RESUMO
Background Paradoxical flare of pemphigus following rituximab infusion has been reported previously, however, its incidence or risk factors have not been studied in detail. Objectives To evaluate the clinical and immunological predictors associated with post-rituximab paradoxical pemphigus flare. Materials and Methods This was a prospective cohort study including adult patients with pemphigus vulgaris or foliaceus who were treated with rituximab. Patients were administered 1000 mg of intravenous rituximab on days 0 and 14 (Rheumatoid arthritis (RA) protocol), with or without oral prednisolone and/or conventional immunosuppressive agents. Baseline clinical and immunological predictors of post-rituximab pemphigus flares were assessed. Results Fifty patients (mean age 40.44 ± 12.36 years) with a mean pemphigus disease area index (PDAI) score of 27.8 ± 15.48 were administered rituximab. Post-rituximab flare occurred in 10 (20%) patients after a mean of 14.1 ± 4.33 days after the first rituximab infusion. The mean baseline PDAI score (36.4 ± 11.7 vs. 25.6 ± 15.7, P = 0.02) and serum anti-Dsg1 levels (1216.8 ± 850.1 vs. 592 ± 562.12 RU/mL, P = 0.03) were statistically significantly higher in patients experiencing a flare. Using ROC-curve analysis, a PDAI score of 328 (OR 8.3, 95% CI 1.5-44.7) was 80% sensitive and 67.5% specific in predicting post-rituximab flare, while serum anti-Dsg1 level of 31137.78 RU/ml had a sensitivity of 60% and specificity of 85%. There was no significant difference in terms of affected body surface area, type of pemphigus, starting prednisolone dose, oral immunosuppressive adjuvant, serum anti-Dsg3, serum anti-AchRM3, and peripheral CD19+ B cell population. Limitations Our study is limited by a relatively small sample size. Immunological factors were not evaluated at the time of pemphigus flare. Though these unexpected pemphigus flares are likely to be associated with rituximab infusion, the possibility of spontaneous disease exacerbation cannot be entirely excluded. Conclusions Patients with more severe pemphigus or high serum anti-Dsg1 are at risk of post-rituximab paradoxical flare, and may benefit from rituximab administration under close monitoring.
RESUMO
Interleukin-33 (IL-33) acts as an 'alarmin', and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT.