Somatic Syndromes Research Articles

Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis

BackgroundCommonly clinically diagnosed with relapsing polychondritis (RP), vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) is a recently identified autoinflammatory disease caused by UBA1 somatic mutations. The low frequency and dynamic changes challenge the accurate detection of somatic mutations. The present study monitored these mutations in Chinese patients with RP. We included 44 patients with RP. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood. Droplet digital polymerase chain reaction (ddPCR) was performed to screen low-prevalence somatic variants.ResultsMultiple ddPCR detections were performed using available blood samples collected at different follow-up time points. Three male patients were UBA1 somatic mutation carriers. Sanger sequencing detected the somatic UBA1 variant c.122T > C (p.Met41Thr) in two male patients. Initial ddPCR confirmed the variant in the two patients, with allele fractions of 73.75% and 88.46%, respectively, while yielding negative results in other patients. Subsequent ddPCR detected the somatic variant (c.122T > C) with low prevalence (1.02%) in another male patient from blood samples collected at a different time point, and confirmed dynamically fractional abundance in one patient with VEXAS, with allele fractions of 73.75%, 61.28%, 65.01%, and 73.75%. Nine patients assessed by ddPCR at different time points remained negative.ConclusionWe report UBA1 variants in patients with RP in the Chinese population for the first time. Multiple ddPCR detections from samples collected at different time points can enhance sensitivity and should be considered for patients with initial negative ddPCR results.

Clinical-haemostasis assessment of anaesthesia regimens in dogs with the somatic type of pain response

The article investigates into the influence of somatic pain syndrome during osteosynthesis on dogs’ clinical parameters and haemostasis. It was found, that the best variant for osteosynthesis operations in dogs is acepromazine-butorphanol-propofol-ketamine anaesthesia. This regimen has provided complete analgesia in half the time recovery of dogs without significant changes in heart rate (HR), respiratory rate (RR), blood pressure (BP), and haemoglobin saturation (SpO2) during surgery. Acepromazine-ketamine-thiopental anaesthesia has showed pronounced analgesia with a decrease in HR and BP. Xylazine-ketamine-thiopental anaesthesia, under apparent analgesia, led to hypotension (decreased HR, BP) and hypoxia (decreased RR, SpO2). The hypercoagulable syndrome was recorded in dogs of all experimental groups before surgery. It indicates the urgent need for its correction in the postoperative period. The data obtained will optimize the selection of drugs’ combinations for dogs' anaesthesia, taking into account the type of pain response.

Structural Model of Personality Traits and Illness Perception with Functional Disability in Functional Somatic Syndromes in Patients with Coronary Artery Disease Based on the Mediating Role of Self-Care Behavior

Objective: Heart diseases, including coronary artery disease, are among the three main causes of death alongside cancer and stroke in most countries. The current study aimed to predict functional disability in functional somatic syndromes in patients with coronary artery disease based on personality traits and illness perception, considering the mediating role of self-care behavior. Methods and Materials: This study, with applied objectives and a correlational research design, was conducted using the structural equation modeling approach. The statistical population included all patients with coronary artery disease in the city of Amol in the year 2022, from which 250 individuals were purposefully selected. Data collection tools included the World Health Organization Disability Assessment Schedule (2014), the McCrae and Costa Personality Traits Questionnaire (1985), the Illness Perception Questionnaire (2006), and the Self-Care Questionnaire (2003). The statistical technique used was structural equation modeling with full latent variables. SPSS version 26, AMOS version 24, and R version 4.2.0 software were used for statistical data analysis. Findings: The results showed that all five personality dimensions, illness perception, and self-care significantly explain the variance in functional disability (P<0.01). Additionally, the mediating role of self-care behavior was significant in the relationship between functional disability and four personality dimensions: extraversion, openness to experience, agreeableness, conscientiousness, and illness perception (P<0.01). Conclusion: It can be concluded that functional disability in functional somatic syndromes in patients with coronary artery disease can be predicted based on their personality traits and illness perception, taking into account the mediating role of self-care behavior.

The potential of psychosomatic therapy approaches for the development of new treatments for functional somatic syndrome

The potential of psychosomatic therapy approaches for the development of new treatments for functional somatic syndrome

Neuroticism, perceived stress, adverse life events and self-efficacy as predictors of the development of functional somatic disorders: longitudinal population-based study (DanFunD).

Functional somatic disorder (FSD) is a unifying diagnosis that includes functional somatic syndromes such as irritable bowel, chronic widespread pain (CWP) and chronic fatigue. Several psychological factors are associated with FSD. However, longitudinal population-based studies elucidating the causal relationship are scarce. To explore if neuroticism, perceived stress, adverse life events (ALEs) and self-efficacy can predict the development of FSD over a 5-year period. A total of 4288 individuals who participated in the DanFunD baseline and 5-year follow-up investigations were included. FSD was established at both baseline and follow-up, with symptom questionnaires and diagnostic interviews. Neuroticism was measured with the short-form NEO Personality Inventory, perceived stress with the Cohen's Perceived Stress Scale, ALEs with the Danish version of the Cumulative Lifetime Adversity Measure and self-efficacy with the General Self-Efficacy Scale. Associations were investigated with multiple logistic regression models. Perceived stress predicted incident FSD, irritable bowel, CWP and chronic fatigue (odds ratios: 1.04-1.17). Neuroticism predicted incident FSD and chronic fatigue (odds ratios: 1.03-1.16). ALEs predicted incident FSD, CWP and chronic fatigue (odds ratios: 1.06-1.18). An increase in perceived stress from baseline to follow-up was associated with incident FSD, irritable bowel, CWP and chronic fatigue (odds ratios: 1.05-1.22). Contrary, an increase in self-efficacy seemed to be a protective factor (odds ratios: 0.89-0.99). High neuroticism, high perceived stress and a high number of ALEs are risk factors for the development of FSD. Particularly perceived stress seems to be an important contributor to the onset of FSD.

Clinical characteristics, disease trajectories and management of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: a systematic review.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered autoinflammatory condition characterised by somatic mutation of the UBA1 gene. The syndrome leads to multi-system inflammation affecting predominantly the skin, lungs and bone marrow. We undertook a systematic review of the multisystem features and genotypes observed in VEXAS syndrome. Articles discussing VEXAS syndrome were included. Medline, Embase and Cochrane databases were searched. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers. From 303 articles, 90 were included, comprising 394 patients with VEXAS. 99.2% were male, with a mean age of 67.1 years (SD 8.5) at disease onset. The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 59); Sweet's syndrome (n = 24); polyarteritis nodosa (n = 11); and myelodysplastic syndrome (n = 10). Fever was reported in 270 cases (68.5%) and weight loss in 79 (20.1%). Most patients had haematological (n = 342; 86.8%), dermatological (n = 321; 81.5%), pulmonary (n = 297; 75.4%%) and musculoskeletal (n = 172; 43.7%) involvement, although other organ manifestations of varying prevalence were also recorded. The most commonly reported mutations were "c.122T > C pMET41Thr" (n = 124), "c.121A > G pMET41Val" (n = 62) and "c.121A > C pMet41Leu" (n = 52). Most patients received glucocorticoids (n = 240; 60.9%) followed by methotrexate (n = 82; 20.8%) and IL-6 inhibitors (n = 61, 15.4%). One patient underwent splenectomy; 24 received bone marrow transplants. VEXAS syndrome is a rare disorder affecting predominantly middle-aged men. This is the first systematic review to capture clinical manifestations, genetics and treatment of reported cases. Further studies are needed to optimise treatment and subsequently reduce morbidity and mortality.

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry

IntroductionVacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious...

Stress Response Pattern of Heart Rate Variability in Patients with Functional Somatic Syndromes.

Functional somatic syndromes (FSSs) represent a clinically important group of disorders that are often stress-related. Their autonomic pathophysiology, including reduced heart rate variability (HRV), has been reported. However, the response pattern to mental stress and recovery in FSSs remains unclear. Thus, we aimed to clarify the pattern of autonomic stress response and recovery to mental arithmetic stress in patients with FSS compared to that in healthy controls. This cross-sectional study included 79 patients with FSS who visited the Department of Psychosomatic Medicine at a university hospital in Japan and 39 healthy controls. Following a mood questionnaire and obtaining epidemiologic information, HRV was measured during three periods (5 min each): relaxation baseline resting, stress (mental arithmetic task), and post-stress recovery period. The HRV analysis included inter-beat interval, low frequency power, and high frequency power. Compared to healthy controls, patients with FSS exhibited significantly higher scores on the mood questionnaire, prolonged duration of illness, and decreased functionality in daily activities. While the healthy control group showed a pronounced stress response pattern with a significant decrease in vagal HRV and recovery, the FSS group showed a "flat" vagal stress response pattern, and the HRV in the FSS group was lower at relaxation baseline, remained low during the stress, and did not change post stress. Patients with severe FSS exhibit an altered stress response pattern. Our results could provide significant clues for the diagnosis and treatment of such patients, as well as useful insights into the relationship between stress and illness.

Long-term outcomes and immune profiling in children with multisystem inflammatory syndrome (MIS-C).

Existing follow-up data after MIS-C is limited. to investigate the long-term consequences in children who have undergone MIS-C. The retrospective study included 93 children. The identified changes were divided into the following periods: occurred within first 6 months, 1 year, 2 years, and more than 2 years after MIS-C. Besides, 31 children underwent prospective immunophenotyping of peripheral blood and the determination of cytokines during the acute period of the disease and after discharge. Outpatient monitoring events included pneumonia (9.6%), somatic disorder syndrome (11.8%), visual impairment (7.5%), joint damage (6.6%), weight changes (2.2%), and MIS-C recurrence (2.2%). A study of the cardiovascular system showed a statistically significant decrease in the frequency of the right and left heart dilatation, left ventricular dysfunction, pericarditis, pulmonary arterial hypertension, coronaritis, mitral regurgitation. But at the same time an increase in pulmonary and tricuspid valve regurgitation and arrhythmias compared with the acute period was detected. Most of the changes took place within first year of observation. Immune profiling showed reconstitution of CD3, CD4 T-lymphocytes, NK-cells, maintenance of a high relative value of CD8, reduction of CD19+ B-cells, expression of CD3-HLA-DR+, CD25, CD279, CD95. After the history of MIS-C, children in the long-term follow-up had various somatic disorders and disease recurrence. Most patients (64.1%) showed subclinical signs of myocardial involvement within first year of observation. Low expression of CD95 may justify an certain role in the pathogenesis of the disease.

Prevalence and Outcome of Vexas Syndrome in Unrelated Hematopoietic Stem Cell Transplantation

Introduction Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a newly identified monogenic disorder defined by somatic UBA1 mutations in hematopoietic progenitor cells, resulting in bone marrow failure (BMF) and systemic inflammation. This syndrome is frequently associated with myelodysplastic syndrome (MDS) or plasma cell dyscrasia. Although high-dose corticosteroids alleviate symptoms and cytopenia, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potentially curative treatment. This study evaluated the safety and efficacy of unrelated HSCT for treating VEXAS syndrome and its prevalence in patients with hematologic diseases. Methods We conducted retrospective screening for UBA1 mutations in patients with BMF or plasma cell neoplasms who underwent their first HSCT from unrelated donors in Japan between 1995 and 2020. Pre-HSCT blood DNA samples and clinical data were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Multiplex real-time PCR was used to detect the most common pathogenic UBA1 mutations, including p.M41L (c.121A>C), p.M41V (c.121A>G), and p.M41T (c.122T>C), with detection limits of 0.13%, 0.5%, and 1%, respectively. The presence of these mutations was confirmed using Sanger sequencing and droplet digital PCR. In addition, we examined UBA1 mutations in 2 patients previously diagnosed with MDS but suspected of having VEXAS syndrome based on specific clinical features. Results Among 4340 patients with either BMF or plasma cell neoplasms who underwent unrelated HSCT, 1771 had available pre-HSCT blood DNA samples. The diagnoses of the 1771 patients included MDS (n = 1264), acquired aplastic anemia (n = 375), inherited BMF syndromes (n = 89), plasma cell neoplasms (n = 23), and other acquired BMF syndromes (n = 20). The median patient age at HSCT was 46 (range, 0-75; interquartile range, 20-59) years old, and the male-to-female ratio was 1.6:1. Pathogenic UBA1 mutations were detected in 2 of the 1771 patients (0.11%), both of whom were male MDS patients older than the median age (cases 1 and 2); thus, the prevalence of VEXAS syndrome within this patient subgroup was 0.36%. Both patients received chemotherapy before unrelated donor bone marrow transplantation (BMT), including induction chemotherapy and azacitidine, and achieved complete and partial responses, respectively. In addition, UBA1 mutations were detected in the 2 MDS patients at Kanazawa University Hospital (cases 3 and 4). Case 3 also underwent unrelated BMT after experiencing cytopenia relapse and inflammatory symptoms during corticosteroid reduction. The clinical characteristics and outcomes of the 4 patients with VEXAS syndrome are summarized in Table 1. Variant allele frequencies (VAFs) of UBA1 mutations ranged from 2% to 71%. The 3 patients who underwent unrelated BMT received fludarabine and busulfan-based conditioning regimens and graft-versus-graft disease (GVHD) prophylaxis with tacrolimus + methotrexate or cyclosporine + methotrexate. All 3 patients achieved neutrophil and platelet engraftment. One patient required systemic corticosteroids for acute skin GVHD. One patient died of idiopathic interstitial pneumonia 5 months after BMT. The other 2 patients were alive without relapse, chronic GVHD, or other complications at 18 and 28 months after BMT. Discussion Our results support the curative potential of allogeneic HSCT for VEXAS syndrome without excessive toxicity. The occurrence of transplant-related mortality due to idiopathic interstitial pneumonia may be related to the reported poor outcome of the p.M41V mutation following non-transplant therapy. The low prevalence of VEXAS syndrome in the current cohort may be due to the late age of onset and the rare progression to advanced MDS. The low VAFs of UBA1 mutations in the 2 patients who responded to chemotherapy before HSCT may indicate the efficacy of chemotherapy in selectively eradicating UBA1 mutant clones. Our rapid, sensitive, and cost-effective screening method for VEXAS syndrome can help optimize treatment strategies for this rare disease in future studies.

M41 and Non-M41 UBA1 Variants Differ in Their Alteration of Hematopoiesis

Background: UBA1 variants have recently been described as causative to the somatic hematoinflammatory disease VEXAS Syndrome. Previously, the features of M41 and non-M41 variants regarding their diagnoses and inflammatory transcriptome in comparison to other patients (pts) diagnosed with hematological malignancies (HM) have been described ( Leukemia 37, 1080-1091, 2023). Given that UBA1 impairment also affects hematopoiesis with no evidence of malignancy, we characterized the effect of UBA1 variants on hematopoiesis including symptomatic pts without malignant diagnoses. Aim: (1) Evaluate the hematological phenotype of UBA1 M41 and non-M41 variants detected in an unbiased cohort of symptomatic pts; (2) compare the transcriptomic profiles of M41 and non-M41 variants with healthy and pathogenic hematopoiesis. Patients and method: Screening of 12,643 pts suspected of HM for UBA1 variants (complete coding region) by targeted sequencing. Patients were diagnosed with HM based on 2022 WHO Classification. Whole transcriptome sequencing was performed for 1297 samples (Control n = 56, CCUS n = 218, MDS n = 771, CMML n = 228, UBA1 M41 n = 16, non-M41 n = 8). UBA1 samples were selected based on availability of sample material with preference given to pts without co-mutations. K-means clustering followed by filtering with consensus score (>0.6) by ConsensusClusterPlus was used to define transcriptomic clusters. DEG was defined as |logFC| > 1.5 and adjusted p < 0.05. ToppFun was used for GO analysis with default settings. Results: We identified 116 pts harboring UBA1 putative somatic variants (0.9%), consisting of 64 pts (0.5%) harboring M41 variants (M41 pts) and 52 pts (0.4%) harboring non-M41 UBA1 variants (non-M41 pts). As known, the majority (60/64 [94%]) of M41 pts were only suspected of HM (n = 51) or were diagnosed with MDS (n = 9) and other WHO entities such as MM were the minority. The tendency was weaker in non-M41 pts (36/52 [69 %], consisting of suspected HM n = 25, MDS n = 11; 16/52 [31%], other WHO entities). Of interest, ring sideroblasts (RS) were observed in 9/36 (25%) M41 pts and 11/28 (39%) non-M41 pts with staining available. SF3B1 was negative in 7/9 M41 pts and 8/11 non-M41 pts. Furthermore, RS ≥ 15% were observed in 4 non-M41 pts, two of which had no other co-mutations, suggesting the involvement of non-M41 variants in RS generation. To understand the effect of UBA1 in hematopoiesis, we compared the expression of marker genes of hematopoiesis of M41 and non-M41 pts with healthy individuals, pts diagnosed with CCUS, MDS, or CMML. The reference groups were constructed by k-means clustering based on 212 genes standardly recognized as relevant in hematopoiesis, and pts with the strongest differentiation bias are shown (Figure). The known myeloid bias and B-cell decrease of M41 pts were observable, and half of the M41 pts had at least a weak membership to clusters with some myeloid bias (Cluster 2 and 4). The observed myeloid bias could either be granulocytic or monocytic and the tendency was not homogenous among M41 pts. In contrast, half (n = 4) of the non-M41 pts belonged to the erythroid bias Cluster 5, which is enriched in pts carrying SF3B1 variants, and 3 belonged to Cluster 5 without SF3B1 variants. Neither M41 nor non-M41 pts clustered with transcriptomic groups of uni-lineage differentiation bias (Cluster 1, 3 and 6), and only one non-M41 pt clustered with the healthy controls, suggesting low risk but pathogenic hematopoiesis. To further understand the erythroid bias in non-M41 variants, we performed DEG and GO analysis. As erythroid bias comparators, we chose male pts in Cluster 5 diagnosed with MDS- SF3B1 (n = 14) and Cluster 6 diagnosed with MDS-bi TP53 (n = 8), and male controls (n = 30). The pt with a SF3B1 variant was excluded from the non-M41 group. Compared to controls, both the non-M41 group and Cluster 5- SF3B1 had upregulated heme synthesis, sharing upregulation of SF3B1-targets ABCB6 and PPOX. Cluster6-bi TP53 was more characterized by the downregulation of myeloid genes, which was not shared with non-M41 pts. Prognostic marker WT1 was upregulated in non-M41 group compared to Cluster 5- SF3B1 but not to controls or Cluster6- biTP53. Conclusions: UBA1 M41 variants confer myeloid bias but do not lead to the uni-lineage differentiation bias seen in pts with high risk mutations. Isolated UBA1 non-M41 pts can have RS ≥ 15%, and manifest erythroid bias similar to MDS- SF3B1 but higher expression of prognostic marker WT1.

Functional Somatic Syndromes Are Associated With Varied Postoperative Outcomes and Increased Opioid Use After Spine Surgery: A Systematic Review.

Systematic Review. To perform a systematic review assessing the relationship between functional somatic syndromes (FSSs) and clinical outcomes after spine surgery. A systematic review of online databases (PubMed and Web of Science) through December 2021 was conducted via PRISMA guidelines to identify all studies investigating the impact of at least one FSS (fibromyalgia, irritable bowel syndrome (IBS), chronic headaches/migraines, interstitial cystitis, chronic fatigue syndrome, multiple chemical sensitivity) on outcomes after spine surgery. Outcomes of interest included patient reported outcome measures (PROMs), postoperative opioid use, cost of care, complications, and readmission rates. A total of 207 records were identified. Seven studies (n = 40,011 patients) met inclusion criteria with a mean MINORS score of 16.6 out of 24. Four studies (n = 21,086) reported postoperative opioid use; fibromyalgia was a strong risk factor for long-term opioid use after surgery whereas the association with chronic migraines remains unclear. Two studies (n = 233) reported postoperative patient reported outcome measures (PROMs) with mixed results suggesting a possible association between fibromyalgia and less favorable PROMs. One study (n = 18,692) reported higher postoperative complications in patients with fibromyalgia. Patients with fibromyalgia and possibly migraines are at higher risk for prolonged postoperative opioid use and less favorable PROMs after spine surgery. There is limited research on the relationship between other Functional somatic syndromes (FSSs) and outcomes following spine surgery. Growing evidence suggests the variation in outcomes after spine procedures may be attributed to non-identifiable organic patient factors such as FSSs.

Clinical outcomes, medical costs, and medication usage patterns of different somatic symptom disorders and functional somatic syndromes: a population-based study in Taiwan.

Somatic symptom disorders (SSD) and functional somatic syndromes (FSS) are often regarded as similar diagnostic constructs; however, whether they exhibit similar clinical outcomes, medical costs, and medication usage patterns has not been examined in nationwide data. Therefore, this study focused on analyzing SSD and four types of FSS (fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, functional dyspepsia). This population-based matched cohort study utilized Taiwan's National Health Insurance (NHI) claims database to investigate the impact of SSD/FSS. The study included 2 615 477 newly diagnosed patients with SSD/FSS and matched comparisons from the NHI beneficiary registry. Healthcare utilization, mortality, medical expenditure, and medication usage were assessed as outcome measures. Statistical analysis involved Cox regression models for hazard ratios, generalized linear models for comparing differences, and adjustment for covariates. All SSD/FSS showed significantly higher adjusted hazard ratios for psychiatric hospitalization and all-cause hospitalization compared to the control group. All SSD/FSS exhibited significantly higher adjusted hazard ratios for suicide, and SSD was particularly high. All-cause mortality was significantly higher in all SSD/FSS. Medical costs were significantly higher for all SSD/FSS compared to controls. The usage duration of all psychiatric medications and analgesics was significantly higher in SSD/FSS compared to the control group. All SSD/FSS shared similar clinical outcomes and medical costs. The high hazard ratio for suicide in SSD deserves clinical attention.

Clonal Bone Marrow Plasma Cells Are Common in Patients with Vexas Syndrome

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder. Its prevalence increases with age, reaching 5.3% at 70 years and older. MGUS progression rate to multiple myeloma (MM) or lymphoplasmacytic malignancies is about 1% per year. Patients with autoimmune diseases are at increased risk for developing MGUS and MM. VEXAS ( vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome), an autoinflammatory disorder caused by somatic mutations in ubiquitin-activating enzyme, UBA1 gene, has been associated with plasma cell disorders, specifically MGUS, but the rate of progression is unknown. Cyclin D1, important in cell cycle progression, is regulated by ubiquitin-proteasome mediated degradation, and deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. We aim to assess marrow characteristics of plasma cell disorders (MGUS and MM) in VEXAS, and the impact of a defective UBA1 gene product on protein expression of cyclin D1. Methods We assessed 28 patients with VEXAS for the presence of plasma cell disorders, and studied the clinical and laboratory characteristics of those with clonal plasma cells (PC) in the marrow. Bone marrow biopsies and aspirates were evaluated by morphology, immunohistochemistry (IHC) dual staining CD138/cyclin D1, dual staining MUM-1/CD20), in situ hybridization (Kappa and Lambda light chains) and flow cytometry (FC) using antibodies for CD45, CD19, CD20, CD38, CD138, CD56, CD27, CD81, and cytoplasmic Kappa and Lambda immunoglobulins. Serum free kappa and lambda light chains, IgG, IgM, and IgA, and level of M paraprotein by serum protein electrophoresis with immunofixation were obtained. Fluorescent in situ hybridization (FISH) analysis for MM was performed in most patients with clonal PCs. Results Patients' characteristics are shown in Table 1. Eight out of 28 (28.6%) patients with VEXAS syndrome, all males, had clonal plasma cells in their bone marrows: 3 MGUS, and 5 MM (3 smoldering, SMM; 2 active MM). Median age at diagnosis of plasma cell disorder was 69.5 years (range 60-75). All patients had pathogenic UBA1 somatic mutations (5 M41T, 1 each with M41V, M41L, and splice). Clinically, monoclonal protein size was small, with no specific selection of the type of M protein. Strikingly, most (7/8) clonal plasma cells showed cyclin D1 expression by IHC (dual immunohistochemical stain cyclinD1/CD138 shows double-positive plasma cells; figure not shown), displaying nuclear immunoreactivity in 6 cases, and cytoplasmic immunoreactivity in 1 case. FC showed positive CD20 expression of clonal plasma cells in 4 cases, dim to negative CD19 expression in 4 cases, variable CD56 (positive in 3 cases, partial positive in 1 case, negative in 2 cases), dim to negative CD27 in 3 cases, dim to negative CD81 in 3 cases. FISH for MM revealed: t(11;14) in 4 cases, gain of 11q (CCND1) in 2 cases (in one case, CCND1 gain was present in addition to t(11;14); in the second case, CCND1 gain was associated with gains of 1q and 17p(TP53). The cyclin D1-negative MM case was negative for t(11;14) but had t(4;14). All cases with t(11;14) were positive for cyclin D1 by IHC (nuclear staining). The one MM case with negative nuclear staining for cyclin D1 but positive cytoplasmic staining, was negative for t(11;14) but had gain of 11q (CCND1).One patient evolved from SMM to active MM after 4 years. No evolution to MM was seen in patients with MGUS with median follow-up of 30 months. Conclusions Patients with VEXAS have a high prevalence of clonal plasma cell disorders. Clonal plasma cells in VEXAS patients are associated with t(11;14), and with nuclear cyclin D1 expression by IHC. Cytoplasmic cyclin D1 staining in the absence or weak nuclear staining was observed with CCND1 gain and absence of t(11;14). Cytoplasmic cyclin D1 expression may be related to lack of cyclin D1 protein degradation by a defective UBA1 gene product. Our results suggest that defective UBA1 and autoinflammation pose an increased risk for developing MGUS or multiple myeloma.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Vexas Syndrome: A Systematic Review and Meta-Analysis

Introduction: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome presents as an auto-inflammatory disorder with overlapping hematological and rheumatological features. It is caused by mutation in UBA1 and is often refractory to treatment. Corticosteroids and Janus Kinase (JAK) inhibitors are being used for symptomatic treatment. Here, we review the literature for the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with VEXAS Syndrome. Methods: Following the preferred reporting items for systemic reviews and meta-analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Register of Controlled Trials, and Clinicaltrials.gov) using MeSH terms and keywords for “VEXAS Syndrome” AND “treatment” from the date of inception to May 31, 2023. Our search produced 100 results, and duplicates were removed. After excluding irrelevant and review articles during primary and secondary screening, six studies were included which mentioned the outcomes of allogeneic hematopoietic stem cell transplantation in adult VEXAS syndrome patients. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 18 patients from six studies reporting the outcomes of allogeneic HSCT in VEXAS syndrome patients were included for this systematic review and meta-analysis. (Table 1) The median age of the participants was 59.5 years (43-69) and all the patients were male. The median follow-up time was 11.6 months (0.4-67). Manifestations of the disease included myelodysplastic syndrome (MDS) 38.9% (n=7), refractory inflammatory symptoms 16.7% (n=3), transfusion dependent disease 16.7% (n=3), myelofibrosis (MF) 5.6% (n=1), MDS plus MF 5.6% (n=1), systematic lupus erythematosus 5.6% (n=1), multiple myeloma 5.6% (n=1), and IgG4-related disease 5.6% (n=1). Donor type was matched unrelated 50% (n=9), matched related 33.3% (n=6), mismatched unrelated 11% (n=2), and the donor type was unknown for one patient. The source of stem cells was peripheral blood and bone marrow in 83.3% (n=15) and 5.6 % (n=1) of the patients, respectively, while it was not reported for 11% (n=2) of the patients. The pooled overall survival (OS) at a median of 6 (0.4-67) months was 93.3% (95% CI 0.67-0.1, I 2=0%, p=0.64, n=18). The incidence of acute graft versus host disease (GvHD) grade I-II, acute GvHD grade III-IV, and chronic GvHD was 17% (n=3), 11% (n=2), and 11% (n=2), respectively. Among the 3 patients who died, one patient expired due to sepsis, multiorgan failure, and cardiac arrest, second patient due to infection, and the third patient due to severe hypoxic pneumonia. Conclusion: Allogeneic HSCT has shown promising results in treating patients with VEXAS syndrome with good overall survival and acceptable incidence of graft versus host disease. However, considering the small sample size more studies should be done to consolidate these findings.

Clinical Manifestations Are Evolving and Progressive in Patients with Vexas Syndrome

Introduction Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 and characterized by systemic autoinflammation and hematologic manifestations. Clinically, disease progression appears heterogenous, with differing degrees of organ involvement seen in individual patients over time. Disease mortality is high, and to date only UBA1 variant, presence of MDS or significant cytopenia, and clonal hematopoiesis have been associated with worse overall survival. Prospective data are currently lacking on evolution of symptoms and organ involvement. We characterized disease evolution over time and looked at the benefit of prescribed therapies in our prospective cohort of VEXAS patients. Methods Forty-four VEXAS patients with a confirmed UBA1 mutation have been enrolled in our study at the National Institutes of Health (NIH) since 2019. We collected demographic data and clinical history, and performed standardized evaluations including peripheral blood counts, inflammatory markers, serum protein electrophoresis, and bone marrow biopsies. All patients were screened for eligibility and suitability for hematopoietic stem cell transplant (HSCT) on a phase II clinical trial (NCT05027945). Patients who did not undergo HSCT received recommendations for medical therapy. Results Subjects were male with median age of 67 years (50 - 79) and 95% were of White ethnicity. The most common UBA1 variant was M41T (n=19, 43%) followed by M41L (n=15, 34%), M41V (n=7, 16%), and splice motif mutations (n=4, 7%). Median variant allele fraction (VAF) of the cohort was 73%; M41T (76%), M41L (70%), M41V (58%), splice (61%). Thirty-six (82%) patients initially presented with skin lesions and/or arthralgias. Other initial manifestations included fever (27%), fatigue (25%), chondritis (14%), pulmonary (11%) and ocular/orbital (9%). Interestingly, only one patient presented with symptomatic anemia. At the time of first NIH clinic visit patients had manifestations of VEXAS disease for median of 6 years (range 1 - 11). Only 20% (9/44) had no active symptoms. Fatigue (39%) was most common followed by skin rash, arthralgias, pulmonary, and neurologic manifestations (Figure). Twenty-three percent had developed transfusion dependent anemia. Eleven patients (25%) had bone marrow findings meeting criteria for myelodysplastic syndrome (MDS); one patient had MDS-EB1. Venous thromboembolism was documented in 18 patients (40%). Thirteen patients (30%) had plasma cell disorder, four of whom had multiple myeloma (MM). All except one patient were receiving prednisone at NIH evaluation, with median dose of 20mg (range 5mg-50mg). Sixteen patients (36%) had elevated CRP despite glucocorticoids and steroid-sparing agents. In 66% of patients, concomitant steroid-sparing agents were used, most frequently IL-6 inhibitors (n=9), or JAK inhibitors (n=6). Other agents included erythropoietin stimulating agents (n=2), canakinumab (n=2), adalimumab (n=2), methotrexate (n=2), and azacytidine, azathioprine, colchicine, dapsone, ustekinumab in one patient each. Two patients were on MM directed therapies. At last follow-up, 8 patients (18%) had died, 6 patients (14%) were post HSCT, and 9 patients (20%) were pursuing HSCT. The indication for HSCT was refractory inflammation in two patients and progressive marrow failure in four. Twenty-one patients continued medical management: 15 (35%) with controlled inflammation on their respective regimens and 6 (14%) with progressive hemato-inflammatory manifestations. Of these six patients, one was non-compliant with therapy other than prednisone and other five were deemed unfit for HSCT due to poor performance status (n=2), age (n=2), or kidney disease (n=1). Conclusion Clinical manifestations of VEXAS syndrome evolve and progress with time. Severe cytopenia is rare at disease onset. Our observations indicate that biologics directed at JAK-STAT pathway, IL-6, IL-1 and hypomethylating agents may provide qualitative benefit in one-third of cases evidenced by controlled disease, but are not steroid sparing. HSCT is a curative approach, but, the timing is not well established. Most challenging are patients who have exhausted all effective steroid-sparing agents, require high dose of glucocorticoids, and are not a HSCT candidate. Development of effective therapies for VEXAS is a research priority to improve outcomes.

Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers.

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2 vaccination of healthy controls (N = 89; 71 females; mean/median age: 39/49 years) were compared with corresponding values of PACVS-affected persons (N = 191; 159 females; mean/median age: 40/39 years) exhibiting chronic fatigue/dysautonomia (≥three symptoms for ≥five months after the last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25-50%, p < 0.0001), increases in two receptor antibodies (by 15-25%, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by increased Angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/mL, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/mL, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/mL, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers.

Are Sexual Assaults Related to Functional Somatic Disorders? A Cross-Sectional Study.

An increasing number of sexual assaults (SAs) are being reported. This study investigated associations between SA and FSD, conceptualized as bodily distress syndrome (BDS), and five functional somatic syndromes (FSSs): chronic widespread pain (CWP), irritable bowel (IB), chronic fatigue (CF), multiple chemical sensitivity (MCS), and whiplash-associated disorder (WAD). Participants (n = 7493) from the population-based cohort Danish Study of Functional Disorders (DanFunD) completed questionnaires on FSD, emotional distress, SA, and sociodemographics. Risk ratios (RRs) for each FSD and emotional distress were calculated in nine models with SA as the primary exposure using generalized linear models with binomial family and log link and were adjusted for other potential risk factors. The results showed that SA was associated with single-organ FSD (RR = 1.51; 95% CI = 1.22-1.87), multi-organ FSD (RR = 3.51; 95% CI = 1.89-6.49), CWP (RR = 1.28; 95% CI = 0.83-1.98), IB (RR = 2.00; 95% CI = 1.30-3.07), CF (RR = 1.81; 95% CI = 1.42-2.32), WAD (RR = 2.62; 95% CI = 1.37-5.03), MCS (RR = 3.04; 95% CI = 1.79-5.17), emotional distress (RR = 1.75; 95% CI = 1.21-2.54), and health anxiety (RR = 1.65; 95% CI = 1.10-2.46). Overall, SA victims experienced significantly more somatic symptoms than individuals not exposed to SA. Adjusting for physical and emotional abuse did not change the observed associations. Our results suggest a large impact of SA on the overall somatic and mental health of SA victims. Due to the cross-sectional study design, further studies are required.

Exploring the Enigma of VEXAS Syndrome: A New Frontier in Medicine

In the realm of modern medicine, the discovery of novel diseases often presents both challenges and opportunities. VEXAS syndrome, an acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome, is a striking example of a unique monogenic disorder that has recently come to light. This syndrome represents a bridge between the worlds of rheumatology and hematology, and its clinical manifestations have left clinicians and researchers perplexed. In this editorial, I will delve into the complexity of VEXAS syndrome, exploring its clinical features, genetic underpinnings, and the quest for effective treatments. Furthermore, I will discuss how VEXAS syndrome may serve as a prototype for a new class of diseases that blur the boundaries between hematopoiesis and inflammation.

La linea dei sintomi in un disturbo da sintomi somatici

The case of a 10-year-old boy affected by somatic disorder syndrome is presented. The graphic representation of symptoms and adverse events together with a timeline helped the mother to interpret her child’s disorder and to manage fears and anxieties.