thereafter (P

Luciana Scalone,1 Piercarlo Sarzi-Puttini,2 Luigi Sinigaglia,3 Carlomaurizio Montecucco,4 Roberto Giacomelli,5 Giovanni Lapadula,6 Ignazio Olivieri,7,8,† Angela Maria Giardino,9 Paolo Angelo Cortesi,1 Lorenzo Giovanni Mantovani,1 Monica Mecchia9On behalf of the CARA Study Group1Centre of Research on Public Health, University of Milano-Bicocca, and CHARTA Foundation, Milan, Italy; 2Rheumatology Unit, L. Sacco University Hospital, 3Rheumatology Unit, G. Pini Hospital, Milan, Italy; 4University of Pavia School of Medicine, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 5Rheumatology Unit School of Medicine, University of L’Aquila, L’Aquila, Italy; 6Rheumatology Unit, University of Bari, Bari, Italy; 7Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Potenza, Italy; 8Madonna delle Grazie Hospital of Matera, Matera, Italy; 9MSD Italy, Rome, Italy†Dr Ignazio Olivieri passed away on July 28, 2017Objective: To estimate preferences in relevant treatment characteristics evaluated by different groups involved in the management of patients with rheumatic diseases.Subjects and methods: We surveyed patients with rheumatic diseases, and rheumatologists, nurses, and pharmacists with experience in treatment with/provision of biologic drugs for these patients. Through a discrete choice experiment, participants evaluated 16 possible scenarios in which pairs of similarly efficacious treatments were described with six characteristics: 1) frequency of administration; 2) mode and place of administration; 3) manner, helpfulness, efficiency, and courtesy of health personnel; 4) frequency of reactions at the site of drug administration; 5) severity of generalized undesired/allergic reactions; and 6) additional cost. The direction and strength of preferences toward each characteristic level and the relative importance of each characteristic were estimated through a random-effects conditional logistic regression model.Results: In total, 513 patients, 110 rheumatologists, 51 nurses, and 46 pharmacists from 30 centers in Italy participated. Characteristics 3, 4, and 6 were the most important for every subgroup; 1 was least important for patients and rheumatologists, 2 was least important for pharmacists, and 2 and 5 were least important for nurses. For characteristic 2, pharmacists preferred subcutaneous self-injection with a syringe; nurses preferred assisted infusion at an infusion center close to the patient’s home; patients and rheumatologists preferred subcutaneous self-injection with a pen.Conclusion: The different preferences for some characteristics shown by the different groups can play an important role, together with purely clinical aspects, in the choice and consequent benefit of treatments, contributing also to a more satisfactory use of resources.Keywords: preferences, biologic drugs, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, decision making

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces Fibroblast Growth Factor 23 (FGF-23), causing hyperphosphaturia, hypophosphatemia, low 1,25(OH)2D and osteomalacia. Tumor localization is critical, diagnostic delay ranges from 2.5 to 28 years and to date surgical removal is considered effective treatment. We retrospectively evaluated patients with definite diagnosis of TIO referred to a tertiary Rheumatology Center between September 2000 and May 2020, investigating clinical management and disease outcome. We included 17 patients: 10 (58.8%) were females, mean age at diagnosis was 55.3 ± 13.9 years (mean ± standard deviation), with a diagnostic delay from symptoms onset to tumor detection of 6.6 ± 6.25 years. Biochemical data were: serum phosphorus 1.3 ± 0.4 mg/dL (Reference Range: 2.5–4.6), serum 1,25(OH)2D 31.8 ± 22.9 ng/mL (RR: 25–86), intact FGF-23, 358.9 ± 677 pg/mL (RR: 25–45); 24 h-Urine Phosphorus was increased in only 2 patients, while tubular reabsorption of phosphate (TRP) was decreased in all patients confirming a renal phosphate wasting. In 2013 68Ga- DOTA-based PET/CT was introduced in routinely practice and diagnostic delay was consistently reduced (from 8.6 ± 7.9 to 4.3 ± 2.4 years). Thirteen patients underwent surgery, one patient underwent radiofrequency ablation; 3 patients, not eligible for surgery, were treated only with supplements of phosphorus and calcitriol. One was started on Burosumab after several unsuccessful surgical attempts. After surgery or ablation, 8 patients had complete remission, 3 TIO persistence, and 3 had overtime relapse. Relapses were observed only in patients who previously underwent closed biopsy. To our knowledge, this is the widest European cohort of TIO patients in the last two decades. We confirm a usual diagnostic delay and recommend a stepwise diagnostic approach. Tumor biopsy is not recommended due to the potential cell spilling. Surgery is generally considered a definitive treatment, even though other approaches have been successful in curing TIO. Active surveillance on possible recurrence is always needed. Burosumab appears a promising therapy.

Objective Various studies have shown that overweight and obesity are central features of FM, but the real impact of a high BMI on clinical severity in patients with FM is still controversial. The aim of this study was to analyse the relationships between BMI categories and measures of symptom severity and functional impairment using data from a Web-based registry of patients with FM. Methods Adult patients with an ACR 2010/2011 diagnosis of FM underwent a complete physical examination and laboratory tests and were asked to complete a package of questionnaires covering their sociodemographic and treatment details, in addition to the following disease-specific questionnaires: the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status questionnaire (ModFAS) and the Polysymptomatic Distress Scale (PDS). Results A total of 2339 patients were recruited and divided into two weight categories, underweight/normal (U/N, n = 1127, 48.2%) and overweight/obese (O/O, n = 1212, 51.8%). The total and subscales of FIQR, ModFAS and PSD scores were significantly higher in the O/O patients, as were all the mean scores of the individual FIQR items (P Conclusion Our findings demonstrate that O/O patients with FM are significantly more impaired than U/N patients in all the symptomatological and functional domains as measured using the FIQR, ModFAS and PDS, thus suggesting that being O/O has an additional effect on symptoms and function.

Objective To establish optimal cut-off values for the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromialgia Assessment Scale (FAS 2019mod), and the Polysymptomatic Distress Scale (PDS) in order to distinguish five levels of FM disease severity. Methods Consecutive FM patients were evaluated with the three clinimetric indices, and each patient was required to answer the anchor question: ‘In general, would you say your health is 1 = very good, 2 = good, 3 = fair, 4 = poor, or 5 = very poor?’—which represented the external criterion. Cut-off points were established through the interquartile reconciliation approach. Results The study sample consisted of 2181 women (93.2%) and 158 men (6.8%), with a mean age of 51.9 (11.5) years, and mean disease duration was 7.3 (6.9) years. The overall median FIQR, FAS 2019 mod and PDS scores (25th–75th percentiles) were respectively 61.16 (41.16–77.00), 27.00 (19.00–32.00) and 19.0 (13.00–24.00). Reconciliation of the mean 75th and 25th percentiles of adjacent categories defined the severity states for FIQR: 0–23 for remission, 24–40 for mild disease, 41–63 for moderate disease, 64–82 for severe disease and >83 for very severe disease; FAS 2019 mod: 0–12 for remission, 13–20 for mild disease, 21–28 for moderate disease, 29–33 for severe disease and >33 for very severe disease; PDS: 0–5 for remission, 6–15 for mild disease, 16–20 for moderate disease, 21–25 for severe disease and >25 for very severe disease. Conclusions Disease severity cut-offs can represent an important improvement in interpreting FM.

Objective. To provide estimates of patients with rheumatoid arthritis (RA) eligible for biotechnological therapy and to evaluate their healthcare costs. Method. An observational analysis was performed based on data-linkage between administrative databases of selected Italian Regional/Local healthcare departments. Data were then re-proportioned to the Italian population. Patients with RA diagnosis defined by discharge diagnosis and/or exemption code during 01/01/2013- 31/12/2017 were included. The criteria applied to evaluate the elegibility for biotechnological therapy were: 1) methotrexate (MTX)-treatment failure ≥6 months and start of a different conventional-synthetic diseasemodifying antirheumatic drugs (csDMARD); 2) corticosteroid ≥6 months with dosage ≥7.5 mg/die; 3) MTX-contraindication (therapy or hospitalization for renal damage/interstizial lung disease/hepatic failure). Mean annual costs per patient included drugs, hospitalizations, outpatient services. Results. Data re-proportioned to the Italian population estimated 318,328 RA patients: 43,361 with, 274,967 without biotechnological agents. Among the latter, 26,487(9.6%) patients met ≥1 criteria applied for eligibility: 1,896 had MTX-treatment failure and started another csDMARD; 15,833 received corticosteroid ≥7.5 mg/die; 7,788 had MTX-contraindication. Regarding patients fulfilling two criteria, 107 had MTX-treatment failure followed by another csDMARDs and corticosteroid ≥7.5 mg/die, 53 were treated with another csDMARDs after MTX-treatment failure and also presented MTX-contraindication, 810 had corticosteroid ≥7.5 mg/die and MTX-contraindication. Mean total annual costs for patients estimated eligible for biotechnological therapy was € 3,132, of which € 177 related to drugs indicated for RA and € 2,955 related to other direct costs. Conclusions. According to our estimates, around 10% RA patients not currently treated with biotechnological agents are eligible for such therapies, highlighting a trend of under-use in clinical practice for RA management.

Objective.Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T.Methods.Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model).Results.A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02–1.19), smoking (OR 1.32, 95% CI 1.08–1.63) and high number of tender joints (OR 1.03, 95% CI 1.02–1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50–0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model.Conclusion.Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].

Marco A Cimmino,1 Massimiliano Parodi,1 Francesca Barbieri,1 Stefano Bombardieri,2 Giuseppe Zampogna,1 Annamaria Iagnocco,3 Alberto Batticciotto,4 Luca Maria Sconfienza,5,6 Luigi Sinigaglia,7 Fabrizio De Benedetti,8 Fabiola Atzeni,9 Piercarlo Sarzi-Puttini10 1Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy; 2Rheumatology Unit, Santa Chiara Hospital, University of Pisa, Pisa, Italy; 3Academic Rheumatology Centre, Università degli Studi di Torino, Turin, Italy; 4Rheumatology Unit ASST-Settelaghi, Ospedale di Circolo – Fondazione Macchi, Varese, Varese, Italy; 5IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 6Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy; 7Rheumatology Unit, G. Pini Hospital, Milan, Italy; 8Division of Rheumatology, IRCCS, Bambin Gesù Paediatric Hospital, Rome, Italy; 9Rheumatology Unit, University of Messina, Messina, Italy; 10Rheumatology Unit, L. Sacco University Hospital, Milan, ItalyCorrespondence: Piercarlo Sarzi-PuttiniReumatology Department, L. Sacco University Hospital, ASST Fatebenefratelli – Sacco, Via G.B. Grassi, 74, Milan 20157, ItalyTel +39 02 39042208Email piercarlo.sarziputtini@gmail.comObjective: This open-label study evaluated the effects of combined tocilizumab (TCZ) and disease-modifying antirheumatic drugs (DMARDs) on magnetic resonance imaging (MRI) changes in synovial membrane enhancement, bone marrow edema (BME), and erosions in the wrist and hand joints of rheumatoid arthritis (RA) patients inadequately responding to DMARDs alone.Methods: The efficacy of intravenous TCZ 8 mg/kg administered every four weeks for 48 weeks was evaluated on six occasions. The primary endpoints were the changes in the extent and degree of wrist synovitis as measured using the RA MRI Score (RAMRIS) and dynamic, gadolinium-enhanced 0.2T MRI (DCE-MRI). A number of different parameters of DCE-MRI were evaluated.Results: Fifty-eight patients were treated, eight of whom (13.8%) discontinued the study prematurely. The mean RAMRIS significantly decreased after two weeks and the decrease was maintained for up to 48 weeks. By week 4, the mean RAMRIS synovitis score had significantly decreased from baseline (− 0.804± 1.575; p=0.018), but not the mean early enhancement (REE) or relative enhancement (RE). However, there were significant decreases in RE at week 24, in REE and Ntotal (total number of enhancing voxels)*IRE (initial rate of enhancement) at weeks 12, 24 and 48, and in Ntotal*ME (maximal enhancement) at weeks 24 and 48. Mean BME decreased from baseline to week 48, and bone erosions did not progress. The patients’ clinical parameters significantly improved from baseline until week 48.Conclusion: TCZ in combination with DMARDs improved wrist synovitis, BME and clinical parameters, without any progression in bone erosions. The RAMRIS for synovitis rapidly improved from as early as two weeks after the first TCZ infusion. (Funded by F. Hoffmann–La Roche; ACTRACE EudraCT No. 2009 012185-32).Keywords: tocilizumab, rheumatoid arthritis, wrist, synovitis, low-field MRI, dedicated MRI

ObjectivesTo investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target.MethodsRA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 ResultsIn total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52).ConclusionIn daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Objective.The Outcome Measures in Rheumatology Soluble Biomarker Working Group initiated an international, multicenter, prospective study, the Rheumatoid Arthritis (RA) BIODAM cohort, to generate resources for the clinical validation of candidate biomarkers predictive of radiographic progression. This first report describes the cohort, clinical outcomes, and radiographic findings.Methods.Patients with RA from 38 sites in 10 countries starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required to adhere to a treat-to-target strategy. Biosamples (serum, urine) were acquired every 3 months, radiography of hands and feet every 6 months, and ultrasound of hands and feet every 3 months in a subset. Primary endpoint was radiographic progression by the Sharp/van der Heijde score.Results.A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. At baseline, the majority was female (76%), mean age 55.7 years, and mean disease duration 6.5 years. Patients had a mean of 8.4 swollen and 13.6 tender joints, 44-joint count Disease Activity Score (DAS44) 3.8, 77.7% rheumatoid factor–positive or anticitrullinated protein antibody–positive. Percentage of patients in DAS and American College of Rheumatology remission at 2 years was 52.2% and 27.1%, respectively. Percentage of patients with radiographic progression (> 0.5) at 1 and 2 years was 38.2% and 59.9%, respectively.Conclusion.The RA BIODAM prospective study succeeded in generating an extensive list of clinical, imaging (2343 radiographs), and biosample (4638 sera) resources that will be made available to expedite the identification and validation of biomarkers for radiographic damage endpoints. (Clinicaltrials.gov: NCT01476956, clinicaltrials.gov/ct2/show/NCT01476956)

Background:Fibromyalgia syndrome (FM) is characterised by a complex symptom spectrum, dominated by the presence of chronic widespread pain, fatigue and unrefreshing sleep. FM affects between 2 and 3% of the general population. It is a condition that mainly involves middle-aged women, although it is increasingly being diagnosed in younger people. The severity of symptoms can vary greatly between individual patients, and is influenced by many factors (e.g. sex, body mass index) [1]. To date, there is little information about changes in severity in accordance with patient age.Objectives:The aim of this study was to investigate variations in symptom severity in FM patients according to age categories.Methods:A cross-sectional study of adult FM patients diagnosed according to the American College of Rheumatology 2010/2011 criteria was performed. The case series was included from an Italian national registry [2]. Patients were grouped according to five age categories: 18-40 years, 41-50 years, 51-60 years, 61-70 years, over 71 years. Symptom severity was assessed through the revised Fibromyalgia Impact Questionnaire (FIQR) and domains, including FIQR physical function (items 1-9), FIQR health status (items 10-11), and FIQR symptoms (items 12-21). Between-group characteristics were analysed using one-way analysis of variance (ANOVA).Results:This study included a total of 2889 patients, 403 aged 18-40 years, 756 aged 40-50 years, 1035 aged 50-60 years, 528 aged 60-70 years, and 167 over 70 years, respectively. The mean (standard deviation [SD]) score of the total FIQR was 52.68 (11.82). Total FIQR and individual domains all showed a normal distribution. Analysing the data by age category, there were statistically significant differences between the categories for the total FIQR (p = 0.030). The age categories with the highest disease severity were those above 71 years (FIQR 62.14, SD 22.45), and between 51-60 years (FIQR 60.31, SD 22.89) (Table 1). Significant differences between age categories were also found for the domains physical function (p = 0.006) and health status (p = 0.012), but not for the domain symptoms (p = 0.164).Table 1.Mean values of FIQR total score and domains according to age categories.FIQR and domains18-40 years41-50 years51-60 years61-70 years≥71 yearsp*FIQR total, mean (SD)57.90 (21.76)59.25 (23.30)60.31 (22.89)57.13 (23.59)62.14 (22.45)0.030FIQR physical function, mean (SD)15.51 (7.56)16.44 (7.77)16.77 (7.51)15.96 (7.82)17.68 (7.26)0.006FIQR health status, mean (SD)11.19 (5.85)11.24 (5.99)11.49 (5.93)10.57 (6.11)12.21 (5.97)0.012FIQR symptoms, mean (SD)31.32 (10.48)31.56 (11.32)32.10 (11.01)30.68 (11.47)32.24 (11.34)0.164Abbreviations and legend. FIQR = revised Fibromyalgia Impact Questionnaire; SD = standard deviation; * = one-way analysis of variance (ANOVA).Conclusion:Distinguishing the disease severity in FM patients according to age categories, a bimodal distribution emerges, with the disease severity being greatest in patients over 71 years and in the 51-60 years decade. The main differences in severity, according to what can be detected through the FIQR, are attributable to the domains physical function and health status, which show higher scores in the two classes with higher severity.References:[1]Sarzi-Puttini P et al., Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol 2020; 16: 645–660.[2]Salaffi F et al., The Italian Fibromyalgia Registry: a new way of using routine real-world data concerning patient-reported disease status in healthcare research and clinical practice. Clin Exp Rheumatol 2020; Suppl 123: 65-71.Acknowledgements:Società Italiana di Reumatologia (SIR) and Italian Ministry of HealthDisclosure of Interests:None declared

Background The most effective drug for the maintenance therapy of severe forms of lupus nephritis (LN) is still a matter of debate. Objectives To compare efficacy and safety of cyclosporine (CYA) with mycophenolate mofetil (MMF) and with azathioprine (AZA) in the long-term maintenance therapy of LN. Methods Ninety-six patients (pts) (93 females, mean age 31.98±12.78 years) with SLE and biopsy proven LN (16 pts:class III; 64 pts:class IV; 16 pts:class V ISN/RPS). Fifty-six pts entered this study at diagnosis of LN and 40 during a course of a LN flare. Twenty-five pts (30%) had Glomerular Filtration Rate (eGFR) 60ml/min and proteinuria 60ml/min and proteinuria >0.5/die, no response: eGFR Results At the beginning of maintenance therapy, the mean serum creatinine and eGFR were similar in the 3 groups (0.92±0.26mg/dl, eGFR 109,9±49,5ml/min in CYA, 0.86±0.4mg/dl, eGFR 119±44,6 in MMF, 0.85±0.3mg/dl, eGFR 106,6±43,9ml/min in AZA). Proteinuria was higher in CYA group (CYA:2.03±1.7g/day; MMF:0.77±0.8g/day; AZA:1.2±1.1g/day). At the beginning of maintenance therapy, complete, partial and no response were 26.6%, 60%, and 13.4% in CYA, 53.1%, 43.8% and 3.1% in MMF and 38.2%, 58.8% and 3% in AZA group (Fig 1). At 1 year, after 6 months of maintenance therapy, in CYA group the percentage of pts in complete remission increased to 73% (vs 65.6% in MMF and 40% in AZA), at 5 years it was 80% (vs 83% in AZA and in MMF) and 88% at 10 years vs 70% in MMF and 68% in AZA (Fig 2,3,4). The percentage of non-responsive pts was stable from 1 to 10 years in the CYA group (around 13%), it slightly increased in MMF group (from 3.1 to 13,5%) and in AZA group (from 15 to 24%). During the study, SLE flares occurred in 30% of CYA group, 41% in MMF and 32% of the AZA. The average time from the beginning of the study and the first flare was 3.95±2.76years in CYA, 3.62±1.60 in MMF and 5.9±2.37 in AZA. No side effects were reported in 90% of pts treated with CYA, in 81.3% with MMF and in 85.3% with AZA group. Conclusion This is the first study comparing these 3 drugs as maintenance therapy in the long term. After 10 years of observation, CYA, AZA and MMF have proven to be effective in consolidating and maintaining the remission of LN. Of interest are the results achieved in the CYA group. Despite worse clinical conditions at the beginning of maintenance therapy, CYA allowed a rapid achievement of LN remission in the great majority of pts compared to AZA and MMF. Remission persisted over 10 years of observation. The number and type of flares and of side effects were not different between groups. Reference [1] Moroni G, et al. 2006 Disclosure of Interests Lorenza Maria Argolini: None declared, Elena Elefante: None declared, Francesca Saccon: None declared, Valentina Binda: None declared, Maria Gerosa: None declared, Luigi Sinigaglia Speakers bureau: Yes, I,ve been invited speaker by Amgen, Ely Lilly, UCB, Abbvie, Roche and BMS., Piergiorgio Messa: None declared, Andrea Doria: None declared, Marta Mosca Paid instructor for: GlaxoSmithKline, Lilly, UCB, Gabriella Moroni: None declared

Background: In the last few years, it has been reported a secular change of Paget disease of bone (PDB), expressed as a reduction of prevalence1 and severity, assessed by disease extent2. Objectives: To retrospectively evaluate the baseline clinical and demographic characteristics of a contemporary cohort of patients affected by PDB, compared with a cohort of a previous decade3. Methods: Data were retrospectively extracted from a monocentric registry, which included PDB patients at their first evaluation in a tertiary rheumatology Center between January 2000 and September 2018. Descriptive data of baseline characteristics included demographics, presenting manifestation and diagnostic procedures (diagnosed by chance or by investigations requested for specific clinical manifestations), extent of PDB, and biochemical data. Patients were divided into two groups according to the year of first evaluation: group 1 before July 2007, group 2 after July 2007. Comparisons between the two groups were performed by T test and chi-square test; logistic regression was used to analyze the association between disease extent and other collected variables. Results: The overall population included 368 patients (males (M) 57.6%, mean age at diagnosis [± standard deviation, SD] 62.0±12.4 yrs). Diagnosis was made by chance in 43.8% cases, 54.3% patients had symptoms at disease onset; 49.5% was monostotic, mean serum alkaline phosphatase at presentation (sALP) was 198.5±167.5 UI/L. Group 1 included 217 patients (M 56.2%, mean age at diagnosis 61.0±11.6 yrs, 6.5% family history of PDB; 45.6% diagnosed by chance, 51.2% had symptoms at disease onset, mean sALP 218.9±11,7, 43.3% monostotic). Group 2 included 151 subjects (M 59.6%, mean age at diagnosis 64.3±11.1 yrs, 7.3% family history of PDB; 41.1% diagnosed by chance, 62.9% had symptoms at disease onset, mean sALP 162.7±14,2,58.3% monostotic). Poliostotic disease was significantly higher in Group 1 vs Group 2 (p=0.007), and the odd to have a poliostotic disease was higher in Group 1 [OR 1.82 (IC 1.2-2.8), p Conclusion: Our data confirm the reduction of clinical severity, assessed by the proportion of skeleton involved, and the decrease of biochemical markers over time. The reduction of the disease extent is consistent with a serological biomarker of the disease, such as mean sALP levels. References [1] Michou L, et al. JBS2016;83: 650–655. [2] Tan A, Ralston SH. Calcif Tissue Int2014;95:385–392. [3] Varenna M, et al. J Rheum2010;37:155-160. Disclosure of Interests: Chiara Crotti: None declared, Francesca Zucchi: None declared, Andrea Becciolini: None declared, Luigi Sinigaglia Speakers bureau: Yes, I,ve been invited speaker by Amgen, Ely Lilly, UCB, Abbvie, Roche and BMS., Massimo Varenna: None declared

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.

Objective The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. Methods We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18–55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). Results At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A “Disease Knowledge Index” (DKI) was created to investigate the degree of patients’ information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. Conclusion Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

Background:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces fibroblast growth factor-23 (FGF-23), causing hyperphosphaturia, hypophosphoremia, low 1,25(OH)2VitD3and osteomalacia. Locating the tumor is critical, because lesions are typically small, benign mesenchymal tumors, anywhere in the body; the delay between onset of symptoms and diagnosis ranges from 2.5–28 years. Surgical removal is the only effective therapeutic approach.Objectives:To retrospectively evaluate patients affected by TIO, investigating clinical management and disease outcome.Methods:We retrospectively collected data of patients affected by TIO referred to a tertiary Rheumatology Center between Sep 2000 and Jan 2020.Results:We included 16 patients with a definite diagnosis of TIO, mean age±standard deviation 62.4±14.6 yrs, 56.2% females, mean age at symptoms onset 48.0±14.3 yrs (53.8±13.1 at diagnosis). Mean diagnostic delay between symptoms onset and tumor detection was 6.8±6.4 yrs. All patients complained bone pain, muscle weakness, and fractures before diagnosis of TIO. Biochemical findings were: mean serum Phosphorus (PS) 1.4±0.4 mg/dL (reference range (RR) 2.5-4.6), mean serum Calcium 9.4±0.7 mg/dL (RR 8.4-10.2), mean serum 1,25(OH)2VitD330.5±23.4 ng/L (RR 25-86). Intact-FGF-23 was dosed in 9 patients, always resulting elevated: mean 396.6±707.3 pg/mL (RR 25-45). PTH was increased in 30% of cases, while serum alkaline phosphatase was increased in 87.5%. 24h-Urine Phosphorus (PU) was increased in only 13% of patients, but, when renal phosphate wasting by tubular reabsorption of phosphate (TRP) was calculated, PU resulted increased in all.Tumor was localized in all cases (Fig.1) and were localized in bone and soft tissue, by using functional imaging, followed by anatomical techniques. Before the introduction in routinely practice of68Ga-DOTATATE-PET-CT in 2013, Octreoscan-SPECT/CT and18F FDG-PET were used as imaging modalities. Since 2013, diagnostic delay consistently reduced, from 8.6±8.3 yrs (7 patients) to 4.5±2.6 yrs (9 patients), confirming higher diagnostic accuracy of68Ga-DOTATATE-PET-CT.Figure 1.13 patients underwent surgery; in two cases surgery was not possible due to tumor location, so pharmacological support with phosphate supplements and calcitriol was started; a patient underwent to TC-guided radiofrequency ablation. After surgery, 7 patients experienced a complete remission, 3 had a persistence of the disease, and 3 an overtime relapse, even after a longstanding normalization of PS (6 years). After surgical tumor removal, PS significantly increased in few days (from 1.36±0.39 to 2.9±1.1, p=0.0001), while iFGF-23 levels tended to rapidly decreased (from 396.6±707.3 to 62.8±78.4). Before the introduction of68Ga-DOTATATE-PET-CT, 6 patients underwent to imaging-guided closed biopsy to confirm tumor localization; by using68Ga-DOTATATE-PET-CT only 2 subjects had closed biopsy. Furthermore, in our population only patients who had biopsy to detect the lesion (7 patients) had relapses compared to patients who did not.Conclusion:To our knowledge, this is the widest European cohort of patients affected by TIO reported in the last two decades. We confirm an important delay between symptoms onset and diagnosis. To locate tumor, a stepwise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging, preferring68Ga-DOTATATE-PET-CT. Tumor biopsy is not recommended due to the potential cell spilling. Surgery is considered the only definitive treatment, aiming to a wider excision. Active surveillance is always needed, due to the possible relapses, even after a long period of complete clinical and biochemical remission.Disclosure of Interests: :Chiara Crotti: None declared, Francesca Bartoli: None declared, Maria Manara Consultant of: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Speakers bureau: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Primo Andrea Daolio: None declared, Francesca Zucchi: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Luigi Sinigaglia: None declared, Massimo Varenna: None declared

Background Rheumatoid arthritis(RA) is frequently complicated by other comorbid diseases that may drivetherapeutic strategy or interfere with achieving clinical response. Objectives To retrospectively evaluate the impact of comorbidities on treatment choice, 12-month clinical response, and 24-month retention rate in a cohort of RA patients treated with a first-line subcutaneous tumour necrosis factor alpha inhibitor (TNFi). Methods Study population was extracted from a local registry which included all RA patients receiving adalimumab (ADA) or etanercept (ETN) as first-line biologic drug between January 2001 and December 2013. The prevalence of common RA comorbidities was computed and the study population was stratified according to Rheumatic Disease Comorbidity Index ([RDCI 1 ] RDCI=0 vs RCDI≥1) for evaluating the role of comorbidities on the choice between ETN and ADA; the prescription of concomitant methotrexate (MTX); and the impact of comorbidities on 1-yearDisease Activity Score 28 (DAS28-ESR) remission and EULAR good-moderateresponse rates. The 24-month retention rate was computed by the Kaplan-Meiermethod and a Cox proportional hazard model was developed to examine the role ofRDCI and other baseline factors as predictors of TNFi persistence. Results 310 RA patients (153ADA and 157 ETN) were included (female 82.1%, mean±standard deviation (SD) age 53.6±13.1 years, mean disease duration 11.6±9.2 years, mean baseline DAS 285.28±1.21, RF positivity 76.4%, mean HAQ 1.39±0.56). 41.2% of patients had atleast one comorbidity (overall mean RDCI 0.73) and the prevalence of conditions is reported in table 1. The proportion of patients with RCDI≥1 was similar in the subgroup receiving or not concomitant MTX (55.1% versus 44.8%, respectively; p=0.57) and similar (p=0.22) in patients treated with ADA (44.8%) or ETN (37.8%). No individual comorbidity was associated with the prescription of MTX or the choice between the two TNFis. No difference was found in therates of both EULAR good-moderate response (61.3% vs 53.7%, p=0.175) and DAS28-ESR remission (31.4% vs 27.2, p=0.463) according to baseline RDCI score. On the other hand, elevated RDCI is a predictor of biologic drug discontinuation (Hazard Ratio [HR] 1.17, confidence interval [95% CI] 1.00-1.37;p=0.04), where as treatment with ETN (HR 0.50, 95% CI 0.35-0.71; p Conclusions in our real-life experience, the baseline presence of comorbidity seemed to not influence the prescription of concomitant MTX and to not drive the choice between ADA and ETN. Comorbidities did not affect 1-year clinical response, but were associated with a higher risk of TNFi discontinuation over a 2-year follow-up period. The use of ETN and concomitant treatment with MTX were both strong predictors of drug persistence. Reference: 1. England BR, Sayles H, Mikuls TR, et al. Validation of the rheumatic diseasecomorbidity index. Arthritis Care Res 2015;67(6):865-72. Disclosure of Interest: None declared

Background Rheumatic Diseases (RD) frequently affect women during reproductive age, therefore counselling on family planning is crucial for their quality of life. Children’s outcome is a major topic, but no large studies are available. Objectives To assess the long-term health conditions of children born to women with RD in a large multicentre cohort. Methods 24 Rheumatology Centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to consecutive patients (18–55 years) in September 2015. Data were analysed dividing children upon maternal diagnosis: Chronic Arthritides (CA) and Connective Tissue Diseases (CTD). Results Data were collected for 320 children (166 males, 52%) born to 184 mothers (63 CA and 121 CTD). At the time of interview, children had a mean age of 17.1±9.6 years. Preterm delivery ( Conclusions In this long-term follow-up of children born to mothers with RD in this large, multicenter study of randomly interviewed women each AIID did not display a significantly increased frequency as compared to the literature; only coeliac showed a mild increased frequency. Children with LD had a tendency to cluster in the group of mothers with CTD, especially after maternal diagnosis (4/63, 6.3%), with a higher frequency as compared to general paediatric population. No significant relationships between ND/LD and prematurity, intrauterine drug exposure or maternal autoantibodies were identified. Acknowledgements Statistical analysis supported by an unrestricted grant by UCB Pharma. The authors wish to thank Patients Associations and Participants to the survey. Disclosure of Interest None declared

Background Disease activity significantly impacts on work ability of patients with Rheumatoid Arthritis (RA). Biologic agents can control disease activity, but their effects on productivity outcomes were not adequately investigated in Italian population. Objectives Aim of the study was to evaluate the impact of biologic therapy on work productivity outcomes in a cohort of biologic-naive patients with active RA from northern Italy. Methods This is a multicentre prospective study on patients with active RA in working age (18–65 years), scheduled to undergo their first biologic treatment. Demographics and clinical data were collected at baseline and at 6 and 12 months, together with productivity outcomes assessed with the RA-specific work productivity survey (WPS-RA)1 and the Health and Labour Questionnaire (HLQ)2. Primary outcome was the productivity loss or gain after 1 year of treatment. Results We included 100 patients from 7 rheumatology centres in northern Italy with active RA [mean DAS28: 5,1 (SD 0,9), median SDAI: 25,2 (IQR 18,7–33,2)]. Most of them were females (85%), with a mean age of 49,1 (SD: 10,3) years and a median disease duration of 7 (IQR: 3–14) years. Patients were treated with TNF-inhibitors (68%), Abatacept (24%) or Tocilizumab (8%). At baseline 39 patients were unemployed. After 1 year of treatment, 85 patients were still on follow-up, with an improvement in all indexes of disease activity [mean DAS28: 2,8 (SD 1,3), median SDAI: 5,1 (IQR 1,9–12,9)]. A significant reduction in number of days of work missed (absenteeism) and of reduced productivity (presenteeism) was observed in employed subjects, as well as a significant decrease in number of days missed of household work and social activities in all the study population (table 1). Conclusions One year of treatment with biological drugs was associated with a significant improvement in outcomes related to productivity both within and outside home in a cohort of patients with RA. References [1] Osterhaus JT. Arthritis Res Ther. 2009;11:R73. [2] Van Roijen L. Int J Technol Assess Health Care1996;12:405–15. Disclosure of Interest M. Manara: None declared, R. Caporali: None declared, R. Gorla: None declared, E. Fusaro: None declared, R. Pellerito: None declared, P. A. Rocchetta: None declared, P. Sarzi Puttini: None declared, S. Capri Consultant for: Pfizer, L. Sinigaglia: None declared

Background Rheumatic Diseases (RD) frequently affect women during reproductive age, therefore counselling on family planning is crucial for their quality of life. Children’s outcome is a major topic, but no large studies are available. This study aimed at assessing the long-term health conditions of children born to women with RD. Methods 24 Italian Rheumatology Centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to consecutive patients (aged 18–55) during September 2015. Data were analysed dividing children upon maternal diagnosis: Chronic Arthritides (CA) and Connective Tissue Diseases (CTD). Results Data were collected for 320 children born to 184 mothers (63 CA and 121 CTD). At the time of interview, children had a mean age of 17.1±9.6 years. Pre-term delivery ( The occurrence of an autoimmune/inflammatory disease (AIID) and/or neurodevelopmental disorders (ND)/learning disabilities (LD) is reported in table 1. Twelve children (3.7%) were diagnosed with an AIID, mostly coeliac disease (8/12, 67%). Eleven children (3.4%) were diagnosed as having a ND and/or LD by a Paediatric Neuropsychiatrist. Data of in utero exposure to maternal autoantibodies and/or anti-rheumatic drugs were retrieved for 280 children (87.5%) and a comparison was performed between affected (n=11) and not-affected children (n=258). No association was found with ND/LD and in utero exposure to autoantibodies (ANA, anti-Ro, anti-dsDNA, aPL) or drugs (HCQ,AZA or steroids), neither with sex, preterm birth, birth weight or maternal diagnosis. Conclusions The long-term follow-up of children born to mothers with RD did not raise particular concerns in terms of relevant health problems. In particular, each AIID did not display a significantly increased frequency as compared to the literature. Children with ND/LD had a tendency to cluster in the group of mothers with CTD, especially after maternal diagnosis, with a higher frequency as compared to GPP (7.9% vs 3%). Our data suggest that the development of ND/LD in children of patients with RD cannot be linked exclusively to maternal disease. The results of this study can be reassuring for patients with RD about problems in the offspring possibly related to their disease.

Objectives To evaluate the 2-year retention rate of golimumab compared with etanercept and adalimumab as second-line biologic agent in rheumatoid arthritis (RA) patients who failed a previous tumor necrosis factor inhibitor (TNFi). Methods Data on RA patients treated with a second-line subcutaneous TNFi were extracted from a multicentric Italian cohort (the LORHEN registry). The analysis was limited to etanercept, adalimumab and golimumab in the period when all were available in Italy (since October 2010). The 2-year retention rate was calculated by Kaplan-Meier method and the comparative risk for discontinuation among individual TNFi was compared by a stratified log-rank test. Results One hundred and ninety-five RA patients treated with etanercept (n = 76), adalimumab (n = 68) or golimumab (n = 51) were included in the analysis. The 2-year retention rate (40% with a median time-on-drug of 12.9 months in the whole population) was significantly lower for adalimumab (31.2%, P = 0.018) and numerically lower for etanercept (39.8%, P = 0.068) compared with golimumab (53.4%) because of a higher discontinuation rate due to adverse events (P = 0.042 and P = 0.038 versus golimumab, respectively). Drug survival was greater in concomitant synthetic disease modifying anti-rheumatic drug (sDMARD) users (44.2%) compared with TNFi monotherapy (22.5%, P = 0.036). No difference was found in survival analysis according to first-line TNFi reason for discontinuation and pattern of TNFi switch (antibody-receptor, antibody-antibody or receptor-antibody). Conclusions Our real-life data confirmed switching to a second TNFi as a good option for treating first-line TNFi failures in RA, especially in combination with sDMARDs. Second-line golimumab showed an overall better 2-year drug survival compared with adalimumab and etanercept.

Objectives To review the available evidence concerning the possibility of discontinuing and/or tapering the dosage of TNF inhibitors (TNFi) in RA patients experiencing clinical remission or low disease activity. Methods A systematic review of the literature concerning the low dosage and discontinuation of TNFi in disease-controlled RA patients was performed by evaluation of reports published in indexed international journals (Medline via PubMed, EMBASE), in the time frame from 8 April 2013 to 15 January 2016. Results We analysed the literature evaluating the efficacy and the safety of two different strategies using TNFi, decreasing dosage or discontinuation, in patients experiencing clinical remission or low disease activity. After the analysis of online databases, 25 references were considered potentially relevant and 16 references were selected. The majority of data concerned etanercept and adalimumab. Results suggested the induction of stable clinical remission or low disease activity by using TNFi followed by a dosage tapering and/or discontinuation of such drugs may be associated with the maintenance of a good clinical response in a subset of patients affected by early disease. Conclusion RA patients treated early with TNFi and achieving their therapeutic clinical targets seem to maintain their clinical response after tapering or discontinuing TNFi. These data may allow physicians a more dynamic and tailored management of RA patients.

Background Rheumatic diseases (RD) predominantly affect young women during reproductive age. Pregnancy, contraception and family planning (FP) are crucial for the quality of life of these patients. Objectives We aimed to investigate 9women9s health9 through a self-reported questionnaire. Answers from patients with connective tissue diseases (CTD) vs chronic arthritis (CA) were compared. Methods 24 centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to women with RD (18–45years) regularly attending their outpatient clinics. Results Answers were collected from 249 CTD vs 149 CA patients. Their desire to have children was influenced by RD in 40% of cases: half of them reduced the number of children they wanted (Table 1). 39% CA vs 29% CTD were afraid of being mother because of disability. 24% CTD vs. 18% CA had at least one miscarriage; 21% CTD vs. 2% CA had more than one. 31% CTD and 34% CA were never asked about their desire to have children. 61% CTD vs 70% CA received counselling about contraception, given by a gynaecologist (G) (58% vs 64%), rheumatologist (R) (22% vs 14%) or both (7% vs 9%). 60% in both groups received a counselling before pregnancy: 34% vs 39% from R and G, 14% vs 22% by R. This positively changed family planning in 64% vs 59%. We created a Knowledge Index (based on the average of the normalized performed scores on 6 key questions for different sections): 55% CTD patients vs 44% CA had a medium-high score. A higher score directly correlated with the desire to became pregnant and with a multidisciplinary counselling. Conclusions This survey suggested that CTD have a major impact on FP and family size, possibly mediated by the increased rate of miscarriages as compared to CA. Concerns about reproductive issues could be positively overcome by adequate counselling. Rheumatologists should implement the discussion about FP and the compatibility of drugs with pregnancy in the management of young women with RD, especially those with CTD for whom contraception and pregnancy have particular implications. Acknowledgements Statistical analysis supported by an unrestricted grant by UCB Pharma Thanks to Patients9 Associations and Participants Disclosure of Interest None declared

Background Chronic rheumatic conditions such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are associated with severe morbidity and significant impairment of patients9 health related quality of life (HRQoL). Several treatments are available but not all the patients respond positively to them. Biologic therapies such as anti-TNFα agents are shown to benefit who fail or have partial responses to standard DMARD therapy. Objectives Within a multicenter stated preferences study (CARA Study), we assessed HRQoL in patients with RA, AS and PsA, and estimated relationship of HRQOL with the different diagnoses, clinical characteristics and biological treatment experience. Methods Patients with RA, AS, or PsA, who at the time of enrollment were following a treatment (experienced) or received a first prescription (naive) of treatment with biological drugs were enrolled. Together with preferences data, clinical and HRQOL information was reported. HRQoL was assessed with the recently developed and successfully validated version of the EQ-5D-5L, which allows to obtain a description of health (in 5 domains and 5 levels of severity each), a measure (EQ-VAS) and a valuation (utility) of health. Multiple linear regression analyses were conducted to assess the association between EQ-5D VAS score and the utility with age, sex, diagnosis, treatment experience, years from symptoms onset and years from diagnosis. Results 513 patients were enrolled (mean±SD =50.0±13.6, 42.5% female). As regards the diagnosis, 33.9% had RA, 34.9% PsA and 31.2% AS. The mean±SD time from the symptoms onset was 10.8±9.4 and from the diagnosis was 8.0±8.2 years. Almost half of the patients (47.4%) were naive to the biological treatment. Patients reporting severe or extreme problems were: 7.1% in mobility, 3.6% in self-care, 10.3% in usual activities, 18.6% in pain/discomfort, 5.5% in anxiety/depression. The mean±SD of the VAS was 60.4±20.5 and of the utility was 0.773±0.116. From the regression model the VAS and utility are significantly (p Conclusions Patients naive to biological treatment have significat lower levels of HRQoL, suggesting that their current situation is not satisfactory and need to start with a more effective treatment. Disclosure of Interest L. Sinigaglia: None declared, L. Scalone: None declared, P. Sarzi-Puttini: None declared, C. Montecucco: None declared, R. Giacomelli Grant/research support from: MSD, G. Lapadula: None declared, I. Olivieri: None declared, A. Giardino Employee of: MSD Italia, G. Didoni Employee of: MSD Italia, P. Cortesi Grant/research support from: Gilead, L. Mantovani: None declared, M. Mecchia Employee of: MSD Italia

Background Methotrexate (MTX) is the DMARD of first choice in the treatment of rheumatoid arthritis (RA). Objectives To investigate the clinical characteristics and describe therapeutic approaches in RA patients ongoing MTX not achieving a DAS28 “low disease activity” score. Methods This is a case-control analysis including 186 patients (mean age±SD, 61±12 years, 16% males) who did not achieve a DAS28 “low disease activity” score (defined by a value ≤3.2) and 558 age- and gender-frequency-matched (1:3), randomly selected controls (mean age age±SD, 61±13 years) who achieved a DAS28 “low disease activity” from the original cohort investigated in the MARI study. The MARI study enrolled RA patients on treatment for at least 12-month with MTX. Demographic, clinical, laboratory and pharmacological characteristics of patients recorded at baseline visit were considered for the current analysis. We first compared the characteristics of patients who reached the endpoint with those of subjects who did not by univariate analyses, thereafter, we performed a multivariate model to identify predictors of not achieving the endpoint. We further investigated the therapeutic approaches in patients not achieving the endpoint. Results Compared to patients with a DAS28 ≤3.2, subjects not achieving the endpoint presented with a significant higher (mean±SD) weight and BMI (DAS28 ≤3.2: 25±4 versus DAS28 >3.2: 26±5, P=.022), and longer duration of symptoms (months±SD) before the RA diagnosis (11±15 versus 15±20, P=.009). A higher proportion of subjects within the group not achieving the endpoint presented with polyarticular disease (DAS28 ≤3.2: 57% versus DAS28 >3.2: 96%, P 3.2 (P=.004). In the logistic regression analysis, the variables predictive of a DAS28 >3.2 were polyarticular disease (OR 4.0, 95% CI 2.4–6.7, P 3.2: 13% versus DAS28 ≤3.2: 4%, P Conclusions Our results identified a number of variables potentially associated the risk of not achieving a DAS28 “low disease activity” score in RA patients ongoing MTX treatment. Longitudinal studies are warranted. Disclosure of Interest None declared

Background Rheumatic diseases (RD) affect women during reproductive age. Children9s outcome is a major topic for counselling on family planning, but no large studies are available. Objectives We aimed at assessing the long-term health conditions of children born to mothers with RD through a self-reported questionnaire. Methods 24 Rheumatology Centers distributed the questionnaire (65 multiple choice and 12 open-answer questions) to consecutive women with RD attending their outpatient clinic during September 2015. Data were compared according to maternal diagnosis (MD) -chronic arthritis (CA) or connective tissue disease (CTD)- and to the timing of pregnancy (before or after MD of RD). Results The survey yielded data about 269 children born to 184 mothers (63 CA, 121 CTD). According to MD, children had a mean age of 17.1 (±9.6 SD) and 14.4 (±9.0 SD) years at the time of interview, and male children were 52/93 (56%) and 91/176 (52%), respectively. Twenty-nine children in the CA group (31.2%) and 64 in the CTDs group (36.4%) were born after MD of RD. Pre-term delivery (before 37 weeks) was observed in 48 cases (17.8%), mostly children born to mothers with CTD (37/48, 77%). Regarding school performance, 12 children (4.5%) repeated one year of school, in 7 cases for indolence, in 3 for learning disabilities (LD)/health problems (HP), in 2 for family problems. Eleven of these children were born before MD. Overall, 9 children (3.3%) were diagnosed with a LD and 53 children were affected by HP requiring either hospitalization or evaluation by a Specialist (Table). Three children (1%) were affected by autoimmune disease. Conclusions The long-term follow-up of children born to women with RD is reassuring of an outcome similar to that of the general pediatric population (GPP). Autoimmune diseases are not frequent. Problems seem to cluster in children born to CTD, especially after MD, with a higher frequency of LD (6.3% vs 2.5–3.5% of GPP), but no particular pattern of exposure to maternal autoantibodies nor drugs was observed. Acknowledgements Statistical analysis supported by an unrestricted grant by UCB Pharma Thanks to Patients Associations and Participants to the survey Disclosure of Interest None declared

Background The development of biologic therapies has created a more complex decision-making process to select the treatment option for patients. In order to optimize the appropriateness of the decisions, it is necessary to be informed and aware of the preferences of the interested parties and the influence of their experiences on their preferences for the different treatments. Objectives To estimate preferences of relevant treatment characteristics valued by the different subjects involved in the management of patients with rheumatic diseases. This abstract focuses on patients9 preferences. Methods We involved patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA), who according to clinical practice, at the time of data collection had for the first time a prescription of (naive), or received treatment with (experienced) biological drugs for at least 3 months in the last 12 months. Through a Discrete-Choice-Experiment, the participants valued 16 possible scenarios in which pairs of similarly effective treatments were described with 6 characteristics including 2–4 possible levels each: (1) frequency of administration; (2) mode and place of administration; (3) hospitality, service, efficiency and courtesy of health personnel; (4) frequency of reactions at the site of drug administration; (5) generalized undesired reactions or allergic reactions involving the whole body; (6) additional contribution added as healthcare taxes to be paid by all the citizens to make available the treatment to target patients. Results 513 patients from 30 centres through Italy participated, balanced for diagnosis and treatment experience (around 20% of each subgroup). Characteristics 4, 3 and 6 were the first, second and third most important ones for every subgroup, the fourth most important characteristic was 1 (experienced RA), 5 (naive AS), and 2 for the other subgroups. Across all the subgroups, patients generally preferred very satisfactory levels of (3), infrequent (4), mild (5), and no (6). Instead, for characteristics (1) and (2) the patients generally preferred the frequency, mode and place of administration that were closer to those actually experienced or prescribed. Conclusions Taking into account the different opinions of patients on at least some treatment characteristics could guide the conduction of good choices aimed to optimize benefits and to allocate efficiently resources. Disclosure of Interest L. Sinigaglia: None declared, P. Sarzi-Puttini: None declared, L. Scalone: None declared, C. Montecucco: None declared, R. Giacomelli Grant/research support from: MSD, G. Lapadula: None declared, I. Olivieri: None declared, A. Giardino Employee of: MSD Italia, P. Cortesi Grant/research support from: Gilead, L. Mantovani: None declared, M. Mecchia Employee of: MSD Italia

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics’ registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p

Background The management of patients with rheumatologic diseases (RDs) involves a complex interaction between different parties such as patients, physicians, pharmacists. The development of biologic therapies has created a more complex decision-making process to select the treatment option for patients. To optimize the appropriateness of the decisions, it is necessary to be informed and aware of the preferences of the interested parties. Objectives To estimate preferences of relevant treatment characteristics with biological agents valued by the different subjects involved in the management of patients with rheumatic diseases. Methods We involved patients with RDs, rheumatologists, nurses and pharmacists with experience in the treatment with/provision of biological drugs of these patients. Through a Discrete-Choice-Experiment, the participants valued 16 possible scenarios in which pairs of similarly effective treatments were described with 6 characteristics including 2–4 possible levels each: (1) frequency of administration; (2) mode and place of administration; (3) hospitality, service, efficiency and courtesy of health personnel; (4) frequency of reactions at the site of drug administration; (5) generalized undesired/allergic reactions; (6) additional cost: since the Italian NHS pays treatment costs, we included possible additional cost as monthly healthcare taxes for all the citizens, to make available the treatment to all target patients. relative importance of each characteristic was estimated through a random-effects conditional logistic regression model. Results 513 patients, 110 rheumatologists, 51 nurses and 46 pharmacists from 30 centres through Italy participated. Characteristics (3), (4) and (6) were the most important for every subgroup, while (1) was the least important for patients and rheumatologists, (2) the least important for the pharmacists, (2) and (5) the least important for the nurses. The four subgroups were consistent in preferences towards the specified levels of characteristics (1) and (3) to (6). However, as for characteristic (2), pharmacists preferred autonomous subcutaneous injection with syringe, nurses preferred assisted infusion at an infusional center close to patient9s place, patients and rheumatologists preferred autonomous subcutaneous injection with pen. Conclusions Different subjects show different preferences for some treatment characteristics, which together with pure clinical aspects can play an important role in the choice and consequent success of treatments. Disclosure of Interest P. Sarzi-Puttini: None declared, P. Cortesi Grant/research support from: Gilead, L. Sinigaglia: None declared, C. Montecucco: None declared, R. Giacomelli Grant/research support from: MSD, G. Lapadula: None declared, I. Olivieri: None declared, A. Giardino Employee of: MSD Italia, G. DIdoni Employee of: MSD Italia, L. Scalone: None declared, L. Mantovani: None declared, M. Mecchia Employee of: MSD Italia

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.

Background The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). Methods and findings This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: −0.85, p < 0.001, 95% CI −1.28 to −0.42) and 6 months (β: −1.05, p < 0.001, 95% CI −1.50 to −0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: −1.04, p < 0.001, 95% CI −1.52 to −0.55) and 6 months (β: −1.24, p < 0.001, 95% CI −1.75 to −0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. Conclusions In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Trial registration The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481., Roberto Giacomelli and co-authors study treatment of comorbid rheumatoid arthritis and type 2 diabetes via interleukin-1 blockade., Author summary Why was this study done? A growing body of evidence suggests the inflammatory contribution to type 2 diabetes (T2D) as observed in rheumatoid arthritis (RA). Interleukin-1 (IL-1) would be a common pathogenic mediator in T2D and RA, suggesting a possible common therapeutic target. We investigated whether IL-1 inhibition with anakinra, a human IL-1-receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). What did the researchers do and find? In a multicentre, open-label, randomised controlled trial, 39 participants with RA and T2D (age 62.72 ± 9.97 years, 74.4% female sex) were randomised to anakinra or to TNFi in order to evaluate the efficacy of these drugs in controlling the metabolic alterations of T2D. Anakinra showed a significant improvement of metabolic alteration (reduction of percentage of glycated haemoglobin [HbA1c%]) after both 3 months and 6 months of therapy (crude difference of 0.93 HbA1c% between groups), whereas TNFi did not show any significant improvement on these features. No severe adverse events, hypoglycaemic episodes, or deaths were observed. What do these findings mean? Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Managing the inflammatory disease and the metabolic comorbidity by an agent inhibiting IL-1 may lead to a consequent beneficial impact on participants’ compliance, their overall cardiovascular (CV) risk, and the burden of healthcare costs. Our study has some limitations, mainly due to open-label design, and future studies are necessary to fully clarify this topic.

Cystic angiomatosis (CA) is a rare disease characterized by multifocal hemangiomatous and/or lymphangiomatous lesions of the skeleton with possible visceral organ involvement. The exact pathogenetic mechanism of the disease is still unknown. We describe a patient affected by CA of bone treated with surgical procedures and subsequently with intravenous aminobisphosphonates for 7 years. During the follow-up progression of lesions, the painful symptoms, markers of bone turnover, computed tomographic examination, and bone mineral density were evaluated. Aminobisphosphonate therapy showed an immediate effectiveness in reducing bone pain, with a significant decrease in circulating bone alkaline phosphatase and stable radiological findings during clinical follow-up. In addition, at baseline, high levels of bone biomarkers and cytokines (osteoprotegerin, osteopontin, and interleukin-6) capable of controlling bone metabolism and angiomatosis were identified. Aminobisphosphonate treatment produced a decrease of all these increased markers. Local cell therapy with bone marrow osteoblast precursors did not produce any measurable clinical improvement. Aminobisphosphonate therapy represents an elective treatment for bone angiomatosis syndromes, but further studies are necessary to understand the molecular basis of these disorders and of their pharmacological treatment.

Hypertension and related cardiovascular diseases are reported to be associated with osteoporosis. A nutritional pathway related to dairy intake has been postulated for both diseases. The aim of this study was to assess calcium intake from dairy sources as a possible pathogenic link between osteoporosis and hypertension. This was a cross-sectional observational study performed on 3,301 postmenopausal women referred for a densitometry screening. Osteoporosis was diagnosed by lumbar dual-energy X-ray absorptiometry and hypertension was defined by blood pressure data and/or the use of antihypertensive medication. Dairy food consumption was evaluated using a weekly food-frequency questionnaire. The odds of being affected by osteoporosis, hypertension, or both diseases were calculated for quartiles of dairy intake by logistic regression analyses. Women with hypertension were affected more frequently by osteoporosis (33.2 vs. 23.3 %; p = 0.000), and there was a higher prevalence of hypertension among women with osteoporosis (32.2 vs. 22.5 %; p = 0.000). The proportion of women with hypertension, osteoporosis, and both diseases significantly increased across decreasing quartiles of dairy intake. A dairy intake in the lowest quartile was a significant predictor of osteoporosis [OR (95 % CI): 1.43 (1.12, 1.82)] and hypertension [OR (95 % CI): 1.46 (1.15, 1.85)] when compared to the highest quartile. Similarly, a low dairy intake was associated with increased odds to have both the diseases [OR (95 % CI): 1.60 (1.10, 2.34)]. From these results we conclude that osteoporosis and hypertension are associated in postmenopausal women, and a low dairy intake may increase the risk of both diseases, acting as a possible pathogenic link.

Objective. Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of this multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. Methods. Eighty-two patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open label the same regimen of neridronate. Results. Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm (95% CI 52.5, 40.5) vs 22.6 mm (95% CI 28.8, 16.3) for placebo group (P < 0.0001). Significant improvements vs placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients was referring symptoms linked to CRPS-I. Conclusion. In patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I. Trial registration: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/, 2007-003372-18.

Objective. The aim of this study was to assess whether the effectiveness of bisphosphonate infusion in patients with complex regional pain syndrome type I (CRPS-I) is influenced by variables related to patient and/or disease characteristics. Methods. This is a retrospective analysis of patients referred in the last five years to our rheumatologic tertiary care center, all fulfilling the Budapest CRPS-I diagnostic criteria and treated with three different bisphosphonate schedules (clodronate, pamidronate, and neridronate). For every subject, demographic and clinical variables were retrieved and retrospectively analyzed. We identified variables that independently influenced the therapeutic outcome of patients by a logistic regression analysis. For exploratory purposes, the effectiveness of the different bisphosphonate treatments employed was compared. Results. Among the 194 patients included in the analysis, the overall therapeutic response rate was 71.6%. Logistic regression analysis showed that the independent predictive variables for therapeutic effectiveness were disease duration (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.72–0.96 for a one-month increment), fracture as a predisposing event (OR = 3.23, 95% CI = 1.29–8.03), and “warm” disease subtype (OR = 4.88, 95% CI = 1.57–15.20). These variables were found to influence the odds of responsiveness when analyzed together with age at onset, gender, and disease localization. No significant difference in therapeutic effectiveness was found by comparing the three different bisphosphonate schedules employed. Conclusion. Early disease, fracture as a predisposing event, and “warm” disease subtype are predictors of responsiveness to bisphosphonate treatment in patients with CRPS-I.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts’ experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Despite the recent advances in understanding the pathogenesis of oncogenic osteomalacia, a rare paraneoplastic syndrome related to an excessive production of the phosphaturic hormone fibroblast growth factor 23 (FGF-23) by the tumor, the clinical diagnosis of this entity is still to be considered a clinical challenge, with an usual delay in the identification and treatment of affected patients that may lead to severe consequences for the individual’s quality of life. In this issue, Mathilde M. Bruins Slot-Steenks and colleagues report on a typical case of oncogenic osteomalacia in which a long delay from symptoms onset to correct clinical diagnosis had occurred, as well as a long time before tumor was identified and therefore an effective treatment could be established [1]. From a clinical point of view, it could be hard to suspect an osteomalacia in the initial phases of the disease, since most patients report only nonspecific symptoms such as weakness or diffuse pain, that could be identified as related to muscle or joint involvement, thus mimicking other common clinical conditions. The occurrence of fractures could highly help in the diagnosis, but a low bone mineral density at presentation may be lacking in some patients [2]. Laboratory findings suggestive of oncogenic osteomalacia are hypophosphatemia associated with renal wasting of phosphate, and inappropriate normal or low levels of 1,25OH vitamin D despite normal or mildly elevated parathyroid hormone values. These features are directly related to the effect of FGF-23, which inhibits on one hand tubular phosphate reabsorption, and on the other 1α-hydroxylase activity [3]. However, serum phosphate is frequently not included in routine blood chemistry testing, and hypophosphatemia, when detected, is frequently not regarded as relevant in the clinical judgment. Moreover, renal phosphate wasting is not always evident and it can be often revealed only after a specific evaluation, as in the case reported in this issue. Furthermore, 1,25OH vitamin D level is not routinely assessed and usually it is looked for only when a specific diagnostic hypothesis has been formulated. The dosage of circulating FGF-23 has been performed in some cases as a further help in the diagnosis of oncogenic osteomalacia. This assay however is currently not easily available in everyday clinical practice. Moreover, other phosphatonines have recently been postulated to be implicated in the pathogenesis of phosphaturic osteomalacia related to the tumor, such as fibroblast growth factor 7 [4]. Once the disease has been suspected based on clinical and laboratory findings, and after having ruled out other possible genetically determined renal phosphate-wasting syndromes due to FGF-23 excess, tumor detection is essential to confirm the diagnosis. Tumors responsible for oncogenic osteomalacia are often small, difficult to locate and slowly growing (strange tumors in strange places). Nowadays most osteomalacia-associated tumors are classified under a single histopathologic entity and referred as phosphaturic mesenchymal tumor-mixed connective tissue variant. Due to the high expression of receptors for somatostatin in most of these neoplasms, imaging techniques involving these receptors have been utilized for tumor localization. Whole-body scintigraphy with a radiolabelled somatostatin analogous (Tc-99 octreotide or In-111 pentetreotide) was the first choice in the past, but it provides only * Luigi Sinigaglia luigi.sinigaglia@gpini.it

Dr. Bonara: A 30-year-old woman was admitted to our emergency department (ED). In the past history, she had prolonged estrogen-progestinic treatment. In April 1999, she was admitted to the Infectious Diseases Department at the Polyclinic in Messina for acute pericarditis (the episode resolved quickly, and the patient was discharged without any therapy). At the end of February 2009, she had a sore throat and fever unresponsive to nonsteroidal anti-inflammatory drugs (NSAIDS) and amoxicillin. On March 7, the patient came to the ED for the persistence of fever, and the onset of diffuse myalgias and sternal pain. The electrocardiogram showed sinus tachycardia, widespread ST elevation (Fig. 1); chemistries: troponin I 15.81 ng/mL (\0.15), AST 111 U/L, ALT 32 U/L, CK 449 U/L, CRP 35 mg/dL, Hb 11.8 g/dL, Ht 30%, MCV 86 fL, WBCs 21,120/lL ? neutrophils 91%. The echocardiogram showed no alterations of the left ventricle (normal size, wall thickness and segmental contraction), EF 55%, mild mitral regurgitation, no pericardial effusion; chest X-ray: normal. Dr. Rietti (cardiologist): Clinical presentation, blood tests, and electrocardiogram were suggestive for myopericarditis; the patient was then hospitalized at the Department of Cardiology. During the hospitalization there was evidence of a pericardial effusion (measured by ultrasound: 8 mm in short axis view in diastole, Fig. 2) with dyskinesia of the interventricular septum and hypokinesia of the right ventricle, and the occurrence of a pleural effusion (first left and then bilateral); the presence of intermittent fever was confirmed. Blood tests showed marked neutrophilic leukocytosis (WBCs 20,000/lL, neutrophils 75%) and increased acute-phase proteins (CRP 35 mg/dL). Marked proteinuria (1.66 g/dL) with hypoalbuminemia was also detected (albumin 1.4 g/dL). All investigations of infective and autoimmunity diseases were negative. The patient was treated with acetylsalicylic acid (2 g daily). On March 12, a nephrological consultation was requested because of persistent proteinuria and cylindruria.

Objective.Paget’s disease of bone (PDB) is a focal disorder of skeletal remodeling that can lead to bone pain, deformity, and fractures, but it can often be asymptomatic for a long time. This study investigated which factors may distinguish patients with clinical manifestations from asymptomatic patients.Methods.The study group consisted of 224 patients with PDB referred to our Bone Disease Unit. For all patients, data were collected about clinical and demographic variables and diagnostic procedures. Logistic regression analyses were used to assess the role of recorded variables on the odds of being diagnosed clinically rather than by chance.Results.Among the 124 patients with clinical manifestations leading to the diagnosis (55.4%), 36 subjects complained of bone pain, 32 articular pain, 42 back pain, 2 headache; 9 had fractures in Paget bone, and 3 had bone deformity. In 100 patients (44.6%) PDB was diagnosed by chance. At the multivariate analysis, only the number of bones involved (OR for 1 site increment = 1.18, 95% CI: 1.007–1.402; p = 0.04) acted as an independent predictor for a clinical diagnosis. Some skeletal localizations were associated with a clinical diagnosis: the involvement of lumbar spine (OR = 2.085, 95% CI: 1.024–4.224; p = 0.043) was more likely in symptomatic patients; pelvis and tibia showed a borderline statistical significance. The skull was predictive for asymptomatic PDB.Conclusion.A systematic laboratory screening including serum alkaline phosphatase of an older subject complaining of bone pain, articular pain, or back pain is the sole strategy to improve the diagnostic sensitivity for PDB.

Background:High calcium intakes seem to be ineffective at reducingbonelossinearlypostmenopausalwomen.However,theinverse relation between calcium intake and body weight can attenuate the negative effect of a low dietary calcium intake. Objective: The objective was to assess the role of dietary calcium and body mass index (BMI) on osteoporosis, defined according to World Health Organization criteria as a lumbar bone density 2.5 SD below the T score. Design: This was a cross-sectional, retrospective, observational study conducted in 1771 healthy, early postmenopausal women, who were not taking calcium supplements at the first densitometric evaluation. Weekly frequency of dairy food consumption was used to estimate the relative intake of dietary calcium. Total dairy intake was classified into 4 categories by quartile cutoffs. Multiple logistic regression analyses were used to study this sample. Results: BMI and prevalence of overweight showed significant inverse trends with increasing dairy intake. Calcium intake was not associated with osteoporosis when overweight was not considered. However, when overweight was considered in the analysis, women withthelowestcalciumintakeweremorelikelytohaveosteoporosis (odds ratio: 1.46; 95% CI: 1.12, 1.89; P 0.008) than were women with the highest calcium intake. Conclusions: In early postmenopausal women, a low dietary calcium intake may increase the risk of osteoporosis, but its negative effect can be offset by the greater BMI found in women with a low calcium intake. Am J Clin Nutr 2007;86:639–44.

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.

Pancreatic polypeptide (PP) islet cell tumors are usually not associated with a distinct clinical syndrome, although some reports suggest that they can cause a watery diarrhea syndrome similar to vasoactive intestinal polypeptide (VIP) cell tumors. We report the case of a young woman with an unusual presentation of a pancreatic neuroendocrine tumor mainly secreting PP. The patient developed a reversible hypokalemic rhabdomyolysis very likely secondary to the presence of the tumor. The myopathy resolved following the restoration of normokaliemia using potassium supplementation and a partial laparoscopic pancreasectomy. Isolated cases of hypokalemic rhabdomyolysis induced by intestinal diseases have been described in literature but these did not include gastroenteropancreatic neoplasms. We suggest that pancreatic neuroendocrine tumors should be added to the list of intestinal diseases capable of producing hypokalemic myopathy.

The aim of this study was to evaluate the efficacy of intravenous pamidronate in patients with transient osteoporosis of the hip (TOH). Thirteen men and three women (mean age 38.3 years, range 30-49) were recruited. The diagnosis was made by means of radiographs, bone scintigraphy, and magnetic resonance imaging (MRI). Pamidronate (45 mg) was intravenously administered three times, once every third day. The outcome measures included a clinical assessment using a pain visual analog scale (VAS; range 0-100), and the WOMAC functional impairment score (FUI; range 0-100). The bone mineral density (BMD) of the total hip and femoral neck was measured using dual-energy X-ray absorptiometry (DXA). Clinical assessments were made before treatment (T(0)) and 1 month later (T(1)), and the densitometric measurements at T(0), and then after 2 (T(2)) and 4 months (T(4)). A further MRI scan was made 3 months after treatment. In comparison to the unaffected side, there was a significant decrease at T(0) in the BMD of both the total hip (median 16.6%, range 8.5%-29.1%, p0.00001) and femoral neck (median 22.5%, range 12.0%-34.2%, p0.00001). By T(1), both VAS and FUI had decreased significantly (p0.00001). By T(2), the total hip and femoral neck BMD had increased by 10.9% (range 2.7%-23.6%, p0.00001) and 12.3% (range 7.8%-26.9%, p0.00001), respectively, and all patients were asymptomatic. By T(3), the MRI findings had normalized in all patients and, at T(4), there was a further increase in BMD. None of the patients experienced symptom relapse during the follow-up of 39.5 +/- 17.7 months. These results suggest that a short course of pamidronate is effective in treating TOH, and leads to a prompt and long-lasting recovery.