Systemic Connective Tissue Disorder Research Articles

Mixed connective tissue disease

Mixed connective tissue disease (MCTD), also known as Sharp's syndrome, is a rare systemic connective tissue disorder that characterized by a combination of some features of systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis with the presence of antibodies to soluble nuclear ribonucleoprotein (anti-U1-RNP) in high titers. The most common clinical manifestations of MCTD include Raynaud's phenomenon, hand edema, muscle weakness, arthralgia/arthritis, and esophageal hypotonia. The course of the disease is mostly benign; however, there are severe cases with damage to the lung, kidneys, cardiovascular system and central nervous system. Poor prognosis and the highest mortality rate are associated with pulmonary hypertension. The diagnosis of MCTD is difficult due to the absence of unified diagnostic criteria and lack of specific manifestations at the onset of the disease. Furthermore, there are no generally accepted guidelines for MCTD treatment. The paper considers the modern concepts of MCTD, its current diagnostic criteria, clinical and immunological features, and treatment.

A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability.

Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations. It is associated with a significant risk of intellectual disability, a feature which distinguishes it from Marfan and Loeys-Dietz syndromes. SGS is mainly caused by mutations in the SKI gene, a repressor of TGF-β activity. Most SKI mutations are found in exon 1 of the gene and are located in the R-SMAD domain, a proposed hotspot for de novo mutations. Here, we report on a de novo SKI mutation located in the DHD domain of SKI. By adding our finding to previously reported de novo SKI mutations, a new mutational hotspot in the DHD domain is proposed. Our patient presented with a lipomeningomyelocele, tethered cord, and spina bifida but with no SGS-related clinical findings apart from a marfanoid habitus and long slender fingers. Specifically, she did not have an intellectual disability, craniofacial, or cardiovascular abnormalities. By comparing the clinical findings on patients with mutations in the R-SMAD and DHD domains of SKI, we propose that mutations in those domains have different effects on TGF-β activity during embryonic development with resulting phenotypic differences.

Progressive multifocal leukoencephalopathy in Finland: a cross-sectional registry study

ObjectiveTo investigate if progressive multifocal leucoencephalopathy (PML) incidence has increased in Finland like in the neighbouring Sweden.MethodsNational administrative registries were searched for all PML admissions aged 16 years or more in 2004–2014 on all neurological and internal medicine wards in Finland. The mortality data of the patients was extracted from the national causes of death registry. National level data on annual predisposing drug use was obtained from the national pharmaceutical authority.ResultsWe identified 35 PML cases (57% male) with a peak in 2010–2011 that amounted to 49% of all cases. The annual incidence for the entire study period was 0.072/100,000 person-years (95% CI 0.050–0.10) with no temporal trend (p = 0.18). Mean age was 57 years (22–88 years) with no sex difference (p = 0.42). Neoplasms (60%), HIV infection (17%) and systemic connective tissue disorders (CTD, 14%) were the most common predisposing conditions. MS was recorded in three cases (9%). The national level use of drugs that predispose to PML increased during the study period, with the exceptions of alemtuzumab and fludarabine. Overall survival was 85% at 90 days, 79% at 1 year, and 66% at 5 years. Survival was worst in patients with malignancy and best in patients with CTD.ConclusionsPML most often occurs in patients with malignancies and patients with HIV or CTD cover a third. PML incidence in Finland is lower than in Sweden and shows no temporal trend despite increasing use of predisposing drugs. Mortality after PML varies according to the predisposing condition.

Frequency and spectrum of outpatient musculoskeletal diagnoses at a pediatric hospital in Kenya.

Chronic pediatric musculoskeletal (MSK) conditions are a major cause of morbidity. The burden of pediatric rheumatic diseases in East Africa is largely unknown. The purposes of this study were to estimate frequencies and assess the spectrum of MSK-related diagnoses using ICD-10 diagnostic codes among outpatients at a pediatric hospital in Kenya and to evaluate the accuracy of the assigned codes used for the 'arthropathies' category. All pediatric outpatient diagnoses classified under the ICD-10 codes for 'diseases of the MSK system and connective tissue' (M00-M99) recorded between January and December 2011 were extracted from the electronic medical record system at Gertrude's Children's Hospital (GCH). For each of the ten MSK disease categories, frequencies were calculated. The assigned ICD10 code for cases in the 'arthropathies' (M00-M25) category was assessed by two rheumatologists. MSK diagnoses (n = 1078) accounted for 0.5% of all GCH outpatient consults available for analysis. 'Soft tissue disorders' were the most frequent MSK diagnoses (n = 614, 57%), followed by 'arthropathies' (n = 332, 30.8%), 'dorsopathies' (n = 81, 7.5%), 'osteopathies and chondropathies' (n = 39, 3.6%), and 'other' disorders (n = 12, 1.1%). No patients were classified in the category of 'systemic connective tissue disorders'. In cases classified as 'arthropathies', there was poor agreement (Kappa 0.136) between the ICD10 code assigned by the treating physicians and that assigned by the rheumatologists. However, when the rheumatologists' classification was loosened, agreement was moderate (Kappa 0.533). This study provides estimates of the frequency of outpatient MSK diagnoses at a pediatric hospital in Kenya in 2011. MSK diagnoses were not rare. Despite limitations of administrative databases to estimate frequencies of specific diagnoses, they provide a snapshot of the overall burden and spectrum of MSK conditions.

Connective Tissue Disorders in Childhood: Are They All the Same?

Systemic connective tissue disorders are characterized by the presence of autoantibodies and multiorgan system involvement. Juvenile systemic lupus erythematosus with or without associated antiphospholipid syndrome; juvenile dermatomyositis; sclerodermiform syndromes, including systemic and localized sclerodermas and eosinophilic fasciitis; mixed connective tissue disease; and Sjögren syndrome are the disorders that affect children most frequently. Diagnosis is difficult, because the clinical presentation of patients is diverse, from mild to severe disease. In addition, all organs may be affected. However, a variety of imaging techniques are now available to investigate rheumatic disease in children. These imaging modalities offer the potential for earlier diagnosis and improved assessment of therapeutic response. This article reviews the main connective tissue disorders that affect children, highlighting their key imaging features on images acquired with different diagnostic imaging modalities and correlating these features with clinical and pathologic findings, when available. ©RSNA, 2019.

Prevalence of rheumatic diseases in Russia

Aim : To estimate the prevalence of the rheumatic diseases in an epidemiological study. Materials and methods: During a questionnaire survey among 76 162 adult individuals in 12 regions of the Russian Federation, those with complaints of joint pain and swelling were selected and a group (n = 4894) was formed at random for subsequent clinical assessment by rheumatologists to identify main rheumatic diseases. In all regions, the study was conducted according to the unified protocol, with the unified strategy of the population selection and the use of unified questionnaires. Diagnoses were made based on widely adopted classification criteria for rheumatic diseases. Results: For the first time in Russia it was found that among adult Russian population, the life-time prevalence of joint pain (mostly knee and hip) was 39.5%, whereas that of joint swelling amounted to 26%. From those, arthralgias eventually disappear in 8% and arthritis, in 7%. Among all rheumatic clinical entities, knee and/or hip osteoarthritis ranks the first, with its prevalence calculated to all adult population of Russia above 18 years of age being 13%. The prevalence of rheumatoid arthritis was 0.61%, of ankylosing spondylitis, 0.1%, psoriatic arthritis, 0.37%, reactive arthritis, 0.42%, gout, 0.3%, and of systemic connective tissue disorders (systemic lupus erythematosus, systemic sclerosis, dermatomyositis/polymyositis, Sjogren's syndrome, systemic vasculitis, etc), 0.11%. Conclusion: The true prevalence of the rheumatic diseases found in the epidemiological study was higher than the data of the official statistics as follows: 2.5-fold for rheumatoid arthritis, 5-fold for osteoarthritis, 3.5-fold for spondyloarthritis and 3-fold for systemic connective tissue disorders. The results obtained showed an underestimation of the rheumatic diseases and incomplete data in the country statistics. This might be related to low referral levels for medical care due to significant distances of the vast regional areas from the specialized centers, as well as with insufficient qualification of primary care physicians in the field of rheumatology. All together, this leads to inevitable and serious misdiagnoses and low registration of the rheumatic diseases.

Investigating the effects of methyl‐β‐cyclodextrin on aortic function & structure in a mouse model of Marfan syndrome using high frequency ultrasound imaging

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin‐1 gene leading to various complications in multiple organs. However, aortic aneurysm is considered as the most life‐threatening complications that may lead to aortic dissection, rupture, and sudden death. Previous studies have shown that transforming growth factor β (TGF‐β) and angiotensin II type 1 receptor (ATII/AT1R) signaling play important roles during the progression of MFS aneurysm. Interestingly, both pathways are shown to be regulated by caveolin‐1 (Cav‐1), a structural protein within caveolae, which is highly expressed in vascular smooth muscle and endothelial cells. Studies in Cav‐1 knock‐out mice have reported that Cav‐1 is required for normal ATII/AT1R signalling, while having inhibitory effects on TGF‐β pathway and endothelial nitric oxide (eNOS) activity. Considering the complexity of caveolae and CAV‐1 regulatory functions, we propose to investigate the effects of caveolae (CAV‐1) disruption by the cholesterol depleting agent methyl‐β‐cyclodextrin (MβCD) on the progression of aortic aneurysm in a mouse model of MFS. Four‐week old MFS (Fbn1C1039G/+) and control C57BL/6 mice received intra‐peritoneal injection of MβCD (500 mg/kg) twice a week, and cardiac and aortic structure and function were measured at 3 and 6 months of age using Vevo 2100 high resolution ultra sound imaging system (FUJIFILM VisualSonics). Measurements for aortic annulus, sinus of Valsalva, sinotubular junction diameters, and pulse wave velocity showed an increase in MFS mice at 3 and 6 months of age as compared to control; all these effects were exacerbated in MFS mice treated with MβCD, indicating that disruption of caveolae structure in MFS mice has negative impact on aortic wall structure and function. Furthermore, the dimensions of the left ventricle were also evaluated by the measurements of interventricular septum in systole and diastole. Cardiac function was evaluated measuring the cardiac output, stroke volume, ejection fraction, which showed no difference in MFS and control mice in the presence or absence of MβCD treatment. Early and atrial ventricular filling velocities were decreased in MFS mice at the age of 3 and 6 months as compared to controls. However, MβCD treatment resulted in an increase in both early and atrial velocities in MFS mice. Using the tail‐cuff method we also measured the blood pressure of these animals. The measurements showed higher systolic and diastolic values in control and MFS groups treated with MβCD, confirming that caveolae has an inhibitory effect on eNOS activity in mice. This study provides insights into the role that caveolae may play during the progression of aortic aneurysm in MFS mice, and warrant further investigation into the potential value of CAV‐1 as a therapeutic target in MFS associated aortic aneurysm.Support or Funding InformationThis study is supported by funding from The Marfan Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fibrillin-1 insufficiency alters periodontal wound healing failure in a mouse model of Marfan syndrome

ObjectiveMarfan syndrome (MFS) is a systemic connective tissue disorder caused by insufficient fibrillin-1 (FBN-1), a major component of microfibrils that controls the elasticity and integrity of connective tissues. FBN-1 insufficiency in MFS leads to structural weakness, which causes various tissue disorders, including cardiovascular and periodontal disease. However, the role of FBN-1 insufficiency in the destruction and regeneration of connective tissue has not yet been clarified. To investigate the role of FBN-1 insufficiency in tissue destruction and regeneration. DesignWe used a ligature-induced (LI) periodontal disease model in fbn-1-deficient mice (fbn-1c1039G/+ mice) with MFS and investigated the regeneration level of periodontal tissue and as an inflamatic marker, the expression of the matrix metalloproteinase (mmp)-9 and tumor necrosis factor (tnf)-α. ResultsInterestingly, fbn-1c1039G/+ mice exhibited slowed wound healing compared with wild type mice, but periodontal tissue destruction did not differ between these mice. Moreover, fbn-1c1039G/+ mice exhibited delayed bone healing in association with continuous mmp-9 and tnf-α expression. Furthermore, inflammatory cells were obvious even after the removal of ligatures. ConclusionThese data suggest that fibrillin-1 insufficiency in fbn-1c1039G/+ mice interfered with wound healing in connective tissue damaged by inflammatory diseases such as periodontal disease.

Simultaneous Distinction of Monospecific and Mixed DFS70 Patterns During ANA Screening with a Novel HEp-2 ELITE/DFS70 Knockout Substrate

Systemic autoimmune connective tissue disorders are characterized by circulating antinuclear antibodies (ANA). Although there are several technologies available for ANA screening, indirect immunofluorescence (IIF) using Human epithelial cells-2 (HEp-2) substrate remains the primary and recommended method because of its superior sensitivity. HEp-2 substrates can detect a multitude of patterns resulting from autoantibody binding to various protein and nucleic acid autoantigens distributed throughout the nucleus and cytoplasm of the cells. The great diversity of monospecific and mixed patterns resulting from positive reactions on HEp-2 substrate also complicate the interpretation and accuracy of reporting. One specific example which received utmost attention recently is the dense fine speckled 70 (DFS70) pattern resulting from autoantibodies that specifically bind to a protein called lens epithelium derived growth factor (LEDGF). Lack of clear association with a specific systemic autoimmune disease and high prevalence in healthy populations have made accurate interpretation of DFS70 pattern important. Accurate distinction of DFS70 pattern from disease-associated patterns using conventional HEp-2 substrate is challenging. Moreover, frequent co-occurrence of DFS70 pattern along with disease-associated patterns such as homogeneous, speckled, and mixed homogeneous-speckled patterns complicate the IIF interpretation. The goal of this paper is to demonstrate the utility of a novel engineered HEp-2 IIF substrate that retains all advantages of conventional HEp-2 substrate while simultaneously providing the ability to distinguish DFS70 pattern with high confidence in both monospecific and mixed ANA positive examples. The new substrate is further able to unmask disease-associated ANA patterns previously concealed by DFS70 pattern.

Simultaneous Distinction of Monospecific and Mixed DFS70 Patterns During ANA Screening with a Novel HEp-2 ELITE/DFS70 Knockout Substrate.

Systemic autoimmune connective tissue disorders are characterized by circulating antinuclear antibodies (ANA). Although there are several technologies available for ANA screening, indirect immunofluorescence (IIF) using Human epithelial cells-2 (HEp-2) substrate remains the primary and recommended method because of its superior sensitivity. HEp-2 substrates can detect a multitude of patterns resulting from autoantibody binding to various protein and nucleic acid autoantigens distributed throughout the nucleus and cytoplasm of the cells. The great diversity of monospecific and mixed patterns resulting from positive reactions on HEp-2 substrate also complicate the interpretation and accuracy of reporting. One specific example which received utmost attention recently is the dense fine speckled 70 (DFS70) pattern resulting from autoantibodies that specifically bind to a protein called lens epithelium derived growth factor (LEDGF). Lack of clear association with a specific systemic autoimmune disease and high prevalence in healthy populations have made accurate interpretation of DFS70 pattern important. Accurate distinction of DFS70 pattern from disease-associated patterns using conventional HEp-2 substrate is challenging. Moreover, frequent co-occurrence of DFS70 pattern along with disease-associated patterns such as homogeneous, speckled, and mixed homogeneous-speckled patterns complicate the IIF interpretation. The goal of this paper is to demonstrate the utility of a novel engineered HEp-2 IIF substrate that retains all advantages of conventional HEp-2 substrate while simultaneously providing the ability to distinguish DFS70 pattern with high confidence in both monospecific and mixed ANA positive examples. The new substrate is further able to unmask disease-associated ANA patterns previously concealed by DFS70 pattern.

Cutaneous manifestations of juvenile onset lupus erythematosus: A clinical study

Introduction: Juvenile-onset systemic lupus erythematosus (SLE) is one of the most common systemic autoimmune connective tissue disorders in children. Studies focusing on the mucocutaneous manifestations of childhood lupus are scanty in literature. Objectives: This study was an attempt to describe the cutaneous changes seen in Pediatric Lupus and to correlate with the histopathological and immunofluoresecence findings. Methods: This was a retrospective study. All children under the age of 18 years who were diagnosed to have SLE according to the ACR criteria and presented to the dermatology outpatient department during a period of 1 year were included in the study. Details including clinical features, investigation findings including immunological tests and skin biopsy findings were noted. The analysis was performed using descriptive statistical tools such as percentage and frequency. Results: A total of 14 cases, average age at presentation was 10.14 years. Among the cutaneous manifestations, the most common presenting feature was urticarial vasculitis. Malar rash was seen in 57% of cases. Other cutaneous features seen were diffuse alopecia, oral ulcers. Antinuclear antibody was positive in all cases. Conclusion: Pediatric lupus tends to have a more aggressive course than adult lupus. Early diagnosis and treatment is necessary to prevent progression and development of complications.

A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations.

Deletions encompassing TAK1-binding protein 2 (TAB2) associated with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole-exome sequencing (WES) disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C-terminal zinc finger domain essential for activation of TAK1 (TGFβ-activated kinase 1)-dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers-Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development.

Health-Related Quality of Life in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a systemic connective tissue disorder most often caused by mutations in collagen type 1 related genes. Patients with OI suffer from multiple fractures and various degrees of growth deficiency and bone deformity. It is unknown whether the systemic effect of defect collagen type 1 influences the quality of life in patients with OI. We therefore aimed to investigate health-related quality of life (HRQoL) in a well-characterized cohort of adult patients with OI. We included 85 adult patients with mild to severe OI (types I, III, and IV) and obtained information about skeletal- and non-skeletal phenotypes and patient demographics. We investigated physical and mental HRQoL using a validated questionnaire, SF-36, and compared the data to values obtained in a population without OI. Patients with mild, moderate, and severe OI all had lower mean scores on domains describing physical HRQoL and a lower mean physical component score compared to the general population, p<0.001. Patients with severe OI had lower mean scores on physical HRQoL, p<0.05. The scores on domains reflecting mental HRQoL were more inhomogenously affected, but did not differ significantly from the general population. OI has an impact on physical and some aspects of mental HRQoL. The scores on physical health were correlated to severity of the OI disease. The mental component score in the OI patients was unaffected and comparable with the general population.

Evaluation of clinical significance of с.2956G&gt;A (rs112287730) polymorphism in FBN1 gene in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant inherited systemic disorder of connective tissue with many clinical manifestations in the cardiovascular, skeletal, and ocular systems. MFS is caused by mutations in the fibrillin-1 (FBN1) gene. To date, about 2000 FBN1 pathogenic variants that cause MFS or related phenotypes have been described. The c.2956G>A, p.Ala986Thr substitution (exon 25) in the FBN1 gene is described in the SNP database as rs112287730 with allele frequency of 0.02%. Although numerous published data exist, the clinical significance of this variant is unknown. Some studies identify this substitution as probably a pathogenic mutation, and others, as a polymorphism. Among Russian Marfan patients, the heterozygous c.2956G>A substitution was identified in four probands; three of them had familial history. To determine the clinical significance of this substitution, a segregation analysis of DNA samples of affected and unaffected family members was conducted. In the first case, a segregation of the c.2956G>A substitution with the disease was observed in the family: this substitution was detected in the heterozygous state in the three affected members, but not in the one unaffected member. However, the opposite observation occurred in the second familial case: three affected members did not have the c.2956G>A substitution, whereas it was found in one unaffected member. In addition, the molecular-genetic analysis of 110 ethnically unrelated unexplored individuals was performed. The c.2956G>A substitution was identified in two of 220 examined chromosomes (allele frequency 0.9%). Thus, it was established that the c.2956G>A substitution appears to be a polymorphism (nonpathogenic variant) and cannot cause MFS.

Moderately Elevated Homocysteine Does Not Contribute to Thoracic Aortic Aneurysm in Mice

Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA.Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA.Methods: Murine fibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk.Results: Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet.Conclusions:Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.

RXRB Is an MHC-Encoded Susceptibility Gene Associated with Anti-Topoisomerase I Antibody-Positive Systemic Sclerosis

Systemic sclerosis is a systemic autoimmune and connective tissue disorder associated with the human leukocyte antigen locus. However, the functional relationship between human leukocyte antigen gene(s) and disease development remains unknown. To elucidate major histocompatibility complex-linked systemic sclerosis genetics, we performed genotyping of major histocompatibility complex-borne microsatellites and HLA-DPB1 alleles using DNA obtained from 318 anti-topoisomerase I antibody-positive patients and 561 healthy controls, all of Japanese descent. Those results revealed two major histocompatibility complex haplotypes associated with systemic sclerosis. Exome sequencing and targeted analysis of these risk haplotypes identified rs17847931 in RXRB as a susceptibility variant (P= 1.3× 10-15; odds ratio [OR]= 9.4) with amino acid substitution p.V95A on the risk haplotype harboring HLA-DPB1∗13:01. No identical variant in the other haplotype including DPB1*09:01 was observed, though that haplotype also showed a significant association (P= 8.5× 10-22; OR= 4.3) with systemic sclerosis. Furthermore, the number of risk factors was shown to be a predominant factor, as individuals with two factors had elevated risk (P= 6.7× 10-13; OR= 30.2). We concluded that RXRB may be involved in antifibrotic activity in skin and chromatin remodeling.

Vasculitic Ulcers in a Young Female with Dermatomyositis: An Unusual Case

Background: Vasculitic ulcers are one of the rarer cutaneous manifestations of dermatomyositis. They are considered to be a predictor of underlying malignancy. Case Report: We describe a case of extensive cutaneous vasculitic ulcers in a young female patient of dermatomyositis without a background of systemic connective tissue disorder or malignancy. Therapy with steroids and methotrexate resulted in swift remission in the patient. Conclusion: Cutaneous leukocytoclastic vasculitis in a patient of dermatomyositis shows good response to steroids complemented by steroid sparing agents.

Autoprotilátky u systémových onemocnění pojiva a ANCA asociovaných vaskulitid, jejich vztah k intersticiálním plicním procesům a prognóze

Lung disease, including interstitial lung disease (ILD), is a frequent complication of systemic connective tissue disorders (CTD) and ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis (AAV). Pulmonary manifestations are prognostic factor of CTDs and vasculitis. Autoantibodies assessment is a part of differential diagnosis algorithm of lung diseases. Autoantibodies importance is mainly clinical-diagnostic. Using detection of some autoantibodies it is possible to determine prognosis of lung involvement, especially in CTDs.Key words: autoantibodies - connective tissue disease - interstitial lung diseases - prognosis - vasculitis.

Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type

Joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients.

Pathophysiology and therapeutic options in osteogenesis imperfecta: an update

Pathophysiology and therapeutic options in osteogenesis imperfecta: an update Evelise Brizola,1 Temis M Félix,2 Jay R Shapiro3 1Bone and Osteogenesis Imperfecta Department, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 3Osteoporosis and Metabolic Bone Disorders Center, Bethesda, MD, USAAbstract: Osteogenesis imperfecta (OI) is a rare, heritable systemic disorder of bone and connective tissue, which in almost 90% of cases is due to mutations affecting the normal synthesis of type I collagen. In 1979, four OI phenotypes were categorized which where inherited as autosomal dominant characteristics. Individuals with OI present both genetic and phenotypic variabilities. Major characteristics of OI are bone fragility, blue sclerae, dentinogenesis imperfecta, short stature, scoliosis, and joint hyperextensibility. Both autosomal dominant and recessive inheritance are now recognized. Advances in molecular diagnosis have led to a major expansion in our understanding of the genetic basis for different OI phenotypes. To date, sequence variants in 17 genes are described as causative of OI. These genes regulate the synthesis of type I collagen pro-alpha polypeptide chains, proteins involved in type I collagen processing in the endoplasmic reticulum and proteins involved in osteoblast function. These new genetic associations have also led to uncertainty with regard to the current classification of OI phenotypes. Bisphosphonates have been widely used to improve bone mass and decrease fractures in both children and adults with OI. While effective in many but not all children when administered for 2–4 years, bisphosphonates have not proven effective in adults with OI. Studies are limited for treatment of adults with teriparatide and denosumab. Advances have been reported in the surgical management of OI. Although the role of physical therapy in the management of children and adults was previously described, this important treatment modality is significantly underutilized. Keywords: osteogenesis imperfecta, sequence variants, collagen, bisphosphonates, bone, treatment