Deiminált fehérjeantigének szerepének vizsgálata a rheumatoid arthritis patomechanizmusában és diagnosztikájában = Study of the role of deiminated protein antigens in the pathomechanism and diagnosis of rheumatoid arthritis

Eredmények: 1. Szintetikus peptidekkel igazoltuk, hogy a citrullin nélkülözhetetlen az anti-filaggrin típusú , rheumatoid arthritisre (RA) specifikus antitestek által felismert epitópok szerkezetében. A többszörösen citrullinált szekvenciák reaktivitása nagyobb, azonban a citrullin környezetében lévő aminósavak is szerepet játszanak az epitóp kialakulásában. Rövidített peptidekkel a filaggrin fehérje egyik centrális epitópját azonosítottuk. RA betegek szérumában és synoviális folyadékában peptidfelismerés tekintetében homológ ellenanyagok jelenlétét igazoltuk. 2. Összefüggést találtunk a RA-re hajlamosító HLA-DRB1 allotípus hordozás és a citrullált peptid specifikus antitest termelés között, míg a PAD4 gén genetikai változékonysága és az anti-CCP antitestek megjelenése nem mutat kapcsolatot a hazai populációban. 3.A familáris és spodatrikus RA genetikai háttere és patomechanizmusa eltérő. 4. Anti-CCP antitestek nem termelődnek polymyalgia rheumaticában, mely a HLADRB1*0401 csökkent előfordulásával magyarázható. 5. Az anti-CCP antitestek előfordulása RA-s betegeinkben 68,6%, egyéb kötőszöveti betegségekben 3-5%. | Results: Using synthetic peptides we proved that the presence of citrulline is essential in creation the epitopes targeted by IgG of patients with rheumatoid arthritis (RA). Multiplied substitution of arginies to citrullines increases the reactivity of the epitopes to RA IgG, although the nature of surrounding amino acids play also role in antigenicity. Using shortened citrullinated peptides one of the central epitopes of human filaggrin has been identified. IgG in paired serum and synovial fluid samples of RA patients showed similar recognition pattern, and a highly significant correlation was found between the reactivity of sera and synovial fluids to one of the central epitopes of filaggrin. We found correlation between the presence of HLA-DR SE epitopes and the presence of anti-CCP antibody in patients with RA. No association was found between anti-CCP antibody production and the haplotypes of PAD4 gene in RA patients of Hungarian population. Familiar and sporadic RA differ in their genetic background and pathomechanism. No anti-CCP antibody was found in patients with polymyalgia rheumatica, that could be explained by the decreased frequency of the allele HLA-DR*0401. Prevalence of anti-CCP antibodies in our RA patients was 68,6%, while 3-5% in other connective tissue diseases

Comparative analysis of IL6 and IL6 receptor gene polymorphisms in mastocytosis

Mastocytosis is a rare disease with reported high interleukin-6 (IL6) levels influencing disease severity. The present study investigated polymorphisms within the genes that encode IL6 and its receptor (IL6R) in relation to mastocytosis development in a case-control design. Analysis of the IL6R Asp358Ala polymorphism showed that carriers of the AA genotype had a 2.5-fold lower risk for mastocytosis than those with the AC or CC genotypes. No association with mastocytosis was found for the IL6-174G/C polymorphism, however, it may influence the effect of IL6R polymorphism. To the best of our knowledge this is the first study analysing IL6/IL6R polymorphisms in mastocytosis

Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: Results of a pilot study

BACKGROUND: Psoriasis is associated with higher incidence of atherosclerotic comorbidities. Sustained arterial wall inflammation mediated by common cytokines of psoriasis and atherogenesis precedes atherosclerotic plaque development. Increased intima-media thickness (IMT) is an accepted indicator of subclinical atherosclerosis and has been reported in severe psoriasis. OBJECTIVE: This pilot study aimed to clarify whether effective long-term tumor necrosis factor-alfa inhibition decreases IMT in psoriasis. METHODS: In 16 patients with severe psoriasis, the Psoriasis Area and Severity Index score was calculated before therapy (etanercept, infliximab, adalimumab) and after 6-month treatment. Simultaneously, carotid and brachial IMT was measured by high-resolution, B-mode ultrasonography. Difference between initial and 6-month IMT values was determined for monitored arteries collectively and separately in carotid and brachial arteries. RESULTS: All of 16 patients achieved Psoriasis Area and Severity Index 75, and 14 of 16 achieved Psoriasis Area and Severity Index 90 improvement. In the group of patients without initial calcified atherosclerotic plaques (13 of 16) significant IMT decrease was detected when arteries were measured collectively (P = .0002). Initial and follow-up data differed significantly also at individual analysis of carotid (P = .011) and brachial (P = .006) arteries. Eleven of 13 patients had initial carotid IMT exceeding age-adjusted normal values. The other group (3 of 16) with initial manifest plaques showed increasing IMT tendency. Their baseline ultrasonography revealed carotid IMT above the upper limit of healthy adults' age-adjusted values. LIMITATIONS: Study limitation involves small patient numbers, self-controlled study design, and lack of patients' stratification according to common cardiovascular risk factors. CONCLUSION: In our pilot study effective tumor necrosis factor-alfa inhibition was found to decrease IMT in psoriatic patients without irreversible atherosclerotic plaques. Further analysis is recommended to confirm and complete our primary observations

Cutaneous malignancies in patients with Parkinson’s disease at a dermato-oncological university centre in Hungary

BackgroundThe possible correlation between melanoma and Parkinson’s disease (PD) has been intensively studied. In this work, we aimed to assess the coincidence of skin malignancies and PD at a dermato-oncological university centre in Central-Eastern Europe, Hungary.MethodsFrom 2004 to 2017, a retrospective analysis of the centre’s database was performed based on International Statistical Classification of Diseases-10 codes.ResultsOut of the patients who visited the clinic during the study period, 20,658 were treated for malignant skin tumours. Over the 14 years, 205 dermatological patients had PD simultaneously, 111 (54%) of whom had at least one type of skin malignancy: melanoma (n=22), basal cell carcinoma (BCC) (n=82), or squamous cell carcinoma (SCC) (n=36) (in some patients, multiple skin tumours were identified). Compared to the age- and sex-matched control group, patients with PD had a significantly lower risk for basal cell carcinoma (OR, 0.65; 95% CI, 0.47–0.89, p=0.0076) and for all skin tumours (OR, 0.74; 95% CI, 0.56–0.98, p=0.0392) but not for melanoma.ConclusionsWe found a decreased risk of all skin tumours and basal cell carcinoma and an unchanged risk of melanoma among patients with PD. However, it should be kept in mind that some large-scale meta-analyses suggest a higher incidence of melanoma after a diagnosis of PD, indicating the importance of skin examination in this vulnerable population

Anti-PD-1 Monotherapy in Advanced Melanoma—Real-World Data from a 77-Month-Long Retrospective Observational Study

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related adverse events (irAEs). The majority of the available data are based on clinical trials, where the investigated subjects often do not adequately represent the general patient population of the everyday practice. Although there is a niche of objective biomarkers for the future treatment response of ICIs, certain studies suggest that irAEs may be predictive. The aim of this study was to carry out a retrospective analysis of treatment data from patients with advanced melanoma, treated with a single anti-PD-1 agent (pembrolizumab or nivolumab) during a 77-month-long period. Treatment efficacy and occurrence of adverse events were analyzed to identify potential predictive markers. Primary and secondary endpoints were the overall survival (OS) and progression-free survival (PFS). In our cohort, we demonstrated that the occurrence of more than one irAE showed a correlation with response to PD-1 ICI therapy and improved the OS and PFS. Our study suggests, that the grade of toxicity of the irAE may affect the survival rate

Real-World Experience with Cemiplimab Treatment for Advanced Cutaneous Squamous Cell Carcinoma—A Retrospective Single-Center Study

Background: The systemic treatment of advanced cutaneous squamous cell carcinoma (cSCC) has seen significant developments in recent years. The anti-PD1 inhibitor cemiplimab has demonstrated efficacy in clinical trials, but real-world data are still limited. Here, we aimed to evaluate the efficacy and the safety of cemiplimab in a real-world clinical setting. Methods: A retrospective analysis was carried out for all patients who received at least two doses of cemiplimab at our department between February 2020 and January 2023. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and adverse events (AEs) were evaluated. Results: Twenty-five patients were included with a median age of 78 (65–82) years. The median treatment duration was 48 (16–72) weeks. Five (20%) patients were immunocompromised. Sixteen patients (64%) developed AEs, including 36% serious AEs (SAEs) of grade ≥ 3. Six patients (24%) were withdrawn from treatment due to the occurrence of AEs. Among the 25 patients, 52% showed an objective response (3 complete and 10 partial responses), 76% had controlled disease and 24% experienced progression. Among the five immunocompromised patients, the ORR was 60%, while the DCR was 80%. Conclusions: This retrospective real-world study revealed that locally advanced or metastatic cSCC could be effectively treated with cemiplimab even in elderly, polymorbid and immunocompromised patients