Gianfranco Gigliucci

Restoration of peripheral blood natural killer and B cell levels in patients affected by rheumatoid and psoriatic arthritis during etanercept treatment.

Etanercept (ETN) is an anti‐tumour necrosis factor (TNF)‐α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti‐TNF‐α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good–moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment.

Downregulation of immunoglobulin-like transcript-4 (ILT4) in patients with psoriatic arthritis.

Objective The immunoglobulin-like transcript-4 (ILT4) is an inhibitory receptor that modulates the activity of innate immune agents. We determined the expression of ILT4 and analysed the relationship with the expression of costimulatory proteins and tumor necrosis factor-α (TNF-α) production in monocytes from patients with psoriatic arthritis (PsA) starting anti-TNF treatment. Methods Peripheral blood monocytes from 15 healthy controls and from 16 patients with PsA were activated in vitro by CD40 ligand (CD40L) and analyzed for ILT4, CD40, CD80 and CD86 expression, and spontaneous lipopolysaccharide (LPS)-induced TNF-α production by flow cytometry, before and after treatment with adalimumab. Results The percentage of ILT4-negative monocytes was greater in PsA patients compared to controls and negatively correlated with DAS44. Normal monocytes treated with sera of PsA patients showed a reduced expression of ILT4 compared with monocytes exposed to sera from controls. CD40, CD80 and CD86 expression was higher in patients compared to controls. Both spontaneous and LPS-induced TNF-α production was restricted to ILT4-negative monocytes and was greater in PsA patients compared to controls. Finally, twelve weeks-treatment with adalimumab resulted in a significant increase of ILT4 expression and a decrease of costimulatory molecules expression in PsA patients, compared to pre-therapy levels. Conclusions These data support the possibility that changes in the immunophenotype of monocytes play a role in the pathogenesis of PSA. Thus, modulation of the expression of ILT4 may represent an enticing new therapeutic target.

A 2-year observational study on treatment targets in psoriatic arthritis patients treated with TNF inhibitors

The aim of this study was to evaluate clinical remission and MDA in PsA patients who started TNF-inhibitors (TNFi) treatment with a 2-year follow-up. Concomitant therapies as well as comorbidities were assessed. Level of concordance of clinimetric indices and the potential predictive factors of remission/MDA were also evaluated. Clinical and laboratory evaluations were prospectively performed in PsA patients at baseline (T0) and after 22 (T22), 54 (T54), and 102 (T102) weeks of treatment. Disease activity and disability were assessed using DAS28, CPDAI, DAPSA, MDA, and HAQ-SpA. The Pearson correlation coefficient, univariate, and multivariate binary logistic regression were performed. A total of 221 PsA patients were included. Cardiovascular diseases and metabolic syndrome (MetS) resulted as the most frequent comorbidities. Clinical remission was achieved by over a half of the patients during the follow-up. Use of concomitant therapies, such as csDMARDs and steroids, was significantly reduced during the follow-up. Agreement among indices of treatment targets by k-statistics was excellent for CPDAI and DAPSA and good for MDA and DAS28 or DAPSA. Female sex and MetS resulted as negative prognostic factors of clinical remission and MDA at all the time points. TNFi are highly effective in achieving treatment targets in PsA patients. DAS28, CPDAI, DAPSA, and MDA show a good agreement. Female sex and MetS are associated with a lower probability to achieve remission in PsA patients.

Expression of immunoglobulin-like transcript 4 as an inhibitory receptor in patients with psoriatic arthritis.

Objectives To investigate the presence of immunoglobulin-like transcript (ILT)4 and costimulatory proteins (CD40, CD80 and CD86), as well as tumour necrosis factor (TNF)-α production in antigen-presenting cells (APCs) from patients with psoriatic arthritis, before and after treatment with the antitumour necrosis factor-α therapy, adalimumab. Methods Peripheral blood monocytes from patients with psoriatic arthritis and healthy controls were cultured with CD40 ligand (CD40L) to stimulate differentiation to APCs. Cell-surface phenotype was analysed via fluorescence-activated cell sorting. Results CD40L-stimulation resulted in significantly more ILT4+ monocytes in cultures from control subjects (n = 21) than those from patients (n = 20). ILT4-positivity on CD40L-stimulated monocytes was negatively correlated with disease activity in patients. Adalimumab treatment resulted in significant increases from baseline in ILT4-positivity, and in decreases in CD40, CD80 and CD86-positivity in monocytes from patients. Conclusion The effect of adalimumab on monocyte surface phenotype may be due to modification of the inflammatory milieu associated with therapy-induced reduction of disease activity in psoriatic arthritis.

AB1026 Achieving Minimal Disease Activity and Remission in Psoriatic Arthritis Patients Treated Continuously with TNF Inhibitors for 2 Years in The Real Life

Background Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy commonly associated with psoriasis. Minimal disease activity (MDA) and remission represent treatment targets. However, their assessment is to date an unmet need in PsA patients. Objectives Aim of the study was to prospectively evaluate MDA and remission in PsA patients who were treated with subcutaneous TNF inhibitors (iTNF), every 3/6 months for 2 years. Methods Clinical and laboratory data from 221 PsA patients were analyzed (F:M=1.3, age 55±13 years, disease duration 12.3±6.1 years) at baseline (T0), after 22 (T22), 54 (T54) and 104 (T104) weeks from the beginning of TNFi (adalimumab n=94; etanercept n=84; golimumab n=43). Values of DAS28-CRP, CPDAI, and DAPSA were calculated, and MDA/remission were assessed at the all the time points. MDA was defined as the occurrence of 5/7 criteria, while remission was assessed as DAS28-CRP<2.6, DAPSA≤3.3, and CPDAI<2. Occurrences of comorbidities such as cardio-vascular, renal, respiratory, infectious, metabolic, neuropsychiatric and thyroid diseases were registered. Concomitant therapies (steroids and csDMARDs) and predictive factors of remission were analyzed in accordance with the above-mentioned scores. The Chi-square test was used to compare the remission rate at the follow-up and to analyze the predictive factors. Cohens kappa analysis was performed to measure the concordance between clinimetric scores: kappa ≥0.6 was considered as a good agreement and kappa ≥0.8 was considered as an excellent agreement. Results Prevalence of patients on DAS28 and DAPSA remission was significantly higher at T104 comparing to T0, T22 and T54 while patients on MDA and CPDAI remission were more frequent at T104 compared with T0 and T22 (Figure1A). At all the time points, a good concordance between MDA and DAS28<2.6 occurred (k=0.63) and an excellent concordance was obtained between MDA, CPDAI<2 and DAPSA≤3.3 (k=0.81). At T22, patients with thyreopathies achieved the CPDAI remission in a lower percentage compared to patients without thyreopathies (P=0.02, OR=3.3) (Figure 1B). At T104, the female sex was associated with a lower prevalence of patients on DAS28 remission (P=0.005, OR=2.3) and MDA (P=0.01, OR=2.7) while a lower percentage of patients with metabolic comorbidities was on DAS28 remission with the respect to patients without them (P=0.02, OR=3.3) (Figure1B). Patients on concomitant steroid therapy were fewer at T22/54/104 with the respect to T0 (P<0.0001 for all the comparisons) while the rate of patients on csDMARDs was lower at T104 compared with T0 (P<0.01). Conclusions In clinical practice, MDA and remission were achieved in a high prevalence of PsA patients during TNFi treatment with a rate that increased from 22 to 104 weeks. Tapering of the concomitant treatment was thus allowed. Predictors as thyreopathies, female sex, and metabolic comorbidities were associated with a lower probability to achieve clinical remission. Disclosure of Interest None declared

AB0092 Downregulation of immunoglobulinlike transcript 4 (ilt4) in patients with rheumatoid arthritis

Background Rheumatoid arthritis (RA) is characterized by destruction of juxtaarticular cartilage and bone due to excessive activation of inflammatory cells of which the underlying mechanisms are not fully elucidated. Macrophages may play a major role in the process of inflammation and tissue destruction since they are the predominant source of interleukin (IL)-1β and tumor necrosis factor (TNF)-α that are central to the pathogenesis of RA. Leukocyte immunoglobulin-like receptors (LILRs) are emerging as critical regulators of the threshold and amplitude of leukocyte activation, and perturbed expression of LILRs may contribute to uncontrolled inflammation (1). In particular, the inhibitory LILR-2, also called the immunoglobulinlike transcript 4 (ILT4), which is predominantly expressed on macrophages, provides inhibitory signals (2). Thus, it is tempting to speculate that decreased ILT4 expression on macrophages in RA may lead to a chronic activation of these cells and thereby result in exaggerated inflammation. Objectives To investigate the expression of ILT4 and the relationship between ILT4 and pro-inflammatory cytokine production in monocytes from RA patients before and after anti-TNF-a therapy. Methods Surface expression of ILT4 and lipopolysaccharide (LPS)-induced TNF-a and IL-1b production were analysed by FACS on circulating monocytes from 13 patients with RA and 10 age and sex matched healthy controls, before and after 12-weeks therapy with anti-TNF-a mAb. Results ILT4 expression was significantly decreased on both CD14+/CD16- and CD14-/CD16+ monocytes from RA patients as compared to controls. In addition, a significant reduction in the ability to upregulate ILT4 surface expression under condition of activation by granulocyte-macrophage colony stimulating factor (GM-CSF) was documented in moncytes from RA patients with respect to cells from controls. Monocytes from both, patients and controls, did not spontaneously produce proinflammatory cytokines. However, after LPS stimulation TNF-a and IL-1b production was significantly increased in patients compared to controls. This increased cytokine response was not due to a enhanced susceptibility of monocytes from RA patients to LPS but rather to an expansion of the ILT4- monocyte subset, since TNF-a and IL-1b expression was almost exclusively observed in this cell subset. Twelve-weeks treatment with anti-TNF-a mAb resulted in a significant increase of monocyte ILT4 expression, ILT4 response to GM-CSF activation and in a significantly reduced proinflammatory cytokine expression, compared with pre-therapy levels. Conclusions The finding that RA patients display a low expression of monocytic ILT4, which may lead to more severe tissue damage and impairment of the control of autoreactive cells by upregulating the proinflammatory and antigen-presenting functions of monocytes, suggests that drugs targeting this molecule may have significant therapeutic value for the management of patients. References Colonna M, et al. J Exp Med. 1997;186:1809-18 Chang CC, et al. Nat Immunol 2002;3:237-43 Disclosure of Interest None Declared