Elena Aurrecoechea

Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients

OBJECTIVE To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids. METHODS A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose. RESULTS The mean age ± standard deviation of patients was 69 ± 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6-19) months, the C-reactive protein level had fallen from 1.9 (1.2-5.4) to 0.2 (0.1-0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20-81) to 12 (2-20)mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10-45) to 5 (2.5-10)mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis. CONCLUSION TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.

Circulating cytokines in active polymyalgia rheumatica

Objective: To characterise the circulating cytokine profile and the cellular source of circulating cytokines in polymyalgia rheumatica (PMR). Methods: The study included 34 patients with active untreated PMR and 17 age-matched healthy controls (HC). Circulating cytokines were measured by cytometric bead array and ELISA. Intracellular cytokines were assessed in CD3+ and CD14+ cells by flow cytometry. Cytokines in cell culture supernatants were also determined after polyclonal stimulation of patients’ peripheral blood mononuclear cells. Results: Circulating levels of interleukin-6 (IL6) were significantly higher in subjects with active PMR than in HC. Corticosteroid (CS) treatment was followed by a decrease in the level of IL6. Intracellular cytokine staining showed that circulating monocytes did not produce higher amounts of proinflammatory cytokines in patients with PMR than in HC. There was a discordance between serum levels and cytokine-producing monocyte and T cells, and it was not possible to demonstrate a Th1 bias in the peripheral compartment. Conclusions: Active PMR is characterised by increased serum levels of IL6, but not of other proinflammatory cytokines, that are rapidly suppressed by CS treatment. As circulating monocytes do not show increased production of proinflammatory cytokines, IL6 may be mainly produced in the inflamed tissue. A study of the circulating cytokine profile and its cellular source may provide a clue to new therapeutic options.

Phagocyte dysfunction in polymyalgia rheumatica and other age-related, chronic, inflammatory conditions

This study was conducted to evaluate phagocyte function in patients with age‐related chronic inflammatory conditions. It included 95 patients with PMR, 17 with GCA, 40 with EORA, and 25 age‐matched HCs. Serum IL‐8 was determined with a bead array. The chemotactic capacity, phagocytic ability, and oxidative burst activity of circulating leukocytes were determined with flow cytometry kits. Patients with active chronic inflammatory diseases showed a significant increase in circulating levels of IL‐8 that remained elevated in patients with PMR or EORA, despite treatment. No correlation was found between circulating IL‐8 and the migratoty capacity of neutrophils. Neutrophils from patients with active EORA without stimulus and after fMLP stimuli showed a higher capacity to migrate than those of the HCs (P=0.033). The phagocytic activity of granulocytes in the patients with GCA was significantly higher than in the HCs and the patients with PMR or EORA (P<0.05). The percentage and MFI of phagocytes that produce ROIs when stimulated with Escherichia coli was significantly reduced in neutrophils and monocytes from the patients with age‐restricted inflammatory conditions. We concluded that the effector functions of phagocytes, determined to be chemotaxis, phagocytosis, and oxidative burst, are deregulated in age‐restricted inflammatory disorders and may have a pathogenic role.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease

PURPOSE To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

THU0326 Short and long-term follow-up with adalimumad in refractory uveitis associated to behÇet's disease. multicenter study of 74 patients

Objectives To evaluate the efficacy of adalimumab (ADA) in short and long term follow-up in refractory uveitis of Behçets disease (BD) Methods Multicenter study. Ocular inflammation was evaluated according to “SUN working Group” (Am J Ophthalmol 2005;140:509–516), and the macular thickening with OCT. A comparison was carried out between baseline, and follow-up visits. Results are expressed as mean±SD or median [IQR]. Continuous variables were compared with Wilcoxon test. Results We studied 74 patients/132 affected eyes (39M/35W); mean age 38.7±11.3. The ocular pattern was panuveitis (n=45), posterior uveitis (n=14), anterior uveitis (n=14) and intermediate uveitis (n=1). Before ADA, systemic treatment with corticosteroids, iv metilprednisolone (n=23), Cyclosporin A (58), azathioprine (33), metotrexate (31) and other drugs (28) was used. The dose of ADA was 40 mg/2 weeks/ sc in monotherapy (n=22) or combined (n=52). Most patients showed a rapid and progressive improvement (TABLE). The 24 patients (37 affected eyes) with CME showed a significant improvement. ADA was optimized in 23 (31.1%) that were in remission for 15.3±9 months. Interval of administration was increased to 3 (n=6), 4 (13), 5 (1), 6 (1) and 8 weeks. After a mean follow-up of 13.0±9.7 months after optimization, 21 patients were stable and 2 had a severe flare. In 4 patients ADA was stopped after 35.2±9.3 months in remission. The main adverse effects observed were lymphoma (n=1), pneumonia (1), and 2° bacteriemia by E. Coli (1) Conclusions ADA was effective in short and long-term follow-up in refractory uveitis associated to BD. Optimization or even suspension of ADA is possible. Disclosure of Interest None declared

FRI0270 Tocilizumab Compared to Anti-TNFα Agents in Refractory Aortitis

Background Aortitis is often refractory to conventional immunosuppressive (IS) therapy. The use of biological therapy, such as tocilizumab (TCZ) and anti-TNFα agents, had been reported. Objectives Our aim was to compare the efficacy of TCZ with anti-TNFα therapy in patients with aortitis. Methods Retrospective multicenter study of patients with aortitis refractory to traditional IS agents. Results We studied 44 patients (36 W/8 M; 51±19 years); 25 with TCZ and 19 with anti-TNFα agents (IFX=14, ADA=3, and ETN=2). Baseline features of patients on TCZ compared to the antiTNFα group (always in this order) showed a) mean age: 58±20 vs 42±13 years (p=0.003), b) women: 84% vs 79%, (p=0.97), c) underlying conditions: Takayasu arteritis, 8 vs 11 cases (p=0.08); giant cell arteritis, 15 vs 2 (p=0.0025); relapsing polychondritis, 1 vs 1 (p=0.59); ulcerative colitis, 0 vs 1 (p=0.88); Crohns disease, 0 vs 1 (p=0.88); Behçets disease, 0 vs 1 (p=0.88); sarcoidosis, 0 vs 1 (p=0.88); psoriatic arthritis, 0 vs 1 (p=0.88); and idiopathic aortitis, 1 vs 0 (p=0.88) d) mean of previous traditional IS agents (1.1 vs 1.7, p=0.069) and biological therapies (0.3 vs 0.1, p=0.23). After 3 months of treatment, most patients in both groups had experienced a clinical and acute phase reactants improvement, as well as a reduction of the corticosteroid dose. This favorable response was maintained over time (Table). The improvement observed by imaging techniques was similar in both groups. After a median follow-up of 12 [9-17] vs 16 [12-36] months (p=0.014), TCZ was withdrawn due to severe neutropenia (n=1); recurrent pneumonia (n=1); cytomegalovirus infection (n=1) and systemic lupus erythematosus (n=1). Other adverse effects were thrombocytopenia (n=1) and infusional hypotension (n=1). One patient died due to a stroke in the setting of an infective endocarditis, and another one discontinued TCZ because of inefficacy. In the anti-TNFα group, 3 patients on IFX discontinued due to inefficacy (n=1), recurrent pneumonia (n=1) and severe infusional reaction (n=1). Conclusions Biological therapy appears effective and relatively safe in patients with aortitis refractory to traditional IS drugs. In this series, TCZ seems to be slightly more effective than antiTNFα agents. Disclosure of Interest None declared

FRI0470 Comparative Study of Infliximab versus Adalimumab in Patients with Refractory Uveitis Due to BehÇEt's Disease. Multicenter Study of 125 Cases

Objectives To compare the efficacy and safety of infliximab (IFX) versus adalimumab (ADA) as first biologic drug in refractory uveitis due to Behçets disease (BD) for 1-year period. Methods Multicenter study of 125 patients with BDs uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. IFX (3-5 mg/kg at 0, 2, and 6 weeks and then every 4-8 weeks) was used in 75 cases and ADA (usually 40 mg every 2 weeks) in 50 cases. The main comparative outcome measures were improvement of visual acuity (VA) (at least 20%), complete inactivity of anterior chamber inflammation, vitritis, and retinal vasculitis as well as macular thickness <250 microns. A bivariate and logistic regression analysis was performed for every previous outcome between ADA vs IFX (SPSS20.0 package). Results 125 patients (223 affected eyes) were studied. No statistically significant differences at baseline were observed between IFX vs ADA groups in sex (♂/♀; 41/34 vs 29/21; p=0,71), mean age (39,2±9.39 vs 36,14±12,7; p=0.12), HLA B51 positive (75% vs 75%), uveitis duration before anti TNF-α onset (median [IQR]; 36 [12-71] vs 24 months [12-60]; p=0.4), VA (0,47±0,26 vs 0,52±0,27; p=0,29), anterior chamber cells (median [IQR]; 0,5 [0-2] vs 1,5 [0-2]; p=0,2), retinal vasculitis (73,2% vs 75%; p=0,95); macular thickness (285,90±90,15 vs 312,02±106,57; p=0,25), combined treatment (82.7% vs 77,6%; p=0.481), basal degrees of immunosuppression (mean ± SD; 11.35±5.67 vs 9.65±4.68; p=0.09). There were a better non-statistical respond with ADA in improvement of VA, complete inactivity of anterior chamber inflammation, and macular thickness <250 microns, and with IFX in inactivity of vitritis, and retinal vasculitis (Table) Conclusions Our study suggests that ADA and IFX do not show statistical differences at one year in refractory uveitis of BD. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4766

AB0464 Biologic therapy in aortitis: a multicenter study of 30 patients

Background Aortitis is the inflammation of the aortic wall, regardless of the underlying condition. It can occur alone or associated with other causes. Aortitis is often refractory to standard immunosuppressive therapy. Objectives To assess the efficacy and side-effects of biological therapy in patients with inflammatory aortitis. Methods Multicenter study of 30 patients diagnosed of inflammatory aortitis due to different underlying conditions. The diagnosis of aortitis was based on imaging (CT angiography, MR angiography, PET or echocardiogram). Results We studied 30 patients (27women/3men); mean age±SD, 47.07±18.62 years. The underlying etiologies were: Takayasu arteritis (TKY) (16 cases), giant cell arteritis (GCA) (7), relapsing polychondritis (2), sarcoidosis (1), ulcerative colitis (1), Sjögren’s syndrome (1), Behcet’s syndrome (1) and idiopathic aortitis (1) (Table). In 3 of 30 patients, biological therapy had to be discontinued: 1 GCA with tocilizumab (TCZ) because of neutropenia, 1 GCA with infliximab (IFX) for infusional reactions and 1 TKY with IFX for recurrent pneumonia. Of the remaining 27 patients undergoing biologic therapy, 13 were receiving TCZ (6 TKY, 5 GCA, 1 relapsing polychondritis and 1 idiopathic aortitis), 11 IFX (7 TKY, 2 GCA, 1 Behcet’s syndrome, and 1 relapsing polychondritis), 2 were receiving etanercept (2 TKY), 2 rituximab (1 TKY and 1 Sjögren’s syndrome) and 2 adalimumab therapy (1 ulcerative colitis and 1 sarcoidosis). Switching from a biologic therapy to another occurred in 8 cases. It was due to inefficacy in 7 cases and allergic reaction in 1 case. After a median [interquartile 25-75] follow-up of 16 [11-24] months most patients experienced clinical improvement and a reduction of ESR levels (from 42.6±29.4 mm/1st h to 14.8±14.6 mm/1st h). This fact made possible a reduction in the dose of corticosteroids (prednisone: 25.8±20.5 mg/day to 4.6±3.9 mg/day). Conclusions Our results indicate that biological therapy seems to be an effective and safe therapeutic option in inflammatory aortitis refractory to conventional immunosuppressive therapy. Disclosure of Interest None Declared

Análisis del polimorfismo rs20541 (R130Q) del gen de la IL-13 en pacientes con enfermedades inflamatorias crónicas asociadas al envejecimiento

OBJECTIVE To investigate whether there is association between the rs20541 (R130Q) polymorphism in the IL-13 gene with disease susceptibility and clinical subsets in patients with elderly-associated inflammatory chronic diseases. MATERIAL AND METHODS 78 patients with giant cell arteritis (GCA), 174 with polymyalgia rheumatica (PMR), 90 elderly-onset rheumatoid arthritis (EORA), and 465 healthy controls from the same geographic area were studied. The rs20541 (R130Q) polymorphism in the IL-13 gene was evaluated by PCR-RFLP. Circulating levels of IL-13 were measured by ELISA. RESULTS A higher frequency of the AA genotype [2.349 (0.994-5.554)], as well as the allele A [1.589 (1.085-2.328] and the A carriers [1.656 (1.021-2.686)] (p<0.05) was observed in the GCA patients. No significant differences were observed in the PMR and EORA patients as compared with the healthy controls. Neither difference was observed among the different disease groups studied. In GCA patients, differences in the genotype were associated with a worse prognosis. In PMR patients, the AA genotype was associated with higher levels of serum IL-13 than the GA one. However, such an association was not detected for controls and the other disease groups. CONCLUSIONS GCA is more frequent in carriers of the rs20541 (R130Q) polymorphism in the IL-13 gene. The utility of this polymorphism to predict the GCA prognosis must be confirmed in studies with a higher number of patients.

Utilización de terapias hiperestrogénicas en el lupus eritematoso sistémico

The use of treatments that increase the estrogenic levels has been usually deemed risky in lupus patients. Past studies about the utilization of oral contraceptive drugs and hormone replacement therapy (HRT) have shown contradictory results. More recently, prospective studies about this issue suggest that either oral anticonceptive and HRT can be used in patients with stable disease without special risk for increments in clinical activity. Neither, it has been observed an association with the development of arterial or venous thrombosis. Although, to this regard, several methodological limitations preclude to establish definitive conclusions. Regarding to the use of assisted reproduction techniques in lupus patients, only retrospective data are available. Overall they indicate that the real risk of disease worsening is quite low, being the flares mostly mild when these procedures are performed in patients with stable disease.