V. Ibba

Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort

The use of biologic drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. The aim of this study was to describe the features of biologics-induced autoimmune renal disorders (AIRD) through a systematic review and a cohort study of 707 adult patients affected with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (SA) and Psoriatic Arthritis (PsA). The literature search identified 2687 articles of which 21 were considered relevant for the present study, accounting for 26 case reports. The cohort analysis retrieved 3 cases. According to clinical manifestations and kidney histology the identified AIRD cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Twenty-two out of 29 cases with AIRD were reported in patients affected by RA, 5 in AS and 2 in PsA. The biologic drug most frequently associated with development of AIRD was Etanercept (15 cases, 51.7%), followed by Adalimumab (9 cases, 31.0%) and Infliximab (3 cases, 10.3%) while Tocilizumab and Abatacept were reported in 1 case (3.4%) for each. Thirteen out of 29 (44.8%) cases were classified as affected by IARD, 12 (41.3%) as GNSV and 4 (13.9%) as GNLS. Worse prognosis was associated with GNSV and lack of biologic withdrawal. Although rare, AIRD may be life-threatening and may lead to renal failure and death. If AIRD occurs, biologic drugs must be stopped and patient should be treated according to clinical manifestations and kidney biopsy findings.

Absence of epicardial coronary stenosis in patients with systemic sclerosis with severe impairment of coronary flow reserve

Systemic sclerosis (SSc) is known to be characterised by a diffuse microvascular pathological process leading to cutaneous and visceral changes and to related clinical manifestations. Both necropsy studies1,2 and in vivo investigations3–5 have shown that in a number of patients with SSc there is evidence of a coronary microvascular disease, while coronary artery disease does not exceed that seen in a control group. In particular, myocardial perfusion defects on thallium-201 scintigraphy usually occur in the absence of angiographic evidence of coronary stenosis.3 Recently, we used a new and non-invasive method of contrast enhanced, transthoracic, second harmonic echo Doppler in patients with SSc to evaluate the coronary flow reserve (CFR), a functional variable measuring the ability of the coronary microvasculature to adapt its lumen to a vasodilating stimulus.6 We detected a significant reduction of the CFR …

Multiple Septic Bursitis and Spontaneous Achilles Tendon Tear in Systemic Lupus Erythematosus

To the Editor: We describe a 31-year-old woman who was admitted because of fever and polyarthritis of 1 week’s duration. Six months before, she was diagnosed with systemic lupus erythematosus (SLE) on the basis of nonerosive polyarthritis, painless oral ulcers, positive antinuclear antibody (IFI-Hep2) titer of 1:10,240 with homogeneous pattern, and anti-dsDNA (Farr assay) value of 146 IU/l (normal 0–7 IU/l). At admission she denied any dyspnea, chest pain, rash, dysuria, diarrhea, or intravenous drug abuse. She was receiving methylprednisolone 32 mg/qd, hydroxychloroquine 400 mg/qd, and methotrexate 15 mg/week plus folic acid, but she also reported that in the last month her doctor prescribed a course of 3 consecutive daily pulses of methylprednisolone 500 mg, because of exacerbation of articular manifestations. On examination she presented with hyperpyrexia (up to 40°C), shaking chills, and severe inflammation of the left ankle retrocalcaneal region and the bilateral metatarsophalangeal joints (Figure 1). Musculoskeletal manifestations appeared to be out of proportion to SLE disease activity. Heart and chest examinations were unremarkable. She reported itching and painful defecation without blood-streaked stools and mucopurulent discharge. Figure 1. Erythema and swelling of the left retrocalcaneal region, the left first and third, and the right first and fifth metatarsophalangeal joints. Perineal inspection demonstrated perianal fissures and erythema, suggesting a bacterial skin infection, in the absence … Address correspondence to Dr. Piga; E-mail: matteopiga{at}alice.it

FRI0384 Safety and efficacy of oral cyclophosphamide long-term therapy in systemic sclerosis: experience of a single-centre.

Background Interstitial lung disease (ILD) is very common in systemic sclerosis (SSc) and represents the leading cause of death. Despite its toxicity, cyclophosphamide (CYC) remains one of the most effective therapy. However, limited data about optimal dosage, duration therapy and best way of administration are available. It has been suggested that a prolonged CYC regimen might be more effective than a shorter course. Objectives To evaluate safety and response to oral long-term treatment with CYC in combination with low or medium steroids dose in patients with ILD-SSc. Methods Twenty two patients with ILD-SSc treated with oral CYC, were retrospectively included in this study. A complete clinical examination, included evaluation of European disease activity score and Mesdger’ severity scale score, high-resolution (HRCT) scan, pulmonary function tests (PFTs) were performed before starting therapy, and annually therefore during 10 years of follow-up [86.6 (47.4) months]. Patients were treated with oral CYC at the dosage of 50 mg/day, for consecutive 10-15 days monthly, for a mean of 63.8 (34.2) months, in association with oral prednisone at low (<10 mg/day; n = 9) or medium (> 10 mg/day; n = 13) doses. Results The cumulative CYC dosage reached was 39 (28.7) g, (range 6-122). After the first year of therapy, differences with baseline results for diffusion lung capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) were less than 15% and 10 % respectively, indicating that they remained almost stable. Moreover, in 13 patients who discontinued CYC, DLCO continued to improve more than 10% after 24 months, compared with baseline. In multivariate analysis, an improvement of more than 15% in DLCO after CYC discontinuation significantly correlated with limited cutaneous SSc, early disease, severe ILD, elevated acute phase serum proteins. HRCT documented a regression of ground glass (GG) pattern in 77% of patients. Decrease of GG was mostly detected in the first year of therapy (P < 0.01) and when GG was the predominant pattern. Disease activity estimated by European disease activity score, improved significantly after the first year (P < 0.01) and then stabilized during the follow-up. Medsger severity scale score remained overall stable. Modified Rodnan skin score remained unchanged. Ten out of 22 patients (45%) developed adverse events (reversible and no life-threathening) that require drug withdrawal in seven cases. Three patients died for not related drug causes. No side effects were reported after drug withdrawal. Conclusions Oral CYC long-term therapy seem to be as effective as the intravenous pulse route and with comparable side effects. In our series, it ameliorated and/or stabilized lung function and HRCT pattern, maintaining favorable results after long time of discontinuation. Therapy was overall well tolerated with no severe adverse events. Disclosure of Interest: None Declared

FRI0418 Male Gender but Not HLA-B27 Positivity or Occurrence of Uveitis as Severity Prognostic Factor in Sardinian Ankylosing Spondylitis Patients

Background Susceptibility to develop Ankylosing Spondylitis (AS) is strongly influenced by the presence of the HLA-B27 gene, but much less defined are prognostic factors which may predict erosions and new bone formation lesions leading to organic damage and spinal ankylosis. Given the differences in the genetic background among populations, it is conceivable that prognostic factors may also mirror this genetic variability. Objectives The main aim was to study, in a cohort from the genetic isolate of Sardinia, possible clinical prognostic factors which may predict a more severe spinal damage as assessed by a validated radiological score. Methods Medical history, clinical and radiological data from 100 consecutive patients with AS were collected in a tertiary referral rheumatology clinic; 73 were male (mean age 44.9±10.5; disease duration 18.3±10.6 years) and 27 females (mean age 44.5±13.0; disease duration 14.9±8.9 years). Radiological cervical and lumbar spinal assessment was performed by means of the mSASSS index, sacro-iliac joints were evaluated according to New York criteria. Rx films were blindly assessed by an expert rheumatologist (GP) and by a radiologist (MM). Results were expressed as mean or median, according to numerical distribution. Statistical analysis was performed by means of GraphPad Prism software according to Mann-Whitney and Spearmans tests. Results Analysis of data revealed a good inter-observer and intra-observer agreement 0.94 (0.91–0.97) and 0,95 (0,88–0,96), respectively. Radiological spinal and sacroiliac joint severity indexes were positively correlated with patients age and disease duration (p<0.0001). mSASSS was shown to correlate with BASDAI, BASFI and BASMI (p=0.002, p<0.0001 and p<0.0001, respectively) while New York sacroiliac score was found to correlate with BASMI only (p<0.0001). Radiological spinal involvement resulted more severe in male vs female patients (mSASSS 8; 3.5–33 vs 4; 1–10, p=0,008), mainly due to a greater involvement of the lumbar tract with similar cervical severity. These objective data are in contrast to clinical metrology and patient reported outcomes which showed similar BASMI and BASFI scores and lower BASDAI (2.5±2.1 vs 3.9±2.3, p=0.02) in male versus female. Interestingly, the occurrence of an extra-articular feature such as acute anterior uveitis (AAU) did not result to be a severity prognostic factor (p=ns). Furthermore, it is noteworthy that no statistical differences were noted comparing HLA-B27 positive patients for radiological severity (mSASS 6.5; 2–19) vs HLA-B27 negative (mSASS 8.5; 2–45 p=ns), as well as for disease activity, functional and metrology indexes (BASDAI 2.8±2.3 vs 3.9±2.3; BASFI 2.7±2.6 vs 3.4±2.9; BASMI 2.3±2.4 vs 3.8±3.1; p=ns). Finally, mSASSS or sacroileiitis indexes were not correlated with anti-TNF treatment. Conclusions In AS patients from the genetic isolate of Sardinia, male gender but not HLA-B27 positivity or occurrence of AAU is associated with a more severe radiological outcome. Disclosure of Interest None declared

AB0542 Disease Flares in a Monocentric Cohort of Patients with Systemic Lupus Erythematosus: Incidence, Clinical and Laboratory Characteristics, Associated Factors and Treatment

Background Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease which is characterized by disease flares during maintenance treatment. Objectives To evaluate the incidence of flares, the possible association with clinical and serological factors and their therapeutic management in a monocentric SLE cohort. Methods Clinical and laboratory data of 143 patients with SLE, diagnosed between 1997 and 2012 according to the 1982 ACR/ARA and followed-up at the Centre of Rheumatology of the University Hospital of Cagliari, Italy, were retrospectively collected. For the purposes of the study a flare was defined and classified as severe or mild/moderate, according to a modified version of the SELENA-SLEDAI index. For each patient demographic, clinical (in agreement with the BILAG2004-index) and laboratory features as well as medication ongoing at enrolment and in the 6 months prior to the flares were recorded. Then, all these were used as covariates in the univariate statistical analysis. Results During the follow-up (5.43±4.2yr) at least one disease flare was recorded in 41 out of 143 patients (28,7%) for a total of 63 flares, with an incidence rate of 8.1 flares per 100 patient-years. 53.9% of the flare was classified as severe. Active clinical manifestations at the time of flare were: musculoskeletal (66.7%), mucocutaneous (41.3%), systemic (38.1%), hematologic (31.7%), vasculitic-vasculopathic (25.4%), kidney (22.2%), neurological (22.2%), cardio-respiratory (4.7%). At the univariate statistical analysis, the factors significantly associated with the development of flare were: level above cut off values of 7 IU/dl for Farr assay anti-dsDNA (OR: 2.66; p=0.0272) and low dose corticosteroidal monotherapy in the absence of combined treatment with immunosuppressive drugs (OR: 3.42; p=0.0080). From a sub-analysis performed on 29 flares, for which it was possible to review the anti-dsDNA changes in at least two measurements during the six months preceding flare, in 17 cases (59%) there was a rise in anti-dsDNA level greater than 20% before or concurrently of flares. As regards the therapeutic approach in 79.4% of cases the therapy with immunosuppressant or antimalarials has been modified: in the 47.6% of cases a new drug was added, in 17.5% was switched, in 15.0% the dosage was increased. Only the 30% of flares treated by modification of therapy with immunosuppressants, with or without increase of dosage of corticosteroids, was followed by another flare in the time interval of the study. Fifteen changes of therapy with immunosuppressant (with or without increase of dosage of corticosteroids) for the isolated increase in anti-DNA were recorded: only one of these cases was followed by a flare: a significant difference with the number of flares which followed the adjustement of therapy at clinical relapse (p=0,0482) was found. Conclusions In our series the increase of anti-dsDNAds antibodies (Farr assay) levels above 20% of the six-months previous values or the maintenance treatment with corticosteroidal monotherapy alone were predictors of the occurrence of flares. The study highlights the need for close follow up of anti-dsDNA antibodies levels and the importance of immunosuppressants and/or antimalarials for the maintenance therapy. Disclosure of Interest None declared

THU0185 Biologics-Induced Autoimmune Renal Abnormalities: Systematic Literature Review and Analysis of A Monocentric Cohort of 707 Adult Patients Affected by Rheumatic Disease

Background The use of biological drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. Objectives To describe the features of biologics-induced autoimmune renal abnormalities (AIRA) through a systematic review and the analysis of 707 adult patients with inflammatory rheumatic disease (IRD) followed-up in a third level center of Rheumatology. Methods Using PubMed a systematic review was carried out according to PRISMA guidelines and included the following Mesh terms: “Arthritis, Rheumatoid” OR “Arthritis, Psoriatic” OR “Spondylitis, Ankylosing” AND “infliximab” OR “TNFR-Fc fusion protein” OR “golimumab” OR “adalimumab” OR “certolizumab pegol” OR “rituximab” OR “tocilizumab” OR “abatacept” AND “Glomerulonephritis” OR “Nephrotic Syndrome” OR “Nephrosis, Lipoid”. Last Medline was performed on the 31/08/2013. A retrospective analysis of 707 adult patients with IRD, of which 427 Rheumatoid Arthritis (RA), 168 Ankylosing Spondylitis (AS) and 112 Psoriatic Arthritis (PsA), treated with biologics between 2004 and 2013, was performed. All patients have been prospectively followed-up and have had blood tests and urine analysis at least three times per year. The aim was to identify those patients that developed biologics-induced AIRA. According to clinical manifestations and kidney histology the cases identified by systematic review and cohort analysis were classified as: A) Glomerulonephritis associated with systemic vasculitis (GNSV), B) glomerulonephritis in lupus-like syndrome (GNLS), C) other autoimmune renal disorders (OARD). Results The literature search identified 1687 articles from which 22 were considered relevant for the present study for a total of 28 case reports. The retrospective cohort analysis retrieved 3 cases. Data have been pooled. Twenty-three patients identified were on biologics treatment because RA, 4 had AS and 4 had PsA. TNF-alpha blockers were responsible for AIRA in all identified cases: 17 etanercept, 9 adalimumab and 7 infliximab. AIRA usually appeared within 12 months since the beginning of anti-TNF-alpha therapy, but 8 cases were diagnosed later. The 31 cases identified were classified as: 12 with OARD (5 membranous GN, 3 IgA nephropathy, 1 mesangial GN, 1 minimal change GN, 1 necrotizing GN, 1 not biopsied), 11 with GNSV (3 necrotizing-crescentic GN, 2 necrotizing GN, 2 pauci-immune GN, 1 Schönlein-Henoch IgA nephropathy, 3 not biopsied), 8 with GNLS (1 class III, 3 class IV, 4 not biopsied). Age at onset was younger in GNLS (38.9±13.6 years, 7 female) than in OARD (54.7±13.0 years; 6F) and GNSV (48.6±14.5 years, 6F). Better prognosis was associated with GNLS (75% complete and 25% partial resolution) and treatment with corticosteroids and immunosuppressant, whilst worse prognosis was associated with GNSV, OARD and lack of anti-TNF-alpha withdrawal. End stage renal failure was reported in 2 cases with GNSV and 1 with OARD whilst 1 dead was reported in GNSV. Conclusions Patients with IRD may suffered from biologics-induced AIRA which are apparently associated only with anti-TNF-alpha and although rare they may be life-threatening. If AIRA occur biologics must be discontinued and the patient should be treated according to clinical manifestations and biopsy findings. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4524

AB0608 Elevated Circulating Tumor-Associated Antigens in Systemic Sclerosis: Association with Lung Fibrosis

Background Some tumor-associated antigens (TAAs), apart from cancer cells, are expressed on the surface of inflammatory cells. The production of some TAAs may also be increased in some autoimmune diseases including systemic sclerosis (SSc). Objectives To assess serum carcinoembryonic antigen (CEA), CA-15.3, CA 125, CA-19.9 levels in SSc patients, and to identify any possible associations with lung involvement parameters. Methods Eighty-two SSc patients (70 females and 12 males), mean age 64±13 years (range 34-91), disease duration 6±5 years (range 1-27), were consecutively studied. None of the patients ever had any malignancies. Serum TAAs determination were considered and all patients underwent to high-resolution scan (HRCT) and pulmonary function tests (PFTs). CEA, CA 19.9, CA 15.3 and CA125 were determined by electrochemiluminescence immunoassays; the normal upper limit determined by the manufacturer, were as follows: CEA <2.5 ng/ml, CA19.9 <33 U/ml, CA 15.3 <46.5 U/ml, CA125 <21 U/ml. Results CEA was elevated in 28 (32%) of SSc patients, CA 19.9 in 7 patients (9%), CA 15.3 in 28 patients (36%), CA 125 in 6 patients (8%). Lung fibrosis at HRCT significantly associated with CEA (p<0.0003, r=0.4), CA15.3 (p<0.001, r=0.4), and CA125 (p<0.01, r=0.3) while no association was seen for CA 19.9. Forced vital capacity (FVC) significantly associated only with CA 15.3 (p=0.0001), and diffusion lung capacity for carbon monoxide (DLCO) only with CEA (p=0.04). There was an inverse correlation between CA 15.3, FVC and DLCO (r= -0.52 and r= -0.44, respectively). Conclusions The production of some TAAs may be elevated in SSc patients; CEA, CA15.3, and CA125 may have a negative prognostic role, being associated with lung fibrosis as documented by HRCT and PFTs. Further studies on higher proportion of patients could be addressed for identifying a surrogate biomarker, among TAAs, for lung involvement in SSc, to assess extent of the disease and possibly with prognostic significance. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5074

FRI0160 Comparable Amount of Free Heavy Chain and β2M in the Cytoplasm of Ex Vivo Peripheral Blood Mononuclear Cells of B*2705 Ankylosing Spondylitis Patients VS B*2705 and B*2709 Healthy Subjects Does not Support the UPR Theory. Influence of ERAP1 Polymorphisms

Background Ankylosing Spondylitis (AS) is a chronic inflammatory disease of the spine strongly associated with the majority of HLA-B27 alleles, with the exception of B*2709 and B*2706. Genome wide association studies (GWAS) have revealed that besides HLA-B27, other genes are involved in AS pathogenesis, such as ERAP1, an ER aminopeptidase that is implicated in peptide trimming thus influencing B27-peptide-β2microglobulin (β2m) complex stability. Several theories have been proposed to explain the B27 association with AS. Among them, the unfolded protein response (UPR) theory suggests that the tendency of B27 trimeric complex to misfold determines free heavy chain (FHC) accumulation in the endoplasmic reticulum, leading to a stress response and activation of pro-inflammatory pathways. Objectives To our knowledge this is the first ex vivo study investigating the intracellular (ic) level of FHC and β2m in peripheral blood mononuclear cells (PBMC) and the possible influence of ERAP1 allelic variance in HLA-B27 positive AS patients and healthy subjects (HSs) bearing the AS-associated (B*2705) and the non-AS-associated (B*2709) allele. Methods The ic amount of FHC and β2m in CD14+ cells from ex vivo PBMC was evaluated in 12 HLA-B*2705 patients with AS, 12 HLA-B*2705 HSs and 12 HLA-B*2709 HSs by flow cytometry analysis. HC10 (gift of Dr. Chella David) and TU99 clone (BD Biosciences, USA) monoclonal antibodies were used to detect FHC and β2m, respectively, and quantified by comparison with standard beads (antibody binding capacity ABC units, Dako Denmark). Cells were fixed and permeabilized by the Intraprep Permeabilization technique (Beakman Coulter, USA) according to standard procedure. Patients and controls were also genotyped for two ERAP1 SNPs associated with AS (rs27044 C/G and rs30187 C/T). Optimized allelic discrimination assays were purchased from Applied Biosystem (Life Technologies, Italy). Values were expressed as mean ± standard deviation. Differences between AS patients and healthy subjects were analyzed by Mann-Whitney U test. Results FHC expression in AS patients was 37486±30346 compared to B*2705 HSs 35673±16723 and B*2709 HSs 26683±10592 ABC units (p=ns). β2m quantity was also not significantly different in AS patients 174930±90441 compared to B*2705 HSs 156471±123855 and B*2709 HSs 153478±42117 ABC units (p=ns). The majority of AS patients and HSs were heterozygous for both rs27044 (C/G) and rs30187 (C/T) SNPs; the intracellular amount of FHC and β2m in the PBMC of the analysed cohorts appeared not influenced by ERAP1 allelic distribution, as shown in Fig. 1. Figure 1 Conclusions This study shows equal amount of FHC and β2m in the cytoplasm of B*2705 AS patients compared to B*2705 and B*2709 healthy controls, regardless of ERAP1 allelic variance. These data, therefore, do not provide support to the UPR theory in the pathogenesis of AS. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4442

SAT0297 Non-Invasive Assessment of Silent Liver Fibrosis in Patients with Systemic Sclerosis

Background Although up to 90% of patients systemic sclerosis (SSc) have been estimated to have gastrointestinal involvement, liver disease (without any cause other than SSc itself) has been reported only rarely in this disease. Liver biopsy is considered the gold standard for an accurate assessment of liver fibrosis. However, it is an invasive and expensive tool, so there has been increasing interest in non-invasive assessment evaluation of liver stiffness (LS) by transient elastography (TE) which have been recently demonstrated to be useful for the diagnosis of various grades of fibrosis in the course of chronic liver diseases. Objectives To evaluate the presence of liver fibrosis in a series of SSc patients, without any functional sign of liver disease and any cause other than SSc itself, and to identify any possible associations with demographic data, disease duration and disease phenotype. Methods Thirty-nine SSc patients (33 females and 6 males) without liver diseases, mean age 63.4±13.2 years, disease duration 10.5±8,67 years, and a sex- and age-matched control group, were consecutively studied. LS was evaluated using TE (Fibroscan; Echosens, Paris, France) and measured in kPa. We adopted 5.3 kPa as the cutoff for abnormal LS values. Results Seventeen (43.5%) SSc patients had abnormal LS values when patients were classified into two groups according to the cutoff (group A <5.3 kPa, group B >5.3 kPa); the median LS value was 4 kPa in group A and 7.1 kPa in group B. There were no significant differences between the two groups in disease duration, demographics, laboratory variables or disease characteristics. Among medications, a significant difference for patients on endothelin receptor antagonist therapy was seen in group B (P=0.02). Conclusions TE suggested, in a non-invasive fashion, liver fibrosis in 43.5% of our SSc patients, as a result of a primary hepatic involvement. LS measurement could be suggested for checking silent liver fibrosis in SSc, even in absence of abnormal liver function serological tests. However, further studies are required to investigate whether treatment regimens can influence the progression of liver fibrosis, or if they should be modified when abnormal LS values are identified. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3523