Combinations of scleroderma hallmark autoantibodies associate with distinct clinical phenotypes

Systemic sclerosis (SSc) is characterized by the presence of SSc-specific or SSc-associated antibodies (SSc-Abs): anti-topoisomerase I (ATA), anti-centromere (ACA), anti-RNA polymerase III (ARA), anti-U3RNP (U3RNP), anti-U1RNP (U1RNP), anti-PmScl (PmScl), anti-Ku (Ku) and anti-Th/To (Th/To), each being associated with specific clinical features and prognosis. The detection of more than one SSc-Abs in SSc patients is rare and only few data about these patients' clinical phenotype is available. The aim of our study was to evaluate the frequency and the disease's features associated with the presence of > 1 SSc-Abs positivity in a large cohort of SSc patients. The autoantibody profiles of 2799 SSc patients from February 2001 to June 2017 were retrospectively reviewed. Patients with > 1 SSc-Abs were identified. Clinical features were collected and compared to a large historical cohort of SSc patients with single SSc-Ab positivity. SSc patients were excluded if previously treated with rituximab, intravenous immunoglobulins or stem cell transplantation. Non-parametric tests were used for statistical analysis. Nearly 5% of SSc patients from our cohort had ≥ 2 autoantibody positivity, and 2.3% (n = 72) had ≥ 2 SSc-Abs positivity. Th e most common combination was U1RNP and ATA (35%). These patients were younger than patients with single autoantibody positivity and showed more commonly a diffuse cutaneous SSc form. They also had higher rates of overlap features compared to ATA patients. Other combinations included U1RNP and ACA (13%), ATA and ACA (7%) and U1RNP and PmScl (5%). In our study we observed that, while infrequently, SSc patients can present with a combination of two SSc-Abs and that the double positivity can influence their clinical phenotype compared to patients with single SSc-Ab positivity. The importance of re-testing SSc-Abs in patients with changing clinical phenotypes was also highlighted, as this may confer a differing risk stratification

Periostin expression in uninvolved skin as a potential biomarker for rapid cutaneous progression in systemic sclerosis patients: a preliminary explorative study

ObjectivesThis study aimed to evaluate periostin serum levels and skin expression in patients with systemic sclerosis (SSc).MethodsWe enrolled 35 patients with diffuse (d-SSc) or limited (l-SSc) SSc, 15 patients with very early diagnosis of systemic sclerosis (VEDOSS), and 30 sex-matched healthy controls. Periostin serum levels were determined by an enzyme-linked immunosorbent assay (ELISA). Periostin skin expression was determined by immunohistochemistry (IHC) on paired involved and uninvolved 5-mm skin biopsy samples in a subgroup of 10 d-SSc and 10 L-SSc patients. A 12-month follow-up was considered.ResultsWe included 50 patients (mean age 53.1 ± 16.1 years; women 94%; mean disease duration 38.2 ± 45.1 months; anti-centromere 50%; anti-Scl70 40%), 35 of them with a definite SSc (68.8% l-SSc; 31.4% d-SSc; mean mRSS 9.0 ± 7.2) and 15 with VEDOSS; 30 controls were also included in this study. Periostin serum levels were higher in SSc patients compared to controls (32.7 ± 8.0 ng/mL vs. 27.7 ± 7.3 ng/mL; p < 0.001), while these levels were comparable among different groups of patients (29.7 ± 6.9 ng/mL in VEDOSS, 33.4 ± 7.8 ng/mL in lc-SSc; and 34.0 ± 8.5 in dc-SSc; p = ns). SSc patients with digital ulcers had higher periostin serum levels (36.2 ± 7.9 ng/mL vs. 30.6 ± 7.3 ng/mL, p < 0.02). Samples from the involved skin of l-SSc and d-SSc patients showed a significant dermal expression of periostin; an identical periostin expression was evident in the uninvolved skin of patients with d-SSc. In 7 out of 10 L-SSc patients, periostin expression was absent on uninvolved skin. In the remaining three l-SSc patients, a mild periostin expression on IHC was detectable on uninvolved skin and all of these three l-SSc patients presented a dramatic skin progression.ConclusionPeriostin skin expression may be a useful biomarker to indicate the presence of a disease at a higher risk of rapid cutaneous involvement

Guidelines for the use and interpretation of diagnostic methods in adult food allergy

Food allergy has an increasing prevalence in the general population and in Italy concerns 8 % of people with allergies. The spectrum of its clinical manifestations ranges from mild symptoms up to potentially fatal anaphylactic shock. A number of patients can be diagnosed easily by the use of first- and second-level procedures (history, skin tests and allergen specific IgE). Patients with complex presentation, such as multiple sensitizations and pollen-food syndromes, frequently require a third-level approach including molecular diagnostics, which enables the design of a component-resolved sensitization profile for each patient. The use of such techniques involves specialists' and experts' skills on the issue to appropriately meet the diagnostic and therapeutic needs of patients. Particularly, educational programs for allergists on the use and interpretation of molecular diagnostics are needed

Case report: Cytopenias in VEXAS syndrome - a WHO 2022 based approach in a single-center cohort

VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by cytopenias and macrocytic anemia. Dyshematopoiesis is a frequent finding in chronic inflammatory conditions and therefore, cytopenias are not easily classified in VEXAS patients. Here we report a series of 7 patients affected by VEXAS associated cytopenias, treated at our center. The use of NGS, together with morphological assays, integrated with the WHO 2022 criteria, allowed to identify three subsets of VEXAS associated cytopenias: ICUS (idiopathic cytopenia of uncertain significance), CCUS (clonal cytopenia of uncertain significance) at high risk of clonal evolution, and MDS. This approach could help to better understand the nature of VEXAS associated cytopenias and to guide the use of specific targeted treatments in order to achieve long lasting responses

Case report: Successful use of mepolizumab for immune checkpoint inhibitors–induced hypereosinophilic syndrome in two patients with solid malignancies

Hypereosinophilic syndrome (HES) represents a group of blood disorders characterized by an absolute eosinophil count (AEC) > 1.5 × 103/μl in the peripheral blood, which eventually extravasate and cause organ damage. It can be primary or secondary to infections or tumors. The infiltration of eosinophils in tissue and organs is associated with different disorders and, in some cases, with life-threatening manifestations. Albeit the pathogenesis of HES in patients with solid tumo\rs is not yet clarified; recently, HES has also been described as an immune-related adverse event in patients with solid tumors receiving immune checkpoint inhibitors. Treatment of HES is still debated, especially in patients with concomitant solid tumors, and different drugs including imatinib, hydroxyurea, interferon-ɑ, glucocorticoids, and the monoclonal antibody targeting circulating IL-5 mepolizumab have been proposed according to the underlying cause and the severity of HES. Herein, we describe, for the first time, the successful use of mepolizumab for the treatment of immune checkpoint–induced HES in two patients with metastatic solid tumor

Subclinical giant cell arteritis in new onset polymyalgia rheumatica:A systematic review and meta-analysis of individual patient data

Objectives: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). Methods: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). Results: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). Conclusion: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed

Guidelines for the use and interpretation of diagnostic methods in adult food allergy

Food allergy has an increasing prevalence in the general population and in Italy concerns 8 % of people with allergies. The spectrum of its clinical manifestations ranges from mild symptoms up to potentially fatal anaphylactic shock. A number of patients can be diagnosed easily by the use of first- and second-level procedures (history, skin tests and allergen specific IgE). Patients with complex presentation, such as multiple sensitizations and pollen-food syndromes, frequently require a third-level approach including molecular diagnostics, which enables the design of a component-resolved sensitization profile for each patient. The use of such techniques involves specialists' and experts' skills on the issue to appropriately meet the diagnostic and therapeutic needs of patients. Particularly, educational programs for allergists on the use and interpretation of molecular diagnostics are needed

Genome-wide association study identifies the first germline genetic variant associated with Erdheim Chester disease

[Objective] Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study.[Methods] After quality controls, a cohort of 255 ECD patients and 7,471 healthy donors was included in this study. Afterwards, a logistic regression followed by in silico functional annotation was performed.[Results] A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (p-value=2.75x10-11; OR=2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.[Conclusion] Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.This work was supported by the project “Genome-wide and epigenome-wide association study in patients with Erdheim-Chester Disease”, funded by by Histio UK, and supported in part by the Intramural Research Program of the National Human Genome Research Institute and Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039). M.A.H. is a recipient of a Miguel Servet fellows hip (CP21/00132) from Instituto de Salud Carlos III. L.O.F. was supported by a Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI/10.13039/501100011033.Peer reviewe

Efficacy of canakinumab in patients with Still's disease across different lines of biologic therapy: real-life data from the International AIDA Network Registry for Still's Disease

Introduction: The effectiveness of canakinumab may change according to the different times it is used after Still's disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment.Methods: Patients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still's disease. Seventy-seven (51 females and 26 males) patients with Still's disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent.Results: No statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment.Conclusion: Canakinumab has proved to be effective in patients with Still's disease, regardless of its line of biologic treatment

Covid-19 And Rheumatic Autoimmune Systemic Diseases: Role of Pre-Existing Lung Involvement and Ongoing Treatments

The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations