Anti-topoisomerase Antibodies Research Articles

Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort

ObjectivesTo untangle the association between smoking and systemic sclerosis (SSc).MethodsIn the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression...

Neurological, cardiac, musculoskeletal, and renal manifestations of scleroderma along with insights into its genetics, pathophysiology, diagnostic, and therapeutic updates.

Scleroderma, also referred to as systemic sclerosis, is a multifaceted autoimmune condition characterized by abnormal fibrosis and impaired vascular function. Pathologically, it encompasses the persistent presence of inflammation, abnormal collagen buildup, and restructuring of blood vessels in various organs, resulting in a wide range of clinical symptoms. This review incorporates the most recent scientific literature on scleroderma, with a particular emphasis on its pathophysiology, clinical manifestations, diagnostic approaches, and treatment options. A comprehensive investigation was carried out on numerous databases, such as PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar, to collect pertinent studies covering diverse facets of scleroderma research. Scleroderma presents with a range of systemic manifestations, such as interstitial lung disease, gastrointestinal dysmotility, Raynaud's phenomenon, pulmonary arterial hypertension, renal complications, neurological symptoms, and cardiac abnormalities. Serological markers, such as antinuclear antibodies,anti-centromere antibodies,and anti-topoisomerase antibodies,are important for classifying diseases and predicting their outcomes. The precise identification of scleroderma is crucial for promptly and correctly implementing effective treatment plans. Treatment approaches aim to improve symptoms, reduce complications, and slow down the progression of the disease. An integrated approach that combines pharmacological agents, including immunosuppressants, endothelin receptor antagonists, and prostanoids, with nonpharmacological interventions such as physical and occupational therapy is essential for maximizing patient care. Through the clarification of existing gaps in knowledge and identification of emerging trends, our goal is to improve the accuracy of diagnosis, enhance the effectiveness of therapeutic interventions, and ultimately enhance the overall quality of life for individuals suffering from scleroderma. Ongoing cooperation and creative research are necessary to advance the field and achieve improved patient outcomes and new therapeutic discoveries.

Prevalence of the limited vs. extensive scleroderma-related interstitial lung disease at the time of diagnosis of SSc-ILD based on Goh et al. criteria. Systematic review and meta-analysis

IntroductionGoh et al. proposed in 2008 a classificatory algorithm of limited or extensive SSc-ILD. The prevalence of both at the time of diagnosis of SSc-ILD is not known with exactitude. MethodsThe review was undertaken by means of MEDLINE and SCOPUS from 2008 to 2023 and using the terms: "systemic", "scleroderma" or "interstitial lung disease" [MesH]. The Newcastle-Ottawa Scale was used for the qualifying assessment for observational studies and the Jadad scale for clinical trials. The inverse variance-weighted method was performed. ResultsTwenty-seven studies were initially included in the systematic review and meta-analysis (SRMA). Of these, 17 studies had no overlapping data. They reported data from 2,149 patients, 1,369 (81.2%) were female. The mean age was 52.4 (SD 6.6) years. 45.2% of the patients had the diffuse subtype and 54.8% had the limited or sine scleroderma subtype. A total of 38.7% of the patients showed positive antitopoisomerase antibodies (ATA) and 14.2% positive anticentromere antibodies (ACA). The mean percentage of forced vital capacity (FVC) at baseline was 80.5% (SD 6.9) and of diffusing capacity of the lungs for carbon monoxide (DLco) was 59.1% (SD 9.6). Twelve studies presented SSc-ILD extension data adjusted for PFTs and were included in the meta-analysis. The 10 observational cohort studies were analyzed separately. The overall percentage of limited extension was estimated at 63.5% (95%CI 55.3–73; p < 0.001) using the random-effects model. Heterogeneity between studies (I2) was 9.8% (95%CI 0–68.2%) with the random-effects model. Extensive pulmonary involvement was estimated at 34.3% (95%CI 26–45.4; p < 0.001). Heterogeneity between studies (I2) was 0% (95%CI 0–61.6%) with the random-effects model. ConclusionThe overall percentage of limited SSc-ILD at the time of diagnosis of SSc-ILD was estimated at 63.5% and extensive at 34.3%.

Extended autoantibody panel in Turkish patients with early-stage systemic sclerosis: Coexpressions and their influences on clinical phenotypes.

To investigate the frequency and clinical relevance of an extended autoantibody profile in patients with systemic sclerosis(SSc). In this cross-sectional study, serum from 100 consecutive patients was subjected to indirect immunofluorescence (IIF)(HEp-20-10/primate liver mosaic) and Systemic Sclerosis Profile by EUROIMMUNto evaluate anti-nuclear antibodies(ANA) and autoantibodies against 13 different autoantibodies in patients with SSc less than 3 years. Ninety-three of 100 patients were positive for ANA byIIF. Fifty-three patients showed single positivity, 26 anti-topoisomerase antibodies (anti-Scl70 ab), 16 anticentromere antibodies (ACAs), six anti-RNA polymerase III antibodies (anti-RNAPIII ab), one anti-Ku antibody, one anti-PM/Scl100 antibody, two anti-PM/Scl75 antibodies, one anti-Ro52 antibody, whereas 32 patients had multiple autoantibody positivities. Among classic SSc-specific autoantibodies, anti-Scl70 and anti-RNAPIII abs showed the highest cooccurrence (n = 4). One patient was simultaneously positive for anti-RNAPIII ab and ACA, and one was positive for ACA and anti-Scl70 ab. The clinical features were not statistically different between single and multiple autoantibody-positivity for classic SSc-specific autoantibodies (ACA, anti-Scl70 ab, and anti-RNAPIII ab), except for digital ulcer in the multiantibody positive ACA group (p = .019). Based on our results, coexpression of autoantibodies is not uncommon in SSc patients. Although autoantibodies specific to SSc in early disease show generally known clinical features, it remains to be investigated how the coexpression of autoantibodies will affect clinical presentation.

Esclerosis sistémica sine esclerodermia en una mujer con anticuerpos antinucleares centroméricos, afectación pulmonar y digestiva: Reporte de caso

Sine entities are rare in rheumatology. In progressive systemic sclerosis there is a variant of the limited cutaneous form called systemic sclerosis sine scleroderma, whose central feature is the lack of skin involvement, but visceral involvement is present. Positive anti-topoisomerase or anti-centromere antibodies confirm the diagnosis. We present the case of a 63-year-old woman with interstitial lung disease, intestinal transit involvement and Raynaud's phenomenon, with high titers of ANA with a centromeric pattern and positivity for anti-topoisomerase antibodies. When faced with a patient with Raynaud's phenomenon, visceral involvement and elevated ANA, specific antibodies should be requested for the diagnosis of systemic sclerosis in its sine variety.

The phenotype of mixed connective tissue disease patients having associated interstitial lung disease

ObjectiveWe aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity. MethodsThis international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements. Results300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001). ConclusionIn this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease.

Disturbed Antioxidant Capacity in Patients with Systemic Sclerosis Associates with Lung and Gastrointestinal Symptoms.

The correct balance between reactive oxygen species and antioxidant defense in an organism is disturbed in oxidative stress. To assess oxidative balance in 36 SSc patients and 26 healthy controls (HCs), we measured reactive oxidative metabolites (ROMs), total antioxidant capacity (TAC), lipid peroxidation (measuring 4-HNE), and DNA oxidative damage (measuring 8-OHdG) in serum. Furthermore, DNA breaks in leukocytes of 35 SSc patients and 32 HCs were evaluated using COMET. While we report high ROMs for both SSc patients and age/sex matched HC samples, there was a significant increase in TAC in SSc patients as compared to HCs, and thus also a significantly higher oxidative stress index in SSc patients. TAC was significantly higher in SSc patients with ILD and gastrointestinal involvement, as well as in patients with anti-topoisomerase antibodies. We observe no difference in serum lipid peroxidation status or oxidative DNA damage. However, SSc patients had significantly more leukocyte DNA breaks than HCs; the most damage was observed in patients treated with immunosuppressives. Thus, our study confirms presence of oxidative stress and increased DNA damage in leukocytes of SSc patients; however, it points toward increased antioxidant capacity, which needs to be further studied.

Anti-carbamylated protein antibodies in systemic sclerosis

BackgroundTo investigate the presence of different isotypes of anti-carbamylated protein (CarP) antibodies in systemic sclerosis (SSc) patients and its association with skin involvement.MethodsSera of 194 SSc patients from the Leiden CCISS cohort, fulfilling ACR/EULAR 2013 criteria and a clinical diagnosis of SSc, 83 patients with other connective tissue diseases/Raynaud’s Phenomenon, 24 rheumatoid arthritis patients and 98 age and sex-matched healthy controls were tested for the presence of anti-CarP IgG, IgA and IgM, determined by ELISA. Clinical characteristics, that were evaluated in SSc patients, included age, anti-topoisomerase antibodies (ATA), anti-centromere antibodies (ACA) and modified Rodnan Skin Score (mRSS).ResultsThe SSc patients were 55 (SD:13) years and 155 (80%) were female. Forty-four (23%) patients tested positive for ATA, and 80 (42%) ACA. The median mRSS was 2 (range: 0; 47).Prevalence of anti-CarP IgG was higher in SSc patients than in healthy controls (8% vs 3%, p = 0.007. Prevalence of anti-CarP IgA and IgM and levels of anti-CarP isotypes were comparable between SSc patients and healthy controls.Fifteen (8%) SSc patients tested positive for anti-CarP IgG, 16 (8%) for anti-CarP IgA, and 36 (19%) for anti-CarP IgM. There were no significant correlations between age and levels of anti-CarP isotypes. No correlation between anti-CarP IgG levels and mRSS was found (r = 0.141, p = 0.049), nor for anti-CarP IgM and IgA levels. Anti-CarP IgA levels were higher in ATA compared to ACA positive SSc patients (ATA: 616 aU/ml [359; 1103]; ACA: 424 aU/ml [300; 673], p = 0.015).ConclusionSSc patients can test positive for Anti-CarP IgG, IgA and IgM. We do not observe a relevant clinical association between anti-CarP antibody response and skin involvement in SSc.

Anti-topoisomerase, but not anti-centromere B cell responses in systemic sclerosis display active, Ig-secreting cells associated with lung fibrosis

ObjectivesAlmost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these...

Treatment with mycophenolate mofetil is associated with improved nailfold vasculature in systemic sclerosis.

To investigate the evolution of nailfold capillary density in patients with SSc in relation to immunosuppressive treatment and autoantibodies. This was a prospective study cohort. Consecutive newly diagnosed SSc patients were included into this study who, in a retrospective review, had at least two nailfold capillary microscopy measurements performed during the first 48 months of follow-up. Capillary density per 3 mm was measured with widefield nailfold capillary microscopy. Improvement of capillary density per finger and mean capillary density were analysed. Longitudinal measurements of mean capillary density were analysed by generalized estimating equation. Eighty patients (68 women, 12 men) met the inclusion criteria. The median follow-up time was 27 months. Twenty-eight patients had an improved capillary density in per-finger analysis. MMF was associated with fewer numbers of fingers that had worsened in capillary density. Anti-topoisomerase antibodies were associated with low mean capillary density. Anti-RNA polymerase III antibodies were associated with improvement and anti-centromere antibodies with worsening of capillary density in per-finger analysis. MMF treatment was associated with less steep capillary density decline in a moderated generalized estimating equation model including presence of anti-topoisomerase antibodies and the interaction of MMF with follow-up time. Nailfold capillary density improved over time in a substantial proportion of SSc patients. MMF treatment had a positive impact on the evolution of capillary density in these patients. SSc autoantibody phenotype may affect the capillary density development. The data support previous hypotheses that early immunosuppression may favourably affect vascular regeneration in SSc.

Step forward in early recognition of systemic sclerosis: data from the Leiden CCISS cohort

BackgroundSince 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early...

874 A NOT-SO-RARE COMPLICATION OF CONNECTIVE TISSUE DISEASE

Abstract Pulmonary hypertension is a not-so-rare complication of connective tissue diseases and is usually related with an inauspicious prognosis. We present the case of a 67-years-old woman hospitalized for progressive dyspnea. Two-dimensional echocardiography showed numerous features related to pulmonary hypertension (PH) with moderate Mitral Regurgitation. The right cardiac catheterization confirmed mixed PH (pre and post capillary) without chest angio-TC evidence of pulmonary thromboembolism. Thanks to optimized medical therapy (B-Blocker, ACE-i and diuretics), there was a significant clinical improvement documented at discharge. After 1 year, due to recurrence of dyspnea, she was admitted to our medical unit. Her clinical examination showed some of the characteristics of a connective tissue disease. Compared to previous echocardiography, a moderate to mild reduction of MR was documented. Chest CT scan revealed interstitial lung disease likely related to patient's underlying pathology. Immunological screening tests detected the presence of antinuclear (ANA) and anti-topoisomerase (ATA) antibodies. Right heart catheterization documented a worsening of PH with only pre-capillary component. On the basis of the above findings, a diagnosis of CREST syndrome complicated with PH was made, and the patient was started on oral combination of macitentan and riociguat. The frequency of this complication in connective tissue disease, the need for screening tests and different treatment approaches of pre and post capillary pulmonary hypertension is discussed.

Systemic sclerosis-associated interstitial lung disease in the EUSTAR database: analysis by region.

The prevalence and characteristics of SSc-associated interstitial lung disease (SSc-ILD) vary between geographical regions worldwide. The objectives of this study were to explore the differences in terms of prevalence, phenotype, treatment and prognosis in patients with SSc-ILD from predetermined geographical regions in the EUSTAR database. Patients were clustered into seven geographical regions. Clinical characteristics and survival of patients with SSc-ILD were compared among these pre-determined regions. For baseline analyses, 9260 SSc patients were included, with 6732 for survival analyses. The prevalence of SSc-ILD in the overall population was 50.2%, ranging from 44.0% in 'Western Europe and Nordic countries' to 67.5% in 'Eastern European, Russia and Baltic countries'. In all regions, anti-topoisomerase antibodies were associated with SSc-ILD. Management also significantly differed; mycophenolate mofetil was prescribed at baseline in 31.6% of patients with SSc-ILD in 'America (North and South)' and 31.7% in 'Middle East' but only 4.3% in 'Asia and Oceania' (P<0.0001). Patients from 'America (North and South)' and 'Middle East' had the highest survival rate at the end of follow-up (85.8% and 85.2%, respectively). Our study highlights key differences among regions in terms of clinical presentation and prognosis of SSc-ILD. This work also demonstrates that the management of SSc-ILD is highly variable among the different regions considered, suggesting that efforts are still needed for the standardization of medical practice in the treatment of this disease.

Sex-specific risk of anti-topoisomerase antibodies on mortality and disease severity in systemic sclerosis: 10-year analysis of the Leiden CCISS and EUSTAR cohorts.

We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension in two cohorts of people with systemic sclerosis. This study was a 10-year analysis of the prospective Leiden Combined Care in Systemic Sclerosis (CCISS) cohort in the Netherlands and the international European Scleroderma Trials and Research (EUSTAR) cohort. We included participants with systemic sclerosis according to the 2013 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria; available autoantibody status; available skin subtyping; at least one available radiographic assessment of interstitial lung disease; and with a known date of disease onset. People with systemic sclerosis were categorised in six risk groups by sex and autoantibody status (anti-centromere antibody [ACA]-positive female, ACA-positive male, ACA and ATA-negative female, ACA and ATA-negative male, ATA-positive female, and ATA-positive male). We constructed Kaplan-Meier curves and Cox proportional hazard models, accounting for left-truncated survival to prevent bias because the date of disease onset (first non-Raynaud's symptom) preceded the date of cohort entry for all patients. The primary outcome was all-cause mortality and the secondary outcomes were diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension. 445 (63%) of 708 participants between April 1, 2009, and Jan 1, 2022, in CCISS (101 [23%] male and 344 [77%] female) and 4263 (50%) of 8590 between June 1, 2004, and March 28, 2018, in EUSTAR (783 [18%] male and 3480 [82%] female) were eligible for this study. In both cohorts, ATA expression occurred significantly more often in males than in females (39 [39%] of 101 males vs 67 [19%] of 344 females in CCISS; p<0·0001 and 381 [49%] of 783 males vs 1323 [38%] of 3480 females in EUSTAR; p<0·0001). According to estimated survival rates, 30% of ATA-positive males versus 12% of ATA-positive females died in the CCISS cohort and 33% versus 15% died in the EUSTAR cohort within 10 years. After adjustment for age, race, and autoantibody status, male sex remained the most important risk factor for all-cause mortality (HR 2·9 [95% CI 1·5-5·5] in CCISS, p=0·0018; and HR 2·6 [2·0-3·4] in EUSTAR, p<0·0001). We show that the association between male sex and increased mortality in systemic sclerosis cannot be explained by higher ATA prevalence. However, additional research on the effect of sex-specific characteristics on people with systemic sclerosis is required. None.

Sex-specific risk of anti-topoisomerase antibodies on mortality and disease severity in systemic sclerosis: 10-year analysis of the Leiden CCISS and EUSTAR cohorts

<h2>Abstract</h2><h3>Background</h3> We aimed to evaluate sex-specific risk of anti-topoisomerase I antibodies (ATA) on mortality, diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension in two cohorts of people with systemic sclerosis. <h3>Methods</h3> This study was a 10-year analysis of the prospective Leiden Combined Care in Systemic Sclerosis (CCISS) cohort in the Netherlands and the international European Scleroderma Trials and Research (EUSTAR) cohort. We included participants with systemic sclerosis according to the 2013 American College of Rheumatology–European League Against Rheumatism (ACR–EULAR) classification criteria; available autoantibody status; available skin subtyping; at least one available radiographic assessment of interstitial lung disease; and with a known date of disease onset. People with systemic sclerosis were categorised in six risk groups by sex and autoantibody status (anti-centromere antibody [ACA]-positive female, ACA-positive male, ACA and ATA-negative female, ACA and ATA-negative male, ATA-positive female, and ATA-positive male). We constructed Kaplan-Meier curves and Cox proportional hazard models, accounting for left-truncated survival to prevent bias because the date of disease onset (first non-Raynaud's symptom) preceded the date of cohort entry for all patients. The primary outcome was all-cause mortality and the secondary outcomes were diffuse cutaneous systemic sclerosis, interstitial lung disease, and pulmonary hypertension. <h3>Findings</h3> 445 (63%) of 708 participants between April 1, 2009, and Jan 1, 2022, in CCISS (101 [23%] male and 344 [77%] female) and 4263 (50%) of 8590 between June 1, 2004, and March 28, 2018, in EUSTAR (783 [18%] male and 3480 [82%] female) were eligible for this study. In both cohorts, ATA expression occurred significantly more often in males than in females (39 [39%] of 101 males vs 67 [19%] of 344 females in CCISS; p<0·0001 and 381 [49%] of 783 males vs 1323 [38%] of 3480 females in EUSTAR; p<0·0001). According to estimated survival rates, 30% of ATA-positive males versus 12% of ATA-positive females died in the CCISS cohort and 33% versus 15% died in the EUSTAR cohort within 10 years. After adjustment for age, race, and autoantibody status, male sex remained the most important risk factor for all-cause mortality (HR 2·9 [95% CI 1·5–5·5] in CCISS, p=0·0018; and HR 2·6 [2·0–3·4] in EUSTAR, p<0·0001). <h3>Interpretation</h3> We show that the association between male sex and increased mortality in systemic sclerosis cannot be explained by higher ATA prevalence. However, additional research on the effect of sex-specific characteristics on people with systemic sclerosis is required. <h3>Funding</h3> None.

Three Cases of Systemic Sclerosis Within One Family With Different Antibodies and Clinical Features.

Systemic sclerosis (SSc) is a heterogeneous disorder in which both genetic and environmental factors play a role in the pathogenesis.1 Familial occurrence of SSc is uncommon and accounts for < 2% of cases.2 Familial cases tend to have similar autoantibodies and disease features.3 HLA studies suggest that major histocompatibility complex (MHC) genes exert their influence primarily on antinuclear antibody (ANA) expression in SSc.4 Also, skin biology differences to anti-RNA polymerase III (ARA) and antitopoisomerase antibodies (ATA) were studied, suggesting both shared and ANA-specific molecular drivers.5.

Characterization of Venezuelan patients with systemic sclerosis: a study in a tertiary hospital in Caracas

ObjectiveThe aim of the study was to investigate the demographic and clinical characteristics of Venezuelan patients with systemic sclerosis (SSc) seen in a tertiary hospital. MethodsConsecutive patients 18 years and older who fulfilled the 2013 ACR/EULAR classification criteria for SSc and who were followed up in the outpatient clinic of the Division of Rheumatology at the Hospital Universitario de Caracas were selected for the study. Demographic and clinical variables were registered at the time of inclusion using a standard protocol. ResultsForty-eight SSc patients were included; 46 (95.8%) were female; the mean age was 55.1±13.7 (mean±SD) years and all were of Hispanic ethnicity. Thirty-one (64.6%) had limited SSc and 17 (35.4%) had diffuse SSc. The mean duration of disease was 13.4±11.7 (mean±SD) years, 16.74±12.99 years for limited SSc and 7.52±5.25 years for diffuse SSc (p=0.0077). Raynaud's phenomenon was the most frequent manifestation (100%), followed by arthritis (68.8%), telangiectasia (60.4%), dyspnea (60.4%), dysphagia (58.3%) and puffy hands (56.3%). The modified Rodnan Skin Score (mRSS) and the frequency of dyspnea were higher in those with diffuse as compared to limited SSc (p=0.0211 and p=0.0003, respectively). We performed high-resolution computed tomography (HRCT) of the lungs in 31 patients; 14 (45.2%) had evidence of interstitial lung disease (ILD), 11 (68.8%) with diffuse SSc (p=0.0052). The most frequent anti-nuclear antibody pattern was nucleolar, accounting for 18 (42.8%) of the cases. Anti-centromere antibodies were present in 16.7% of the cases and were associated with the limited SSc subset (p=0.0443) and with calcinosis (p=0.0020). Anti-topoisomerase antibodies were associated with ILD (p=0.0077). ConclusionsTypical clinical and serological manifestations were present in this sample of Venezuelan patients with SSc, with an expected distribution according to disease subtype. The autoantibody profile allows clinicians to identify those patients with limited forms of the disease and those without pulmonary involvement.

Gender differences in clinical features and outcomes of a Portuguese systemic sclerosis cohort.

Evidence for the role of sex in the clinical manifestations of systemic sclerosis (SSc) patients is emerging. Some multicenter cohorts have shown that male SSc patients have more severe disease and worse survival. To assess the differences in clinical manifestations and survival in Portuguese SSc patients according to gender. Data from male and female adult SSc patients included in the Rheumatic Diseases Portuguese Register (Reuma.pt) were analysed and compared. Survival was calculated for patients included in Reuma.pt. within the first two years of diagnosis (inception cohort). In total, 1054 adult patients with SSc were included, 12.5% males. No differences in demographic features and comorbidities were found between the sexes, except for a higher rate of cigarette smokers among men. Diffuse cutaneous SSc and anti-topoisomerase antibodies were more prevalent in males than females. Additionally, male patients presented significantly more myositis, interstitial lung disease and gastric involvement. There were no differences in the patterns of drug use between the sexes. During follow-up, more deaths were reported in men than women (12.1% vs 7.3%, p= 0.04). The overall 1-, 3-, and 5-year survivals from diagnosis of the inception cohort (N= 469) for men vs women were 96.4% vs 98.2%, 93% vs 95.9%, and 75.8% vs 93.2%, respectively, with statistically significant differences (p< 0.01). This study confirms the existence of gender differences in clinical and immunological SSc features. Although SSc is less common in men than women, men have a more severe expression of skin and internal organ involvement and worse survival. Key Points • There are differences in SSc disease manifestations between sexes. • Males more commonly have diffuse cutaneous SSc, anti-topoisomerase antibodies, pulmonary and musculoskeletal involvement. • In the inception cohort, men had worse survival rates than women.

Abstract 9710: Prevention of Doxorubicin-Induced Cardiotoxicity Through Targeted Degradation of Topoisomerase 2b

Introduction: Doxorubicin-induced cardiotoxicity is a serious complication of cancer therapy recognized 40 years ago and remains to be a major clinical challenge today. Doxorubicin poisons topoisomerase 2a to kill cancer cells, whereas doxorubicin induces cardiotoxicity through topoisomerase 2b. When topoisomerase 2b was genetically deleted in the cardiomyocytes of adult mice, doxorubicin-induced cardiomyopathy can be prevented. Hypothesis: Pharmacological depletion of topoisomerase 2b in cardiac tissue could prevent doxorubicin-induced cardiomyopathy. Methods: Cell lines were treated with dexrazoxane (100 μM) for different time intervals with or without the proteasome inhibitor MG132 (10 μM). Cell lysates were immunoblotted with anti-topoisomerase 2a or 2b antibodies or anti-actin. Mice were injected with dexrazoxane (100 mg/kg IP) and cardiac tissues were analyzed for expression of topoisomerase 2b over time using western blot analysis. To study the effect of dexrazoxane pre-treatment on doxorubicin-induced chronic heart failure, C57BL/6 mice (n=7) were pre-treated with dexrazoxane (100 mg/kg IP) 8 hours before doxorubicin (5 mg/kg IP). Single injection of dexrazoxane (n=6), doxorubicin (n=8), or saline control (n=6) were also administered to three different cohorts of mice. This protocol was repeated weekly for 5 weeks. Pre-treatment and post-treatment cardiac MRI were obtained to evaluate the change in left ventricular ejection fraction. Results: Dexrazoxane induced a ubiquitin-dependent degradation of topoisomerase 2b, but not 2a in cell lines. In dexrazoxane-treated mice, topoisomerase 2b was not detectable 8 hours after dexrazoxane administration, but gradually returned to normal levels by 48 hours. Dexrazoxane pre-treatment 8 hours before doxorubicin prevented doxorubicin-induced reduction in ejection fraction as determined by cardiac MRI in a chronic heart failure model. Conclusions: Targeted degradation of topoisomerase 2b by dexrazoxane prevented doxorubicin-induced cardiotoxicity. Through selective degradation of topoisomerase 2b, but not 2a, doxorubicin's tumoricidal activity is preserved. This preventive strategy will be tested in a prospective clinical trial in breast cancer patients.

Кальциноз при системній склеродермії: поширеність, клініка, менеджмент, ускладнення

У даному літературному огляді підсумовано сучасні дані щодо епідеміології, патофізіології, діагностики та лікування шкірного кальцинозу у пацієнтів із системною склеродермією (ССД). Проведено аналіз обсерваційних досліджень, що описують частоту кальцинозу при ССД і асоційованих з ним клінічних ознак; молекулярних досліджень, що вивчають потенційні патогенетичні механізми; наведені клінічні випадки, що описують нові діагностичні підходи і методи лікування кальцинозу. Шкірний кальциноз — це відкладення нерозчинного кальцію в шкірі і підшкірних тканинах. Кальциноз — одна з основних, погано керованих клінічних проблем у пацієнтів із ССД, яка зачіпає щонайменше одну четверту частину хворих. Кальциноз асоційований з більшою тривалістю хвороби, дигітальними виразками, акроостеолізом, позитивними антицентромерними і антитопоізомеразними антитілами. Хоча патогенез кальцинозу остаточно невідомий, є докази, що підтверджують роль місцевої хронічної травматизації, хронічного запалення, судинної гіпоксії і дисрегуляції білків кісткового матриксу як потенційних механізмів розвитку цього патологічного стану у пацієнтів із ССД. Діагноз може бути встановлений на основі клінічних даних або за допомогою стандартної рентгенографії. Кілька фармакологічних методів лікування були застосовані у пацієнтів із кальцинозом зі змінними і не такими значущими результатами, у свою чергу, хірургічне видалення депозитів кальцію залишається основним методом лікування.