Comorbidities in the Spondyloarthritis GISEA Cohort: an average treatment effect analysis on patients treated with bDMARDs.

OBJECTIVES: We aimed to investigate the effectiveness of tumour necrosis factor inhibitors (TNFi), anti-interleukin-17 or interleukin-12/23 monoclonal antibodies (anti-IL) on comorbidities in a cohort of patients with spondyloarthritis (SpA), using an average treatment effect (ATE) analysis. METHODS: SpA patients from the multicentre Italian GISEA Registry were divided into groups according to pharmacological exposure: no treatment (G0), TNFi (G1) and non-responders to TNFi switched to anti-IL (G2). In each group, we recorded the prevalence and incidence of infectious, cardiopulmonary, endocrinological, gastrointestinal, oncologic, renal and neurologic comorbidities. Each comorbidity was then fitted for ATE and baseline features were evaluated for importance. RESULTS: The main findings of this study comprising 4458 SpA patients relate to cancer, other gastrointestinal diseases (OGID) and fibromyalgia. ATE showed no increased risk of solid cancer in G1 (0.42 95% CI 0.20-0.85) and G2 (0.26 95% CI 0.08-0.71) vs. G0, with significantly higher incidence in G0 (14.07/1000 patient-years, p=0.0001). Conversely, a significantly higher risk of OGID and fibromyalgia was found in G1 (1.56 95% CI 1.06-2.33; 1.69 95% CI 1.05-2.68, respectively) and G2 (1.91 95% CI 1.05-3.24; 2.13 95% CI 1.14-3.41, respectively) vs. G0. No treatment risk reduction was observed in haematological malignancies, cardiovascular events and endocrinological comorbidities. CONCLUSIONS: Overall, our study confirms the safety of TNFi and anti-IL in SpA patients, albeit with some caveats pertaining to solid cancers, OGID and fibromyalgia. Furthermore, taking into consideration causality with observational data may yield more reliable and relevant clinical information.

Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: preliminary data of a real-life multicenter study.

BACKGROUND: Upadacitinib (UPA) is a selective JAK inhibitor recently approved for the treatment of psoriatic arthritis (PsA). In this post-approval study, we aimed to evaluate the effectiveness and safety of UPA over 24 weeks and identify clinical predictors of response, in a multicentric cohort of patients affected by PsA. METHODS: One hundred and twenty-six patients with PsA treated with UPA were enrolled in 10 Italian centres. UPA effectiveness outcomes, such as the proportion of patients with MDA status, DAPSA remission, and low disease activity, ASDAS-CRP inactive and low disease activity, and change from baseline in DAPSA and ASDAS-CRP scores, were evaluated every 12 weeks until week 24. The proportion of DAPSA minor, moderate, and major improvement, and ASDAS clinically important improvement (CII) and major improvement (MI) were considered as well. All treatment-related adverse events were collected during the observation period. Clinical predictors of MDA response at week 24 were evaluated through multivariate analysis. RESULTS: At baseline, 124/126 (98%) and 54/126 (43%) patients showed peripheral and axial involvement, respectively; 110 (87%) patients were intolerant or resistant to biologic DMARDs.  At 24 weeks, MDA status, DAPSA remission, and ASDAS-CRP inactive disease were achieved in 47%, 23%, and 48% of patients, respectively. Minor, moderate, and major DAPSA improvement was observed in 67%, 39%, and 23%, respectively; while 65% and 35% achieved ASDAS-CRP CII and MI, respectively. The mean change from baseline was 15.9 ± 13.5 (p < 0.001) for DAPSA and 1.21 ± 0.97 (p < 0.001) for ASDAS-CRP. Thirteen patients (10%) discontinued UPA due to a lack of efficacy or non-serious adverse events. No serious adverse events were observed. Male gender (OR 2.54, 95% CI 1.03-6.25 p = 0.043), being naïve to biological DMARDs (OR 4.13, 95% CI 1.34-12.71, p = 0.013) and elevated baseline CRP (OR 2.49, 95% CI 1.02-6.12, p = 0.046) were associated with MDA response at week 24. CONCLUSIONS: This is one of the first real-life studies supporting the effectiveness of UPA and its safety profile in PsA patients. Furthermore, the study identifies predictors of MDA response to UPA treatment at 6 months.

Rheumatoid arthritis and myasthenia gravis: a case-based review of the therapeutic options.

INTRODUCTION: Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients with rheumatoid arthritis present an increased prevalence of myasthenia gravis compared to the general population. While these two diseases share some therapeutic options, such as glucocorticoids, methotrexate, and rituximab, there are no guidelines for treating concomitant disease. We aim to review the available evidence and to discuss the efficacy and safety of the therapeutic options in patients with rheumatoid arthritis associated with myasthenia gravis. METHOD: We described three patients with rheumatoid arthritis associated with myasthenia gravis and we performed a systematic review of the associated literature. RESULTS: A 48-year-old man and two women (48 and 55 years old) with concomitant diagnoses of active rheumatoid arthritis and well-controlled myasthenia gravis are described. They were treated with methotrexate, leflunomide, upadacitinib, and adalimumab. None of them experienced changes in their myasthenic symptoms. We found 9 additional cases from our literature review. Methotrexate, rituximab, upadacitinib, diphenyl sulfone, auranofin, and loxoprofen sodium did not show an impact on the seven patients with previously well-controlled myasthenia. Glucocorticoids, methotrexate, and rituximab proved effective in active myasthenia gravis and arthritis. Conflicting data emerged for Tumor-necrosis factor inhibitors. CONCLUSIONS: Although the available evidence remains scarce, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options. The role of tumor-necrosis factor inhibitors remains uncertain. Eventually, Janus Kinase inhibitors are a novel interesting option for these patients. Key Points • To date, the only evidence on the treatment of patients with rheumatoid arthritis and concomitant myasthenia gravis derives from case reports. • Based on the review of the available case reports and on the cases we described, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options, while the role of Tumor-necrosis factor inhibitors remains uncertain. • Based on the cases we described, Janus Kinase inhibitors are a novel interesting option for patients with concomitant rheumatoid arthritis and myasthenia gravis.

Effectiveness and safety of secukinumab in 608 patients with psoriatic arthritis in real life: a 24-month prospective, multicentre study.

OBJECTIVES: To evaluate in a multicentric Italian cohort of patients with psoriatic arthritis (PsA) on secukinumab followed for 24 months: (1) the long-term effectiveness and safety of secukinumab, (2) the drug retention rate and minimal disease activity (MDA), (3) differences in the outcomes according to the biological treatment line: biologic-naïve patients (group A) versus multifailure (group B) patients. METHODS: Consecutive patients with PsA receiving secukinumab were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical values were recorded at baseline (T0), 6(T6), 12(T12) and 24(T24) months. Effectiveness was evaluated overtime with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug-discontinuation and MDA at T6. Infections and adverse events were recorded. RESULTS: 608 patients (41.28% men; mean (SD) age 52.78 (11.33)) were enrolled; secukinumab was prescribed as first-line biological treatment in 227 (37.34%) patients, as second (or more)-line biological treatment in 381 (62.66%). Effectiveness of secukinumab was shown with an improvement in several outcomes, such as Ankylosing Spondylitis Disease Activity Score (T0=3.26 (0.88) vs T24=1.60 (0.69) ;p=0.02) and Disease Activity Index for Psoriatic Arthritis (T0=25.29 (11.14) vs T24=7.69 (4.51); p<0.01). At T24, group A showed lower Psoriasis Area Severity Index (p=0.04), erythrocyte sedimentation rate and C reactive protein (p=0.03 ;p=0.05) and joint count (p=0.03) compared with group B. At T24, MDA was achieved in 75.71% of group A and 70.37% of group B. Treatment was discontinued in 123 (20.23%) patients, mainly due to primary/secondary loss of effectiveness, and in 22 due to adverse events. Retention rate at T24 was 71% in the whole population, with some difference depending on secukinumab dosage (p=0.004) and gender (p=0.05). CONCLUSIONS: In a real-life clinical setting, secukimumab proved safe and effective in all PsA domains, with notable drug retention rate.

Golimumab effectiveness in biologic inadequate responding patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis in real-life from the Italian registry GISEA.

OBJECTIVE: To evaluate the clinical effectiveness of golimumab in biologic inadequate responder (IR) patients with Rheumatoid arthritis (RA), Spondyloarthritis (SpA), and Psoriatic arthritis (PsA). METHODS: We analyzed 1424 patients on golimumab from the GISEA registry. Drug survival was estimated by Kaplan-Meier analysis in biologic-naïve, 1-biologic IR, ≥2-biologics IR patients. Hazard ratios (HRs) of discontinuing golimumab at 2 years were assessed by multivariate Cox regression. Patients achieving CDAI based low disease activity (LDA) or BASDAI<4 were calculated at 6 and 12 months. RESULTS: In RA (n.370), the 2-years survival on golimumab was 61.4% in 1-biologic IR, 51.9% in≥2-biologics IR, and 73.1% in biologic-naive patients (P=0.002 vs≥2-biologics IR). In SpA (n.502), the survival was similar among 1-biologic IR (80%), ≥2-biologics IR (76.5%), and biologic-naive (74.6%) patients (P>0.05). In PsA (n.552) the survival was 72% in 1-biologic IR, 72.5% in≥2-biologics IR, and 71.8% in naïve-biologic (P>0.05). Predictors of golimumab discontinuation were monotherapy (HR 1.65) for RA, female gender for SpA (HR 2.48) and PsA (HR 1.57). In RA, patients on CDAI-LDA were lower in 1-biologic IR (40%) or≥2 biologics IR (40%) than in biologic-naïve (60%) group at 6 months (P=0.02), but no difference was observed at 12 months. In PsA and SpA, the percentage of patients on CDAI-LDA or BASDAI<4 at 6 months was almost identical across the subgroups. CONCLUSIONS: Golimumab had similar effectiveness in biologic-failure and biologic-naïve SpA and PsA, but seems to be less effective in multi-failure RA patients, especially as monotherapy. The best outcomes were seen in male patients.

Depression is associated with increased disease activity and higher disability in a large Italian cohort of patients with rheumatoid arthritis

Abstract Introduction: Depression is a quite common comorbidity in patients with rheumatoid arthritis (RA) and is thought to influence its severity. This study aims to estimate, in a large cohort of Italian patients with RA, the prevalence of depression and to investigate the clinical correlates of depression in terms of disease activity and disability. Methods: This is a cross-sectional study enrolling 490 outpatients with RA (80% female, mean age 59.5). The Hospital Anxiety and Depression Scale (HADS) was used to assess the presence of depression with a cut-off of 11. We collected data about disease activity and disability with DAS28, TJC-68, PhGA, PGA, VAS, DAS28, SDAI, CDAI and HAQ. Results: Prevalence of depression was 14.3% (95% CI: 11-17%). Depressed patients, when compared with not depressed ones, were found to have higher scores for TJC-68 ( p = 0.011), PhGA ( p = 0.001), PGA ( p = 0.001), VAS ( p = 0.001), DAS28 ( p = 0.007), SDAI ( p = 0.001), CDAI ( p = 0.001) and HAQ ( p = 0.001). Out of the 70 depressed patients, 30 subjects, already known to be depressed in the past, were still depressed at the time of the assessment, with only 11 (15.7%) under antidepressants. A multivariate analysis showed that male sex, higher PGA score, use of antidepressants and higher HAQ score were significantly associated with an increased risk of depression. Conclusions: Our study shows that depression is common in RA and may affect its activity mainly via an alteration in the perception of the disease. Although its important implications, depression is still under-diagnosed and its management is inadequate.

Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort.

Few studies have compared the efficacy of switching from etanercept to adalimumab in the real-life setting in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This study evaluated the 2-year retention rate and 12-month efficacy of adalimumab in RA and PsA patients, previously treated with etanercept. RA and PsA patients from 11 Italian Rheumatology Units received adalimumab after first-line etanercept failure. Two-year adalimumab retention rate was calculated by the Kaplan-Meier method and Cox proportional hazard models were developed to examine predictors of drug persistence. Univariate and multivariate logistic regression analyses were developed to examine potential predictors of 12-month DAS-28 remission. The study population included 117 RA (disease duration of 10.1 ± 7.7 years and baseline DAS28-ESR of 4.97 ± 1.3) and 102 PsA (disease duration of 7.1 ± 5.1 years and baseline DAPSA of 24.6 ± 11.8). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients. Concomitant methotrexate treatment was not associated with increased drug survival in both groups. Similarly, cause of etanercept discontinuation or treatment duration was not associated with retention rate. 12-month remission and low disease activity were achieved, respectively, in 27.3% and 23.9% of RA patients and 27.4% and 23.5% PsA of patients. In multivariate models, etanercept discontinuation due to inefficacy (OR 0.27, 95% CI 1.03-0.73; p = 0.009) and baseline DAS-28 (OR 0.45, 95% CI 0.29-0.69; p < 0.001) remained significant negative predictors of remission in RA patients. No variable was associated with remission in PsA patients. Adalimumab after etanercept failure was highly effective and safe in both RA and PsA patients.

Usefulness of CHA2 DS2 -VASc score to predict mortality and hospitalization in patients with inflammatory arthritis.

BACKGROUND: Inflammatory arthritis including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders at increased risk of morbidity and mortality for which a validated prognostic tool for facilitating clinical management is needed. CHA2 DS2 -VASc (congestive heart failure/hypertension/age diabetes/stroke/vascular disease/age/sex category) score was initially conceived and used to estimate thromboembolic risk in non-valvular atrial fibrillation, and then successfully applied in community populations with sinus rhythm. We tested CHA2 DS2 -VASc-score as a prognosticator of adverse outcomes in patients in sinus rhythm with RA/AS/PsA. METHODS: Between March 2014 and March 2015, 414 patients (214 RA, 75 AS, 125 PsA) in sinus rhythm without cardiac disease were consecutively analyzed and prospectively followed-up. Primary and co-primary end-points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively. RESULTS: Patients were divided into LOWscore and HIGHscore groups if CHA2 DS2 -VASc was = 0/1 point or greater than 1 point, respectively. The HIGHscore group comprised 190 patients who were older with higher prevalence of CV risk factors and arthritis disease activity than 224 LOWscore patients. During a follow up of 36 months, the event rate for primary and co-primary end-point was 37% and 12% in the HIGHscore vs 22% and 4% in LOWscore group (P = .001 and .002 respectively). At multivariate Cox regression analysis CHA2 DS2 -VASc-score was related to primary end-point (hazards ratio [HR] 1.30 [1.07-1.59], P = .009) and co-primary end-point (HR 1.35 [1.01-1.79], P = .04) independently of traditional CV risk factors analyzed individually and indexes of inflammation or disease duration. CONCLUSION: CHA2 DS2 -VASc-score accurately identifies in the mid-term patients in sinus rhythm with RA/AS/PsA at different risks for CV and non-CV mortality and hospitalization.

Rate of serious infections in spondyloarthropathy patients treated with anti-tumour necrosis factor drugs: a survey from the Italian registry GISEA.

OBJECTIVES: To determine the incidence of serious infections (SIs) among the spondyloarthropathy (SpA) patients from the "Gruppo Italiano per lo Studio delle Early Arthritis" (GISEA) registry and treated with tumour necrosis factor (TNF) inhibitors (TNFIs), and to identify the factors associated with the development of the infections. METHODS: This observational study on 3321 GISEA-registered SpA patients collected real-world demographic and clinical data relating to their biological drug treatments. The overall incidence of infections was analysed by type of SpA. RESULTS: A total of 3321 SpA patients (1731 males, 52.2%; mean age 47±13 years; median disease duration 3 years, interquartile range [IQR] 0-8) were eligible for inclusion in the analysis. Two hundred and fifty-nine patients experienced at least one of 391 microbiologically diagnosed SIs, 32% of which were recorded during the first 12 months of treatment. The overall incidence of SIs was 43.9/1000 patient-years of follow-up (95% confidence interval [CI] 39.6-48.4): 29.9/1000 (95% CI 23.1-38.1) among those treated with adalimumab (ADA); 36.1/1000 (95% CI 30.0-43.1) among those treated with etanercept (ETN); and 61.4/1000 (95% CI 53.3-70.5) among those treated with infliximab (INF). The highest incidence was observed among the patients with psoriatic arthritis (PsA), but the difference was statistically significant only in comparison with the patients with undifferentiated SpA (p=0.002), whose incidence of SIs was also lower than in the patients with ankylosing spondylitis (AS) (p=0.034). Multivariate models showed that the number of comorbidities (hazard ratio [HR] 1.29, 95%CI 1.2-1.4; p<0.001), age at the start of TNFi treatment (HR 0.99, 95%CI 0.97-0.99; p=0.030), steroid use (HR 1.40, 95%CI 1.1-1.8; p=0.012) and male sex (HR 0.72, 95%CI 0.5-0.9; p=0.012) were all statistically significant predictors of infection. The factors independently associated with a lower risk of SIs were the use of ETN (HR 0.52, 95%CI 0.4-0.7; p<0.001) or ADA (HR 0.59, 95%CI 0.4-0.8; p=0.002) rather than INF. CONCLUSIONS: The incidence of SIs was higher among patients with PsA or AS than among those with undifferentiated SpA, and among patients treated with INF than among those treated with ADA or ETN. Male sex, steroid use and the number of comorbidities were all factors predictive of SIs.

Postural counseling represents a novel option in pain management of fibromyalgia patients.

BACKGROUND: Chronic pain is a key symptom in fibromyalgia (FM), and its management is still challenging for rheumatologists in daily practice. FM patients show psychological and psychiatric manifestations, going from mood and emotional disorders to depression and alexithymia that negatively impact their quality of life, limiting their daily activities. Since pharmacological strategies have a limited efficacy in FM pain, alternative or complementary non-pharmacological approaches have been introduced in the clinical management of FM. PATIENTS AND METHODS: This is a retrospective study on FM patients (n=52) treated with a novel integrated postural counseling (PC) rehabilitation program carried out by a counselor physiotherapist. The clinical impact of PC was evaluated by 1) a semi-structured interview using an ad hoc modified questionnaire McGill Illness Narrative Interview (MINI) 1 to obtain data on pain management by highlighting everyday experience of living with pain and 2) an FM impact questionnaire (FIQ) total score. RESULTS: Two main structures of narrative emplotment of FM illness were recognized: 1) the cumulative life narrative structure (46.15%) and 2) the broken life (53.85%) narrative structure. Baseline FIQ score was 77.38±7.77, and it was significantly reduced after PC to 39.12±13.27 (P<0.0001). Although well-being still requires further definition as outcome in pain management, it is important for FM patients, dealing with pain-related sensations, thoughts and feelings and limiting their daily activities. In our study, 87.5% of interviewed FM patients reported an improvement in their well-being after PC. CONCLUSION: Our data suggest that an integrated PC program positively impacts chronic pain and fatigue based on self-management strategies. PC allows FM patients to resume their own life and regenerate their own image. Finally, we propose the introduction of the evaluation of the ability to resume daily activities as the target of rehabilitation programs in FM.

Effectiveness of Adalimumab for the Treatment of Psoriatic Arthritis: An Italian Real-Life Retrospective Study.

Background: Few studies have evaluated the effectiveness of adalimumab in the real-life setting in psoriatic arthritis (PsA). Objective: To evaluate the 2-year retention rate of adalimumab in PsA patients. Potential baseline parameters influencing persistence on treatment were also evaluated. Methods: PsA patients from 16 Italian Rheumatology Units treated with adalimumab as first- or second-line biological therapy were retrospectively evaluated. Adalimumab retention rate was evaluated at 12 and 24 months. Logistic regression was used to evaluate the association between predictor variables and adalimumab retention rate. Results: From 424 patients (53.5% male, aged 48.3 ± 12.8 years) who started treatment with adalimumab, 367 (86.6%) maintained treatment for 12 months and 313 (73.8%) for 2 years. At 24-months, Disease Activity in PsA (DAPSA) remission (defined as ≤4) and Low Disease Activity (LDA) (≤14) were achieved in 22.8% and 44.4% of patients, respectively. Adalimumab treatment significantly decreased the number of tender (7.0 ± 5.7 at baseline vs. 2.3 ± 3.5 at 24 months, p < 0.001) and swollen joints (2.7 ± 2.8 at baseline vs. 0.4 ± 0.9 at 24 months, p < 0.001), DAPSA (25.5 ± 10.9 at baseline vs. 11.0 ± 8.4 at 24 months, p < 0.001), PASI (5.3 ± 5.7 at baseline vs. 2.7 ± 2.8 at 24 months, p < 0.001) and CRP (3.8 ± 6.3 at baseline vs. 1.2 ± 1.7 at 24 months, p < 0.001). Among a range of laboratory and clinical variables, only female gender was associated with improved adalimumab persistence at 24 months (OR: 1.98, 95% CI: 1.2-3.2, p = 0.005). Conclusions: Independent of a range of predictor variables, adalimumab was shown to be effective, while maintaining a high retention rate after 2 years in PsA patients.

The influence of comorbidities on the efficacy of tumour necrosis factor inhibitors, and the effect of tumour necrosis factor inhibitors on comorbidities in rheumatoid arthritis: report from a National Consensus Conference.

Objective: To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. Methods: A National Consensus Conference adopted a five-step process to better address the place of TNFi in the treatment of RA. Here we report the work focused on the influence of comorbidities on TNFi efficacy and the effect of TNFi on comorbidities using a Population Intervention Comparison Outcome-based strategy from 8 April 2013 to 15 January 2016. Results: A total of 4453 hits were analysed, of which 10 were eligible for full review. Data show that the presence of comorbidities influences the treatment strategy and several clinical outcomes. The risk of solid cancer is similar in RA patients treated with TNFi or with conventional synthetic DMARDs, and the risk of recurrent breast cancer is not higher in RA patients treated with TNFi. The risk of developing serious infections is higher in RA patients receiving TNFi than conventional synthetic DMARDs. Patients with previous serious infections before starting TNFi are not at increased risk of subsequent serious infection. The hazard rate of hospitalization due to infections is not different among patients remaining on the same TNFi, or switching to a different TNFi or to an agent with another mechanism of action. Longer exposure to TNFi is associated with a reduction in the risk of cardiovascular events. Conclusion: Comorbidities affect RA treatment strategies and the efficacy of TNFi. TNFi treatment may decrease the risk of cardiovascular diseases and their use in patients with previous infection is not associated with a higher risk of recurrences.

Incidence of cancer in patients with spondyloarthritis treated with anti-TNF drugs.

OBJECTIVE: To determine the incidence of cancer in TNF inhibitor (TNFi)-treated spondyloarthritis (SpA) patients entered in the GISEA registry, and identify the factors associated with its development. METHODS: This observational study involved an open cohort of 3321 SpA patients selected from the GISEA registry, designed to collect real-world clinical data concerning patients with RA or SpA treated with biological drugs. The baseline information includes demographics and clinical parameters. The overall incidence of neoplasias was compared to this observed in the general population according to the Italian Association of Medical Oncology. RESULTS: Of the 3321 SpA patients (1731 males, 52.2%; mean age 47±13years; median disease duration three years, interquartile range [IQR] 0-8), 50 developed at least one of 56 malignancies during the follow-up period of up to 12years of treatment with TNFi. The overall incidence was 6.3/1000 patient-years of follow-up (95% confidence interval [CI] 4.7-8.2): 7.3/1000 patient-years (95% CI 4.1-11.8) in those treated with ADA; 6.1/1000 patient-years (95% CI 3.8-9.4) in those treated with ETN; and 5.8/1000 patient-years (95% CI 3.5-9.1) in those treated with INF while in the general population was 5.1/1000 patient-years. Univariate analysis showed that age at the time of starting TNFi (P=0.001), the presence of comorbidities (P=0.012), the number of comorbidities (P<0.001), and HAQ-DI score (P=0.002) were associated with a higher risk of malignancies. Stepwise regression models showed that only previous neoplasia was a significant predictor of a new malignancy. The type of drug was not associated with the risk of malignancy. CONCLUSIONS: The incidence of malignancies among SpA patients treated with the three TNFi was higher than in general population; having had a previous solid cancer is predictive of a new malignancy.

Patient-reported impact of spondyloarthritis on work disability and working life: the ATLANTIS survey.

BACKGROUND: The aim was to establish how patients experience the impact of spondyloarthritis (SpA) on work disability and working life. METHODS: The survey was performed in 17/20 regions in Italy (1 January to 31 March 2013). A multiple-choice questionnaire was published on the official website of the sponsor - the National Association of Rheumatic Patients (ANMAR) - and hard-copies were distributed at outpatient clinics for rheumatic patients. RESULTS: Respondents (n = 770) were of both sexes (56 % men), educated (62 % at high school or more), of working age (75 % aged ≤60 years), and affected by SpA. The most common types diagnosed were ankylosing spondylitis (AS) (39 %) and psoriatic arthritis (PsA) (36 %). Respondents were working full-time (45 %), part-time (8 %) or had retired (22 %); 15 % were unemployed (for reasons linked to the disease or for other reasons, students or housewives). Patients reported disability (39 %), were receiving disability benefits (34 %), were experiencing important limitations that were hindering their professional development/career (36 %) and some had to change/leave their job or lost it because of SpA (21 %). Employed respondents (n = 383) had worked on average 32.2 h in the last 7 days. More hours of work were lost over the last 7 days due to SpA (2.39 h vs 1.67 h). The indirect costs of the disease amounted to €106/week for patients reporting well-being/good physical conditions/improvement and €216/week for those reporting permanent impairment. CONCLUSIONS: Most patients were in the midst of their productive years and were experiencing considerable difficulties in carrying out their job because of the disease: half of them reported disability and one third were experiencing important limitations in their career perspective.

The clinical relevance of early anti-adalimumab antibodies detection in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: A prospective multicentre study.

OBJECTIVES: To evaluate the relevance of anti-adalimumab (anti-ADA) antibodies (Abs) and their relationship with clinical/laboratory features in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: Fifty-eight patients affected with RA, AS and PsA were prospectively enrolled. Clinical/laboratory characteristics, disease activity, anti-ADA, anti-nuclear (ANA), anti-double strand (ds)DNA, anti-extractable nuclear antigens (anti-ENA) and anti-phospholipid Abs (aPL) were evaluated at baseline, 4, 12 and 24 weeks of adalimumab treatment. RESULTS: Anti-ADA Abs were observed in 11/58 (19%) patients; they were detected within the 4th week of therapy in 90.9% of the positive subjects. Anti-ADA positivity was associated with significantly lower mean adalimumab serum levels (P<0.05). Treatment failure was observed in 20/58 (34.5%) patients and was significantly associated with anti-ADA Abs (P<0.05). Mean adalimumab serum levels were significantly lower in patients with treatment failure than in the responders one, both in the whole cohort (P<0.01) and in the group of anti-ADA positive patients (P<0.01). Adverse events happened more often in anti-ADA positive then in anti-ADA negative patients (27.3% vs 14.9%). CONCLUSIONS: Anti-ADA abs could be considered an early marker associated to a poor clinical response to adalimumab treatment. Routine ANA/anti-ENA/aPL monitoring did not reveal as useful tools to predict the development of anti-ADA abs.

Obesity and reduction of the response rate to anti-tumor necrosis factor α in rheumatoid arthritis: an approach to a personalized medicine.

OBJECTIVE: Obesity is a mild, long-lasting inflammatory disease and, as such, could increase the inflammatory burden of rheumatoid arthritis (RA). The study aim was to determine whether obesity represents a risk factor for a poor remission rate in RA patients requiring anti-tumor necrosis factor α (anti-TNFα) therapy for progressive and active disease despite treatment with methotrexate or other disease-modifying antirheumatic drugs. METHODS: Patients were identified from 15 outpatient clinics of university hospitals and hospitals in Italy taking part in the Gruppo Italiano di Studio sulle Early Arthritis network. Disease Activity Score in 28 joints (DAS28), body mass index (BMI; categorized as <25, 25-30, and >30 kg/m(2) ), acute-phase reactants, IgM rheumatoid factor, and anti-cyclic citrullinated peptide antibody values were collected. DAS28 remission was defined as a score of <2.6 lasting for at least 3 months. RESULTS: Six hundred forty-one outpatients with longstanding RA receiving anti-TNFα blockers (adalimumab, n = 260; etanercept, n = 227; infliximab, n = 154), recruited from 2006-2009 and monitored for at least 12 months, were analyzed. The mean ± SD DAS28 at baseline was 5.6 ± 1.4. A BMI of >30 kg/m(2) was recorded in 66 (10.3%) of 641 RA patients. After 12 months of anti-TNFα treatment, a DAS28 of <2.6 was noted in 15.2% of the obese subjects, in 30.4% of the patients with a BMI of 25-30 kg/m(2) , and in 32.9% of the patients with a BMI of <25 kg/m(2) (P = 0.01). The lowest percentage of remission, which was statistically significant versus adalimumab and etanercept (P = 0.003), was observed with infliximab. CONCLUSION: Obesity represents a risk factor for a poor remission rate in patients with longstanding RA treated with anti-TNFα agents. A personalized treatment plan might be a possible solution.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: comparison of adalimumab, etanercept and infliximab in the GISEA registry.

OBJECTIVE: To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS: The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS: 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS: Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis.

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis.

TNF-like cytokine (TL1A) is a newly identified member of the TNF superfamily of ligands that is important for T cell costimulation and Th1 polarization. However, despite increasing information about its functions, very little is known about expression of TL1A in normal or pathological states. In this study, we report that mononuclear phagocytes appear to be a major source of TL1A in rheumatoid arthritis (RA), as revealed by their strong TL1A expression in either synovial fluids or synovial tissue of rheumatoid factor (RF)-seropositive RA patients, but not RF-/RA patients. Accordingly, in vitro experiments revealed that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes (IC), polyethylene glycol precipitates from the serum of RF+/RA patients, or with insoluble ICs purified from RA synovial fluids. Monocyte-derived soluble TL1A was biologically active as determined by its capacity to induce apoptosis of the human erythroleukemic cell line TF-1, as well as to cooperate with IL-12 and IL-18 in inducing the production of IFN-gamma by CD4(+) T cells. Because RA is a chronic inflammatory disease with autoimmune etiology, in which ICs, autoantibodies (including RF), and various cytokines contribute to its pathology, our data suggest that TL1A could be involved in its pathogenesis and contribute to the severity of RA disease that is typical of RF+/RA patients.