Structured request form in musculoskeletal radiology examinations (CONCERTO): results of an expert Delphi consensus-structured radiology request form for correct classification of patients to undergo radiological examinations of the Italian Society of Medical and Interventional Radiology (SIRM), the Italian Society of Rheumatology (SIR) and the Italian Society of Orthopedics and Traumatology (SIOT).

PURPOSE: To describe a Delphi consensus for the realization of a structured radiology request form for patients undergoing musculoskeletal imaging. METHODS: A steering committee (four radiologists, a rheumatologist and an orthopedic surgeon) proposed a form to an expert panel (30 members, ten radiologists, ten rheumatologists and ten orthopedic surgeons). Through an online survey, the panelists voted on their level of agreement with the statements of the form using a 10-point Likert scale (1: no agreement; 10: total agreement) in a three-round process. A combination of two distinct criteria, a mean agreement level ≥ 8 and a percentage of at least 75% of responses with a value ≥ 8, was deemed as acceptable. RESULTS: The form achieved high median ratings in all the assessed key features. During the first round, all items met the threshold to be advanced as unmodified in the next round. Additional proposed items were considered and introduced in the next round (six items in Section 1, five items in Section 2, ten items in Section 3, 11 items in Section 4, six items in Section 5, eight items in Section 6, ten items in Section 7 and eight items in Section 8). Of these items, in round 3, only six reached the threshold to be integrated into the final form. CONCLUSIONS: Implementation of a structured radiology request form can improve appropriateness and collaboration between clinicians and radiologists in musculoskeletal imaging.

Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM.

OBJECTIVES: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy. METHODS: Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations. RESULTS: In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: -0.04, 0.33) for 2 vs 0 visits; and +0.08 units (-0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval. CONCLUSIONS: In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.

Sociodemographic factors in fibromyalgia: results from the Italian Fibromyalgia Registry.

OBJECTIVES: Fibromyalgia (FM) is a chronic musculoskeletal pain syndrome of unknown aetiopathogenesis. Its development and maintenance are related to the interplay of biological, psychological, and contextual factors. Among the contextual factors, sociodemographic aspects are poorly elucidated. This study aimed to evaluate the relationships between sociodemographic/clinical factors and symptom severity measures using a web-based registry of patients with FM. METHODS: Adult patients with an ACR 2010/2011 diagnosis of FM underwent a clinical evaluation and were asked to complete questionnaires covering their sociodemographic data (gender, age, marital status, educational level), and disease-specific measures (the revised Fibromyalgia Impact Questionnaire (FIQR), and the Polysymptomatic Distress Scale (PDS)). RESULTS: Data relating to 3,221 patients (3001 women and 220 men) was collected. The ANOVA showed significant difference in mean FIQR scores when the five marital conditions (cohabiter, married, separated/divorced, single, widowed) were compared (F 3.321, p<0.01). While males and females were found to have comparable FIQR scores, the interaction between gender and marital status indicated that separated/divorced males have higher FIQR scores (F 5.684, p=0.001). The multiple regression analysis demonstrated that patients who reported lower educational level experienced more severe FM symptoms, as scored with FIQR (p<0.0001). CONCLUSIONS: Our results indicated that being male and separated/divorced is associated to higher severity of FM symptoms, as rated with FIQR. Furthermore, a relationship between educational level and FIQR scores has been detected. This study supports the importance of collecting simple SES measures to identify environmental risk factors for FM severity.

Fibromyalgia severity according to age categories: results of a cross-sectional study from a large national database.

OBJECTIVES: The role of age in influencing the severity of fibromyalgia (FM) is still controversial. The aim of this study is to define the contribution of age in the severity of FM from data from a large national database. METHODS: This cross-sectional study included adult patients with FM diagnosed according to the 2010/2011 American College of Rheumatology criteria. Disease severity was assessed with the revised Fibromyalgia Impact Questionnaire (FIQR) and the modified Fibromyalgia Assessment Status (FAS 2019mod). Patients were grouped into five age categories (between 18-40 years, between 41-50 years, between 51-60 years, between 61-70 years, and ≥71 years). Differences in disease severity between groups were assessed by one-way analysis of variance (ANOVA). RESULTS: The study included 2889 patients (199 males and 2690 females), mean age of 52.58 (±11.82) years, with a mean FIQR score of 59.22 (±22.98) and a mean FAS 2019mod of 25.50 (±8.66). Comparing the mean values of the various indices between age categories, there were no statistically significant differences between the groups for FIQR total score and FAS 2019mod. However, the 60-70 years category showed the lowest scores for both scales. The main difference emerged for the FIQR physical function subscale, where the ≥71 years category showed significantly higher scores (p<0.05) compared the 18-40 years category. CONCLUSIONS: The severity of FM has a significant level of stationarity according to age categories. Patients between 60-70 years have a lower disease burden. Physical function is the health domain with the most significant difference between the groups.

Increased COVID-19 mortality in patients with rheumatic diseases: results from the CONTROL-19 study by the Italian Society for Rheumatology.

OBJECTIVES: To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy. METHODS: We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results. RESULTS: We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29-4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55-2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs. CONCLUSIONS: Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases.

The Immunologic Profile of Vitamin D and Its Role in Different Immune-Mediated Diseases: An Expert Opinion.

Historically, vitamin D is recognized as an essential component for the maintenance of the musculoskeletal system. The immunomodulatory role of vitamin D in health and disease has gained much interest in recent years due to the many pathologies that share underlying immunological features where vitamin D has been shown to exert a potential role. Evidence from pre-clinical studies show that vitamin D elicits biological effects on both the innate and adaptive immune systems. Furthermore, in vivo studies have shown that administration of vitamin D can lead to changes in or the development of a range of immune-related diseases. This encourages the hypothesis that data derived from clinical and epidemiological studies connect vitamin D with the incidence and severity of many immune-mediated disorders such as rheumatoid arthritis, diabetes, and infectious diseases. Since some other immune-mediated diseases share similar features to that of viral infection such as COVID-19, in this review, we examined these other areas and the role of vitamin D in these diseases.

The association between body mass index and fibromyalgia severity: data from a cross-sectional survey of 2339 patients.

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 < 0.001 for all). 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.

Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MARTE study.

BACKGROUND: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years. METHODS: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation). RESULTS: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001). CONCLUSIONS: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.

Impact of one-year treatment with biotechnological drugs on work ability in patients with rheumatoid arthritis in Italy: a prospective real-life study.

OBJECTIVES: We aimed to evaluate the impact of biologic therapy on work productivity outcomes in an Italian real-life cohort of biologic-naïve patients with active rheumatoid arthritis (RA). METHODS: This observational prospective multicentre study enrolled RA patients in working age with an active disease who started their first biologic agent. Every patient completed the RA-specific Work Productivity Survey (WPS-RA) at each clinical evaluation (baseline, 6 and 12 months). The primary outcome of the study was the productivity gain at 12 months from the beginning of the biologic treatment, compared to baseline, assessed in terms of absenteeism and presenteeism reduction, both for employed and unemployed subjects. Linear regression analyses were performed to assess the impact of patient- and disease-related variables on productivity gain. RESULTS: Overall, 100 patients were enrolled and 85 completed the study. All indexes of disease activity and functional ability were significantly improved from baseline already at 6 months. At 12 months, the 55 employed subjects showed a significant reduction in the mean number of days of work missed (absenteeism) and of reduced productivity (presenteeism). A significant reduction in the mean number of days of household work missed was observed for all patients. At multivariate analysis, functional disability had a significant negative impact on all parameters of household work productivity, while the achievement of a low disease activity or remission was inversely correlated with presenteeism. CONCLUSIONS: One year of treatment with a biological drug significantly impacts on the disease activity and work ability of RA patients and allows economic gains due to productivity improvement.

Definition of fibromyalgia severity: findings from a cross-sectional survey of 2339 Italian patients.

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.

COVID-19 in rheumatic diseases in Italy: first results from the Italian registry of the Italian Society for Rheumatology (CONTROL-19).

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments.

Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study.

OBJECTIVE: To investigate the association between baseline disease activity and the occurrence of flares after adalimumab tapering or withdrawal in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The PREDICTRA phase IV, randomised, double-blind (DB) study (ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients) enrolled patients with RA receiving adalimumab 40 mg every other week who were in sustained remission ≥6 months. After a 4-week, open-label lead-in (OL-LI) period, patients were randomised 5:1 to DB adalimumab taper (every 3 weeks) or withdrawal (placebo) for 36 weeks. The primary endpoint was the association between DB baseline hand and wrist MRI-detected inflammation with flare occurrence. RESULTS: Of 146 patients treated during the OL-LI period, 122 were randomised to taper (n=102) or withdrawal (n=20) arms. Patients had a mean 12.9 years of active disease and had received adalimumab for a mean of 5.4 years (mean 2.2 years in sustained remission). Overall, 37 (36%) and 9 (45%) patients experienced a flare in the taper and withdrawal arms, respectively (time to flare, 18.0 and 13.3 weeks). None of the DB baseline disease characteristics or adalimumab concentration was associated with flare occurrence after adalimumab tapering. Approximately half of the patients who flared regained clinical remission after 16 weeks of open-label rescue adalimumab. The safety profile was consistent with previous studies. CONCLUSIONS: Approximately one-third of patients who tapered adalimumab versus half who withdrew adalimumab experienced a flare within 36 weeks. Time to flare was numerically longer in the taper versus withdrawal arm. Baseline MRI inflammation was not associated with flare occurrence. TRIAL REGISTRATION NUMBER: NCT02198651, EudraCT 2014-001114-26.

The Italian Fibromyalgia Registry: a new way of using routine real-world data concerning patient-reported disease status in healthcare research and clinical practice.

OBJECTIVES: Fibromyalgia (FM), the most frequently encountered cause of widespread musculoskeletal pain, affects an estimated 2% of the general Italian population. However, it is not a homogeneous clinical entity, and a number of interacting factors can influence patient prognosis and the outcomes of standardised treatment programmes. Registries are a source of high-quality data for clinical research, but relating this information to individual patients is technically challenging. The aim of this article is to describe the structure and objectives of the first Italian Fibromyalgia Registry (IFR), a new web-based registry of patients with FM. METHODS: The IFR was developed to collect, store, and share information electronically entered by physicians throughout Italy who are members of the Italian Society of Rheumatology and have a particular interest in FM. It has a web-based architecture that uses two separate servers and an encryption algorithm to ensure the confidentiality and integrity of the exchanged data. The questionnaires included on the platform are the Revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status (ModFAS), and the Polysymptomatic Distress Scale (PDS). RESULTS: The registry includes data relating to 2,339 patients (93.2% female) who satisfied the 1990 or 2010/2011 American College of Rheumatology Classification Criteria for Fibromyalgia at the time of diagnosis. At the time of this analysis, the patients had a mean age of 51.9 years (SD 11.5) and a mean disease duration of 7.3 years (SD 6.9). The majority were married (71.3%), and generally well educated. The overall median FIQR, ModFAS and PDS scores and 25th-75th percentiles were respetively 61.16 (41.16-77.00), 8.91 (41.16-77.00), and 19.0 (13.00-24.00). The six highest scoring items indicating the greatest impact of the disease on the patients related to fatigue/energy (7.18), sleep quality (6.87), tenderness (6.69), pain (6.68), stiffness (6.66), and environmental sensitivity (6.35). A high proportion of the responding patients reported experiencing pain in the neck (80.46%), upper back (68.36%), and lower back (75.05%). CONCLUSIONS: The IFR is the most comprehensive FM registry in Italy, and provides healthcare professionals with a secure, reliable, and easy-to-use means of monitoring the patients' clinical progression, treatment history and treatment responses. This can help clinicians to plan patient management, facilitates research study patient recruitment, and provides the participating pain clinics with statistics based on real-world data. It also helps address the Italian Ministry of Health long-term goal of using precision medicine for chronic pain prevention and treatment. It is hoped that the IFR will enhance both scientific research and clinical practice.

Dynamic Contrast-Enhanced MRI Confirms Rapid And Sustained Improvement Of Rheumatoid Arthritis Induced By Tocilizumab Treatment: An Italian Multicentre Study.

OBJECTIVE: 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).

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To 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. METHODS: RA 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 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In 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). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Correction to: Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts.

Following publication of the original article [1], it was brought to our attention that the AOSD Consensus Group was incorrectly tagged and therefore not searchable. The publishers apologize for this error.

Outcomes and Findings of the International Rheumatoid Arthritis (RA) BIODAM Cohort for Validation of Soluble Biomarkers in RA.

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).

Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Data from the International RA BIODAM Cohort.

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].

Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion. METHODS: A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still's disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. 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. In the third step, the voting results were analyzed, and the statements were finalized. RESULTS: Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A 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 the first and as a 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 response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment. CONCLUSIONS: 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.

Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial.

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 (ß: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (ß: -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 (ß: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (ß: -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.