Graves’ orbitopathy (GO) is the most common extrathyroidal manifestation of Graves’ disease (GD). Our aim was to assess the efficacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves’ Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age ± standard deviation 51 ± 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 ± 0.25 vs. 0.9 ± 0.16; p = 0.0001), CAS (4.64 ± 1.5 vs. 1.05 ± 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 ± 4.1 vs. 16.73 ± 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 ± 2.1 months, low disease activity (CAS ≤ 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or inefficacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.

IntroductionPatients with axial spondyloarthritis (axSpA) have a high disease burden mainly due to the rheumatic disease itself, and also exhibit accelerated atherosclerosis, that leads to a higher incidence of cardiovascular (CV) disease. Accordingly, the identification of biomarkers of CV risk and inflammation in axSpA patients is clinically relevant. In this sense, given the beneficial functions exerted by the adipomyokine irisin in processes related to CV disease and inflammation, our aim was to assess, for the first time, the role of irisin as a genetic and serological biomarker of subclinical atherosclerosis, CV risk and disease severity in axSpA patients.MethodsA large cohort of 725 Spanish patients with axSpA was included. Subclinical atherosclerosis (presence of plaques and abnormal carotid intima-media thickness values) was evaluated by carotid ultrasound. Four irisin polymorphisms (rs16835198 G/T, rs3480 A/G, rs726344 G/A, and rs1570569 G/T) were genotyped by TaqMan probes. Additionally, serum irisin levels were determined by ELISA.ResultsLow irisin levels were linked to the presence of plaques (p=0.002) and atherogenic index values ≥4 (p=0.01). Serum irisin were positively correlated with C-peptide levels (p<0.001) and negatively correlated with visual analogue scale and Bath Ankylosing Spondylitis Metrology Index (p<0.05 in all the cases). Moreover, lower irisin levels were observed in patients with sacroiliitis and in those with a negative HLA-B27 status (p<0.001 and p=0.006, respectively), as well as in those treated with non-steroidal anti-inflammatory drugs and conventional disease-modifying antirheumatic drugs (p<0.001 and p=0.002, respectively). Interestingly, the TT genotype and the T allele of rs16835198 were less frequent in axSpA patients with ASDAS >2.1 (Odds Ratio (OR): 0.48 [0.28-0.83] and OR: 0.73 [0.57-0.92], respectively, p=0.01 in both cases). Additionally, the frequency of rs1570569 T allele was higher in these patients (OR: 1.46 [1.08-1.97], p=0.01). Furthermore, the GGGT haplotype was more frequent in patients with ASDAS values >2.1 (OR: 1.73 [1.13-2.66], p=0.01).ConclusionsOur results indicate that low serum irisin levels could be indicators of the presence of subclinical atherosclerosis, high CV risk and more severe disease in axSpA patients. In addition, irisin may also constitute a genetic biomarker of disease activity in axSpA.

Background Vaspin is a novel anti-inflammatory adipokine associated with cardiovascular (CV) disease and inflammation in chronic inflammatory conditions different from axial spondyloarthritis (axSpA). Given the high incidence of CV disease (mainly due to accelerated atherosclerosis) exhibited by axSpA patients, we wondered if vaspin could also be a key molecule in this process. However, data on the role of vaspin regarding atherosclerotic disease in the context of axSpA is scarce. For this reason, we aimed to evaluate the implication of vaspin, at the genetic and serological level, in subclinical atherosclerosis and CV risk in axSpA. Methods This study included 510 patients diagnosed with axSpA. Carotid ultrasound (US) was performed to evaluate the presence of subclinical atherosclerosis. Three vaspin gene variants (rs2236242, rs7159023, and rs35262691) were genotyped by TaqMan probes. Serum vaspin levels were assessed by enzyme-linked immunosorbent assay. Statistical analysis was performed using STATA® v.11.1. Results Serum vaspin levels were significantly higher in female patients than in males and also in obese patients when compared to those with normal weight (p < 0.05). At the genetic level, we disclosed that the minor allele of rs2236242 (A) was associated with lower serum vaspin levels in axSpA, while the rs7159023 minor allele (A) was linked to higher serum levels (p < 0.05). When the three polymorphisms assessed were combined conforming haplotypes, we disclosed that the TGC haplotype related to high serum levels of vaspin (p = 0.01). However, no statistically significant association was observed between vaspin and markers of subclinical atherosclerosis, both at the genetic and serological level. Conclusions Our results revealed that vaspin is linked to CV risk factors that may influence on the atherosclerotic process in axSpA. Additionally, we disclosed that serum vaspin concentration is genetically modulated in a large cohort of patients with axSpA.

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ObjectiveImmune checkpoint blockade therapy (ICBT) increases the anti-tumoural function of the immune system, but it can also induce immune-related adverse events (irAEs). Our aim was to assess the irAEs due to ICBT in patients from a single centre of Northern Spain. MethodsWe set up an observational study of patients treated in monotherapy with ICBT targeted against cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) for solid organ tumours. All patients were followed up in a single University Hospital from March 2015 to September 2018. ResultsWe studied 102 patients (63 men/39 women); mean age 60.6±9.7 years, with lung (n=63), melanoma (n=21), kidney (n=11), gastric (n=3), colon (n=3) or bladder (n=1) cancer. Only 7 patients had a previous diagnosis of an immune-mediated disease, specifically: psoriasis (n=2), psoriatic arthritis (n=1), systemic lupus erythematosus (n=1), spondyloarthitis (n=1), rheumatoid arthritis (n=1) and cutaneous lupus (n=1). One of the following ICBT was administered: nivolumab (n=52), pembrolizumab (n=35), atezolizumab (n=10) and ipilimumab (n=5). After a mean follow-up time of 14.4±7.7 months since ICBT onset, 87 (85.3%) patients had experienced irAEs, mostly gastrointestinal, thyroid and musculskeletal manifestations including inflammatory arthralgia (n= 8), arthritis (n= 6) and myositis (n=2). ICBT was discontinued in 41 patients but it was reintroduced in 30 of them after resolution of the adverse event, with a good tolerance in all cases. Thirty-six (41.4%) of the 87 patients required specific treatment (prednisone, levothyroxine, and thiamazol) for the irAEs. Conclusion irAEs are frequent in patients undergoing ICBT. Almost half of the patients that have irAEs require treatment.Musculoskeletal manifestations are not uncommon.

Background/purposeThe manifestations of uveitis are well established in axial spondyloarthritis (ax-SpA), but not in psoriatic arthritis (PsA). We aimed to assess, in a large unselected series of PsA: (A) the frequency and clinical features of uveitis; (B) its association with PsA activity, the impact of disease and functional disability, and (C) its relationship with the biological treatment. In addition, a literature review was performed.MethodsRetrospective longitudinal study of PsA patients from a single referral hospital. PsA was classified according to the CASPAR criteria, and uveitis was diagnosed by experienced ophthalmologists.ResultsWe studied 406 patients with PsA (46.3±12.3 years). Uveitis was observed in 20 (4.9%). Uveitis was acute in all cases, anterior (80%), unilateral (80%) and recurrent (50%). Patients with uveitis had a higher prevalence of HLA-B27 (45% vs 7.5%, p<0.0001), sacroiliitis on MRI (25% vs 8.3% p=0.027), ocular surface pathology (10% vs 0.8%, p=0.021), and median PsA impact of Disease Score (5.9 (2.1–6.8) vs 1.25 (0.0–3.0), p=0.001) and Bath Ankylosing Spondylitis Functional Index (4 (1.6–5) vs 1.0 (0.0–3.5), p=0.01) than patients without uveitis.The exposure adjusted incidence rate (episodes/100 patients-year) of uveitis before versus after biological treatment decreased with anti-TNFα monoclonal antibodies (56.3 vs 9.4) and increased with etanercept (ETN) (6.03 vs 24.2) and secukinumab (SECU) (0 vs 50) (including only one patient treated in the last two cases).ConclusionThe prevalence of uveitis in patients with PsA was about 5%. The pattern was similar to that observed in ax-SpA. Uveitis was associated with a worse quality of life and greater functional disability. The uveitis exposure adjusted incidence rate decreased with anti-TNFα monoclonal antibodies and increased with ETN and SECU.

Background:The prevalence of inflammatory bowel disease (IBD) in ankylosing spondylitis (AS) has been reported to range between 6%-15%. As occurs with axial spondyloarthrtitis (axSpA), patients with IBD have an increased risk of cardiovascular (CV) events because of a process of accelerated atherosclerosis1. However, it is unknown whether the presence of IBD confers an increased cardiovascular CV risk in patients with axSpA.Objectives:To compare the atherosclerotic burden, CV events, CV risk factors and disease related factors including structural damage in axSpA patients with and without IBD.Methods:Cross-sectional analysis of the AtheSpAin cohort, a Spanish multicenter cohort designed for the study of atherosclerosis in axSpA, comparing axSpA patients with and without concomitant IBD. Background information on CV and disease-related factors was reviewed. Data on CV risk and disease status at the time of the study were also obtained, including the structural damage assessed by the presence of syndesmophytes, the severity of the sacroiliitis (defined as grade 3 or 4 according to New York criteria), and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Carotid ultrasound (US) was performed in all patients at the time of the study, including measurement of carotid intima-media wall thickness (cIMT) and plaque detection according to the Mannhein consensus criteria.Results:A set of 886 axSpA patients were included. 829 (93.6%) of them had no concomitant IBD, which was present in 57 (6.4%) patients. Age, sex and AS/nr-axSpA ratio were comparable in both groups (Table 1. next page). Patients with IBD were characterised by a lower prevalence of HLA B27 (46% vs 72%, p=0.01) and a higher presence of concomitant psoriasis (21% vs 10%, p=0.01)Regarding peripheral disease (history of synovitis, enthesitis, dactylitis) and hip involvement, no differences were found between both groups. There were either no differences in the structural damage found in patients with and without IBD (Table 1. next page).With respect to the management of the disease, prednisone (21% vs 13%, p = 0.03), DMARDs (54% vs 35%, p = 0.01) and anti-TNFα therapy (54% vs 31%, p = 0.00) were more commonly used in the group with IBD, while treatment with NSAIDs was more frequent in patients without IBD (81% vs 70%, p = 0.04).Regarding CV risk features, smoking was more frequent in patients without IBD (34% vs 21%, p = 0.045) (Table 1. next page). No differences were observed neither in the lipid profile or blood pressure at the time of the study, nor in the prevalence of CV events (5% vs 4%, p=0.99) (Table 1) and the subclinical atherogenic burden assessed both by the presence of carotid plaques (31% vs 37%, p=0.45) and the cIMT (645 ± 147 mm vs 636 ± 112 mm, p = 0.64) (Table 1. next page).Conclusion:The presence of IBD does not confer additional CV risk to axSpA. In our series, patients with axSpA and IBD showed a lower frequency of HLA B27 and a higher prevalence of psoriasis.Table 1.axSpA without IBD (n=829)axSpA with IBD (n=57)pMen/Women, n272/55715/420.33Mean age (years) ±SD at the time of study49 ± 1349 ± 100.99AS/nr-AxSpa656/17345/120.97History of CV risk factors Current smoker285 (34)12 (21)0.045 Obesitty Dyslipemia280 (34)16 (28)0.42 Hypertension223 (27)16 (28)0.79 Diabetes Mellitus60 (7)4 (7)0.99 Chronic Kidney Disease20 (2)2 (4)0.65History of cardiovascular events, n (%)40 (5)2 (4)0.99Structural damage at the time of studyPresence of syndesmophytes, n (%)307 (37%)23 (49%)0.66mSASSS5 (1-15)6 (3-23)0.64Severe sacroiliitis (grade 3,4), n (%)436 (53)34 (60)0.42CV data at the time of studyCarotid plaques261 (31)21 (37)0.45IMT (mm)645 ± 147636 ± 1120.64IMT >= 0.9 mm46 (6)0 (0)0.066Abbreviations: AS = ankylosing spondylitis. AxSpA= axial spondylitis. CV = cardiovascular. IBD = Inflammatory bowel disease. IMT = intima-media wall thickness. Nr-axSpA = no-radiographic axial spondylitis.Disclosure of Interests:None declared

Background:Infliximab and adalimumab therapy has significantly improved the prognosis of patients with non-infectious refractory uveitis. However, there is not enough evidence for the use of other anti-TNF drugs such as Certolizumab Pegol (CZP).Objectives:To evaluate the efficacy and safety of CZP in uveitis secondary to Immune-Mediated Inflammatory Diseases (IMID).Methods:Multicenter study of 39 patients with uveitis due to IMID refractory to glucocorticoids and conventional immunosuppressants. Efficacy of CZP was evaluated with the following ocular parameters: best corrected visual acuity (BCVA), anterior chamber cells, macular thickness and presence of retinal vasculitis. Efficacy of CZP was compared between baseline, 1st week, 1st and 6th month, and 1st and 2nd year. Statistical analysis was performed with the STATISTICA software (Statsoft Inc. Tulsa, Oklahoma, USA).Results:39 patients/56 affected eyes (18 men/21 women) with a mean age of 40.5±11.9 years were studied. IMIDs included were: spondyloarthritis (n=17), psoriatic arthritis (6), Crohn (3), JIA (2), Behçet (2), reactive arthritis (2), rheumatoid arthritis (1), relapsing polychondritis (1), pars planitis (1), Birdshot (1) and idiopathic uveitis (3). Uveitis pattern was as follows: anterior (n=30), posterior (4), panuveitis (3) and intermediate (2).Previous CZP, patients received: oral prednisone (n=18) methylprednisolone bolus (1), methotrexate (22), azathioprine (10), cyclosporine (4), leflunomide (2), mycophenolate mofetil (2) and cyclophosphamide (1). 77% of patients had received previous biological therapy, with a mean of 1.6±1.2 biological drugs per patient. Gestational desire was the reason for prescribing CZP in 8 patients. CZP was administered in monotherapy in 16 patients and in the remaining 23 patients combined with conventional immunosuppressants.After a median follow-up of 24 [6-36] months, most of the ocular variables analysed showed a rapid and significantly sustained improvement (Table). CZP was discontinued in 11 patients for the following reasons: remission (n=1), insufficient response of ocular symptoms (n=1) and limited response of extraocular manifestations (n=9). No serious adverse effects were reported.Conclusion:CZP seems to be effective and safe in patients with refractory uveitis due to IMID.TableBaseline1stweek1stMonth6thMonth1styear2ndyearBCVA (mean±SD)0.77±0.290.77±0.30*0.82±0.29*0.85±0.26*0.86±0.27*0.88±0.23*Tyndall (median [IQR])0 [0-2]0 [0-2]0 [0-1]*0 [0-0]*0 [0-0]*0 [0-0]*OCT (mean±SD)355±61.5-284.1±40.4*-224.8±121.1*-Retinal Vasculitis (eyes affected, %)2 (3.6)0 (0)0 (0)0 (0)0 (0)0 (0)*p<0.05Disclosure of Interests:José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Vanesa Calvo-Río Grant/research support from: MSD and Roche, Speakers bureau: AbbVie, Lilly, Celgene, Grünenthal, UCB Pharma, Lara Sanchez-Bilbao Grant/research support from: Pfizer, Iñigo González-Mazón: None declared, Ignacio Torre-Salaberri: None declared, Álvaro García Martos: None declared, Amalia Sanchez-Andrade: None declared, Ángel García-Aparicio: None declared, JR De Dios-Jiménez Aberásturi: None declared, ANA URRUTICOECHEA-ARANA: None declared, Olga Maíz: None declared, Raul Veroz Gonzalez: None declared, Andrea García-Valle: None declared, Sergio Rodríguez Montero: None declared, Roberto Miguélez: None declared, Vega Jovani: None declared, Marisa Hernández-Garfella: None declared, Arantxa Conesa: None declared, Olga Martínez González: None declared, Paula Rubio Muñoz: None declared, Belén Atienza-Mateo: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Ricardo Blanco Grant/research support from: AbbVie, MSD, and Roche, Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, and MSD