Matteo Filippini

Serious infections during anti-TNFα treatment in rheumatoid arthritis patients ☆

The objective was to estimate the incidence of serious infections in the patients treated with anti-TNFalpha agents for rheumatoid arthritis (RA) recorded in the Lombardy Rheumatology Network (LORHEN) registry. The study inclusion criteria were met by 1064 of the 1114 patients with long-standing RA, 519 treated with infliximab, 303 with adalimumab, and 242 with etanercept; their mean age was 55.8 years and the mean duration of RA 9.4 years. Seventy-three patients (6.9%) experienced a total of 74 serious infections, an incidence rate for all treatment courses of 35.9 per 1000 patient-years (95% confidence interval [95% CI] 27.66-44.13). Most were lower respiratory tract (34.2%) or skin and soft tissue infections (20.5%). Of the 1064 patients, the 790 treated with anti-TNFalpha after March 2002 underwent screening tests for LTBI; five patients developed active tuberculosis. Three patients died of septic shock. The type of anti-TNFalpha agent did not seem to affect the incidence or site of the infections. Both univariate and multivariate analyses identified age at the start of anti-TNFalpha treatment (p=0.008), baseline erythrocyte sedimentation rate ([ESR] p=0.014), and the concomitant use of corticosteroids (p=0.029) as significant predictors of infections. There was no statistically significant difference in risk between the anti-TNFalpha agents.

Treatment of rheumatoid arthritis with anti-TNF-alpha agents: A reappraisal

It has been found that tumour necrosis factor(TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA), and the development of drugs targeting this molecule has extended the therapeutical approaches to RA patients. A number of observational studies of large patient series have also been published over the last few years, many of which have been based on national registries designed to monitor the efficacy and safety of anti-TNF agents, and allow healthcare institutions to control expenditure. Registry data can also help in identifying clinical and laboratory findings capable of predicting response. It has been suggested that the percentage of responding patients is lower in everyday clinical practice than that observed in RCTs, possibly because of patient selection, the use of a washout period before inclusion (which may artificially increase disease activity), and differences in doses, co-morbidities and adherence to therapy. A number of safety concerns have been raised since the introduction of anti-TNF agents, and they are now contraindicated in patients with advanced heart failure; however, the most widely debated current issues regard infections and neoplastic diseases. Moreover, the marketing of new and expensive biological agents has made strictly necessary to create systems capable of monitoring their safety and effectiveness in everyday practice, including the use of longitudinal observational studies. As the first published registry of anti-TNFalpha-treated patients in Italy, Lombardy Rheumatology Network (LORHEN) is already making its contribution in this direction.

Anti-TNFα therapy in a cohort of rheumatoid arthritis patients: Clinical outcomes

OBJECTIVE To assess the effectiveness of anti-TNFalpha agents by analysing the principal clinical outcomes in patients with active rheumatoid arthritis (RA). METHODS 1010 patients who received no clinical benefit from previous treatment with methotrexate and/or other DMARDs, were subsequently treated with one or more of the anti-TNFalpha agents. RESULTS After the first six months of anti-TNFalpha therapy, 29% of the patients showed a good and 47% a moderate European League Against Rheumatism (EULAR) response, and this positive result was maintained after two years of follow-up. Their median Disease Activity Score based on the erythrocyte sedimentation rate and the evaluation of 28 joints (DAS28) decreased from 5.94 at baseline to 4 after six months (p<0.001; Delta 1.94), and further significant responses were also observed after 12, 18 and 24 months; their median 36-month DAS28 score reflected mild disease activity. The median Health Assessment Questionnaire (HAQ) score fell from 1.34 at baseline to 1 after six months of therapy (Delta 0.34; p<0.05), and a further significant reduction was observed during the second and third year of follow up. CONCLUSIONS Especially when combined with DMARDs, anti-TNFalpha drugs can induce a good clinical response regardless of the particular molecule used, whereas their combination with steroids does not seem to improve disease outcomes at any time during follow-up.

Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2-year prospective study

IntroductionThe diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.MethodsSerial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up.ResultsAnti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration.ConclusionsPresence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level.

Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: Results from the GISEA register

INTRODUCTION Rituximab (RTX) is a monoclonal anti-CD20 antibody approved for the treatment of rheumatoid arthritis (RA) in association with methotrexate (MTX). OBJECTIVES To evaluate the efficacy and safety of RTX-MTX combination therapy compared with RTX alone in the treatment of RA. METHODS We analyzed data from a prospective cohort study, the Italian biologic register GISEA, to investigate the efficacy and safety of rituximab. Moreover, the adverse events (AE) and the causes of discontinuation therapy were analyzed. RESULTS We identified 338 RA patients, 162 treated with RTX and 176 with RTX-MTX. After 52 and 104 weeks of therapy the disease activity score in 28 joints and the Health Assessment Questionnaire Score were available in 168 patients (78 with RTX-MTX and 60 with RTX alone), showing significant reduction without differences among the two groups. AE were reported in 142 patients (42%), for a total of 368 recorded side effects. The majority (90.5%) of AE were mild to moderate in severity. Comparable percentages of severe AE were reported in the 2 groups (9.9% for RTX alone and 9.3% for RTX+MTX). A poor disease control was observed in 14.2% and 13.5% of patients treated with RTX+MTX and RTX, respectively; while 12 patients (4.5% in RTX+MTX, and 2.5% in RTX group) suspended therapy for AE. CONCLUSIONS RTX showed a good efficacy and safety profile in the real-life management of RA patients regardless of the association with MTX.

Effects of Anti-TNF Alpha Drugs on Disability in Patients with Rheumatoid Arthritis: Long-Term Real-Life Data from the Lorhen Registry

This study involving 1033 patients with RA confirms the effectiveness of etanercept, adalimumab, and infliximab in reducing RA-related disability even in patients with a history of highly active and longstanding RA. Moreover, we found that the improvement in disability was biphasic, with a marked improvement during the first year of anti-TNF therapy, followed by slower but significant recovery over the subsequent four years.

FRI0053 Comparison of the Risk of Developing Comorbities and Adverse Events by Type of Diagnosis: Results from the Lorhen Registry

Background The relationship between systemic rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) and various comorbidities has long been debated, and it has also been observed that patients with RA and SpA develop adverse events during anti-TNF therapy. Objectives The primary aim of this multicenter study was to identify the most frequent comorbidities and adverse events (AEs) in RA, PsA and AS patients on the basis of the data in the LORHEN register. The secondary aim was to identify the effect of biological anti-TNF on adverse events development. Methods The study involved 2253 patients with RA (mean age 46.21±14.7 years; mean disease duration 14.8±8.9 years; F(%)=82.0%), 372 with long-standing PsA (mean age 41.2±13.5 years; mean disease duration 11.6±7.6 years; F(%)=38.3%), and 410 with AS (mean age 36.8±13.3 years; mean disease duration 11.6±8.9 years; F(%)=47.7%), all of whom had been treated with biological drugs for at least six months or had discontinued therapy due to serious adverse events. Of the RA patients, 34.4% had been treated with two DMARDs before receiving biological therapy, whereas the majority of PsA and AS patients had been treated with only one DMARD (respectively 40.22% and 39.85%). Many patients were treated with low-dose corticosteroids (<7.5 mg/day): 94.72% of the RA patients, 75.41% of the PsA patients, and 55.92% of the AS patients. Most of the patients were treated with the anti-TNF agents ADA, IFN, ETN, GOL and CTZ, but some RA patients were treated with ABA or TCZ. Logistic regression analysis corrected by age, gender, disease duration, smoking habit, study centre and therapy or diagnosis if appropriate were used. Results Many of the patients suffered from comorbidities, particularly hypertension (20.13% of the RA patients, 10.36% of the PsA patients, and 7.28% of the AS patients), cardiovascular diseases (CVD; respectively 2.15%, 0.35% and 1.53%), dyslipidemia (4.05%, 3.93% and 1.92%), osteoporosis (12.53%, 3.21% and 5.75%). The most frequent adverse events were infections (48.7%, 34.15% and 30.32%), neoplasias (5.03%, 5.28% and 4.07%), and CVD (4.82%, 2.85% and 1.81%). The odds ratios (ORs) for the risk of a comorbidity between the different disease groups were: PsA vs RA: 0.35 (95% CI 0.24-0.50); PsA vs AS: 0.81 (95% CI 0.53-1.23); and RA vs AS: 2.33 (95% CI 1.59-3.39). The ORs of developing an adverse event were: PsA vs RA: 0.48 (95% CI 0.35-0.66); PsA vs AS: 0.96 (95% CI 0.66-1.41); and RA vs AS: 1.99 (95% CI 1.38-2.86). The ORs of the effect of anti-TNF vs no anti-TNF therapy on adverse events were 0.68 (95% CI 0.42-1.10) in the RA group; 5.49 (95% CI 1.12-26.92) in the PsA group; and 3.38 (95% CI 0.42-27.11) in the AS group. Conclusions Our results suggest that patients with RA are at greater risk of having comorbidities and developing adverse events than those with AS, but not those with PsA. The effect of anti-TNF therapy on the development of adverse events is greater in AS and PsA patients than in RA patients. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4432

FRI0072 Predictors of response to anti-TNF therapy in ra patients with moderate disease activity compared to those with high disease activity according to DAS28 scores’

Background Studies have found that patients who start anti-TNF therapy with lower DAS28 scores are more likely to achieve disease remission (defined using a DAS28 <2.6). However no studies have previously evaluated predictors of response in RA patients with moderate disease activity (MDA) (DAS28 >3.2–5.1) compared to those with high disease activity (HDA) (DAS28 >5.1). Objectives The aim of this study was to identify the clinical factors that predicted a good clinical response to anti-TNF in RA patients who had been divided into two groups according to baseline DAS28 scores (moderate: >3.2–5.1 and high: >5.1) and entered into the Lombardy Rheumatology Network (LORHEN) registry after five years of treatment with anti-TNF agents. Methods We entered into the study all patients with no previous exposure to biologic agents who were starting one of the three available anti-TNF agents (ETN, IFN or ADa), and who had been both included in the LORHEN register and followed-up for a minimum of twelve months by 1999. The prospective protocol included information on demographics, the clinical characteristics of the patients and response measures. Disease activity at baseline and after 12 six months was assessed using the DAS28, and response was evaluated according to the EULAR improvement criteria. Potential predictors of response were identified using multivariate binary logistic regression models. Results The study involved 1300 patients with established RA (326 ETA, 385 ADA, 589 INF), of whom 975 with high, and 325 with moderate, clinical activity were included in the analysis of clinical efficacy. At the start of therapy, patients had a mean age of 54.66±13.74 years, a disease duration of 7.49±7.88 years, and a baseline DAS-28 of 5.77±1.05 (HDA 6.23±0.71 vs. MDA 4.37±0.51, respectively). After a mean of twelve months, 21.39% of the patients had achieved a DAS-28 of ≤2.6 (HDA 16.17% vs. MDA 37.3%; P=0.0001) and were considered to be in remission. A total of 324 had achieved a good EULAR response (HDA 203 vs. MDA 121). A higher probability for good EULAR response in patients with HDA was associated with male gender (F vs M - OR 0.42, 95% CI 0.27-0.63; p:0.0001), a low baseline erythrocyte sedimentation rate (ESR) (OR 0.99, 95% CI 0.98-1.00; p:0.03), or an absence of comorbidities (OR 2.15, 95% CI 1.52-3.04 p:0.0001); in patients with MDA this was associated with no corticosteroids having been used (OR 2.06, 95% CI 1.12-3.77; p:0.02) and with male gender (F vs M - OR 0.48, 95% CI 0.27-0.85; p:0.01).Age, disease duration, RF and previous use of DMARDs did not predict response in this cohort of patients, but patients with HDA without concomitant comorbidities were more likely to achieve a good clinical response. Male gender was associated with a good EULAR response in both subgroups. Conclusions We found that the percentage of patients with long-standing RA and MDA treated with anti-TNF agents who achieved remission as outpatients in the community was higher than those with HDA. Furthermore, those factors that predicted good EULAR were different in patients with MDA compared to those with HDA, with the exception of male gender. Disclosure of Interest None Declared

AB0313 Factors predicting disability in patients affected by long-standing rheumatoid arthritis treated with anti-TNF drugs: An observational study

Background HAQ (Health Assessment Questionnaire) is related to working ability, the need for specialist examinations and the quoad vitam prognosis; so it is an appropriate means of summarising outcomes, as well as the direct and indirect costs of the disease, as has been shown by pharmacoeconomic analyses. Moreover evenafter 20 years of treatment with traditional or biological DMARDs, joint damage evaluated using the Larsen and Sharp score isless than 40% of the highest possible score and the reversibility of the HAQ score is close to 70%even in the case of late arthritis. Objectives This article describes the findings of an observational study designed to evaluate disability in patients with long-standing rheumatoid arthritis (RA) treated with anti-TNF agents. Theaims were to define the main predictors of disability during biological treatment and assess treatment strategies (the use of steroids and traditional DMARDs, a switch to another anti-TNF agent). Methods The study involved 1033 patients attending six Italian rheumatology departments, who werestratified on the basis of various clinical and demographic variables. Drug effectiveness was assessed by analysing disease functional status using the Health Assessment Questionnaire (HAQ). Results Disability significantly decreased after five years of anti-TNF therapy (ΔHAQ: -0.78, p<0.05). The HAQ improvement was less in patients aged >65 years, females, and those with a disease duration of more than 10 years, a higher comorbidity index, greater disease activity and disability at baseline, high titres of rheumatoid factor, and contraindications to combination therapy with traditional DMARDs. Steroids were useful in patients with greater baseline impairment. The patients treated with infliximab had a higher disability index at baseline, but showed greater improvement than those treated with etanercept or adalimumab. The results were confirmed by multivariate analysis. Conclusions The effect of anti-TNF therapy on the disability of patients with long-standing RA is certainly substantial, and the HAQ is a good means of evaluating the efficacy of biological treatment. References Aletaha D, Ward MM. Duration of rheumatoid arthritis influences the degree of functional improvement in clinical trials. Ann Rheum Dis. 2006; 65:227-33. Sokka T, Häkkinen A, Krishnan E, Hannonen P. Similar prediction of mortality by the health assessment questionnaire in patients with rheumatoid arthritis and the general population. Ann Rheum Dis. 2004; 63:494-7. Lloyd S, Bujkiewicz S, Wailoo AJ, Sutton AJ, Scott D. The effectiveness of anti-TNF-a therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis. Rheumatology 2010; 49:2313–21. Disclosure of Interest None Declared