Examination of the Level of Circulating Plasmablasts and Their Characteristics as Diagnostic Tools for Immunoglobulin G4-related Disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a chronic, immune-mediated condition characterized by fibro-inflammatory lesions with lymphoplasmacytic infiltration. Diagnosis traditionally relies on histopathological findings, including the presence of IgG4+ plasma cells. However, due to challenges in biopsy accessibility, additional measures are needed to facilitate diagnosis. OBJECTIVES: To identify additional parameters for characterizing IgG4-RD patients. METHODS: We compared several circulating factors between a cohort of patients with IgG4-RD disease seen at our hospital between 2017 and 2023 and healthy controls. RESULTS: Among 16 suspected patients, 13 were confirmed to have IgG4-RD, and 3 were classified as highly likely. Comparison with controls revealed differences in white blood cell count (WBC) (Folf change (FC) 1.46, P < 0.05), plasmablasts (FC 3.76, P< 0.05), plasmablasts CD38 (FC 1.43, P < 0.05), and CD27 (FC 0.66, P = 0.054), thus highlighting potential markers for IgG4-RD diagnosis. Treatments with steroids/rituximab tend to reduce plasmablast (FC 0.6) and IgG4 (FC 0.28) levels and to increase Gal-3 levels. CONCLUSIONS: Levels of plasmablasts are a significant diagnostic feature in IgG4-RD. Healthy individuals have a lower level of plasmablasts. Elevated Gal-3 in serum of patients with IgG4-RD suggests a role in plasmablast activation. CD38/CD27 expression by plasmablasts emerges as a potential marker. Further research on a larger cohort is needed to confirm these findings.

αvß3 Integrin as a Link between the Development of Fibrosis and Thyroid Hormones in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Key players mediating fibrosis are myofibroblasts (MF) that, following transforming growth factor ß (TGFß) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express αvß3 integrin (a membrane receptor for thyroid hormones) and miRNA-21 that promotes deiodinase-type-3 expression (D3), causing the degradation of triiodothyronine (T3) that attenuates fibrosis. We hypothesized that αvß3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGFß and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (αvß3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, αvß3, miRNA-21, and D3 levels. Blood free-T3 (fT3), miRNA-21 levels, and the modified Rodnan skin score (MRSS) were evaluated in SSc patients. We found that the "fibrotic-ECM" significantly increased the pro-fibrotic characteristics of DF and the levels of miRNA-21, D3, and αvß3, compared to the "normal-ECM." Tetrac significantly inhibited the effects of the "fibrotic-ECM" on the cells. In accordance with tetrac's effect on D3/miRNA-21, a negative correlation was found between the patients' fT3 to miRNA-21 levels, and to the development of pulmonary arterial hypertension (PAH). We conclude that occupying the THs binding site of αvß3 may delay the development of fibrosis.

Thyroid Disorders in Patients with Systemic Sclerosis: Biochemical and Sonographic Characteristics. A Prospective Cohort Study.

BACKGROUND: Patients with systemic sclerosis (SSc) are at increased risk for autoimmune thyroid diseases, but information regarding thyroid nodules and cancer in SSc is scarce. Objectives: To evaluate the thyroid gland in patients with SSc at a single Israeli center. METHODS: Thyroid workup was conducted in consecutive SSc patients: thyroid-stimulating hormone (TSH), free thyroxine (fT4), anti-thyroid peroxidase, and anti-thyroglobulin antibodies, as well as thyroid ultrasound and fine needle aspiration (FNA) when appropriate. RESULTS: Fifty patients, mean age 51.3 ± 13.5 years (44 women) were evaluated. Ten were previously diagnosed with thyroid disease. Median TSH level was 2.0 (normal range 0.23-4 mIU/l) and median fT4 level was 1.0 (normal range 0.8-2.0 ng/dL). Among the 40 thyroid disorder-naive patients, 3 had subclinical hypothyroidism and 5 had positive anti-thyroid antibodies; 22 (44%) had 1-6 thyroid nodules, which were ≥ 1 cm in 12 (24%). Accordingly, six patients underwent FNA, and five were diagnosed as colloid nodules and one as papillary carcinoma. CONCLUSIONS: New cases of clinically significant autoimmune thyroid disease were not detected in our cohort of patients with SSc. Nevertheless, almost half had thyroid nodules. The clinical significance of these findings and their relation to thyroid cancer remains to be determined.

Autoimmune dysautonomia in women with silicone breast implants.

IMPORTANCE AND OBJECTIVES: There is unmet medical need to understand the pathogenic mechanism of the panoply of clinical manifestations associated with silicone breast implants (SBIs) such as severe fatigue, widespread pain, palpitations, dry mouth and eyes, depression, hearing loss etc. We aimed to determine whether autoantibodies against the autonomic nervous system receptors can explain the enigmatic and subjective clinical manifestation reported by women with SBIs. RESULTS: Circulating level of autoantibodies against G protein-coupled receptors (GPCRs) of the autonomic nervous system (adrenergic, muscarinic, endothelin and angiotensin receptors) have been evaluated in symptomatic women with SBIs using an ELISA method. These women with SBIs addressed our clinic due to various subjective and autonomic-related manifestations such as chronic severe fatigue, cognitive impairment, widespread pain, memory loss, sleep disorders, palpitations, depression, hearing abnormalities etc. We report for the first time, a significant reduction in the sera level of anti-ß1 adrenergic receptor (p < 0.001), anti-angiotensin II type 1 receptor (p < 0.001) and anti-endothelin receptor type A (p = 0.001) autoantibodies in women with SBIs (n = 93) as compared with aged matched healthy women (n = 36). Importantly, anti-ß1 adrenergic receptor autoantibody was found to significantly correlate with autonomic-related manifestations such as: sleep disorders and depression in women with SBIs. CONCLUSIONS: Chronic immune stimulation by silicone material may lead to an autoimmune dysautonomia in a subgroup of potentially genetically susceptible women with SBIs. The appearance of autoantibodies against GPCRs of the autonomic nervous system serve as an explanation for the subjective autonomic-related manifestations reported in women with SBIs.

Autonomic Nervous System Indices in Patients with Systemic Sclerosis without Overt Cardiac Disease.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease. OBJECTIVES: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged. METHODS: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls. RESULTS: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups. CONCLUSIONS: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies.

Tumor-like Lesions in Patients with Granulomatosis with Polyangiitis: A Case Series.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis. It usually involves the respiratory tract and kidney. Rarely, tumor-resembling inflammatory changes ensue. OBJECTIVES: To report three unique cases of GPA presenting with tumor-like lesions in various organs. METHODS: We presented three cases of GPA. Case 1 presented with typical upper respiratory symptoms of GPA and a mediastinal mass. Case 2 presented with low back pain, a large retroperitoneal mass, and nodular skin lesions. Case 3 presented with epigastric pain and a paravertebral inflammatory mass. RESULTS: The patients were treated successfully with rituximab. CONCLUSIONS: Clinicians should be aware of this presentation of granulomatosis with polyangiitis, which is known as Tumefaction Wegener's granulomatosis.

Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma.

Multiple myeloma (MM) is an aggressive cancer that originates from antibody-secreting plasma cells. Although genetically and transcriptionally well characterized, the aberrant gene regulatory networks that underpin this disease remain poorly understood. Here, we mapped regulatory elements, open chromatin, and transcription factor (TF) footprints in primary MM cells. In comparison with normal antibody-secreting cells, MM cells displayed consistent changes in enhancer activity that are connected to superenhancer (SE)-mediated deregulation of TF genes. MM cells also displayed widespread decompaction of heterochromatin that was associated with activation of regulatory elements and in a major subset of patients' deregulation of the cyclic adenosine monophosphate pathway. Finally, building SE-associated TF-based regulatory networks allowed identification of several novel TFs that are central to MM biology. Taken together, these findings significantly add to our understanding of the aberrant gene regulatory network that underpins MM.

[CRYOGLOBULINEMIA AND ENDOCARDITIS AS A PRESENTATION OF COXIELLA BURNETII (Q-FEVER) INFECTION].

INTRODUCTION: An infection with Coxiella burnetii (Q FEVER) can be manifested as an autoimmune or rheumatologic disease as it was presented in our patient, showing cryoglobulinemia and massive destruction of the aortic valve. In the differential diagnosis we must consider an infection with Coxiella burnatii which may change the course of the disease and may cause life-threatening manifestations.

Effect of Tocilizumab on Fatigue and Bone Mineral Density in Patients with Rheumatoid Arthritis.

BACKGROUND: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients. OBJECTIVES: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. METHODS: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. RESULTS: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data. CONCLUSIONS: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.

Parathyroid surgery: correlation between pre-operative localization studies and surgical outcomes.

OBJECTIVE: Pre-operative imaging techniques have enabled minimally invasive parathyroid surgery to supersede the traditional approach to hyperparathyroidism (HPT) surgery, which included cervical exploration. Cervical ultrasound (US) and sestamibi scan (MIBI) are commonly performed, but the results of these localization tests do not always match. This study correlated surgical outcomes with pre-operative localization findings, including matched positive US and MIBI studies, one positive study (US or MIBI), conflicting studies or negative results. DESIGN: Retrospective medical record review. PATIENTS: A hundred and sixty nine consecutive patients who underwent parathyroidectomy from January 2005 to December 2012. MEASUREMENTS: Correlation between surgical outcomes and pre-operative localization tests. RESULTS: All patients (134F/35M, 59·6 ± 13·5 years of age) had primary HPT. US and MIBI localization studies matched in 76%, whereas 10·7% had positive MIBI only and 8·3% US only. Studies were negative in 3·6% and contradictory in 1·8%. Minimally invasive parathyroidectomy was performed in 87% of the matched group and 89% of the MIBI-only group. Surgical success rate, defined as postoperative normalization of calcium and PTH levels, was similar in patients with a single positive study (MIBI or US) vs double-matched studies (MIBI and US). Patients were followed up for 6 weeks. Overall, pathology was consistent with adenoma in 95%. DISCUSSION: Parathyroidectomy success rate was similar in patients with primary HPT and MIBI-only or US-only positive localization studies compared to those with matched US/MIBI studies. The results support a clinical algorithm in which positive results from one imaging technique, either MIBI or US, are sufficient to refer a patient for parathyroid surgery.

Colchicine-clarithromycin-induced rhabdomyolysis in Familial Mediterranean Fever patients under treatment for Helicobacter pylori.

Chronic administration of colchicine remains a mainstay of therapy for patients with Familial Mediterranean Fever (FMF). As this medication is a strong CYP3A4 inhibitor, it has the potential to interact with many routinely used medications. One such medication is clarithromycin, itself a strong inhibitor of the same enzyme, and a typical choice for triple therapy eradication of H. pylori. Various sequelae of colchicine-clarithromycin interaction have been documented and can be expected by prescribing physicians, with rhabdomyolysis, though rare, being among the most serious. Review of cases from a tertiary academic medical center and full PubMed/MEDLINE literature review. Despite the prevalence of diseases treated with clarithromycin and the expected drug interaction with colchicine, only two cases in the literature document clinical rhabdomyolysis due to colchicine-clarithromycin interaction. In neither case, however, were patients undergoing treatment for FMF. Herein, we describe the first two cases in the literature of clinical rhabdomyolysis in FMF patients under colchicine therapy after administration of clarithromycin as part of therapy treating H. pylori infection.

Vitamin D Antibodies in Systemic Sclerosis Patients: Findings and Clinical Correlations.

BACKGROUND: Vitamin D is a pivotal factor in calcium homeostasis and exerts immunomodulatory effects. Hypovitamin D has been demonstrated in systemic sclerosis (SSc) patients and may be related to more severe disease of longer duration and with extensive skin involvement. OBJECTIVES: To seek anti-vitamin D antibodies in SSc patients, as found by previous research in patients with systemic lupus erythematosus (SLE). METHODS: The study included 54 SSc patients and 41 volunteers. Immunoglobulin (Ig) G and IgM autoantibody levels against 25(OH)D and 1,25(OH)D were obtained from patients and controls and were compared. SSc patients were assessed for autoantibody profile and disease severity. RESULTS: Vitamin D antibodies were present in 87% of SSc patients and 42% of controls. Higher levels of anti-25(OH)D IgM antibodies were detected in SSc patients compared to controls (0.48 ± 0.22 vs. 0.29 ± 0.29, respectively, P = 0.002); however, IgG levels were lower in the SSc patients. No such discriminative. effect was found regarding anti-1,25(OH)D antibodies between SSc and controls. No correlation was found between,vitamin D antibodies and other autoantibodies, disease severity, or target organ damage. CONCLUSIONS: To the best of our knowledge; this is the first study of these novel, anti-vitamin D antibodies in SSc patients and the first time a correlation between IgM 25(OH) vitamin D antibodies and scleroderma has been identified. Further research on the pathophysiological significance and therapeutic potential of vitamin D is required.

Efficacy and safety of the dietary supplement DBCare® in patients with type 2 diabetes mellitus and inadequate glycemic control.

AIMS: DBCare® (Ace Continental Exports Inc., London, UK) is a traditional Indian herbal food supplement marketed as an antidiabetes remedy. This study evaluated the efficacy and safety of DBCare in patients with inadequately controlled type 2 diabetes mellitus (T2DM) despite oral hypoglycemic treatment. METHODS: A 12-week randomized double-blind placebo-controlled trial was conducted. Patients with T2DM on oral hypoglycemic agents with HbA1C > 7.0% were randomized to receive DBCare or placebo tablets. RESULTS: Thirty-five patients (20 male/15 female; mean age 61.2 ± 7.6 years), with a mean baseline HbA1C of 7.9% ± 0.6%, received DBCare (N = 18) or placebo (N = 17). During the study period, HbA1C declined 0.4 ± 0.7% in the DBCare® group and 0.2% ± 0.8% in the placebo group (p = 0.806). No significant changes occurred in fasting plasma glucose, lipid profile, or homeostasis model assessment throughout the study or in body mass index, waist circumference, or blood pressure values. Hypoglycemic episodes (glucose < 70 mg/dL) were more frequent in the treatment group (7 vs 1, p = 0.043), necessitating a decrease in other hypoglycemic medications in 2 patients. DBCare was generally well tolerated, with mild side effects that were not different from those of the placebo group. CONCLUSIONS: This preliminary study did not demonstrate that DBCare was efficacious in improving glycemic control in inadequately controlled patients with T2DM on oral hypoglycemics. A trend toward improved glycemic control was noted in the DBCare group, which correlates with more frequent hypoglycemic episodes. Further studies are needed to elucidate DBCare's hypoglycemic effect in patients with T2DM in general and in specific clinical settings, such as HbA1C ≥ 8%, short (≤10-year) duration of diabetes, or young age in particular.

Nonpharmacological interventions for 'no-option' refractory angina patients.

Refractory angina pectoris (RAP) defined as chronic anginal chest pain because of coronary artery disease (CAD) is a major problem. The increase in the number of patients with RAP in recent years is because of the increasing aging population and improved survival rates among patients with CAD. Management of patients with RAP is often extremely challenging. In this review, we present several interventional approaches for RAP, including device therapies, lifestyle intervention, and cell therapies. Some of these treatments are currently used in the management of RAP, whereas other treatments are under investigation.