Marco Antivalle

Infliximab-induced lupus in Crohn's disease: a case report

An 18-year-old male patient was under treatment with infliximab at a dose of 5 mg/kg at Weeks 0, 2 and 6 for refractory Crohns disease. In June 2002, the patient was admitted to the Outpatient Clinic of the Rheumatology Unit for arthralgia affecting the small joints, non-pruritic crops of purple skin lesions and malar rash in the face. Serum antinuclear antibodies were positive (1:640 speckled pattern), and anti-double-stranded DNA was positive (1:80); moreover, positivity of anti-extractable nuclear antigen was observed. Antihistone antibodies, lupus anticoagulant and anticardiolipin antibodies were negative. A diagnosis of infliximab-induced lupus was made and the drug treatment was withdrawn. However, 3 months after withdrawal of treatment, the patient still showed clinical and laboratory symptoms of systemic lupus erythematosus. After 6 months of treatment, systemic lupus erythematosus-related symptoms disappeared and anti-double-stranded DNA returned to normal. The patient is currently under treatment with prednisone 20 mg/day for systemic lupus erythematosus and with oral mesalazine 2.4 mg/day for Crohns disease. Treatment with infliximab is known to produce an increase of autoantibodies (antinuclear antibodies, anti-double-stranded DNA), but not clinical disease. This is the first case, to our knowledge, of onset of prolonged infliximab-induced lupus.

Predicting response to anti-TNF treatment in rheumatoid arthritis patients

OBJECTIVE To identify the clinical factors predicting failure or a good clinical response in the cohort of RA patients entered in the Lombardy Rheumatology Network (LORHEN) registry after 3 years of treatment with anti-TNF agents. METHODS We studied the patients who had received anti-TNF agents and been followed up for a minimum of 6 months. Disease activity at baseline and after 6 months was assessed using the DAS28, and response was evaluated according to the EULAR improvement criteria. RESULTS 1005 patients (55.72 years) were included in the analysis. at baseline the DAS-28 was 5.91+/-0.95 and a HAQ score was 1.46+/-0.61. At mean of 14.57 months, 29.9% of the patients achieved a DAS-28 of <or=2.6 (remission). A higher RR for remission was associated with male gender (AHR 1.51, 95% CI 1.14-2.00; p: 0.004) and a lower RR for remission with: prior treatment with >3 DMARDs (AHR 0.077, 95% CI 0.58-1.03; p: 0.074), a high ESR (AHR 0.86, 95% CI 0.81-0.92; p: 0.000), Steinbrockers functional class III/IV (AHR 0.66, 95% CI 0.48-0.90; p: 0.010), a high TJC (AHR 0.97, 95% CI 0.94-0.99; p: 0.011). A 12-month EULAR non-response was observed in 153/821 (18.6%) associated with a higher baseline HAQ score (AOR 1.51, 95% CI 1.03-2.20, p: 0.033), prior treatment with >3 DMARDs (AOR 1.76, 95% CI 1.09-2.85; p: 0.021) and corticosteroid >5 mg/day (AOR 2.05, 95% CI 1.06-3.97; p: 0.034). CONCLUSION We found that only a minority of patients with long-standing RA treated with anti-TNF agents achieve a good clinical response or remission.

Modulating the co-stimulatory signal for T cell activation in rheumatoid arthritis: could it be the first step of the treatment?

Advances in our understanding of the key mediators of chronic inflammation and tissue damage in rheumatoid arthritis (RA) have fostered the development of targeted therapies and greatly expanded the available treatment options. Abatacept, a soluble human fusion protein that selectively modulates the co-stimulatory signal required for full T-cell activation, is approved for the treatment of moderate to severe RA in the United States, Canada, and the European Union. This review summarises the data on efficacy (disease activity, quality of life, prevention of structural damage) and safety from randomised clinical trials of abatacept plus methotrexate in patients with: i) active RA and an inadequate response to methotrexate who are naïve to biological disease-modifying anti-rheumatic drugs; and ii) methotrexate-naïve early RA with poor prognostic factors. Novel imaging outcomes and biological changes induced by abatacept treatment are also briefly reviewed. Optimal use of abatacept as a first-line biological therapy is discussed in light of the current recommendations and guidelines.

Measurement of Serum Klotho in Systemic Sclerosis

Background The aim of our study was to evaluate the serum concentration of klotho in a cohort of systemic sclerosis (SSc) patients compared to that of healthy controls and to correlate its levels with the degree and the kind of organ involvement. Methods Blood samples obtained from both patients and controls were collected and analysed by an ELISA test for the determination of human soluble klotho. Scleroderma patients were evaluated for disease activity through clinical, laboratory, and instrumental assessment. Results Our cohort consisted of 81 SSc patients (74 females, mean age 63.9 ± 13.1 years) and 136 healthy controls (78 females, mean age 50.5 ± 10.7 years). When matched for age, serum klotho concentration significantly differed between controls and patients (p < 0.001). However, in SSc patients, we did not find any significant association between serum klotho and clinical, laboratory, and instrumental findings. Lower serum levels of klotho were detected in 4 patients who were anticitrullinated peptide antibody (ACPA) positive (p = 0.005). Conclusions Our data show a lower concentration of klotho in the serum of SSc patients compared to that of healthy controls, without any significant association with clinical manifestations and laboratory and instrumental findings. The association between serum klotho and ACPA positivity requires further investigation.

SAT0167 Clinical and Ultrasonographic Evaluation in A Cohort of Sustained Remission Rheumatoid Arthritis Patients after Stopping Biologic Therapy: A Single Center Experience

Background Rheumatoid arthritis (RA) patients in clinical remission according to the 2011 ACR/EULAR criteria [1] can develop radiographically revealed hand and foot erosions and joint damage when observed 2-5 years later. Some authors have suggested that ultrasound or MRI should be included in the remission criteria in order to assess disease activity more precisely [2]. Ultrasonography (US) is a useful means of diagnosing and following up patients with RA, and power Doppler (PD) technology can evaluate intra- and peri-articular soft tissue inflammation [3]. Objectives The aim of this prospective study was to evaluate a cohort of patients with RA in sustained remission after stopping biological agents on the basis of clinical and US data. Methods From among the 302 RA patients receiving biological DMARD therapy attending our centre between January 2011 and December 2012, we selected those satisfying the 2011 ACR/EULAR remission criteria (SDAI <3.3 for more than six months) without glucocorticoid therapy and without any PD signal upon metacarpal phalangeal (MCP) US assessment. After stopping biological DMARDs, they underwent clinical and ultrasonographic examinations every two months or in the case of a disease flare. Biological DMARDs were resumed in the patients with an SDAI score of >11.0 and PDUS positivity in at least one MCP joint. Results After one year of follow-up, three (23%) of the 13 patients in sustained remission (3 males, 10 females; mean age 59 years, range 24-78; mean disease duration 8.6 years, range 1-30; 61% rheumatoid factor (RF) positive, 58% anti-cyclic citrullinated peptide antibody (anti-CCP) positive; mean biological DMARD treatment duration 39.3 months, range 12-98; 84% concomitantly treated with methotrexate) experienced a disease flare (mean SDAI 19.7; PDUS positive) and resumed biological DMARD therapy after a mean of 5.3 months. One patient (7%) was PDUS positive, but remained in SDAI remission. Three patients (23%) showed a low level of disease activity without PDUS positivity, and six patients (38.4%) remained in clinical and US remission. Intra-class correlation analysis showed a moderate agreement between SDAI and PDUS (ICC=0.67; p=0.034) Conclusions During the course of a one year follow-up, 23% of a cohort of RA patients in sustained remission (selected by combining US and the 2011 ACR/EULAR remission criteria) experienced a disease flare and needed to resume taking biological DMARDs. References Y. Tanaka et, al. Discontinuation of biologics in patients with rheumatoid arthritis. Clin Exp Rheumatol 2013; 31 (Suppl. 78): S22-S27. DT. Felson, et al. American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials. Artritis Rheum 2011;63: 573–86 A. Iagnocco, et al. Ultrasound imaging for the rheumatologist. XVII. Role of colour Doppler and power Doppler. Clin Exp Rheumatol 2008; 26: 759-62. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4003

WITHDRAWN: Abatacept as a first-line biological therapy

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.autrev.2013.06.008. The duplicate article has therefore been withdrawn.

THU0156 Impact of Verification Bias on the Evaluation of Diagnostic Accuracy of Lung Ultrasound in Rheumatoid Arthritis-Related Related Interstitial Lung Disease

Background Lung ultrasound (LUS) was reported to have a good diagnostic accuracy in the assessment of rheumatoid arthritis-related interstitial lung disease (RA-ILD), as compared to high resolution CT (HRCT), currently considered the diagnostic gold standard. However, partial verification, leading to biased estimates of the accuracy of LUS, is the rule in these studies, as the probability of undergoing HRCT is higher in patients with ILD. Objectives To assess the influence of verification bias in the assessment of the diagnostic accuracy of LUS in the detection of RA-ILD Methods We analyzed the data of a previously reported study comparing the diagnostic accuracy of LUS in comparison with usual clinical practice to detect RA-ILD [1]. LUS was performed in 152 RA patients, and its accuracy in the detection of ILD was compared to 3 clinical algorithms (Alg1: bibasilar crackles and dyspnea; Alg2: as Alg1 + reduced pulmonary function tests (PFTs); Alg3: as Alg1 + positive Chest X-Ray). By design, partial verification was significant: only 71/152 patients were verified with HRCT, 49/152 had PFTs, and 72/152 had Chest X-Ray. Estimated of sensitivity and specificity based on observed data (missing completely at random model MCAR), were compared with the estimates obtained with the Begg-Greenes method (missing at random assumption, MAR) [2], and with multivariate imputation (multivariate imputation by chained equations, MICE) [3]. Results Accuracy estimates based on complete data only (MCAR) differ significantly from the MAR estimates and from MICE results, and tend to inflate sensitivity estimates. Figure 1 reports the point sensitivity and specificity estimates under different assumptions for LUS and the 3 clinical algorithms, and the “ignorance region” as defined by Kosinski and Barnhart [4]. LLUS had the highest diagnostic accuracy. However, LUS estimates of sensitivity and specificity varied from 63.4% to 88.2%, and from 68.5% to 81.3% respectively. Figure 2 reports the influence of estimation model on the likelihood ratios of RA-ILD based on LUS results. LR+ varied from 2.80 to 4.33, and LR- from 0.17 to 0.45. Conclusions Verification bias can severely affect estimates of diagnostic accuracy of LUS in RA-ILD, and should be always taken into account in the interpretation of results. References Antivalle M, et al. Lung Ultrasound Screening for Interstitial Lung Disease in Rheumatoid Arthritis. Comparison with Usual Detection Algorithms in Clinical Practice. Arthritis Rheum 2014;66(suppl): S1301 Begg CB, R.A. Greenes, Assessment of diagnostic tests when disease verification is subject to selection bias. Biometrics 1983;39:207–215. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16:219-42. Kosinski AS, Barnhart HX, Accounting for nonignorable verification bias in assessment of diagnostic tests, Biometrics 2003; 59: 163–171. Disclosure of Interest None declared

SAT0596 Ultrasonographic Evaluation of Subclinicial Enthesitis in Patients Affected by Pediatric Inflammatory Bowel Disease

Background Joint involvement is the most frequent extra-intestinal manifestation of paediatric inflammatory bowel disease (IBD). Various recent studies focused on the clinical prevalence of enthesitis in children and adults with IBD1, and others have demonstrated the ability of ultrasound (US) to visualise the acute and chronic signs of entheseal inflammation with greater sensitivity than a clinical examination, although there is a lack of consensus concerning the US definition of entheseal abnormalities and their prognostic value especially in the paediatric field2. Objectives The aim of this study was to evaluate the prevalence of subclinical entheseal involvement in patients with pediatric IBD using a high frequency ultrasound probe. Methods Twenty-seven pediatric IBD patients (13 with Crohns disease [CD] and 14 with ulcerative colitis [UC]; 15 females and 12 males; mean age 13.7 years, range 7-21 years) without any clinical signs or symptoms of musculo-skeletal involvement and 24 healthy age- and gender-matched controls (14 females and 13 males; mean age 14.2 years, range 8-20 years) underwent an US examination (ESAOTE MyLAB 70 6-18 MHz linear array transducer). Brachial triceps, femoral quadriceps, Achilles, plantar fascia, and proximal and distal patellar entheses were all scored using the 0-136 Madrid Sonographic Enthesis Index (MASEI). Clinical and clinimetrical variables were assessed in both groups (MASES, BASDAI, BASFI, cHAQ, PCAI/PCDAI). Results None of the patients had a MASEI score suggesting early spondyloarthritis involvement but their average score was significantly higher than controls (3.15±2.84 vs 0.96±1.12, p=0.0006). There was also a significantly higher percentage of patients with at least one enthesis with power Doppler (PD) score ≥2 (37% vs 16%; p=0.037) and at least one enthesis with dishomogeneous echostructure (59% vs 0%; p=0.000). There were no between-group differences in terms of erosions (0% vs 0%), calcifications (7.4% vs 12.5%; p=0.656) or structural thickness (37% vs 33.3%; p=0.507). In paediatric IBD group we cannot find correlation between the total MASEI score and gender (p=0.12), age (p=0.20), disease duration (p=0.18) or IBD activity (p=0.83). Conclusions US detectable enthesopathy is frequent in paediatric IBD patients without any clinical signs or symptoms of musculo-skeletal involvement. Further studies involving a larger number of patients are needed to confirm these preliminary data. References Horton DB. et Al. Enthesitis is an Extraintestinal Manifestation of Pediatric Inflammatory Bowel Disease. Ann Paediatr Rheumatol. 2012; 10:1.0 Bandinelli F, Milla M, Genise S, et al. Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease without clinical signs and symptoms of spondyloarthropaty. Rheumatology (Oxford) 2011; 50:1275-9 Disclosure of Interest None declared

AB0541 Relationship Between Ultrasonographic Salivary Glands Abnormalities and Subclinical Cardiovascular Involvement in Patients with Primary SjÖgren Syndrome

Background Different studies showed that systemic inflammation, elevated levels of inflammatory cytokines, and immune dysregulation, typical of the inflammatory autoimmune disease, play a role in accelerated atherosclerosis. However, only few studies showed sub-clinical cardiovascular (CV) involvement in patients with primary Sjögrens syndrome (pSS) (1). Moreover, it has been demonstrated that salivary glands ultrasound (US) score is strictly related to the histological inflammatory abnormalities. Objectives The primary aim of our study was to investigated sub-clinical cardiovascular involvement in pSS patients by means of asymmetric dimethylarginine (ADMA) serum levels, coronary flow reserve (CFR), intima-media thickness (cIMT) and pulse wave velocity (PWV). The secondary aim was to performed salivary glands US and to compare these findings with cardiovascular parameters. Methods Fifty-three consecutive outpatients with pSS (7 M, 46 F; mean age 59.8 range 43-80 yrs; mean disease duration of 59.5 range 6-156 months) without classical CV risk factors and/or known CV diseases, and 22 homogenous healthy controls were enrolled. RF-QIMT and RF-QAS technologies were used to assess IMT and PWV and Dipyridamole transthoracic stress echocardiography to obtain CFR. Plasma ADMA levels, inflammatory markers and autoantibodies were also evaluated. My Lab 70 (Esaote, Florence, Italy) with linear probe (6-18 MHZ) was used to assess salivary glands US according to the scoring system published by Salaffi et al. (2). Results Although within the normal range, CFR in pSS patients was lower than that of the controls (2.6±0.23 vs 3.2±0.32 p<0.0001), whereas PWV and ADMA levels were significantly higher (9.2±1,8m/s vs 6.8±0.9m/s p<0.0001 and 0.76±0.07μM vs 0.54±0.05μM p<0.0001). Although QIMT values were not different in the two groups, the percentage of pSS patients with pathological values was higher (47/53 vs 12/22 p=0.001). Moreover, a significant correlation between salivary glands US score BMI (p=0.001), CRP (p=0.034) and ANA (p<0.0001) was found. However, no correlation between sub-clinical CV index was found (PWV r=-0.205 p=0.140, Q-IMT r=0.261 p=0,06, CRF r=-0.194 p=0.249, ADMA r=0.249 p=0.075). Conclusions Although CFR values were normal, higher ADMA levels, PWV values and percentage of subjects with pathological Q-IMT compared to healthy controls suggest that pSS patients without classical CV risk factors have an early endothelial dysfunction and sub-clinical atherosclerosis. However, no correlation between salivary US score and the sub-clinical CV involvement parameters was found. References Atzeni F, Sarzi-Puttini P, Signorello MC, Gianturco L, Stella D, Boccassini L, Ricci C, Bodini BD, Batticciotto A, De Gennaro-Colonna V, Drago L, Turiel M. New parameters for identifying subclinical atherosclerosis in patients withprimary Sjögrens syndrome: a pilot study. Clin Exp Rheumatol. 2014;32(3):361-8. Salaffi F, Argalia G, Carotti M, Giannini FB, Palombi C. Salivary gland ultrasonography in the evaluation of primary Sjögrens syndrome. Comparison with minor salivary gland biopsy. J Rheumatol 2000;27:1229–36. Disclosure of Interest None declared

THU0349 Assessment of dry eye symptoms in primary fbromyalgia

Background While dry eye symptoms and signs have been frequently reported in fibromyalgia patients, no study so far has specifically investigated the concordance between subjective symptoms and objective findings in this population. Objectives Aim of this study was to assess to whether, in FM patients, dry eye subjective symptoms are correlated to a real reduction of tear production, or mainly reflect a state of altered perception. Methods 158 patients were studied, 66 with fibromyalgia (FM: 62 F, 4 M, mean age 41.83 yrs) and 92 control subjects affected by miscellaneous rheumatic diseases (Controls: 81 F, 11 M, mean age 42.26 yrs). All patients completed the questionnaire used in the diagnosis of Sjögren’s syndrome (SQ) (1), and the McMonnies dry eye questionnaire (McM) (2). Schirmer’s I test (ST) was performed, and a result ≤5 mm after 5 minutes was defined as positive. The impact of FM was assessed by tender points (TP) count, the Widespread Pain Index (WPI), and the Symptom Severity score (SS) (3). Results ST was positive in 91 patients (FM 11/66 (16.7%); Controls 32/92 (34.8%), p=0.009). 91 patients answered affirmatively to at least one of the three questions related to dry eye of the SQ (FM 54/66 (81.8%); Controls 37/92 (40.2%)), including 56 patients with negative ST (FM 43/55 (78.2%); Controls 13/60 (21.7%), p=0.000) (fig 1). By McM, 72 patients (FM: 35/45 (77.8%); Controls 37/82 (45.1%)) were classified as having dry eye, including 46 with negative ST (FM 27/36 (75.0%); Controls 19/53 (35.8%)). SQ and McM questionnaires were fairly well correlated (k =0.760, p=0.000). Logistic regression showed that for both SQ and McM, dry eye symptoms were correlated to age, actual ST results, and to the presence of FM (p<0.000). In FM, dry eye symptoms were correlated to the burden of FM (fig 2). Conclusions This is the first study addressing the concordance between subjective symptoms and objective findings in the assessment of dry eye in FM. Our results show that dry eye symptoms are extremely frequent in FM, but are related to the severity of FM symptoms rather than to the results of Schirmer’s test. References Vitali C, Ann Rheum Dis 2002 Nichols KK, Cornea 2004 Wolfe F, Arthritis Care Res. 2010 Disclosure of Interest None Declared