Manifestation Of Systemic Disease Research Articles

Skin manifestations associated with systemic diseases – Part II

The skin, by reflecting internal processes, externalizes what happens inside the body in many diseases. Thus, the skin, as an organ, extrapolates its functions of protection, barrier and signals the existence of systemic diseases, expanding the importance of the dermatologist beyond the skin surface. Thus, the dermatologist investigates diagnostic hypotheses for conditions related to all systems and refers patients to the appropriate specialty. Combined with examination by a trained eye, the skin, due to its easy access, is still the ideal place for performing biopsies, which often clarify the diagnosis. This manuscript is the second part of the article on cutaneous manifestations of systemic diseases. In the first part, the cutaneous manifestations of the main rheumatologic and granulomatous diseases were described, and vascular manifestations were also addressed. In the present article, it will be discussed how metabolic, cardiovascular, kidney, and gastrointestinal diseases can manifest themselves in the integumentary system. Malignant diseases and their cutaneous implications, will also be discussed. Pruritus and its clinical cutaneous correspondence will be discussed. Finally, an update on cutaneous signs of SARS-CoV2 coronavirus infection will be presented.

Serum interferon-α2 measured by single-molecule array associates with systemic disease manifestations in Sjögren's syndrome.

ObjectivesType I IFN (IFN-I) activation is a prominent feature of primary SS (pSS), SLE and SSc. Ultrasensitive single-molecule array (Simoa) technology has facilitated the measurement of subfemtomolar concentrations of IFNs. Here we aimed to measure IFN-α2 in serum from pSS, SLE and SSc using a Simoa immunoassay and correlate these levels to blood IFN-stimulated gene (ISG) expression and disease activity.MethodsSerum IFN-α2 was measured in patients with pSS (n = 85 and n = 110), SLE (n = 24) and SSc (n = 23) and healthy controls (HCs; n = 68) using an IFN-α Simoa assay on an HD-X analyser. IFN-I pathway activation was additionally determined from serum by an IFN-I reporter assay and paired samples of whole blood ISG expression of IFI44, IFI44L, IFIT1, IFIT3 and MxA by RT-PCR or myxovirus resistance protein 1 (MxA) protein ELISA.ResultsSerum IFN-α2 levels were elevated in pSS (median 61.3 fg/ml) compared with HCs (median ≤5 fg/ml, P < 0.001) and SSc (median 11.6 fg/ml, P = 0.043), lower compared with SLE (median 313.5 fg/ml, P = 0.068) and positively correlated with blood ISG expression (r = 0.66–0.94, P < 0.001). Comparable to MxA ELISA [area under the curve (AUC) 0.93], IFN-α2 measurement using Simoa identified pSS with high ISG expression (AUC 0.90) with 80–93% specificity and 71–84% sensitivity. Blinded validation in an independent pSS cohort yielded a comparable accuracy. Multiple regression indicated independent associations of autoantibodies, IgG, HCQ treatment, cutaneous disease and a history of extraglandular manifestations with serum IFN-α2 concentrations in pSS.ConclusionSimoa serum IFN-α2 reflects blood ISG expression in pSS, SLE and SSc. In light of IFN-targeting treatments, Simoa could potentially be applied for patient stratification or retrospective analysis of historical cohorts.

Limited cutaneous sarcoidosis as an initial manifestation of systemic disease

Limited cutaneous sarcoidosis as an initial manifestation of systemic disease

Lupus pernio: Skin manifestation of systemic disease

62-year-old woman presented to our institution with the chief complaint of slowly progressive exertional dyspnea over the preceding two years in conjunction with a cough and facial rash. Physical examination was remarkable for erythematous to violaceous nodules and plaques around eyes, over eyelids and over the nose (Fig. 1A). Complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate and C-reactive protein were unremarkable. Computerized tomography(CT) of chest Innumerable groundglass nodules again identified in bilateral lungs as well as scattered areas of tree-in-bud pattern (Fig. 1B).

Severe organ manifestations in rheumatic diseases

Several inflammatory rheumatic diseases can severely affect any organ system and require immediate intervention and intensive care admission. The early detection of impending organ failure and the underlying rheumatic disease is of paramount importance for the prognosis and outcome of affected patients. Therefore, a thorough knowledge of the potential life threatening organ manifestations of systemic rheumatic diseases is of particular interest for clinicians working in intensive care. This paper provides an overview of diagnostic steps and therapy of organ manifestations in critically ill patients with underlying systemic rheumatic diseases. The presentation of the relevant systemic rheumatic diseases is structured according to the most important organ systems, i. e. the respiratory system, the kidney and the cardiovascular system. Furthermore, there is a focus in this paper on macrophage activation syndrome (MAS) as a potentially lethal complication of several rheumatic diseases and the catastrophic antiphospholipid syndrome (CAPS) as a rare cause of multi organ failure.

Case Report: Rare Presentation of Dentin Abnormalities in Loeys-Dietz Syndrome Type I

Loeys-Dietz syndrome type 1 (LDS1) is caused by a mutation in the transforming growth factor-beta receptor 1 (TGFBR1) gene. We previously characterized the oral and dental anomalies in a cohort of individuals diagnosed with LDS and showed that LDS1 had a high frequency of oral manifestations, and most affected individuals had enamel defects. However, dentin anomalies were not apparent in most patients in the cohort. In this cohort, we had identified dentin anomalies in a patient with LDS1, harboring mutationTGFBR1c.1459C&amp;gt;T (p.Arg487Trp), and in this report, we present clinical and radiographic findings to confirm the dentin anomaly. The proband had gray-brown discoloration of most teeth typical for dentinogenesis imperfecta (DI). A radiographic exam revealed obliterated or very narrow pulp canals, with maxillary anterior teeth being affected more than the posterior teeth. The son of the proband, who also has the same mutation variant, had a history of DI affecting the primary teeth; however, his permanent teeth were normal in appearance at the time of exam.TGFBR1is expressed by odontoblasts throughout tooth development and deletion ofTGFBR1in mouse models is known to affect dentin development. In this report, we present a rare case of abnormal dentin in two individuals with LDS1. These dental anomalies may be the first obvious manifestation of a life-threatening systemic disease and demonstrate the variable and multi-organ phenotypic effects in rare diseases.

Ligneous conjunctivitis associated with type I plasminogen deficiency: A rare case

Ligneous conjunctivitis is a rare form of chronic, recurrent conjunctivitis characterized by wood-like, fibrinous pseudomembranes, which may be associated with systemic disease manifestations. It has been associated with congenital plasminogen (PLG) deficiency that is inherited with an autosomal recessive pattern due to mutations in the PLG gene and a variety of other genes, leading to disturbed wound healing. In this case report, we present the clinical, laboratory, and histopathological findings of a 36-year-old female patient who presented at the ophthalmology department with complaints of redness, irritation for the previous few weeks, and appearance of membranous lesions mainly on the tarsal conjunctivae. During biomicroscopic examination we found thick, yellowish-white pseudomembranes, and conjunctival proliferation with ligneous induration on the conjunctiva, located on the upper eyelids. Histopathological evaluations showed up ligneous conjunctivitis and laboratory evaluation confirmed a severe plasminogen deficiency (PLG < 2%). The patient was treated with topical fresh frozen plasma (FFP), topical steroids, heparin eye drops, and artificial tear drops daily, without systemic therapy.

Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease.

Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.

From advanced disease to transplantation: an overview of the liver at the time of COVID-19 pandemic.

In 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also known as coronavirus disease 2019 (COVID-19) disrupted global health, causing hundreds of thousands of deaths worldwide. The liver injury appears to be one of the possible systemic manifestations of COVID-19 disease although the mechanisms causing such injury are not entirely clear. At the beginning of the pandemic, patients with chronic diseases, such as liver cirrhosis, or special populations, such as liver transplant recipients, were considered at higher risk of complications and poor clinical outcomes. Thus, the national transplant programmes have been severely hampered by the COVID-19 pandemic. Furthermore, liver transplant patients are potentially more vulnerable to SARS-CoV-2 infection due to immune suppression, ageing, and metabolic or cardiovascular comorbidities. This review analyses the increasing amounts of data collected in recent months concerning liver cirrhosis and liver transplants to understand if this finding is still relevant with respect to COVID-19 manifestations.

A CURIOUS CASE OF NON HODGKIN'S LYMPHOMA OF SMALL INTESTINE PRESENTING AS PERFORATION PERITONITIS

Malignant lymphomas involve small intestine either primarily or as a manifestation of systemic disease. It is rare for Non Hodgkin's lymphoma to affect small intestine and most western type lymphomas are Non Hodgkin's B cell lymphomas. Here we are reporting a rare case of 40 year old male presented to the emergency room with acute abdomen and subsequently found to have non Hodgkin's lymphoma of small intestine presenting as perforation peritonitis. Patient has recovered well from holistic treatment approach and presently receiving chemotherapy under medical oncology.

A blood RNA transcriptome signature for COVID-19

BackgroundCOVID-19 is a respiratory viral infection with unique features including a more chronic course and systemic disease manifestations including multiple organ involvement; and there are differences in disease severity between ethnic groups. The immunological basis for disease has not been fully characterised. Analysis of whole-blood RNA expression may provide valuable information on disease pathogenesis.MethodsWe studied 45 patients with confirmed COVID-19 infection within 10 days from onset of illness and a control group of 19 asymptomatic healthy volunteers with no known exposure to COVID-19 in the previous 14 days. Relevant demographic and clinical information was collected and a blood sample was drawn from all participants for whole-blood RNA sequencing. We evaluated differentially-expressed genes in COVID-19 patients (log2 fold change ≥ 1 versus healthy controls; false-discovery rate < 0.05) and associated protein pathways and compared these to published whole-blood signatures for respiratory syncytial virus (RSV) and influenza. We developed a disease score reflecting the overall magnitude of expression of internally-validated genes and assessed the relationship between the disease score and clinical disease parameters.ResultsWe found 135 differentially-expressed genes in the patients with COVID-19 (median age 35 years; 82% male; 36% Chinese, 53% South Asian ethnicity). Of the 117 induced genes, 14 were found in datasets from RSV and 40 from influenza; 95 genes were unique to COVID-19. Protein pathways were mostly generic responses to viral infections, including apoptosis by P53-associated pathway, but also included some unique pathways such as viral carcinogenesis. There were no major qualitative differences in pathways between ethnic groups. The composite gene-expression score was correlated with the time from onset of symptoms and nasal swab qPCR CT values (both p < 0.01) but was not related to participant age, gender, ethnicity or the presence or absence of chest X-ray abnormalities (all p > 0.05).ConclusionsThe whole-blood transcriptome of COVID-19 has overall similarity with other respiratory infections but there are some unique pathways that merit further exploration to determine clinical relevance. The approach to a disease score may be of value, but needs further validation in a population with a greater range of disease severity.

"What Do You Mean It's Not Cancer?" A Review of Autoimmune and Systemic Inflammatory Diseases Involving the Breast.

Autoimmune and systemic inflammatory diseases represent a heterogeneous group of immune-mediated conditions with a wide range of clinical presentations and various affected organs. Autoimmune diseases can present in the breast as localized disease or as part of systemic involvement. Although breast involvement is uncommon, the spectrum of imaging findings can include breast masses, axillary adenopathy, calcifications, and skin changes, the appearance of which can mimic breast cancer. Common etiologies include diabetic mastopathy, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, idiopathic granulomatous mastitis, sarcoidosis, and Immunoglobulin-G4 related mastopathy. This educational review will present multimodality imaging findings of breast manifestations of systemic inflammatory and autoimmune diseases and coexisting complications. It will also review how these disorders may affect breast cancer risk and breast cancer treatment options, including radiation therapy.

Chronic limb ischemia manifestation in COVID-19 infection: awareness and treatment in primary care

Chronic limb ischemia (CLI) is a type of peripheral arterial disease (PAD) that is still underdiagnosed and undertreated despite the increasing incidence, thus becoming a global health burden. And CLI reflects the local manifestations of a lethal systemic disease — atherosclerosis. If left untreated, chronic limb ischemia can result in major limb loss. In this pandemic era, limb ischemia has become one of several clinical manifestations that occur in patients with COVID-19 infection. Systemic inflammation in COVID-19 infection, direct viral infection, hypercoagulable state, and hyperinflammatory response are responsible for damage to the arterial system, causing endothelial dysfunction. Diagnosing PAD has become a challenge especially in the early stage and in the asymptomatic phase. The untreated condition could lead to the development of CLI. The primary physicians in the primary health facilities hold an important role in the early diagnosis and management of patients with CLI symptoms or with risk factors of CLI, especially in patients who have experienced COVID-19 infection. Due to the limitation of diagnostic testing modalities at primary health facilities, the physician can assess the ankle-brachial index (ABI) to determine the presence of CLI. Management of the disease is different for every patient and is customized based on the other comorbidities. Risk factors should be controlled in order to achieve a better outcome. A good management strategy will improve the quality of life of the patient. This review will discuss the occurrence of CLI in COVID-19 infection.

TLR7 Signaling Drives the Development of Sjögren's Syndrome.

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value.

Oral Health and Its Aetiological Role in Behçet's Disease.

Behçet's disease (BD) is a chronic multi-systemic inflammatory disorder characterised by oro-genital ulcers, cutaneous manifestations, ocular, vascular, neurologic and gastrointestinal involvement. Complex interactions operating on the genetic background e.g.(HLA51), of infectious and other environmental agents, together with immune dysregulation impacts on the pathogenesis of BD. This suggests that the environmental factors triggering immune responses may activate clinical manifestations in genetically susceptible individuals. Since oral health forms the basis of all general health both dental and systemic, it is an important component of both Dentistry and Medicine. Oral ulcers are the most common clinical manifestation of oral mucosal health. Changes in the oral environment consequently acts as an infective and immune trigger. In this review, complex interactions between the oral ulcers, the oral microbiome and immune responses together with the course of oral and systemic disease manifestations in BD are discussed in the context of the aetiologic role of oral health.

Myd88 activation in immune cells governs distinct disease manifestations in primary Sjögren’s syndrome

Abstract Studies in mice and humans identify Myd88 activation as an important driver of autoimmune disease, although the role of this adapter molecule in primary Sjögren’s syndrome (pSS) is poorly understood. In pSS, patients exhibit exocrine gland dysfunction along with serious systemic disease manifestations. Although Myd88-dependent signaling networks are essential for pSS disease pathogenesis, these pathways remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of Myd88 activation in immune cells to local and systemic pSS manifestations. To this end, we generated a novel conditional knockout pSS mouse model lacking Myd88 in the hematopoietic compartment. We found that ablation of Myd88 in immune cells altered inflammatory mediators in salivary tissue, but did not affect the degree of lymphocytic infiltration in exocrine glands or salivary production. Nephritis was diminished and pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells. Finally, we found total IgM titers and autoreactive IgM and IgG were attenuated in pSS mice lacking Myd88 in immune cells. Thus, we demonstrated that Myd88 activation in the hematopoietic compartment is essential for distinct aspects of disease. This study establishes a rationale for design of targeted therapeutics that modulate Myd88 activation in a tissue-specific manner to ameliorate salivary inflammation and systemic disease manifestations characteristic of pSS.

Undiagnosed liver diseases.

The landscape of chronic liver disease has drastically changed over the past 20 years, largely due to advances in antiviral therapy and the rise of metabolic syndrome and associated non-alcoholic fatty liver disease (NAFLD). Despite advances in the diagnosis and treatment of a variety of liver diseases, the burden of chronic liver disease is increasing worldwide. The first step to addressing any disease is accurate diagnosis. Here, we discuss liver diseases that remain undiagnosed, either because they are difficult to diagnose or due to hepatic manifestations of an unrecognized systemic disease. Additionally, their underlying etiology may remain unknown or they represent previously uncharacterized and therefore novel liver diseases. Our goal is to provide a framework for approaching undiagnosed liver diseases which elude standard hepatic diagnostic work-up and whose patterns of disease are often overlooked.

Metabolic Syndrome in Patients with Chronic Obstructive Pulmonary Disease in Medicine Department of a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

The best recognized systemic manifestations of chronic obstructive pulmonary disease include, cardiovascular co-morbidities, cachexia and muscle dysfunction, osteoporosis, anemia, and clinical depression and anxiety. This study was undertaken to find the prevalence of the metabolic syndrome in chronic obstructive pulmonary disease patients who were admitted in the medicine department of a tertiary care hospital. A descriptive cross-sectional study was carried out in the medicine department of Nepal Medical College and teaching hospital between October 2009 and January 2010. Ethical approval was taken from the Intitutional Review Committee. Convenience sampling technique was used. All chronic obstructive pulmonary disease patients were included. Descriptive statistics were used to evaluate baseline characteristics. Point estimate at 90% Confidence Interval was calculated along with frequency and proportion for binary data. Out of 84 patients, the period prevalence of metabolic syndrome is 30 (35.71%) (29.80-40.20 at 90% Confidence Interval) as per the definition by International Diabetes Federation 2006 for South Asians. Among them, 35 (41.67%) were male and 49 (58.33% ) were female. Eight (9.5%) were of age between 40-49 years, 11 (13.1%) between 50-59 years, 27 (32.1%) between 60-69 years and 38 (45.2%) of 70 years and above. The study showed that the prevalence of metabolic syndrome was found to be lower than the previous study done in similar settings.

Current and emerging pharmacotherapy for Gaucher disease in pediatric populations

ABSTRACT Introduction The past decades have witnessed a remarkable improvement in the health of patients with Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, resulting from the availability of enzyme replacement and substrate reduction therapies. Especially in pediatric populations, early diagnosis and initiation of treatment is essential to achieving optimal outcomes. Areas Covered The authors review the literature pertaining to the effectiveness of currently available therapies and describe new pharmacotherapies under development, especially for young patients. Expert opinion For pediatric patients with non-neuronopathic Gaucher disease, there may be new therapeutic options on the horizon in the form of gene therapy or small molecule glucocerebrosidase chaperones. These have the potential to result in a cure for systemic disease manifestations and/or to reduce the cost and convenience of treatment. For children with neuronopathic Gaucher disease, the challenge of targeting therapy to the central nervous system is being explored through new modalities including brain-targeted gene therapy, in-utero therapy, brain-penetrant small molecule chaperones, and other methods that convey enzyme across the blood-brain barrier. Indeed, these are exciting times for both pediatric patients with Gaucher disease and those with other lysosomal storage disorders.

Niemann-Pick disease type A: a case report

BACKGROUND&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. The objective: to enhance the recognition of health care providers about the potential undiagnosed NPD because nonspecific clinical manifestation&#x0D; &#x0D; CASE PRESENTATION &#x0D; A 18-months-old boy was admitted to Dr. Kariadi Hospital with enlarged abdomen since seventh month old with failure to thrive. He also showed progressive loss of neurologic function, microcephaly with open major fontanelle, recurrent pulmonary and systemic infection. Physical examination revealed facial dysmorphic, milestone regression, under-nutrition, crackles in both lungs, hepatosplenomegaly with petechial in extremities and floppy infants. Laboratory investigations showed anemia (9.4 g/dL) and thrombocytopenia (73.000/mm3). The lactate dehydrogenase (482 U/L) and alkaline phosphatase (159, 03 IU/L) were higher than normal. Abdominal ultrasound revealed hepatomegaly with normal parenchyma and splenomegaly without nodule. Skeletal survey revealed Erlenmeyer flask deformity. Foam cell are detected in bone marrow puncture. Retcam examination showed cherry red spot at the macula. Bera revealed auditory neuropathy. The enzyme activity showed normal ?–Glucosidase (5.55 uM/hr) and chitotriosidase (105,8 nmol/ml) but low sphingomyelinases activity (0.30 uM/hr) which confirmed the diagnosis of NPD.&#x0D; DISCUSSION&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. Type A is very rare and a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age. No treatment available for type A and It’s a rare disease in Indonesia. &#x0D; CONCLUSION &#x0D; These investigations were able to diagnose this child as a NPD-Type A. Patient was closely monitored and symptomatic treatment was provided.