Switch or swap strategy in rheumatoid arthritis patients failing TNF inhibitors? Results of a modified Italian Expert Consensus.

Objective: To establish evidence-based and experts' opinion filtered statements on the optimal treatment choice between cycling (switch) and changing mode of action strategies (swap) in RA patients failing TNF inhibitors (TNFis). Methods: The relevant question (switch vs swap) was rephrased into a research question according to the population, intervention, comparison and outcome (PICO) strategy, considering all the available scientific evidence published from the 2013 EULAR set of recommendations up to mid-January 2016. Final statements derived from the retrieved scientific evidence and experts' consensus, with eventual rephrasing through a Delphi method during a national consensus of Italian rheumatologists. Results: From a total of 365 records, 12 studies were finally included. The final statements argued that, until head-to-head comparison data are available, switch and swap can be still considered suitable strategies in RA patients failing first TNFi, even though some data seem to lend more support to a different mode of action-targeted strategy. Conclusion: After failure of first TNFi course, switch and swap can be currently considered as alternative suitable approaches in RA patients.

Recommendations for infectious disease screening in migrants to Western Europe with inflammatory arthropathies before starting biologic agents. Results from a multidisciplinary task force of four European societies (SIR, SER, SIMET, SEMTSI) facing the largest impact of the flow of migrants today.

OBJECTIVES: Inflammatory arthritis needs infectious disease screening before starting a biologic agent, however, few data are known about migrant patients, who represent a peculiar population which requires a multidisciplinary approach among international health specialists and should also be considered by health authorities. For this reason, the Italian and Spanish Societies of Rheumatology (SIR and SER) and Tropical Medicine (SIMET and SEMTSI) promoted a multidisciplinary task force in order to produce specific recommendations about screening and advices to be considered in migrant patients with inflammatory arthritis candidate to receive biological therapy, according to their geographical origin. METHODS: The experts provided a prioritised list of research questions and the eligible spectrum of inflammatory arthritis, biologic drugs and infectious disease were defined in order to perform a systematic literature review. A search was made in Medline, Embase and Cochrane library, updated to March 2015. Ubiquitous infections and HBV, HCV, HIV and tuberculosis that are already considered in national and international recommendations, were not included. The strength of each recommendation was determined. RESULTS: The task force members agreed on 7 overarching principles. The risk of reactivation of selected potentially latent infectious disease was addressed in migrants with inflammatory arthritis candidates for biologics was considered and 15 potentially relevant infections were identified. CONCLUSIONS: Fifteen disease-specific recommendations were formulated on the basis of high level of agreement among the experts panel.

The challenge of the definition of early symptomatic knee osteoarthritis: a proposal of criteria and red flags from an international initiative promoted by the Italian Society for Rheumatology.

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

How the knowledge of fracture risk might influence adherence to oral therapy of osteoporosis in Italy: the ADEOST study.

UNLABELLED: The patients' adherence to osteoporosis treatments is low. In our study population a history of osteoporotic fractures was associated to better compliance and persistence; however, a 12-month randomized study carried out on 816 osteoporotic women showed that providing the patients with their individual fracture risk information did not prove effective. PURPOSE: Several drugs are currently available for the treatment of osteoporosis, but the patients' compliance and persistence with these treatments are low. This study aimed to both analyze the adherence to oral osteoporosis medications among Italian osteoporotic patients (cross-sectional study) and evaluate if providing patients with their individual fracture risk information may improve compliance and persistence (prospective study). METHODS: A total of 3379 osteoporotic patients referred as outpatients for a visit 1 year after receiving a prescription of oral osteoporosis medications for the first time, were enrolled for the retrospective study. Moreover, 816 postmenopausal women receiving an oral prescription for osteoporosis for the first time, were randomized into two groups: group 1 (managed according to standard clinical practice) and group 2 (managed with greater patient involvement and information on the individual risk of major osteoporotic fractures calculated by DeFRA algorithm). RESULTS: In the retrospective study, a history of osteoporotic fractures, the frequency of drug administration and a condition of being overweight/obese had a significant influence on both compliance and persistence. Of the 816 patients enrolled in the longitudinal study, 731 (374 of group 1 and 357 of group 2) attended the 1 year follow-up visit. The percentage of women with high compliance or persistence was greater in group 2 (64.2 vs. 58.1 % and 66.8 vs. 62.6 %, respectively), but without reaching any statistical significance. CONCLUSIONS: Although providing the patients with their individual fracture risk information was not statistically effective, further studies on additional interventions able to improve the patients' perceived risk of fracture are warranted.

The Importance of an Early Diagnosis in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset, making it difficult to reach a correct and prompt diagnosis. OBJECTIVES: To present the difficulties faced by the clinician in making a SLE diagnosis, based on the characteristics at study entry of an Italian cohort of SLE patients with recent onset as compared to two similar cohorts. METHODS: Beginning on 1 January 2012 all patients with a diagnosis of SLE (1997 ACR criteria) and disease duration of less than 12 months were consecutively enrolled in a multicenter prospective study. Information on clinical and serological characteristics was collected at study entry and every 6 months thereafter. RESULTS: Our cohort consisted of 122 patients, of whom 103 were females. Among the manifestations included in the 1997 American College of Rheumatology (ACR) criteria, cutaneous, articular and hematologic symptoms were the most prevalent symptoms at study entry. CONCLUSIONS: Data from the literature confirm that the diagnosis of SLE is challenging, and that SLE is a severe disease even at onset when a prompt diagnosis is necessary for initiating the appropriate therapy.

[Rheumatic diseases and work ability]. / Malattie reumatiche e capacità lavorativa.

Musculoskeletal diseases are tile most frequent cause of pain in the working population. Rheumatic diseases are chronic illnesses, cause of functional impairnment, relevant working disability and absence from work; however, affected patients maintain a significant functional ability. In this context, the "Fit for work" project, operating in Italy since 2012, promotes the management of chronic musculoskeletal conditions through the realization, also in our country, of a rheumatic medical assistance network in behalf of workers affected by rheumatic diseases and other musculoskeletal disabiliting conditions.

Treatment thresholds for osteoporosis and reimbursability criteria: perspectives associated with fracture risk-assessment tools.

The definition of osteoporosis was based for several years on bone mineral density values, which were used by most guidelines for defining treatment thresholds. The availability of tools for the estimation of fracture risk, such as FRAX™ or its adapted Italian version, DeFRA, is providing a way to grade osteoporosis severity. By applying these new tools, the criteria identified in Italy for treatment reimbursability (e.g., "Nota 79") are confirmed as extremely conservative. The new fracture risk-assessment tools provide continuous risk values that can be used by health authorities (or "payers") for identifying treatment thresholds. FRAX estimates the risk for "major osteoporotic fractures," which are not counted in registered fracture trials. Here, we elaborate an algorithm to convert vertebral and nonvertebral fractures to the "major fractures" of FRAX, and this allows a cost-effectiveness assessment for each drug.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Determinants and effects of vitamin D supplementation on serum 25-hydroxy-vitamin D levels in patients with rheumatoid arthritis.

OBJECTIVES: Osteoporosis (OP) and increased risk of fracture are relevant features in patients with rheumatoid arthritis (RA). Low levels of serum vitamin D are frequently reported and correlate with a higher RA activity. This study evaluated factors related with the prescription of vitamin D supplements in RA patients and variables influencing the achievement of adequate vitamin D levels. METHODS: Study population was made up by 1168 consecutive RA patients from 22 Italian rheumatology centers. Demographic and clinical variables data were collected and 25OH serum vitamin D was measured in all patients. Insufficient serum 25OH vitamin D levels were defined as values lower than 20 ng/mL. RESULTS: The majority of patients (56.0%) was not taking vitamin D supplements. Among the 514 supplemented patients, 196 (38.1%) were taking insufficient dosages (≤440 IU/day). Variables related with the prescription of supplements were older age, female sex, previous bone density assessment and OP diagnosis. Among the 318 patients using daily supplements ≥800 IU, 88 patients (27.7%) did not reach adequate levels of vitamin D. In these patients a higher HAQ score (OR for 1 point=1.62, 95% CI: 1.06-2.49; p=0.03) and poor sun exposure (OR=2.38, 95% CI: 1.05-5.55; p=0.04) were predictors of vitamin D insufficiency. CONCLUSIONS: Vitamin D deficiency is common in patients with RA, even in patients who are regularly using supplements. Vitamin D supplementation is often ineffective even at the recommended dose of 800 IU/day in more disabled patients.

The role of eight polymorphisms in three candidate genes in determining the susceptibility, phenotype, and response to anti-TNF therapy in patients with rheumatoid arthritis.

OBJECTIVES: Several single nucleotide polymorphisms (SNPs) have been associated with rheumatoid arthritis (RA) such as peptidylarginine deiminase-4 (PADI4), osteopontin (OPN), and perforin (PRF1) genes. Thus, we aimed at analysing the influence of eight SNPs in these candidate genes on RA susceptibility and their association with laboratory and clinical features in terms of response to anti-TNF therapy. METHODS: We performed a case-control study on 377 Caucasian RA patients and 391 healthy, ethnicity-matched, population-based controls. All subjects were genotyped for PADI4_89/94, PADI4_92, PADI4_104, PADI4_100 in PADI4; -156G/GG and +1239A/C in OPN and A91V and N252S in PRF1 genes. The patients were stratified for shared epitope (SE) HLA-DRB1. rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were analysed. The patients started anti-TNF treatment and they were evaluated at baseline and after 12 weeks. Disease activity was evaluated with DAS28 and response to treatment with EULAR criteria. RESULTS: A statistically significant association between RA and OPN -156G/GG was found (p=0.023). SE was firmly confirmed to be associated with RA (OR=3.68; p<10-10). No other statistically significant association with clinical and laboratory features were observed. CONCLUSIONS: For the first time, in an Italian cohort, we report the association between -156G/GG in OPN gene and RA susceptibility. Short-term response to anti-TNF therapy was not influenced by the genetic variants studied.

Patient preferences in the choice of anti-TNF therapies in rheumatoid arthritis. Results from a questionnaire survey (RIVIERA study).

OBJECTIVE: To identify the determinants of anti-TNF-naive patients' preferences for the route of administration of anti-TNF agents. METHODS: The study was carried out in 50 Italian rheumatology centres (802 patients). All patients completed a 31-item questionnaire addressing their perceptions of current treatment and the preferences for treatment with anti-TNF agents. Statistical methods included analysis of variance (ANOVA), t-test and chi-square test. RESULTS: The response rate to the questionnaire was 97.6%. At the time of the survey, 310 (39.9%) patients were dissatisfied with current treatments, owing to inefficacy, side effects and inconvenience of administration. The i.v. and s.c. routes of administration were preferred by 50.2 and 49.8%, respectively. No significant difference was found in patients by gender, age, RA duration or number of drugs used. Reasons for the choice of i.v. administration were the safety of treatment at the hospital and the reassuring effect of physician presence. The s.c. administration was chosen for the convenience of treatment and in particular for home treatment. Patients dissatisfied with current therapy due to side effects preferred s.c. administration (P = 0.029), whereas patients choosing the i.v. route had slightly higher scores on 'today pain' (P = 0.047) and 'articular pain' (P = 0.023) of the Rheumatoid Arthritis Disease Activity Index (RADAI). CONCLUSIONS: Both i.v. and s.c. treatments were well accepted by patients. However, treatment choice has to be discussed with patients, as individual preference seems to be determined by personal attitudes towards safety and convenience, by past experience and by the perception of current disease status.

Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity.

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.