Systemic Connective Tissue Diseases Research Articles

Non-infectious mixed cryoglobulinemia as a new clinical presentation of mutation in the gene encoding coatomer subunit alpha: a case report of two adult sisters

Cryoglobulinemia is a rare disease characterized by the presence of cryoglobulins in the blood serum. It is usually caused by autoimmune, lymphoproliferative, or infectious factors. The pathogenesis of cryoglobulinemia is not well understood, therefore, genetic testing is very important. We present the case of two adult sisters with different clinical phenotypes of non-infectious cryoglobulinemic vasculitis associated with a rare genetic variant [(Hg38) 1:160323529 C>G, NP_004362.2:p.(Gly203Ala)]. One of the sisters suffered from essential mixed cryoglobulinemia, while the other suffered from cryoglobulinemia associated with systemic connective tissue disease. In both cases, genetic tests revealed a variant in the COPA gene, encoding coatomer subunit alpha. Mutations in the COPA gene are associated with COPA syndrome, an autoimmune interstitial lung, joint, and kidney monogenic disease, found mainly in children. Only 15 pathogenic COPA variants have been reported thus far which suggests that the full spectrum of disease manifestations remains unknown. Ours is the first report of the association of the COPA gene with non-infectious cryoglobulinemic vasculitis in adults. This unexpected finding may direct research into the pathogenesis of cryoglobulinemia and new treatment strategies for this rare disease.

Use of rituximab in the of immunoinflammatory rheumatic diseases combined with Graves' disease (autoimmune polyglandular syndrome in adults): case report and literature review

Rituximab (RTM) is a chimeric (murine and human) monoclonal antibody against B-lymphocytes (CD20). RTM is widely used in hematology for lymphoproliferative diseases and in rheumatology for rheumatoid arthritis, Sjögren's disease, some types of vasculitis and systemic connective tissue diseases. The administration of RTM is associated with a depletion of B-cells mediated by the regulation of apoptosis and cytotoxic effects via complement-dependent and antibody-dependent mechanisms. Considering the pathogenesis of autoimmune damage in Graves' disease (GD), an autoimmune thyroid disease associated with thyrotoxicosis, the use of RTM could be effective in this pathology. We present three patients with a combination of diffuse toxic goiter and rheumatic pathology treated with RTM; different outcomes of GD were observed.

The risk of cancer in pediatric-onset immune-mediated inflammatory diseases – A nationwide study

Background and objectivesAdult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers. MethodsWe used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR). ResultsWe included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4–17.7) years for patients and 10.2 (interquartile range: 5.2–17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8–2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2–16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4–15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1–22.6]). ConclusionsWe found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.

Nintedanib in the treatment of interstitial lung disease in patients with systemic connective tissue diseases

Nintedanib in the treatment of interstitial lung disease in patients with systemic connective tissue diseases

Immunosuppressive therapy of systemic connective tissue diseases in elderly patients

Immunosuppressive therapy of systemic connective tissue diseases in elderly patients

Coronary Artery Aneurysm or Ectasia as a Form of Coronary Artery Remodeling: Etiology, Pathogenesis, Diagnostics, Complications, and Treatment.

Coronary artery aneurysm or ectasia (CAAE) is a term that includes both coronary artery ectasia (CAE) and coronary artery aneurysm (CAA), despite distinct phenotypes and definitions. This anomaly can be found in 0.15-5.3% of coronary angiography. CAE is a diffuse dilatation of the coronary artery at least 1.5 times wider than the diameter of the normal coronary artery in a patient with a length of over 20 mm or greater than one-third of the vessel. CAE can be further subdivided into diffuse and focal dilations by the number and the length of the dilated vessels. Histologically, it presents with extensive destruction of musculoelastic elements, marked degradation of collagen and elastic fibers, and disruption of the elastic lamina. Conversely, CAA is a focal lesion manifesting as focal dilatation, which can be fusiform (if the longitudinal diameter is greater than the transverse) or saccular (if the longitudinal diameter is smaller than the transverse). Giant CAA is defined as a 4-fold enlargement of the vessel diameter and is observed in only 0.02% of patients after coronary. An aneurysmal lesion can be either single or multiple. It can be either a congenital or acquired phenomenon. The pathophysiological mechanisms responsible for the formation of CAAE are not well understood. Atherosclerosis is the most common etiology of CAAE in adults, while Kawasaki disease is the most common in children. Other etiological factors include systemic connective tissue diseases, infectious diseases, vasculitis, congenital anomalies, genetic factors, and idiopathic CAA. Invasive assessment of CAAE is based on coronary angiography. Coronary computed tomography (CT) is a noninvasive method that enables accurate evaluation of aneurysm size and location. The most common complications are coronary spasm, local thrombosis, distal embolization, coronary artery rupture, and compression of adjacent structures by giant coronary aneurysms. The approach to each patient with CAAE should depend on the severity of symptoms, anatomical structure, size, and location of the aneurysm. Treatment methods should be carefully considered to avoid possible complications of CAAE. Simultaneously, we should not unnecessarily expose the patient to the risk of intervention or surgical treatment. Patients can be offered conservative or invasive treatment. However, there are still numerous controversies and ambiguities regarding the etiology, prognosis, and treatment of patients with coronary artery aneurysms. This study summarizes the current knowledge about this disease's etiology, pathogenesis, and management.

The prognostic value of hematological indices in systemic inflammatory diseases of connective tissue

The prognostic value of hematological indices in systemic inflammatory diseases of connective tissue

Autoimmune/inflammatory syndrome induced by adjuvants in a patient after implantation of a polypropylene mesh for inguinal hernia repair (clinical case)

Aim. To report a clinical case of autoimmune/inflammatory syndrome, induced by adjuvants in patient after polypropylene mesh implantation for inguinal hernia repair.Materials and methods. Patient Z., male, 68 years old, was admitted to the hospital presenting muscle weakness and progressive dyspnoea. Interview and physical exam revealed signs of cognitive impairment and memory loss, proximal muscle weakness. Differential diagnosis was made to clarify genesis of symptoms, to rule out polymyositis, other systemic connective tissue diseases, oncologic diseases, hypothyroidism, infectious diseases.Results. Creatine kinase, thyroxine, thyreothropic hormone levels were normal. Clinical and immunological investigation revealed no data on polymyositis or any other systemic connective tissue disease. Yersiniosis, salmonellosis, malaria were ruled out. Chest CT scan, abdomen CT scan, gastroscopy, colonoscopy no data on the presence of malignant neoplasms. PSA level were normal. Electroneuromyography revealed signs of symmetrical axonal type damage to the motor portion of the ulnar nerves on both sides, and demyelinating type damage to the sensory portion. Prednisolone therapy was started at a dose of 40 mg per 24 hour (0.5 mg per kg), which lead to a significant clinical improvement. Based on the therapy response and positive diagnostic criteria (clinical manifestation after polypropylene mesh implantation, typical clinical manifestation – muscle weakness, chronic fatigue, cognitive impairment, neurological manifestations associated with demyelination) patient was diagnosed with autoimmune/inflammatory syndrome, induced by adjuvants (ASIA) after polypropylene mesh implantation for inguinal hernia repair.Conclusion. This clinical case report demonstrates possibility of a persistent course of the disease (symptoms were present for 15 years). Feature of this case is partial clinical improvement due to long-term uncontrolled dexamethasone use, which was prescribed empirically.

Secondary fibromyalgia in children with immune-inflammatory rheumatic diseases

Patients with immune-inflammatory rheumatic diseases (IIRDs) often present with non-inflammatory musculoskeletal pain associated with nociceptive dysfunction, central sensitization, and secondary fibromyalgia (FM). In recent years, an increasing number of publications have appeared dealing with FM in rheumatoid arthritis and systemic connective tissue diseases in adult patients, while this problem is little discussed in pediatric rheumatology, partly due to the differences between the existing diagnostic criteria in children and adults, which complicate the diagnosis of juvenile secondary FM. The consequence of this is often the unfounded prescription or switching of synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs in patients who do not require intensified antirheumatic therapy, but rather psychotherapy and psychopharmacotherapy, as well as the wider use of physical and rehabilitation medicine methods. In a brief narrative review, we tried to trace the investigation of FM in a rheumatological clinic, including children with IIRD, from a historical perspective, to summarize current literature data on this problem and to point out possible solutions.

Histopathological aspects of usual interstitial pneumonia in patients with systemic connective tissue diseases.

Five cases of patients with systemic connective tissue diseases (CTD) who developed connective tissue disease-associated interstitial lung disease (CTD-ILD) with progressive pulmonary fibrosis (PPF) are reported here. Unspecified ILD was diagnosed using high-resolution computed tomography (HRCT). Histologically, all cases were usual interstitial pneumonia (UIP) with findings of advanced (3/5) to diffuse (2/5) fibrosis, with a partially (4/5) to completely (1/5) formed image of a honeycomb lung. The fibrosis itself spread subpleurally and periseptally to more central parts (2/5) of the lung, around the alveolar ducts (2/5), or even without predisposition (1/5). Simultaneously, there was architectural reconstruction based on the mutual fusion of fibrosis without compression of the surrounding lung parenchyma (1/5), or with its compression (4/5). The whole process was accompanied by multifocal (1/5), dispersed (2/5), or organized inflammation in aggregates and lymphoid follicles (2/5). As a result of continuous fibroproduction and maturation of the connective tissue, the alveolar septa thickened, delimiting groups of alveoli that merged into air bullae. Few indistinctly visible (2/5), few clearly visible (1/5), multiple indistinctly visible (1/5), and multiple clearly visible (1/5) fibroblastic foci were present. Among the concomitant changes, areas of emphysema, bronchioloectasia, and bronchiectasis, as well as bronchial and vessel wall hypertrophy, and mucostasis in the alveoli and edema were observed. The differences in the histological appearance of usual interstitial pneumonia associated with systemic connective tissue diseases (CTD-UIP) versus the pattern associated with idiopathic pulmonary fibrosis (IPF-UIP) are discussed here. The main differences lie in spreading lung fibrosis, architectural lung remodeling, fibroblastic foci, and inflammatory infiltrates.

Coexistence of familial Mediterranean fever and seronegative spondyloarthritis: peculiarities of the course

Familial Mediterranean fever (FMF) is an autosomal recessive disease distributed among populations of Mediterranean origin - Armenians, Sephardi Jews, Arabs, Turks. There are numerous clinical observations regarding combination of FMF, as a classical representative of autoinflammatory diseases, with systemic diseases of connective tissue. Seronegative spondyloarthritis (SpA) are the most interesting disorders from this point of view, as far as sacroiliitis - an essential feature of SpA, may also present as a part of joint syndrome in FMF. The main objective of this clinical study was the investigation of the peculiarities of courses of FMF and SpA in case of their coexistence. We studied 126 patients with FMF, SpA and coexistence of both. According to results, patients with the overlap of FMF with SpA had relatively milder course of disease in comparison with each disease separately. Comparative clinical and instrumental characteristics of FMF-associated disorders had shown that in FMF-SpA overlap the symptoms of both diseases are less severe.

Scleroderma and scleroderma-like syndromes.

Systemic sclerosis is a systemic connective tissue disease whose main pathophysiological mechanism is a progressive fibrosis of internal organs and skin leading to thickening and induration. Blood vessels may also be involved. However, systemic scleroderma is not the only disease causing cutaneous sclerosis. There is a group of diseases that mimic scleroderma in their clinical presentation - these are scleroderma-like syndromes. A distinction can be made between syndromes of inflammatory/autoimmune, genetic, metabolic, toxic, drug-induced, occupational, paraneoplastic and syndromes caused by deposition disorders. In the following paper, we have reviewed the literature on scleroderma-like syndromes. We have outlined the factors predisposing to the development of each disease, its pathogenesis, clinical presentation, diagnostic and treatment process and the differences between each syndrome and systemic scleroderma.

Crosstalk between Inflammation and Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Is There a Common Basis?

Cardiovascular disease is the leading cause of morbidity and mortality in patients with rheumatoid arthritis and systemic lupus erythematosus. Traditional cardiovascular risk factors, although present in lupus and rheumatoid arthritis, do not explain such a high burden of early cardiovascular disease in the context of these systemic connective tissue diseases. Over the past few years, our understanding of the pathophysiology of atherosclerosis has changed from it being a lipid-centric to an inflammation-centric process. In this review, we examine the pathogenesis of atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis, the two most common systemic connective tissue diseases, and consider them as emblematic models of the effect of chronic inflammation on the human body. We explore the roles of the inflammasome, cells of the innate and acquired immune system, neutrophils, macrophages, lymphocytes, chemokines and soluble pro-inflammatory cytokines in rheumatoid arthritis and systemic lupus erythematosus, and the roles of certain autoantigens and autoantibodies, such as oxidized low-density lipoprotein and beta2-glycoprotein, which may play a pathogenetic role in atherosclerosis progression.

Advanced Imaging of Gout and Other Inflammatory Diseases Around the Knee.

The knee is one of the most commonly affected joints in the course of inflammatory arthropathies, such as crystal-induced and autoimmune inflammatory arthritis. The latter group includes systemic connective tissue diseases and spondyloarthropathies. The different pathogenesis of these entities results in their varied radiologic images. Some lead quickly to joint destruction, others only after many years, and in the remaining, destruction will not be a distinguishing radiologic feature.Radiography, ultrasonography, and magnetic resonance imaging have traditionally been the primary modalities in the diagnosis of noninflammatory and inflammatory arthropathies. In the case of crystallopathies, dual-energy computed tomography has been introduced. Hybrid techniques also offer new diagnostic opportunities. In this article, we discuss the pathologic findings and imaging correlations for crystallopathies and inflammatory diseases of the knee, with an emphasis on recent advances in their imaging diagnosis.

ВЛИЯНИЕ РЕВМАТОИДНОГО АРТРИТА НА ТЕЧЕНИЕ ЗАБОЛЕВАНИЙ ПАРОДОНТА

The most common chronic systemic autoimmune disease of connective tissue is rheumatoid arthritis, the incidence of which is up to 50% (in Russia). The etiology of rheumatoid arthritis is still not known for certain. Scientists pay special attention to searching and studying the factors influencing the occurrence of this disease. Researchers are interested in periodontitis as a likely factor in the development of rheumatoid arthritis. The literature presents limited data on the study of the characteristics of the course of dental diseases in patients with rheumatoid arthritis, which indicates the need for further study of this issue and clarification of the relationships between the intensity of caries, the condition of periodontal tissues and the temporomandibular joint in this category of patients. The study of these issues is of scientific and practical interest, as it allows us to improve the methods of diagnosis and monitoring of patients with rheumatoid arthritis by a dentist. The purpose of this study is to determine the effect of rheumatoid arthritis on the course of periodontal diseases. Materials and methods. The methodology of the scientific research is based on the analysis of domestic and foreign literature in the eLIBRARY databases; basic and additional methods of examining the patient were carried out. During the clinical examination, we assessed the general condition of the patient with rheumatoid arthritis, his dental and periodontal status. Results and discussion. A clinical examination of a patient with somatic pathology was carried out. Microorganisms of periodontal pockets were determined, the data obtained were compared with a patient who does not have a systemic disease. Conclusions. Patients with rheumatoid arthritis generally have a thin gingival biotype. Immunological parameters of oral fluid (IgA) in rheumatoid arthritis decrease, which indicates a lack of local and general immunity and leads to damage to periodontal tissue. In the future, this scientific research will help us develop optimal methods for diagnosing and treating patients with autoimmune disease.

Antinuclear antibody (ANA) positivity pattern by line immunoassay in a hospital from eastern India: Update from a laboratory perspective.

The existence of more than one antibody in systemic autoimmune rheumatic diseases (SARDs) or connective tissue disease (CTD) along with features of more than one autoimmune disease (AD) in an individual is suggestive of overlap syndrome (OS). Line immunoassay (LIA) can target many autoantibodies in a single approach, thus making the identification of OS feasible. This study aimed to identify the pattern of distribution of antinuclear antibodies by LIA prevalent in a hospital population in eastern India and identify common forms of SARD in this belt based on laboratory findings. A total of 1660 samples received for ANA profile testing by LIA were analysed. Factor analysis was performed with factor loading scores used in the k-means algorithm to identify clustering of various autoantibodies. U1-snRNP positivity was the highest at 16.69%, and the least frequent autoantibody noted was anti-Jo-1 at 0.71% positivity. Based on the outcome of factor analysis, three clusters were determined. Cluster 1 showed a predominance of anti-PM/Scl antibodies, cluster 2 showed a predominance of anti-dsDNA, anti-histone, anti-SmD1, anti-nucleosomes, anti-PCNA, anti-Po, anti-SSA/Ro52, anti-SSA-Ro60, anti-SSB/La, anti-Scl-70, anti-Mi-2, anti-Ku and anti-AMA-M2, and cluster 3 showed a predominance of anti-U1-snRNP. Mixed connective tissue disease (MCTD) and overlap syndrome (OS) are prevalent more than pure form of an AD in our study population. OS may be missed out by monospecific immunoassays and hence adds to diagnostic challenges. LIA may be more useful in identifying specific autoantibodies by a single approach rather than monospecific immunoassays in populations after a positive screen by indirect immunofluorescence (IIF).

Clinical observation of a patient with mixed connective tissue disease in an outpatient practice

Systemic connective tissue diseases are a heterogeneous group of diseases with unclear etiology, the pathogenesis of which is represented by an autoimmune process, a heterogeneous clinical picture and a variable course. Classical variants of the disease that do not cause difficulties in their verification are most common in clinical practice. But some patients have signs characteristic of various connective tissue diseases. This combination of symptoms is called mixed connective tissue disease or “cross syndrome” (Overlap-syndrome). The multi-organ nature of the clinical picture of the disease presents a diagnostic difficulty for the clinician and leads to late diagnosis, ineffective therapy, and disability of the patient. The article presents a clinical case of mixed connective tissue disease in a middle-aged patient. An analysis of literary sources, clinical data, and laboratory results was carried out.

Cardiovascular risk and inflammation in a population with autoimmune diseases: a narrative review.

Juvenile Systemic Connective Tissue Diseases (JSCTD) are a heterogeneous group of chronic autoimmune diseases, associated with dyslipidemia and increased cardiovascular risk are related. Studies from the last 10 years, from 2013 to 2022, on lipid profiles in JSCTD were collected. Different studies on lipid profiles in children affected by JSCTD were selected, because the aim is to analyze the cardiovascular risk and the possibility of atherosclerosis in these patients in whom, sometimes, corticosteroid therapies and immunosuppressants increase the state of dyslipidemia. Several studies have shown that autoimmune diseases with an inflammatory substrate also share abnormalities in lipid profile and increased cardiovascular risk. Specifically, associations have been found between Juvenile Systemic Connective Tissue Diseases and elevated triglycerides, TC-C (Total Cholesterol), LDL-C (Low-Density Lipoprotein), low HDL-C (High-Density Lipoprotein), and increased risk of developing diseases such as myocardial infarction, peripheral vascular disease, pulmonary and arterial hypertension, and atrial fibrillation. Supplementation with alpha-linolenic acid (ALA) on the other hand has also been analyzed with positive results in reducing inflammatory parameters, such as IL-6 (Interleukin-6), CRP (C-reactive protein), and fasting glucose, in subjects with dyslipidemia. These observations suggest that supplementation with ALA, an omega-3 precursor, may positively modulate both the inflammatory status and dyslipidemic conditions in patients with autoimmune disorders.

BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months case-control study.

Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE. To compare the benefits of RTX above SOCT. The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later. Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia. RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT.

“Masks” of fever of unknown origin in children

The article presents an analysis of cases of hospitalized children with fever of unknown origin. Purpose: to study the nosological structure of the causes of fever of unknown genesis in hospitalized children. Material and methods: a retrospective analysis of the medical histories of children hospitalized in the pediatric department was carried out for 2022–2023. All children underwent a comprehensive laboratory and instrumental examination. Results: the largest proportion (43,9 %) were school-age children who, in addition to fever, had complaints of weakness (87,8 %) and decreased appetite (85,4 %). Anemia (51,2 %), acceleration of ESR (47,6 %) and an increase in C-reactive protein (45,1 %) were most often recorded in the analyses. The causes of fever of unknown origin in 65,9 % of children were infectious diseases, in 19,5 % — autonomic dysfunction syndrome with a violation of thermoregulation, in 6,1 % — systemic connective tissue diseases, in 4,9 % — oncological pathology, in 2,4 % — inflammatory diseases of the gastrointestinal tract. The results of the study can be applied in pediatric practice, monitoring of children with infectious pathology.