Preventive effects of early immunosuppressive treatment on the development of interstitial lung disease in systemic sclerosis.

BACKGROUND: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc). METHODS: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression. RESULTS: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups. CONCLUSION: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals.

Clinical significance of the anti-Nucleolar Organizer Region 90 antibodies (NOR90) in systemic sclerosis: Analysis of the European Scleroderma Trials and Research (EUSTAR) cohort and a systematic literature review.

BACKGROUND: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) reported in systemic sclerosis (SSc). Especially due to low prevalence, the clinical relevance of NOR90 in SSc remains uncertain. OBJECTIVES: To analyze the clinical associations of NOR90 in patients with SSc in a multicentric cohort. METHODS: Post-hoc, cross-sectional study of prospectively collected data from the European Scleroderma Trials and Research (EUSTAR) database, with additional information on NOR90. Further, we performed a systematic literature search, using the terms "systemic sclerosis" and "NOR90" across three databases: Medline via PubMed, Scopus, and Thomson Reuters' Web of Science Core Collection, from inception to November 1st, 2023. RESULTS: Overall, 1318 patients with SSc were included (mean age 58.3 ± 13.7 years, 81.3 % female), of whom 44 (3.3 %) were positive for NOR90. Of these, 32 were also positive for one of the SSc-criteria antibodies: 9/44 (20.5 %) for anti-topoisomerase I, 18/42 (42.9 %) for anti-centromere, and 5/40 (12.5 %) for anti-RNA polymerase III. NOR90-positive patients were more frequently female, had lower modified Rodnan skin score (mRSS), and lower prevalence of upper and lower gastrointestinal (GI) symptoms compared to NOR90-negative patients. In multivariable analysis, NOR90 remained significantly associated with lower mRSS and less frequent GI symptoms. The literature search identified 17 articles, including a total number of 87 NOR90-positive out of 3357 SSc patients, corresponding to an overall prevalence of 2.6 %. CONCLUSION: To our best knowledge, this is the largest SSc cohort tested for NOR90 to date, confirming the NOR90 prevalence in SSc patients is around 3 %.

Long-term efficacy, safety and tolerability of secukinumab in children and adolescents with severe chronic plaque psoriasis: Two-year results from a Phase III double-blind, randomized controlled trial.

BACKGROUND: Secukinumab has previously demonstrated sustained efficacy and favourable safety for up to 52 weeks in paediatric patients (children and adolescents aged 6 to <18 years) with severe chronic plaque psoriasis (NCT02471144). OBJECTIVE: To investigate the long-term (104 weeks) efficacy and safety of secukinumab. METHODS: After 52 weeks, patients continued to receive secukinumab low dose (LD [75/150 mg]) or high dose (HD [75/150/300 mg]). Patients on etanercept (0.8 mg/kg) until Week 52 entered follow-up. Data for patients receiving secukinumab LD from the beginning and those switching to secukinumab LD from placebo ('Any secukinumab' LD) and patients receiving secukinumab HD from the beginning and those switching to secukinumab HD from placebo ('Any secukinumab' HD) are presented. ASSESSMENTS: Psoriasis Area and Severity Index (PASI) score, PASI (75/90/100) responses, Investigator's Global Assessment modified 2011 (IGA mod 2011) 0/1 response, Children's Dermatology Life Quality Index (CDLQI) score and CDLQI 0/1 response up to Week 104, and, safety up to Week 104 for all patients and up to 4 years for some patients (~320 patient-years [PY] of treatment). RESULTS: Secukinumab-treated patients showed sustained PASI 75/90/100 and IGA mod 2011 0/1 responses up to Week 104. Throughout the second year of treatment, efficacy was similar for the 'Any secukinumab' LD and HD groups for PASI 75 and IGA mod 2011 0/1 responses. PASI 90/100 responses were mostly comparable between the dose groups up to Week 88, but higher in the 'Any secukinumab' HD than the 'Any secukinumab' LD group at Week 104. Patients achieved a sustained CDLQI 0/1 response that was similar between the 'Any secukinumab' LD (61.1%) and HD (65.0%) groups. Safety data were consistent with the established safety profile of secukinumab. CONCLUSION: Secukinumab demonstrated sustained long-term efficacy (up to 2 years) and a favourable safety profile (~320 PY of treatment) in paediatric patients with severe chronic plaque psoriasis.

The gut microbiome alterations in allergic and inflammatory skin diseases - an update.

The human microbiome is a wide range of microorganisms residing in and on our body. The homeostasis between host immune system and the microbial environment allows mutual benefits and protection. Physiological bacterial colonization is essential for the establishment of organism immunity. The human microbiota ecosystem can be divided into several compartments, out of which intestinal flora strongly affects our health and plays a crucial role in the pathophysiology of many diseases. The gastrointestinal tract, being a major guardian of the immune system, maintains the homeostasis with the commensal microorganisms by tolerating the typical flora antigens. The dysbiosis may trigger an inflammatory response followed by tissue damage or autoimmune processes. The gut microbiome alterations are linked to the pathogenesis of the allergic, cardiovascular, gastrointestinal, metabolic, neurodevelopmental, psychiatric and neurodegenerative diseases and cancer. Moreover, there is increasing evidence connecting the skin condition with the gastrointestinal microbiome, which has been described as the skin-gut axis. The aim of this study was to review the literature regarding the role of the gut microbiome alterations in the pathogenesis of selected allergic and inflammatory skin diseases.

European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.

[Metabolic syndrome in patients with psoriasis]. / Zespól metaboliczny w luszczycy.

Psoriasis is a chronic inflammatory disease of skin, nail plates and joints, which shares similarities with other chronic inflammatory diseases such as rheumatoid arthritis and atherosclerosis. Recent studies indicated that patients with psoriasis are at greater risk for cardiovascular co-morbidities and metabolic syndrome. Published data demonstrates that there is a correlation between the severity of skin changes, cardiovascular co-morbidities and features of metabolic syndrome. Recent research showed that psoriasis plaque shares striking histological features with atherosclerotic one. Both plaques have an elevated level of activated T helper 1 and T helper 17 cells. T helper 1 cells show an overproduction of proinflammatory cytokines such as: TNF-alpha, INF-gamma IL-6 which result in endothelial dysfunction. IL-17 produced by T helper 17 cells have been known to play an important role in the pathogenesis of psoriasis and trigger inflammation in various tissues and organs. In addition, elevated level of serum IL-17 have been observed in unstable coronary artery disease (CAD) as well as in acute myocardial infarction (MI). Physical activity was proved to play a protective role in prevalence of cardiovascular co-morbidities. Recent studies showed that increased physical activity in patients with psoriasis reduce inflammation and risk of cardiometabolic co-morbidities.

Recurrent skin eruption in patient with chronic lymphocytic leukemia and lymphocytic infiltrates of the dermis resembling Sweet's syndrome.

Sweet's syndrome (acute febrile dermatosis) is characterized by fever, peripheral neutrophil leukocytosis, acute onset of tender erythematous skin lesions (papules, nodules or plaques), and histological findings of a dense infiltrate consisting predominantly of mature neutrophils. Malignancy-associated Sweet's syndrome constitutes approximately 21% of patients, the majority of whom suffer from hematologic disorder. We report the case of patient with chronic lymphocytic leukemia with recurrent eruptions of tender, pseudovesiculated nodules and plaques with good response to corticosteroid therapy, resembling Sweet's syndrome. However, histological examination revealed lymphocytic infiltrate in the dermis, which made impossible to establish diagnosis of acute febrile dermatosis according to diagnostic criteria. Association of the skin eruptions with leukemia was implied by improvement of skin lesions after chemotherapy. We present review of the literature reporting cases with atypical histopathological presentations which preceded classical histological appearances, that were mainly associated with hematological malignancies and discuss them in the context of our patient.

Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients.

INTRODUCTION: Systemic sclerosis (SSc) is characterised by disturbed vessel morphology and an overproduction of vascular endothelial growth factor (VEGF). The VEGF gene located on chromosome 6p21.3 has several polymorphisms. OBJECTIVE: To test the hypothesis that disturbed angiogenesis may be related to the genetic background of the VEGF gene. MATERIALS AND METHODS: EUSTAR centres included European Caucasian patients with SSc and matched controls with osteoarthritis. The VEGF gene was genotyped by polymerase chain reaction, followed by restriction enzyme analysis. The 634 C/T and 936 C/G mutations and an 18-base pair insertion/deletion at -2549 of the VEGF promoter region were tested. RESULTS: 416 patients with SSc and 249 controls were included in the study population. Of the patients with SSc, 42% had a diffuse cutaneous subtype, 16% had increased pulmonary arterial pressure and 61% had decreased carbon monoxide diffusion capacity. The genotype frequencies in the patients with SSc and in controls were in Hardy-Weinberg equilibrium. The allele and genotype frequencies of the polymorphisms did not differ between patients with SSc and controls. No association was found between these polymorphisms and disease phenotypes. CONCLUSION: This study shows that there is no association between the three selected functional VEGF polymorphisms and SSc.

Pentoxyfilline treatment does not influence the plasma levels of IL-2 and sIL-2R in limited scleroderma patients.

BACKGROUND: In this study we investigated whether plasma level of IL-2 or sIL-2R shows the clinical disease status. MATERIAL AND METHODS: Plasma levels of IL-2 and sIL-2R were measured by ELISA in 23 patients with limited scleroderma (1SSc-acrosclerosis) and compared with 12 healthy women. RESULTS: Plasma levels of sIL-2R in the group of patients with severe internal organs involvement (3446.1 +/- 1329.7 pg/ml) were significantly higher compared with those with minimal internal organs involvement (1606.4 +/- 507.3 pg/ml). Plasma level of IL-2 in the group of patients with severe internal organs involvement (8.12 +/- 7.77 pg/ml) did not differ much from that of the patients with minimal internal organs involvement (7.42 +/- 9.28 pg/ml). Treatment with pentoxyfilline did not influence the plasma levels of IL-2 and sIL-2R. CONCLUSIONS: We concluded that elevated plasma levels of IL-2 and sIL-2R are markers of internal organ involvement in scleroderma.

Plasma levels of sICAM-1 in patients affected by psoriasis: no relation to disease severity.

The aim of the study was to determine the plasma level of sICAM-1 in acute psoriatic patients in contrast to normal subjects. Moreover, we have tried to answer whether disease severity index (PASI) correlates with plasma level of sICAM-1. We have determined the plasma levels of sICAM-1 by ELISA (Genzyme Corporation) in 23 patients with acute psoriasis before and after the treatment of the disease and in 11 controls. Patients with acute psoriasis have displayed higher levels of sICAM-1 (306.4 +/- 226.8 ng/ml) compared with the controls (141.2 +/- 49.2 ng/ml) and the same patients after clearing of the disease (154.7 +/- 126.7 ng/ml). We have not found any correlation between plasma levels of sICAM-1 and severity index of psoriasis (PASI). We have concluded: the plasma levels of sICAM-1 are not related to disease severity in acute psoriasis. Clearing of the psoriasis is followed by significant fall of plasma sICAM-1.

Is there any correlation between the total number of neutrophils in plasma and concentration of interleukin-8 in psoriatic patients?

INTRODUCTION: Interleukin-8 is a chemotactic agent for neutrophils which causes their simultaneous activation. This cytokine of the chemokines family contributes considerably to the processes observed in the psoriatic epidermis with the participation of neutrophils. MATERIAL AND METHODS: The level of IL-8 in plasma of psoriatic patients during the period of acute and chronic relapses, the number of neutrophils in blood, and the correlation between these parameters were analysed. The study included 55 patients affected by psoriasis (psoriasis severity and activity index ranging from 16.20 to 70.20) and 10 people of the control group. Psoriatic patients were divided into two groups: 'acute psoriasis'--with an acute relapse of the disease (up to one month)--15 patients, and 'chronic psoriasis'--with a longer period of relapse--40 patients. IL-8 plasma levels were determined with the use of the ELISA method. The total number of neutrophils was assessed in blood and smears, and calculations were performed. RESULTS: The results of the study showed higher levels of IL-8 in the plasma of patients with acute psoriasis, however, an elevated number of neutrophils in this group was not statistically significant.

Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised study (ESS-1): echocardiographic substudy--three months follow-up.

The ESS-1 study was designed to evaluate the long-term effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril (10 mg per day) on the cardio-pulmonary system in patients with scleroderma (SSc). We estimated changes in heart diameters, systolic and diastolic left ventricle function and mean values of pulmonary artery pressure after 3 months treatment. The study group comprise 41 patients with SSc. 18 patients received placebo and 23 ones were given enalapril. After 3 months of treatment we did not observe statistically significant differences in heart diameters and left ventricle systolic function parameters between treated group and placebo. Enalapril therapy did not affect left ventricle diastolic function, nevertheless differences in MVA were almost of statistical significance. Echocardiographic signs of pulmonary hypertension were found in 4 patients.

Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised study (ESS-1): ECG exercise testing--three months follow-up.

The ESS-1 study was designed to evaluate the long-term effects of the angiotensin-converting enzyme inhibitor (ACEI) enalapril (10 mg per day) on cardiopulmonary system of patients with systemic sclerosis (SSc). Exercise testing is used not only for estimation of coronary reserve but also physical capacity--the major determinant of quality of life. In each patient included to the ESS-1 study we performed ECG exercise test on treadmill (5 times at intervals of 3 months). The first follow-up was completed by 41 patients (23 patients in enalapril group and 18 in placebo group). The exercise duration in the placebo group was 683 +/- 295 sec and in enalapril group 768 +/- 173 sec. After 3 months of study there were no significant differences in both groups (758 +/- 271 sec and 720 +/- 191 sec respectively). The analysis of ST segment deviation did not provide any significant changes after 3 months of treatment. We conclude that 3 months enalapril treatment did not improve exercise tolerance in patients with systemic sclerosis.

Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised study (ESS-1): pulmonary substudy--effects of three month treatment.

The ESS-1 study is designed to evaluate the long-term effects of enalapril on cardiopulmonary system of patients with systemic sclerosis (SSc). During the one year study period 5 visits are scheduled at 3 months intervals. The effect of 3 months treatment with enalapril (10 mg per day) on lung function was studied in 18 patients with SSc (enalapril group) and compared with controls--23 patients with Ssc (placebo group), mean age, SSc duration, gender and % of patients with dcSSc did not differ significantly in both groups. We performed body plethysmography for total airways resistance (Rtot), and static lung volumes (TLC, ITGV and RV), spirometry for FEV1 and FVC and we measured flow parameters (PEF, FEF). We compared initial lung function (first examination) with results after 3 months treatment (second examination) in the enalapril and in the placebo group. Mean values of Rtot, ITGV and RV did not differ significantly in the enalapril group or in the placebo group before and after treatment but FVC, FEV1 and FEF50 were significantly lower in the enalapril group and did not change in the placebo group after three months. We conclude that 3 month treatment with enalapril worsens spirometry of SSc patients. We did not observe any changes in lung functions in the control group in the same three month period.

Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised study (ESS-1): electrocardiographic substudy--three months follow-up.

UNLABELLED: The ESS-1 study was designed to evaluate the long-term effects of enalapril (10 mg per day) on the cardiopulmonary system of patients with systemic sclerosis (SSc). The 3 months follow-up was completed by 41 patients (23 patients in enalapril group and 18 in placebo group). We analysed conventional time domain signal averaged ECG (SAECG). Late potentials were considered to be present in QRS duration (QRS) was > 114 ms or root mean square of last 40 ms (RMS40) was < 20 microV or terminal signal duration under 40 microV (LAS40) was > 38 ms at 40 Hz. At the beginning of study the prevalence of abnormal SAEG parameters was similar in both groups. We observed one abnormal parameter among 13% of patients in enalapril group and 16.7% of patients in placebo group. There were 2 abnormal parameters in 26.1% of patients in enalapril group and 16.7% of patients in placebo group. After three months of treatment we did not find any patient with 2 parameters of late potentials in enalapril group and only 8.7% of patients with one such parameter. In placebo group no substantial improvement was observed. CONCLUSION: The 3 months enalapril treatment seems to decrease the incidence of late potentials in patients with systemic sclerosis.