The VLA4 (CD49d/CD29) integrin is a cell surface receptor involved in the interaction of lymphoid cells with both extracellular matrix (ECM) and endothelial cells. We have investigated the expression and function of VLA4 fibronectin (FN) receptors on T cells localized in the inflammed synovium of patients with rheumatoid arthritis (RA). A high proportion of T cells in both synovial membrane (SM) and synovial fluid (SF) expressed the activation antigens AIM (CD69) and gp95/85 (Ea2) as well as an increased number of VLA4a and fil adhesion molecules, as compared with peripheral blood (PB) T cells from the same patients. Furthermore, the majority of these activated SF T cells were able to adhere to a 38-kD FN proteolytic fragment containing the connecting segment-i (CS-i) specifically through VLA4 receptors, whereas a significantly lower proportion of PB T cells displayed this capacity. Therefore, our results show that activated T cells selectively localize at sites of tissue injury in RA disease and provide evidence for the in vivo regulation of the expression and function of the VLA4 integrin. This regulatory mechanism may enable T cells either to facilitate migration or to persist at sites of inflammation. (J. Clin. Invest. 1991. 88:546-552.)

Methods: Observational, open-label multicenter study from 40 national referral centers of GCA patients treated with TCZ due to inefficacy or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants, glucocorticoid-sparing effect, prolonged remission and relapses. A comparative study was performed: a) TCZ route (SC vs. IV); b) GCA duration (≤6 vs. >6 months); c) serious infections (with or without); d) ≤15 vs. >15 mg/day at TCZ onset. Results: 134 patients; mean age, 73.0±8.8 years. TCZ was started after a median [IQR] time from GCA diagnosis of 13.5 [5.0-33.5] months. Ninety-eight (73.1%) patients had received immunosuppressive agents. After 1 month of TCZ 93.9% experienced clinical improvement. Reduction of CRP from 1.7 [0.4-3.2] to 0.11 [0.05-0.5] mg/dL (p<0.0001), ESR from 33 [14.5-61] to 6 [2-12] mm/1 st hour (p<0.0001) and decrease in patients with anemia from 16.4% to 3.8% (p<0.0001) were observed. Regardless of administration route or disease duration, clinical improvement leading to remission at 6, 12, 18, 24 months was observed in 55.5%, 70.4%, 69.2% and 90% of patients. Most relevant adverse side-effect was serious infections (10.6/100 patients-year), associated with higher doses of prednisone during the first three months of therapy. Conclusion: In clinical practice, TCZ yields a rapid and maintained improvement of refractory GCA. Serious infections appear to be higher than in clinical trials.

BackgroundInterleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA).Methodology and ResultsData from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06–0.18]; p<0.001) or ACPA (0.34 [0.01–0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18–2.7; p = 0.007).ConclusionsPatients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment.

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Objective. To study the expression of L-selectin, CD43, and CD44 on peripheral blood (PB) and synovial fluid (SF) neutrophils from patients with inflammatory joint diseases, and to investigate the presence of soluble L-selectin in both SF and plasma from patients with acute and chronic arthritis.Methods. PB and SF neutrophils were isolated from 13 patients with rheumatoid arthritis (RA) and 17 patients with various inflammatory joint diseases other than RA. Expression of L-selectin, CD43, CD44, CDlla, and CDllb was determined in both unstimulated and in vitro-activated cells by immunofluorescence flow cytometry. Soluble L-selectin levels were estimated in SF and plasma by a semiquantitative radioimmunoassay.Results. Neutrophils from SF showed diminished expression of L-selectin compared with PB neutrophils; CD43 expression and CD44 expression were decreased

Background Non-infectious aortitis is often refractory to standard immunosuppressive therapy. IL-6 has been implicated in the pathogenesis of aortitis. Objectives Our aim was to assess the efficacy of the anti-IL6 receptor monoconal antibody tocilizumab (TCZ) in a series of patients with refractory non-infectious aortitis. Methods We reviewed 16 patients (14 women/2 men) with refractory aortitis diagnosed by imaging (CT angiography, MR angiography, and/or PET) that were treated with TCZ. Results The mean age ± SD was 51.4±20.1 years. The underlying conditions were: Takayasu arteritis (TakA) (N=7 cases), giant cell arteritis (GCA) (n=7), relapsing polychondritis (RP) (n=1), and aortitis associated with retroperitoneal fibrosis (n=1). TCZ was the first biologic drug used in all patients with GCA, and in the patient with aortitis associated with retroperitoneal fibrosis but in only 2 of 7 TakA patients. In the remaining cases anti-TNF inhibitors were prescribed before TCZ (standard dose was 8 mg/kg/iv/4 weeks). After a mean ± SD follow-up of 11.8±6.6 months most patients experienced clinical improvement, showing reduction of erythrocyte sedimentation rate from 43±36 mm/1st h to 5±4 mm/1st h at last visit. At TCZ onset, 25% of patients had fever and 19% polymyalgia rheumatica. These manifestations disappeared after 3 months of TCZ therapy. A corticosteroid sparing effect was also achieved (from 27.3±17.6 mg/day of prednisone at TCZ onset to 4.2±3.8 mg/day at last visit). TCZ had to be discontinued in a patient because of severe neutropenia. Conclusions TCZ appears to be effective and relatively safe in patients with inflammatory aortitis refractory to corticosteroids or to other biologic immunosuppressive drugs. Acknowledgements This study was supported by a grant from “Fondo de Investigaciones Sanitarias” PI12/00193 (Spain). This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from “Instituto de Salud Carlos III” (ISCIII) (Spain). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2984

The regulation of the cell surface expression of ICAM-3 (CD50) was investigated in human neutrophils. Immunofluorescence flow cytometry analysis revealed a remarkable and very rapid down-regulation of the ICAM-3 cell surface expression upon neutrophil activation with stimulating agents such as phorbol myristate acetate (PMA) or calcium ionophore. A similar low expression of ICAM-3 was observed on neutrophils from patients undergoing hemodialysis with cell-activating cellulosic membranes. Internalization assays with 125I-labeled anti-ICAM-3 monoclonal antibody (mAb) suggested that ICAM-3-down-regulation was due to antigen release from the cell surface towards the outer milieu, rather than to antigen internalization. Immunoprecipitation studies confirmed this down-regulatory effect, and revealed the presence of ICAM-3 in cell-free supernatants from activated neutrophils. Furthermore, the presence of a soluble form of ICAM-3 with a range of concentrations of 0-296 ng/ml in the plasma from healthy human volunteers was detected by using a two-site mAb radioimmunoassay. A proteolytic mechanism likely accounts for this process since protease inhibitors virtually abrogated the PMA-induced down-regulation of ICAM-3. Functional studies showed that anti-ICAM-3 mAb were able to trigger homotypic neutrophil aggregation both before and after ICAM-3 down-regulation, indicating that the fraction of ICAM-3 molecules remaining on the neutrophil surface upon activation are still capable of sustaining cell adhesion. In contrast, the loss of L-selectin (CD62L) on activated neutrophils was almost complete, thus leading to an impairment of L-selectin-mediated neutrophil-endothelial cell adhesion. These results indicate that ICAM-3 is released to the medium upon neutrophil stimulation and that both ICAM-3 and L-selectin have a role in the neutrophil adhesive phenomena.

BackgroundIn Giant Cell Arteritis (GCA) two dominant cytokine clusters have been linked to disease activity, IL-6 – IL-17 axis (Th17) and IL-12 – IFN γ axis (Th1). The first one related to systemic symptoms and the second route responsible for ischemic symptoms. Tocilizumab (TCZ) performs its effect mainly by inhibiting Th17 axis and terminally Th1 route.ObjectivesOur aim was to evaluate the effect of TCZ on ischemic and systemic symptoms throughout the follow-up.MethodsRetrospective, multicenter study of 134 patients diagnosed of GCA on treatment with TCZ. We evaluate the efficacy of TCZ by improving ischemic (visual involvement, headache, jaw claudication) and systemic symptoms (fever, constitutional syndrome, polymyalgia rheumatica (PMR)).ResultsWe evaluated 134 patients (101 w/33 m) and its main symptoms at TCZ onset, TABLE. 73 (54.5%) patients presented PMR followed by headache in 70 (52.2%) cases, constitutional syndrome in 31 (23.1%) and visual involvement in 28 (20.9%) patients. After one month of treatment there was an important clinical improvement, persisting in 13,6% of patients PMR, 10.6% headache and 10.6% visual involvement. Throughout the follow-up, the improvement of ischemic symptoms was slower. At month 12, in 5.6% (4) of patients persisted with visual impairment, and 2.8% (2) patients presented headache and constitutional syndrome. However, the analytical improvement was statistically significant from the first month and sustained during follow-up.ConclusionAccording to the results of our study, we can conclude that in clinical practice, ischemic symptoms take longer to improve than systemic symptoms; being visual affectation the most frequent symptom after 12 months of follow-up.References[1] Soriano A, Muratore F, Pipitone N, Boiardi L, Cimino L, Salvarani C. Visual loss and other cranial ischaemic complications in giant cell arteritis. Nat Rev Rheumatol. 2017; 13:476-84.[2] Ciccia F, Rizzo A, Ferrante A, Guggino G, Croci S, Cavazza A, et al. New insights into the pathogenesis of giant cell arteritis. Autoimmun Rev. 2017; 16:675-83.[3] Calderón-Goercke M. Tocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice. Semin Arthritis Rheum. 2019Jan5. pii: S0049-0172(18)30571-7. Doi: 10.1016/j.semarthrit.2019.01.003. [Epub ahead of print]Disclosure of InterestsMonica Calderón-Goercke: None declared, J. Loricera: None declared, D. Prieto-Peña: None declared, Vicente Aldasoro: None declared, Santos Castañeda Consultant for: Amgen, BMS, Pfizer, Lilly, MSD, Roche, Sanofi, UCB, Ignacio Villa-Blanco: None declared, Alicia Humbría: None declared, Clara Moriano: None declared, Susana Romero-Yuste: None declared, J. Narváez Consultant for: Bristol-Myers Squibb, Catalina Gomez-Arango: None declared, Eva Perez-Pampín: None declared, Rafael Melero: None declared, Elena Becerra-Fernández: None declared, Marcelino Revenga: None declared, Noelia Alvarez-Rivas: None declared, Carles Galisteo: None declared, Francisca Sivera: None declared, Alejandro Olive...