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Objective To investigate the distribution of patient-reported outcomes (PROs) in patients with axial spondyloarthritis (axSpA) initiating a tumor necrosis factor inhibitor (TNFi), to assess the proportion reaching PRO "remission" across registries and treatment series, and to compare patients registered to fulfill the modified New York (mNY) criteria for ankylosing spondylitis (AS) vs patients with nonradiographic axSpA (nr-axSpA). Methods Fifteen European registries contributed PRO scores for pain, fatigue, patient global assessment (PtGA), Bath Ankylosing Spondylitis (AS) Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Health Assessment Questionnaire (HAQ) from 19,498 patients with axSpA. Changes in PROs and PRO remission rates (definitions: ≤ 20 mm for pain, fatigue, PtGA, BASDAI, and BASFI; ≤ 0.5 for HAQ) were calculated at 6, 12, and 24 months of treatment. Results Heterogeneity in baseline characteristics and outcomes between registries were observed. In pooled data, 6 months after the start of a first TNFi, pain score was reduced by approximately 60% (median at baseline/ 6/12/24 months: 65/25/20/20 mm) in patients on treatment. Similar patterns were observed for fatigue (68/32/30/25 mm), PtGA (66/29/21/20 mm), BASDAI (58/26/21/19 mm), BASFI (46/20/16/16 mm), and HAQ (0.8/0.4/0.2/0.2). Patients with AS (n = 3281) had a slightly better response than patients with nr-axSpA (n = 993). The Lund Efficacy Index (LUNDEX)-adjusted remission rates at 6 months for pain/fatigue/PtGA/BASDAI/BASFI/HAQ were 39%/30%/38%/34%/35%/48% for the AS cohort and 30%/21%/26%/24%/33%/47% for the nr-axSpA cohort. Better PRO responses were seen with a first TNFi compared to a second and third TNFi. Conclusion Patients with axSpA starting a TNFi achieved high PRO remission rates, most pronounced in those fulfilling the mNY criteria and for the first TNFi., OBJECTIVE: To investigate the distribution of patient-reported outcomes (PROs) in patients with axial spondyloarthritis (axSpA) initiating a tumor necrosis factor inhibitor (TNFi), to assess the proportion reaching PRO "remission" across registries and treatment series, and to compare patients registered to fulfill the modified New York (mNY) criteria for ankylosing spondylitis (AS) vs patients with nonradiographic axSpA (nr-axSpA).METHODS: Fifteen European registries contributed PRO scores for pain, fatigue, patient global assessment (PtGA), Bath Ankylosing Spondylitis (AS) Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Health Assessment Questionnaire (HAQ) from 19,498 patients with axSpA. Changes in PROs and PRO remission rates (definitions: ≤ 20 mm for pain, fatigue, PtGA, BASDAI, and BASFI; ≤ 0.5 for HAQ) were calculated at 6, 12, and 24 months of treatment.RESULTS: Heterogeneity in baseline characteristics and outcomes between registries were observed. In pooled data, 6 months after the start of a first TNFi, pain score was reduced by approximately 60% (median at baseline/ 6/12/24 months: 65/25/20/20 mm) in patients on treatment. Similar patterns were observed for fatigue (68/32/30/25 mm), PtGA (66/29/21/20 mm), BASDAI (58/26/21/19 mm), BASFI (46/20/16/16 mm), and HAQ (0.8/0.4/0.2/0.2). Patients with AS (n = 3281) had a slightly better response than patients with nr-axSpA (n = 993). The Lund Efficacy Index (LUNDEX)-adjusted remission rates at 6 months for pain/fatigue/PtGA/BASDAI/BASFI/HAQ were 39%/30%/38%/34%/35%/48% for the AS cohort and 30%/21%/26%/24%/33%/47% for the nr-axSpA cohort. Better PRO responses were seen with a first TNFi compared to a second and third TNFi.CONCLUSION: Patients with axSpA starting a TNFi achieved high PRO remission rates, most pronounced in those fulfilling the mNY criteria and for the first TNFi.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a global prevalence of approximately 0.5-1%. Patients with RA are at an increased risk of developing comorbidities (eg, cardiovascular disease, pulmonary disease, diabetes and depression). Despite this, there are limited recommendations for the management and implementation of associated comorbidities. This study aimed to identify good practice interventions in the care of RA and associated comorbidities. METHODS: A combination of primary research (180+ interviews with specialists across 12 European rheumatology centres) and secondary research (literature review of existing publications and guidelines/recommendations) were used to identify challenges in management and corresponding good practice interventions. Findings were prioritised and reviewed by a group of 18 rheumatology experts including rheumatologists, comorbidity experts, a patient representative and a highly specialised nurse. RESULTS: Challenges throughout the patient pathway (including delays in diagnosis and referral, shortage of rheumatologists, limited awareness of primary care professionals) and 18 good practice interventions were identified in the study. The expert group segmented and prioritised interventions according to three distinct stages of the disease: (1) suspected RA, (2) recent diagnosis of RA and (3) established RA. Examples of good practice interventions included enabling self-management (self-monitoring and disease management support, for example, lifestyle adaptations); early arthritis clinic; rapid access to care (online referral, triage, ultrasound-guided diagnosis); dedicated comorbidity specialists; enhanced communication with primary care (hotline, education sessions); and integrating patient registries into daily clinical practice. CONCLUSION: Learning from implementation of good practice interventions in centres across Europe provides an opportunity to more widely improved care for patient

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a global prevalence of approximately 0.5-1%. Patients with RA are at an increased risk of developing comorbidities (eg, cardiovascular disease, pulmonary disease, diabetes and depression). Despite this, there are limited recommendations for the management and implementation of associated comorbidities. This study aimed to identify good practice interventions in the care of RA and associated comorbidities.METHODS: A combination of primary research (180+ interviews with specialists across 12 European rheumatology centres) and secondary research (literature review of existing publications and guidelines/recommendations) were used to identify challenges in management and corresponding good practice interventions. Findings were prioritised and reviewed by a group of 18 rheumatology experts including rheumatologists, comorbidity experts, a patient representative and a highly specialised nurse.RESULTS: Challenges throughout the patient pathway (including delays in diagnosis and referral, shortage of rheumatologists, limited awareness of primary care professionals) and 18 good practice interventions were identified in the study. The expert group segmented and prioritised interventions according to three distinct stages of the disease: (1) suspected RA, (2) recent diagnosis of RA and (3) established RA. Examples of good practice interventions included enabling self-management (self-monitoring and disease management support, for example, lifestyle adaptations); early arthritis clinic; rapid access to care (online referral, triage, ultrasound-guided diagnosis); dedicated comorbidity specialists; enhanced communication with primary care (hotline, education sessions); and integrating patient registries into daily clinical practice.CONCLUSION: Learning from implementation of good practice interventions in centres across Europe provides an opportunity to more widely impr

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a global prevalence of approximately 0.5-1%. Patients with RA are at an increased risk of developing comorbidities (eg, cardiovascular disease, pulmonary disease, diabetes and depression). Despite this, there are limited recommendations for the management and implementation of associated comorbidities. This study aimed to identify good practice interventions in the care of RA and associated comorbidities.METHODS: A combination of primary research (180+ interviews with specialists across 12 European rheumatology centres) and secondary research (literature review of existing publications and guidelines/recommendations) were used to identify challenges in management and corresponding good practice interventions. Findings were prioritised and reviewed by a group of 18 rheumatology experts including rheumatologists, comorbidity experts, a patient representative and a highly specialised nurse.RESULTS: Challenges throughout the patient pathway (including delays in diagnosis and referral, shortage of rheumatologists, limited awareness of primary care professionals) and 18 good practice interventions were identified in the study. The expert group segmented and prioritised interventions according to three distinct stages of the disease: (1) suspected RA, (2) recent diagnosis of RA and (3) established RA. Examples of good practice interventions included enabling self-management (self-monitoring and disease management support, for example, lifestyle adaptations); early arthritis clinic; rapid access to care (online referral, triage, ultrasound-guided diagnosis); dedicated comorbidity specialists; enhanced communication with primary care (hotline, education sessions); and integrating patient registries into daily clinical practice.CONCLUSION: Learning from implementation of good practice interventions in centres across Europe provides an opportunity to more widely impr

Objective: The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice. Methods: The 6 more interesting topics about axSpA patient profiling were identified by the project steering committee and a panel of axSpA Italian experts. A systematic literature review (SLR) was performed for each of the selected topics according to the PICO format. Two rounds of a modified Delphi process were conducted. In the 1st round, the steering committee evaluated the results of the SLR in order to formulate statements for each topic. In the 2nd round, the experts panel discussed, rephrased when needed, and voted the level of agreement (on a 5-point Likert-type scale) for each statement. Consensus was defined as ≥66% agreement. Results: The topics selected for the analysis were the differential efficacy of available bDMARDs on enthesitis/dactylitis, uveitis, radiographic progression and cardiovascular involvement, and the clinical response in non radiographic-axSpA and in patients receiving a second-line bDMARD. The Delphi rounds formulated 19 statements, all reaching the defined level of consensus in a second round including 25 rheumatologists highly skilled in the management of axSpA. Conclusion: Identified consensus statements can help clinicians to apply to routine-care settings the results from clinical studies and international recommendations, providing a guide for individualization of treatment strategy in axSpA patients.

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.

Martina Biggioggero,1 Chiara Crotti,2 Andrea Becciolini,1 Ennio Giulio Favalli1 1Department of Rheumatology, Gaetano Pini Institute, Milan, Italy; 2Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and systemic manifestations, such as anemia, fatigue, osteoporosis, and increased risk for cardiovascular diseases. The pathogenesis of RA is driven by a complex network of proinflammatory cytokines, with a pivotal role of IL-6 and tumor necrosis factor (TNF). The management of RA has been dramatically changed during the last years by the introduction of a treat-to-target approach aiming to achieve an acceptable disease control. Nowadays, TNF inhibitors (TNFis) are the most frequently prescribed class of biologic therapies, but the significant proportion of patients experiencing the failure of a TNFi led to the development of alternative therapeutic options targeted on different pathways. Considering the increasing number of targeted therapeutic options for RA, there is a growing interest in the identification of potential predictors of clinical response to each available mechanism of action, with the aim to drive the management of the disease toward a personalized approach according to the concept of precision medicine. Tocilizumab (TCZ) is the first humanized anti-IL-6 receptor subunit alpha (anti-IL-6R) monoclonal antibody approved for the treatment of RA refractory to methotrexate or TNFis. TCZ inhibits both the cis- and trans-signaling cascades involving the Janus kinase-signal transducer and the activator of transcription pathway, playing a crucial role in modulating not only joint inflammation but also the previously mentioned extra-articular manifestations and comorbidities of RA, such as fatigue, anemia, bone loss, depression, type 2 diabetes, and increased cardiovascular risk. In th

Chiara Crotti,1,2 Martina Biggioggero,3 Andrea Becciolini,3 Ennio Giulio Favalli3 1Department of Clinical Sciences and Health Community, University of Milan, 2Division of Rheumatology, Gaetano Pini Institute, Milan, Italy; 3Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Abstract: In the last few decades, strategies for the management of rheumatoid arthritis (RA) have been increasingly oriented toward more comprehensive control of the disease, taking into account even RA extra-articular manifestations, comorbidities, and the patient’s perception about the disease. The need for improving the shared decision-making process suggested by European League Against Rheumatism recommendations is leading to an increasing interest in the role of patient-reported outcomes (PROs) beside the usual more objective criteria for defining clinical response based on disease-activity composite indices. Measurement of such PROs as pain or fatigue may be significantly influenced by mood disorders often complicating RA, the pathogenesis of which is deeply interconnected with phlogistic processes mediated by proinflammatory cytokines. IL6 is a pleiotropic mediator involved in neuroendocrine and neuropsychological processes, besides its well known effects on immune, cardiovascular, and metabolic systems. Therefore, there is a growing body of evidence about the efficacy of IL6 blockade in PRO improvement in RA patients. Sarilumab is a monoclonal antibody binding both soluble and membrane-bound IL6Rα, inhibiting the IL6-mediated signaling pathway with favorable efficacy and safety profile. This review analyzes the importance of PROs in strategies for the management of RA and the pathogenic mechanisms linking IL6 with the patient’s perception of the disease. Moreover, the main findings from sarilumab randomized controlled trials are summarized in detail, emphasizing the potential role of this IL6 blocker in the holistic treatment of RA. Keywords: r

Ennio Giulio Favalli,1 Andrea Becciolini,1 Martina Biggioggero,2 Ilaria Bertoldi,3 Chiara Crotti,2 Maria Gabriella Raimondo,2 Antonio Marchesoni1 1Department of Rheumatology, Gaetano Pini Institute, Milan, Italy; 2Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy; 3Pfizer Innovative Health, I&I Medical Affairs, Rome, Italy Objective: To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). Patients and methods: The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan–Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. Results: A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the pa

Maria Gabriella Raimondo,1 Martina Biggioggero,1 Chiara Crotti,1 Andrea Becciolini,2 Ennio Giulio Favalli2 1Department of Clinical Sciences and Health Community, Division of Rheumatology, University of Milan, 2Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Abstract: In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the di

Andrea Becciolini,1 Maria Gabriella Raimondo,2 Chiara Crotti,2 Elena Agape,2 Martina Biggioggero,2 Ennio Giulio Favalli1 1Department of Rheumatology, 2Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy Abstract: The introduction of biological agents drastically changed the treatment paradigm of inflammatory arthritides, ameliorating the natural history of the diseases but concomitantly increasing the drug costs due to the manufacturing process. On this concern, biosimilar drugs may represent a valid option for reducing this elevated cost and increasing the availability of these highly effective treatments. Recently, CT-P13, the first biosimilar of infliximab, has been approved with the same indications established for the reference product (RP), and its daily use is progressively increasing. However, the experience with biosimilar drugs in the field of rheumatology is still limited, raising potential doubts and concerns on their correct management in real-life settings. Comparability analysis between CT-P13 and its RP was evaluated in equivalence randomized controlled trials (RCTs) – PLANETRA and PLANETAS – performed on patients with rheumatoid arthritis and axial spondylitis, respectively. CT-P13 and RP showed similar profile in terms of quality, biological activity, safety, immunogenicity, and efficacy. However, the interchangeability between infliximab RP and its biosimilar still represents the most challenging issue because of a lack of a long-lasting experience. To date, reassuring preliminary data on this topic were reported in open-label extensions of PLANETRA and PLANETAS RCTs and in ongoing real-life observational studies. These findings, taken all together, significantly affect the landscape of biosimilar regulatory pathways and strongly support CT-P13 introduction as a great opportunity for expanding the accessibility to these very effective and high

Chiara Crotti,1 Maria Gabriella Raimondo,1 Andrea Becciolini,2 Martina Biggioggero,1 Ennio Giulio Favalli2 1Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, 2Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Abstract: The introduction of biological therapies into clinical practice has dramatically modified the natural history of chronic inflammatory diseases, such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that causes articular damage and has a great negative impact on patients’ quality of life. Despite the wide spectrum of available biological treatments, ~30% of RA patients are still unresponsive, resulting in high disability and increased morbidity and mortality. In the last few decades, the scientific knowledge on RA pathogenesis vastly improved, leading to the identification of new proinflammatory molecules as potential therapeutic targets. Several in vitro and in vivo studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), known to be a hematopoietic factor, is also one of the proinflammatory cytokines involved in macrophage activation, crucial for the pathogenic network of RA. Mavrilimumab, a human monoclonal antibody targeting the subunit α of GM-CSF receptor, was recently developed as a competitive antagonist of GM-CSF pathway and successfully adopted in human trials for mild to moderate RA. Mavrilimumab phase I and phase II studies reported an overall good efficacy and safety profile of the drug, and these encouraging results promoted the initiation of worldwide phase III studies. In particular, 158-week results of phase II trials did not show long-term lung toxicity, addressing the major concern about this target of pulmonary alveolar proteinosis development. However, further clinical studies conducted in larger RA populations are needed to confirm these promising results. This revie

The purpose of the study was to estimate the clinical profile of naïve biological patients with rheumatoid arthritis (RA) starting adalimumab through 3-year calendar periods and their clinical outcomes such as drug survival and global clinical disease control (GCDC). RA patients starting adalimumab as first biological drug between 2003 and 2012 were subdivided in 3-year calendar periods. Survival on therapy was estimated using the Kaplan-Meier analysis. One and 2-year clinical response was assessed by calculating percentage of patients attaining GCDC (28-joint Disease Activity Score (DAS28) ≤ 2.6 + Health Assessment Questionnaire (HAQ) ≤ 0.5), low disease activity (DAS28 ≤ 3.2), remission (DAS28 ≤ 2.6) and good European League Against Rheumatism (EULAR) response. Multivariate regression models were used to assess baseline predictors of drug discontinuation or achievement of clinical remission. We recruited 1695 RA patients. Overall drug persistence at 3 years was 40.6 %, while the global rate of nonswitching patients was 54.7 %. Compared to 2003–2005, initiators in more recent years had a significantly lower 3-year crude drug retention rate (log rank, p < 0.0001) and a significantly higher rate of switching to alternative biologics (log rank, p < 0.0001). No difference in adverse events or effectiveness rate among the calendar periods was found. A substantial proportion of patients (up to 27 %) achieved GCDC at 2 years, regardless of the calendar period. In real-life setting, RA patients starting adalimumab in more recent years had a higher rate of drug discontinuation not related to ineffectiveness or side effects but to switching, probably due to a wider availability of biologics. A meaningful proportion of patients attained GCDC without any difference across calendar periods.