Little is known regarding whether photodynamic therapy (PDT)-induced cell death can substantially compromise macrophages (MΦ), which are important cells in PDT-induced immune responses. Here, parameters of PDT-mediated MΦ cytotoxicity and cytokine production in response to protoporphyrin IX (PpIX) were evaluated. Peritoneal MΦ from BALB/c mice were stimulated in vitro with PDT, light, PpIX, or lipopolysaccharide (LPS). After that, cell viability, lipid peroxidation, Nitric Oxide (NO), DNA damage, TNF-α, IL-6 and IL-10 were evaluated. Short PDT exposure reduced cell viability by 10–30%. There was a two-fold increase in NO and DNA degradation, despite the non-increase in lipoperoxidation. PDT increased TNF-α and IL-10, particularly in the presence of LPS, and decreased the production of IL-6 to 10-fold. PDT causes cellular stress, induces NO radicals and leads to DNA degradation, generating a cytotoxic microenvironment. Furthermore, PDT modulates pro- and anti-inflammatory cytokines in MΦ.
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Background:Anti-tumour necrosis factor alpha (anti-TNF-α) therapy is commonly used to treat inflammatory conditions such as rheumatoid arthritis (RA). Autoantibodies namely antinuclear antibodies (ANA) induced by these treatments are well established. However, anti-TNF-α-induced systemic lupus erythematosus (SLE) is rarely described and its incidence is yet unknown.Objectives:This study aimed to determine the prevalence of ANA seroconversion and to characterize the development of SLE induced by anti-TNF-α therapy in patients with RA over time.Methods:An observational retrospective cohort study was conducted with at least one year of follow-up. Patients with diagnosis of RA, according to American College of Rheumatology criteria (ACR), and registered on Rheumatic Diseases Portuguese Register (Reuma.pt) who started their first anti-TNFα between 2003 and 2019 were included. Patients with positive ANA (titer ≥100) and/or positive double-strand DNA (dsDNA) antibodies and/or with a diagnosis of SLE at their first visit were excluded. Demographic, clinical and laboratory data were obtained by consulting Reuma.pt. As there are no recognized criteria for drug-induced SLE, the diagnosis of SLE induced by anti-TNF-α was considered if there is a temporal relationship between clinical manifestations and anti-TNF-α-therapy, the presence of at least 1 serologic ACR criteria (ANA or anti-dsDNA) and at least 1 nonserologic ACR criteria (arthritis, serositis, hematologic disorder or malar rash) [1]. Continuous variables are presented with mean, standard deviation, median, quartile 1 and quartile 3. Categorical variables are presented with absolute and relative frequencies.Results:A total of 211 patients (mean age of 49.9±10.9 years old; 84.4% female) were included with a median follow-up time of 6 [3-14] years. We found a seroconversion rate for ANA of 75.4% (n=159) with median treatment duration of 31 [8.5-70.5] months. The most common titre was 1/100 with diffuse and speckled patterns. ANA seroconversion was higher for etanercept (47.8%, n=76) than with adalimumab (23.9%, n=38), infliximab (13.8%, n=22), golimumab (12.6%, n=20) or certolizumab (1.9%, n=3). SLE induced by anti-TNF-α occurred in two patients (0.9%) with erosive and seropositive (rheumatoid factor and anti-citrullinated protein antibodies) RA previously treated with two conventional synthetic disease-modifying antirheumatic drugs, including methotrexate. The first patient, a female with 66 years old and 17 years of disease duration, developed SLE after 16 months of infliximab, with constitutional symptoms, abrupt worsening of polyarthritis, ANA titer of 1/320 diffuse pattern and positive dsDNA (248 UI/mL) antibodies. The second patient, a woman with 43 years old and 11 years of disease duration, developed SLE after 41 months of adalimumab with malar rash and ANA titer of 1/320 diffuse pattern, positive dsDNA (285 UI/mL), positive anti-histone antibodies and hypocomplementemia. In these two cases, anti-TNF-α therapy was stopped and recovery was spontaneous without treatment. The first patient switched to adalimumab and the second switched to golimumab without recurrence of SLE for more than ten years.Conclusion:We found a high rate of ANA seroconversion induced by anti-TNFα therapy in patients with RA. However, similar to previous literature, only 0.9% of patients developed SLE with mild manifestations without major organ involvement. Although the drug with the highest ANA seroconversion rate was etanercept, those responsible for induced SLE were infliximab and adalimumab. Patients improved after discontinuation of therapy and tolerated an alternative anti-TNF-α drug without recurrence of induced SLE over time. Therefore, ANA and SLE induced by anti-TNF-α should be considered and reported in the follow-up of RA patients. Further research is needed to explore the impact of this adverse event on the outcomes of treatment over time.References:[1]Hochberg MC. Arthritis Rheum. 1997;40(9):1725.Disclosure of Interests:None declared
Background:In rheumatoid arthritis (RA), autoantibodies namely anticitrullinated protein antibodies (Anti-CCP) have prognostic value, independently predicting radiologic progression. However, the evidence is still controversial about how the autoantibody levels change over time and their role in treatments outcomes and in monitoring disease activity in RA.Objectives:This study aimed to characterize the changes of autoantibodies levels (rheumatoid factor (RF) and Anti-CCP) over time and to explore the association between these autoantibodies and the outcomes of the first anti-tumour necrosis factor alfa (anti-TNF-α) therapy as first biologic agent in RA.Methods:An observational retrospective cohort study was conducted with two years of follow-up. Patients with diagnosis of RA according to American College of Rheumatology (ACR) criteria and registered on Rheumatic Diseases Portuguese Register (Reuma.pt) who started their first anti-TNFα agent (as first biologic) between 2003 and 2018 were included. Patients with positive RA (>30 UI/mL) and/or positive Anti-CCP (>10 U/mL) at their first visit were included. Demographic, clinical and laboratory data were obtained by consulting Reuma.pt. Disease Activity Score for 28 joints [DAS28(3v); DAS28(4v); DAS28(3v; C-Reactive Protein (CRP)), DAS28(4v; CRP), delta DAS28(4v)], Health Assessment Questionnaire (HAQ), delta HAQ, Anti-CCP and RF levels were assessed at baseline, 12 and 24 months. Continuous variables are presented with mean, standard deviation, median, quartile 1 and quartile 3. Categorical variables are presented with absolute and relative frequencies. To examine the differences between Anti-CCP and RF levels at baseline, 12 months and 24 months the Wilcoxon test for paired samples was performed. In order to correlate the Anti-CCP and RF levels with DAS28 variables, delta DAS28(4v), HAQ and delta HAQ at baseline, 12 months and 24 months, a correlation coefficient, Spearman’s coefficient, was used.Results:A total of 116 patients (mean age of 50.2±10.4 years old; 85.3% female) with RA were included with a median disease duration of 10.5 [5-18.5] years and a follow-up time of 8 [5-14] years. About 49% of patients were FR and Anti-CCP positivity, 38% only FR positivity and 13% only Anti-CCP positivity. At baseline, 64 (55.2%) patients had an erosive disease and 50 (43.1%) had extra-articular manifestations. Compared to the baseline (160[74.8-496]), FR levels decreased significantly at 12 months (121[49.1-321.8]) and 24 months (107.5[43.3-332]) with a p=0.017 and p=0.029, respectively. There were no differences in Anti-CCP levels over time. No correlation was found between FR/Anti-CCP levels and different DAS28 variables, DAS28(4v) delta, HAQ, and HAQ delta at 12 months and 24 months.Conclusion:We found that in patients with RA treated with a first anti-TNF-α agent as first biologic, FR levels decreased at 12 months and 24 months follow-up. However, our study failed to demonstrate a correlation between autoantibodies levels and disease activity (DAS28 variables and delta DAS28(4v)), HAQ and delta HAQ. In fact, previous research demonstrated that there is an association between autoantibodies levels and disease activity in RA, nonetheless not being static and increasing with signs of inflammation at baseline. So, further research with large samples is needed to explore this correlation considering the adjustment for confounding inflammatory variables, such as number of swollen or tender joints and morning stiffness.Disclosure of Interests:None declared
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