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Collapsing glomerulopathy (CG) is a form of podocytopathy that is challenging to manage. CG can be idiopathic or associated with other conditions including autoimmune connective tissue diseases. In the setting of autoimmune connective tissue diseases, there are no current guidelines to guide therapy. Here we report a unique and challenging case of CG with mixed connective tissue disease (MCTD) that responded to steroids followed by mycophenolate. In PubMed, we identified three previously reported cases of CG with MCTD in addition to other forms of autoimmune diseases, including Sjogren syndrome, adult-onset still's disease, and vasculitis, etc. We are providing a literature review of collapsing glomerulopathy cases in the setting of autoimmune connective tissue diseases and with MCTD. CG in the setting of autoimmune connective tissue diseases is more common in females and black patients. Response to therapy was inconsistent. Many patients progressed to dialysis despite use of various treatment modalities.

Cutaneous manifestations are common across the spectrum of autoimmune diseases. Connective tissue diseases manifesting in the skin are often difficult to classify and require integration of clinical, histopathologic, and serologic findings. This review focuses on the current understanding of the molecular and immune drivers involved in the pathogenesis of cutaneous lupus erythematosus, dermatomyositis, scleroderma/systemic sclerosis, and mixed connective tissue disease. Recent research advances have led to the emergence of new ancillary tools and useful diagnostic clues of which dermatopathologists should be aware to improve diagnostic accuracy for these diseases.

espanolIntroduccion La capilaroscopia periungueal (CP) es util en la evaluacion del fenomeno de Raynaud tanto primario como secundario, y en el seguimiento de los pacientes con esclerosis sistemica. Nuestro estudio evalua el impacto de la CP en el diagnostico, en funcion del motivo de solicitud y el perfil de autoanticuerpos en la practica clinica diaria. Material y metodos Se incluyeron todos los pacientes con al menos una CP entre junio de 2012 y diciembre de 2017. Se revisaron las historias clinicas y se determino de forma dicotomica (si/no) si la CP contribuyo al diagnostico realizado en la consulta posterior a la realizacion de la CP. Se recogieron datos demograficos, clinicos y de laboratorio, motivo de solicitud de la CP y su relacion con los patrones CP. Resultados De 530 pacientes con una primera CP, 266 se realizaron como estudio de un fenomeno de Raynaud. De estos, en 20 pacientes (3,8%) se realizo un diagnostico de enfermedad del tejido conectivo en la consulta posterior a la CP; 15 fueron diagnosticados de esclerosis sistemica, 4 de conectivopatia indiferenciada y uno de enfermedad mixta. Salvo un paciente diagnosticado de conectivopatia indiferenciada, el resto tenia anticuerpos antinucleares positivos y 11 de ellos, ademas, anticuerpos especificos (9 anticentromero, uno anti-Scl70 y otro, anti-RNPC). La positividad de anticuerpos antinucleares se asocio con una mayor probabilidad de presentar una CP de esclerodermia, y ningun paciente diagnosticado de una enfermedad reumatica tras la CP tenia un patron normal. Conclusion La CP es una tecnica util, pero con impacto limitado en el diagnostico de enfermedades del tejido conectivo. La positividad de los anticuerpos se relaciona con una mayor probabilidad de presentar patrones patologicos en la CP. EnglishIntroduction Nailfold capillaroscopy (NC) is useful in the evaluation of Raynaud's phenomenon, associated with some connective tissue diseases and in the follow-up of patients with systemic sclerosis. Our study evaluates the impact of NC in the diagnosis, according to the reason for the request and profile of autoantibodies in daily clinical practice. Material and methods All patients that undergone at least one NC between June 2012 and December 2017 were included. Clinical records were reviewed and analysed in a dichotomous way (yes/no), to see whether the NC contributed to a change of diagnosis in subsequent consultations. In addition, demographic, clinical and laboratory data were collected, and the relationship with NC patterns evaluated. Results Of the 530 patients who had undergone at least one NC, 266 had Raynaud's phenomenon as primary indication for the technique. Of those, 20 patients (3.8%) had a diagnostic change in the post-NC consultation; 15 were diagnosed with systemic sclerosis, 4 with undifferentiated connective tissue disease and one with mixed connective tissue disease. All patients had, except for one patient diagnosed with undifferentiated connective tissue disease, positive antinuclear antibodies titres, 11 of them had disease specific antibodies (9 anti-centromere, one anti-Scl70 and other anti-RNPC). The positivity of antinuclear antibodies titres was associated with a higher probability of presenting a scleroderma pattern in the NC, and all patients with a specific rheumatological diagnosis had an abnormal NC. Conclusion NC is a useful technique, but with limited impact in the diagnosis of connective tissue diseases. Autoantibody positivity is associated with a greater likelihood of presenting pathological NC patterns.

The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.

Patients with connective tissue diseases may have pulmonary involvement, including interstitial lung disease. Various patterns of interstitial lung disease have been classically described in certain connective tissue diseases. It is now recognized that there is significant overlap between patterns of interstitial lung disease observed in the various connective tissue diseases. Differentiating idiopathic from connective tissue disease-related interstitial lung disease is challenging but of clinical importance. New concepts in the diagnosis of connective tissue disease related interstitial lung disease may prove useful in making the diagnosis.

A 56-year-old woman with mixed connective tissue disease, who was on maintenance immunosuppression, developed asymptomatic left ventricular…, A 56-year-old woman with mixed connective tissue disease, who was on maintenance immunosuppression, developed asymptomatic left ventricular dysfunction, ventricular arrhythmia, and high troponin I. Heart catheterization showed normal coronaries and biopsy-proven, virus-negative lymphocytic myocarditis. A biopsy-guided immunosuppression upgrade effectively treated autoimmune myocarditis, which resulted in ventricular function recovery, resolution of arrhythmia, and of troponin release. (Level of Difficulty: Advanced.), Graphical abstract

This paper represents the research results of echocardiographic study for early prediction of mortality. The classification task is solved by analyzing the echocardiographic data from medical information system. Echocardiographic data of 90000 hearts condition extracted directly from medical information system were analyzed. The considered echocardiographic studies were conducted for patients with CHF, CHD, hypertension, heart arrhythmia, valvular heart disease, autoimmune disease, congenital heart defect, cardiomyopathy, endocrine disease, heart failure, mixed connective tissue disease, cancer, aneurism. Using machine learning methods and neural networks it is possible to make an early prediction of mortality based on instrumental echocardiographic study. It can be offered to clinicians as support for accurate, reasonable saving clinical decisions with minimization risks for patient’s health. The classification task mortality prediction is solved by machine learning methods with 97% ROC curve. The simple echocardiographic test results like FV Simpson, systolic volume, the valves condition, the condition of the ascending aorta and other echocardiographic data are used as predictors. Such a simple approach to solving critical tasks can make the method widely used in clinical practice.

Idiopathic Retroperitoneal fibrosis (RPF) is a fibro-inflammatory disease. In patients with known mixed connective tissue disease (MCTD) it has rarely been described. Our case illustrates a unique presentation of RPF in a patient with MCTD. We emphasise possible links between the two disease processes and the high level of clinical suspicion required to make a diagnosis.

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: COVID-19 is responsible for a large pandemic worldwide Multiple cases have been reported of a hyperinflammatory immune response, similar to cytokine storm syndrome (CSS) usually seen in cancer patients receiving CAR T-cell therapy This can lead to a rapid multi-organ failure in patients Anti-inflammatory medications such as tocilizumab have been used for this condition CASE PRESENTATION: A 22-year-old female with a history of mixed connective tissue disease on hydroxychloroquine (HCQ) and methotrexate presented with 3 weeks of dyspnea, sore throat, cough and fevers She had tested positive for SARS-CoV-2 and her symptoms rapidly worsened despite initial conservative management She was febrile and tachycardic upon presentation Her blood pressure remained normal and she was saturating >98% on ambient air CBC showed lymphopenia of 0 52 10*3/uL Her lactate dehydrogenase was 249 U/L, ferritin was 145 ng/ml, d-dimer was 0 49 ug/ml and CRP was 56 8 mg/L A chest x-ray (CXR) showed bilateral consolidations She continued to deteriorate, with worsening fevers, tachypnea and hypoxia necessitating intubation The following day, a CXR showed worsening bilateral infiltrates and an arterial blood gas revealed a PaO2/FiO2 (PF) ratio of 62 on 100% FiO2, consistent with severe ARDS Paralysis and proning were initiated She failed to improve and repeat lab work showed that ferritin, D-dimer, and CRP values had increased to 843 ng/ml, 3 24 ug/ml and 233 5 mg/L, respectively Her IL-6 level was elevated at 106 8 pg/ml She was given one dose of tocilizumab (8 mg/kg) It resulted in rapid improvement in her clinical status over the next two days Repeat inflammatory markers were decreasing Her PF ratio improved to 254 on an FiO2 of 100% and rapidly weaned on the following day She was later extubated and discharged home with close follow-up DISCUSSION: COVID-19 has been shown to exhibit a wide range of presentations In most cases, the physiologic immune response is appropriately regulated and self-limited In certain patients, an uncontrolled immune activation, also known as CSS has been reported This is associated with pro-inflammatory cytokines such as IL-1 and IL-6 A similar phenomenon was observed in SARS-CoV-1 and MERS-CoV infection Tocilizumab is a monoclonal antibody which targets IL-6 receptors and has shown to have favorable results in COVID-19 patients by suppressing the severe immune response Our patient had rapid improvement, both clinically and in her inflammatory markers after being given the medication CONCLUSIONS: Patients can develop cytokine storm syndrome when suffering from COVID-19 Tocilizumab therapy has been shown to have favorable outcomes as it targets IL-6, a pro-inflammatory marker This case highlights a young patient with a severe presentation that responded remarkably well to tocilizumab Her chronic use of HCQ did not appear to limit the severity of the disease Reference #1: Mehta P, et al COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020;395(10229):1033–1034 Reference #2: D McGonagle, K Sharif, A O’Regan, C Bridgewood The role of cytokines including Interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease Autoimmun Rev, 102537 (2020) Reference #3: Qin C, et al Dysregulation of immune response in patients with COVID-19 in Wuhan, China [published online March 12, 2020] Clin Infect Dis https://doi org/10 1093/cid/ciaa248 DISCLOSURES: No relevant relationships by Japjot Chahal, source=Web Response No relevant relationships by Gaston Habib, source=Web Response No relevant relationships by Dragos Manta, source=Web Response No relevant relationships by Pardeep Masuta, source=Web Response No relevant relationships by Kartik Ramakrishna, source=Web Response

The case is presented of a 52-year-old woman with scleroderma, mixed connective tissue disease, and interstitial lung disease, who developed chronic cytomegalovirus necrotising retinitis while on treatment with prednisone, mycophenolate, and hydroxychloroquine. Initially diagnosed as macular hole, the patient underwent a pars plana vitrectomy. Two months after surgery, due to progressive worsening, the diagnosis was made and treatment started (intravenous and intravitreal ganciclovir). The patient developed severe macular atrophy with final visual acuity of counting fingers. A chronic retinal necrosis can be caused by cytomegalovirus infection in non-HIV patients with partial immune dysfunction from other causes, characterised by a slowly progressive granular retinitis with occlusive vasculitis.

Juvenile systemic lupus erythematosus (jSLE), mixed connective tissue disease (jMCTD), and Sjögren syndrome (jSS) are systemic autoimmune and inflammatory disorders with distinct patterns of organ involvement. All are characterized by autoantibody formation, with antinuclear (ANA) and anti-double-stranded DNA common in jSLE, ANA with high-titer ribonucleoprotein antibody in jMCTD, and Sjögren syndrome A and Sjögren syndrome B antibodies + ANA in jSS. Recognition, monitoring, and management for primary care providers are discussed, focusing on the role of primary physicians in recognizing and helping maintain optimal health in children with these potentially life-threatening diseases.

Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.

The cutaneous manifestations of the common rheumatologic disorders, such as systemic lupus erythematosus, dermatomyositis, and systemic sclerosis, are well known. In contrast, the dermatologic findings of less common rheumatologic disorders, including Sjögren syndrome, mixed connective tissue disease, and relapsing polychondritis, are less widely known. The cutaneous manifestations of these connective tissue disorders are reviewed.

We report a 33-year-old Japanese man diagnosed with mixed connective tissue disease (MCTD) who developed nephrotic proteinuria. Both speckled antinuclear antibody (ANA) and anti-U1 ribonucleoprotein (RNP) antibody were positive, but anti-double-stranded DNA (dsDNA) antibody and anti-Smith (Sm) antibody were negative, while complement levels were normal. Renal biopsy revealed membranous glomerulonephritis (MGN) with diffuse thickening of the glomerular basement membrane (GBM) plus spike and bubble formation. Immunofluorescence demonstrated granular deposits of IgG and C3 along the GBM. Analysis of IgG subclasses showed predominant deposition of IgG1 and IgG4, unlike typical lupus nephritis in which there is predominant deposition of IgG1, IgG2, IgG3, and C1q. Electron microscopy identified numerous large electron-dense deposits (EDD) of various types in the subepithelial region of the GBM, but there were no EDD localized in the mesangium or subendothelium. Based on these findings, MGN was considered to be closely related to MCTD in this patient. Keywords: Membranous glomerulonephritis, Mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a systemic autoimmune rheumatic disease (SARD) characterised by the combination of clinical manifestations of systemic lupus erythematosus (SLE), cutaneous systemic sclerosis (SSc) and polymyositis-dermatomyositis, in the presence of elevated titers of anti-U1-RNP antibodies. Main symptoms of the disease are polyarthritis, hand oedema, Raynaud's phenomenon, sclerodactyly, myositis and oesophageal hypomobility. Although widely discussed, most authors today accept MCTD as an independent entity. Others, however, suggest that these patients may belong to subgroups or early stages of certain definite connective diseases, such as SLE or SSc, or are, in fact, SARD overlap syndromes.

Pulmonary hypertension (PH) is a clinical syndrome that is subdivided into five groups per the World Health Organization (WHO) classification, based largely on hemodynamic and pathophysiologic criteria. WHO Group 1 PH, termed pulmonary arterial hypertension (PAH), is a clinically progressive disease that can eventually lead to right heart failure and death, and it is hemodynamically characterized by pre-capillary PH and increased pulmonary vascular resistance in the absence of elevated left ventricular filling pressures. PAH can be idiopathic, heritable, or associated with a variety of conditions. Connective tissue diseases make up the largest portion of these associated conditions, most commonly systemic sclerosis (SSc), followed by mixed connective tissue disease and systemic lupus erythematous. These etiologies (namely SSc and Lupus) have been grouped together as connective tissue disease-associated PAH, however emerging evidence suggests they differ in pathogenesis, clinical course, prognosis, and treatment response. This review highlights the differences between SSc-PAH and Lupus-PAH. After introducing the diagnosis, screening, and pathobiology of PAH, we discuss connective tissue disease-associated PAH as a group, and then explore SSc-PAH and SLE-PAH separately, comparing these 2 PAH etiologies.

Mixed connective tissue disease (MCTD) is a systemic autoimmune rheumatic disease (SARD) characterised by the combination of clinical manifestations of systemic lupus erythematosus (SLE), cutaneous systemic sclerosis (SSc) and polymyositis-dermatomyositis, in the presence of elevated titers of anti-U1-RNP antibodies. Main symptoms of the disease are polyarthritis, hand oedema, Raynaud's phenomenon, sclerodactyly, myositis and oesophageal hypomobility. Although widely discussed, most authors today accept MCTD as an independent entity. Others, however, suggest that these patients may belong to subgroups or early stages of certain definite connective diseases, such as SLE or SSc, or are, in fact, SARD overlap syndromes.

Introduction: Mixed connective tissue disease (MCTD) is an autoimmune disease that is rare in children. The disease is presented with complex clinical features, so early diagnosis is challenging. Herein we describe the management and outcome of a girl with MCTD associated with macrophage activation syndrome (MAS) and refractory Raynauds’ phenomenon. Case report: A 13-year-old girl was admitted to the pediatric rheumatology ward with mild fever, reduced appetite, 6 kg weight loss (body mass index 15.8), digital ulcers, sclerodactyly, scleroderma, dysphagia, gastroesophageal reflux and arthralgia. She also had photosensitivity, Raynaud’s phenomenon, painless oral ulcers, and malar rash. She developed arthritis of the knees and ankles with limited range of motion. Spirometry showed a restrictive pattern. There was speckled antinuclear antibodies (ANA; 1/1260) and positive β-2-glycoprotein, U1-ribonucleoprotein (U1-RNP), anti-Scl-70 and anti-Ro52 antibodies. Anti-double stranded deoxyribonucleic acid and anti-cyclic citrullinated protein antibodies were negative. Based on clinical and laboratory findings, MCTD was confirmed. The child was treated with steroid, vasodilators, and immunosuppressives. She had an attack of salmon pink rashes, spiky fevers, Koebner phenomenon, serositis, and organomegaly and the diagnosis of associated MAS was held. The patient was treated with pentoxifylline, prednisolone, methotrexate, low dose aspirin, nifedipine, and hydroxychloroquine. On follow up there was refractory digital ulcers and Raynaud’s phenomenon; transthoracic endoscopic sympathectomy was performed and digital ulcers and coldness resolved. Conclusion: MCTD may present with a myriad of rheumatic manifestations and in association with MAS the diagnosis and management may be challenging. Refractory Raynauds’ phenomenon may remarkably improve on transthoracic sympathectomy. Keywords: Mixed connective tissue disease, Systemic lupus erythematosus, Raynaud’s phenomenon, Macrophage activation syndrome, Sympathectomy

Interstitial lung disease (ILD) sometimes becomes a life-threatening complication of systemic autoimmune diseases; however, little is known about the immune response in lung lesions. We aimed to investigate humoural immunity in ILD associated with rheumatoid arthritis (RA), sjögren's syndrome (SjS), and mixed connective tissue disease (MCTD), using bronchoalveolar fluid (BALF) and serum samples from 15 patients with autoimmune disease associated-ILD. We first showed that BALF contained higher titers of disease-related autoantibodies than serum, suggesting the possibility of autoantibody production in lungs. Next, we produced 326 monoclonal antibodies from antibody-secreting cells in BALF, and the reactivity and their revertants, in which somatic hypermutations were reverted to germline, were analyzed. Among 123 antibodies from RA-ILD, 16 disease-related antibodies (anti-modified protein antibodies and rheumatoid factors) were identified, of which one antibody had both properties. The revertant antibodies changed their target modification in a complicated manner, suggesting that the antibodies were selected against various modifications in lungs. Among 146 antibodies from SjS-ILD and/or MCTD-ILD, seven anti-SSA/Ro60 antibodies and 15 anti-RNP antibodies were identified. Some of the anti-RNP antibodies recognized multiple RNP constituent proteins simultaneously, indicating that epitope spreading may progress in lungs. Our results revealed the existence of an active autoimmunity in the lungs of autoimmune disease associated-ILD.

Introduction Patients with mixed connective tissue disease (MCTD) have higher rates of pulmonary arterial hypertension (PAH) than the general population. PAH is a risk for perioperative respiratory and heart failure, and marked edema of colonic stoma after sigmoidectomy. We report a case of sigmoidectomy for sigmoid colon cancer in a patient with PAH associated with MCTD for whom perioperative treatment was planned to control pulmonary arterial pressure (PAP), and a surgical strategy to avoid complications attributable to PAH and MCTD was employed. Case presentation A 52-year-old woman with sigmoid cancer and severe PAH associated with MCTD underwent surgery. We controlled PAH by using intravenous epoprostenol. We selected open surgery without laparoscopy and Hartmann's operation. After surgery, severe perioperative complications were not detected, and the patient discharged from hospital 17 days after the operation. Discussion During surgery under general anesthesia, the mortality rate of PAH is high because of heart and respiratory failure. We planned to switch the PAH treatment from an oral agent to intravenous epoprostenol only in the preoperative period, and selected open surgery. We ligated the inferior mesenteric artery (IMA) and inferior mesenteric vein (IMV) below the branch of LCA to avoid marked edema of stoma. Consequently, we could avoid severe intraoperative and postoperative complications. Conclusions Controlling PAP using epoprostenol, open surgery, stoma and the ligation level for the IMA and IMV preventing are important to avoid perioperative complications of sigmoid colon cancer complicated by severe PAH., Highlights • The patient with PAH complicated by MCTD underwent Hartman’s operation for sigmoid colon cancer. • Control of PAH by epoprostenol preoperatively is important to prevent perioperative cardiac complications. • The level of ligation of the IMA and the LCA is important to avoid severe edema of stoma.

While the relationship between maternal connective tissue diseases and neonatal rashes was described in the 1960s and congenital heart block in the 1970s, the "culprit" antibody reactivity to the SSA/Ro-SSB/La ribonucleoprotein complex was not identified until the 1980s. However, studies have shown that approximately 10-15% of cases of congenital heart block are not exposed to anti-SSA/Ro-SSB/La. Whether those cases represent a different disease entity or whether another antibody is associated has yet to be determined. Moreover, the cutaneous manifestations of neonatal lupus have also been identified in infants exposed only to anti-U1RNP antibodies. In this review, we describe what we believe to be the first case of congenital heart block exposed to maternal anti-U1RNP antibodies absent anti-SSA/Ro-SSB/La. The clinical and pathologic characteristics of this fetus are compared to those typically seen associated with SSA/Ro and SSB/La. Current guidelines for fetal surveillance are reviewed and the potential impact conferred by this case is evaluated.

Background Scurfy mice have a functional defect in regulatory T cells (Treg), which leads to lethal multi-organ inflammation. The missing Treg function results in uncontrolled autoimmune cellular and humoral inflammatory responses. We and others have previously shown that during the course of disease scurfy mice develop severe skin inflammation and autoantibodies including anti-nuclear autoantibodies (ANA). Objective Autoimmune skin inflammation and ANA are hallmarks for the diagnosis of autoimmune connective tissue diseases; therefore we analyzed scurfy mice for typical signs of these diseases. Methods Indirect immunofluorescence was used to specify the ANA pattern in scurfy mice. Skin fibrosis was assessed by cutaneous collagen accumulation (Goldeners trichrome staining), collagen crosslinking/disorganization (Sirus red polarimetry) and quantitative PCR for fibrosis-related transcripts. The cellular components of the inflammatory infiltrates in scurfy skin were analyzed by flow cytometry and intracellular cytokine staining. Results The majority of scurfy mice developed ANA with a predominant AC-5 pattern typical for mixed connective tissue disease, especially scleroderma. Scurfy mice showed higher skin collagen content compared to WT controls with a significant tendency in upregulation of TIMP-1. CD3+CD4+ T cells in scurfy skin exhibited a strong Th2 deviation with a significant increase of IL-4, IL-5 and IL-13, and M2-polarized CD11b+MHCII+ macrophages compared to WT mice. Conclusion We show that Scurfy mice show a predominant AC-5 ANA pattern typical for mixed connective tissue disease as in scleroderma. The autoimmune inflammation in scurfy skin mainly consists of CD4+ T cells with Th2 differentiation and alternatively-activated (M2) macrophages as it is found in scleroderma with advanced fibrosis.

Fibromyalgia (FM) is a confounding factor for diagnosing and assessing rheumatic disease activity. This study sought to assess the extent of this syndrome in rheumatism patients at a French rheumatology department.This monocentric epidemiological study enrolled all patients consulting due to rheumatoid arthritis (RA), spondyloarthritis (SpA), or connective tissue disease (CTD). FM diagnosis was confirmed or excluded according to the rheumatologist opinion and the 1990 American College of Rheumatology (ACR) criteria.We enrolled 691 patients, including 451 women (65.3%), with a mean age of 55.8 years (18-93). Of the enrolled patients, 325 presented with RA, 298 SpA [59 psoriatic arthritis (PsA), 137 ankylosing spondylitis (AS), 64 non-radiographic SpA (nr-SpA), and 38 peripheral SpA], and 71 CTD. The rheumatologist established FM diagnosis in 97 patients (14%), while 55 (8%) fulfilled the 1990 ACR criteria. The frequency of FM was lower in RA patients (4.9% by 1990 ACR criteria; 7.7% by expert opinion) compared to SpA (11.1% by 1990 ACR, p0.05; 17.5% by expert opinion, p0.003) and CTD (11.3% by 1990 ACR, non-significant; 28.2% by expert opinion, p0.001). In the SpA subgroups, FM was more common in the nr-SpA than in PsA or AS (23.9%, 9.6%, and 6.4%, by 1990 ACR, p = 0.001; 37.3%, 13.5%, and 7.2%, by expert opinion, p0.001).FM-like symptoms are commonly associated with rheumatic diseases. The frequency of FM is particularly high in non-radiographic axial SpA, thus raising questions about the specificity of the Assessment of SpondyloArthritis International Society (ASAS) classification criteria.

Case Presentation A 42-year-old woman with mixed connective tissue disease-associated interstitial lung disease underwent bilateral lung transplantation. She had an uneventful surgery and was extubated 3 h later. Induction immunosuppression therapy included methylprednisolone 500 mg intraoperatively, basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation, and methylprednisolone 125 mg intravenously bid for 2 days following surgery. Maintenance immunosuppression therapy consisted of prednisone 20 mg daily, mycophenolate mofetil 750 mg bid, and enteral tacrolimus 0.5 mg bid. Both the donor and the recipient were seropositive for cytomegalovirus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim-sulfamethoxazole, and voriconazole.

Connective tissue diseases (CTDs) are a heterogeneous group of conditions characterized by circulating autoantibodies and autoimmune-mediated organ damage. Common CTDs with lung manifestations are rheumatoid arthritis, scleroderma or systemic sclerosis, Sjögren syndrome, polymyositis/dermatomyositis, systemic lupus erythematosis, mixed connective tissue disease, and undifferentiated connective tissue disease. The most common histopathologic patterns of CTD-related interstitial lung disease are nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, and lymphoid interstitial pneumonia. Drug treatment of CTDs can cause complications, including opportunistic infection.

Childhood rheumatic diseases are associated with negative impacts on the skeleton, related to both the underlying illness and complications of therapy. The effects of medications like corticosteroids are well recognized, leading to reductions in bone mineral density and bone strength and concomitant increases in bone fragility and fracture risk. The impact of factors directly attributable to the underlying disease is not as well recognized. In this article, we review relevant literature to identify data which can contribute to an understanding of the impact of childhood rheumatic disease on the skeleton. We conclude that childhood rheumatic diseases are associated with reductions in bone mineral density and increased risk of vertebral and non-vertebral fractures. These data are strongest for juvenile arthritis, while conclusions are more limited for other rheumatic illnesses, like juvenile systemic lupus erythematosus or juvenile dermatomyositis, due to small numbers of patients studied. Finally, we make recommendations for areas in need of further research. These include the need for long-term longitudinal studies and for data to be collected in patients who have not been treated with corticosteroids.

The treatment of rheumatic and autoimmune skin disease in women who are pregnant or of childbearing potential can present challenges to the dermatologist. We discuss the current approaches to treating lupus erythematosus, antiphospholipid antibody syndrome, dermatomyositis, morphea and systemic sclerosis, mixed connective tissue disease, rheumatoid arthritis, and autoimmune blistering disease in such patients. In the appropriate setting, topical and systemic corticosteroids, hydroxychloroquine, dapsone, azathioprine, and ultraviolet B phototherapy may be safely and cautiously used during pregnancy. Considerations about contraception, planned conception, therapeutic options, and disease control are paramount in optimizing pregnancy outcomes and minimizing risks to both mother and fetus.

Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH.

Background Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset. Methods Here, we report our experience resulting from the integrated — pneumology/rheumatology — approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature. Results After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥ 3 years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p = 0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients. Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF. Conclusion We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants.

Background Orthotopic heart transplantation (OHT) recipients undergo scheduled right heart catheterizations (RHC) and biopsies. Some of these patients who have mixed connective tissue disease (MCTD) are at increased risk of developing pulmonary artery hypertension (PAH). The natural history and impact of immunosuppression on new-onset PAH is unknown. Case A 43 year old male required OHT after the development of lupus cardiomyopathy. Post-transplant he was treated with tacrolimus and mycophenolate. Three years later, he developed significant dyspnea on exertion. His serology was anti-nuclear antibody positive (1:2560, speckled). Over eight months, RHCs performed in the setting of endomyocardial biopsies for surveillance of rejection showed a dramatic change, from normal shortly after transplantation, to a markedly elevated PA pressure of 81/34 (mean 52) mmHg, pulmonary capillary wedge pressure of 7 mmHg, transpulmonary gradient of 45 mmHg, and pulmonary vascular resistance of 9.36 Wood units (Figure 1). The patient's constellation of symptoms and RHC findings supported a diagnosis of MCTD - PAH, despite ongoing immunotherapy. Severe PAH occurred incidentally while being monitored with RHC for another indication. He was treated with tadalafil, ambrisentan, and amlodipine with an improvement in functional class. Conclusions This case describes de novo development of PAH after OHT in a patient with MCTD, despite anti-rejection immunotherapy. This suggests a lack of efficacy of immunosuppression in preventing scleroderma-PAH and highlights the rapidity of onset of this disease. Figure 1. Results of serial right heart catheterizations

Interstitial lung disease is a common and often life-threatening manifestation of different connective tissue disorders, often affecting its overall prognosis. Systemic lupus erythematosus, Sjögren syndrome, and mixed connective tissue disease, although all unique diseases, can have lung manifestations as an important part of these conditions. This article reviews the different pulmonary manifestations seen in these 3 systemic rheumatologic conditions.

Nail-fold capillaroscopy is a non-invasive tool to study the microcirculation and is increasingly being used in dermatology, angiology and rheumatology. More recently, the use of video-capillaroscopy has allowed computer storage of capillaroscopic images (video-capillaroscopy), enabling evaluation of changes in capillaroscopic abnormalities during the follow-up of patients with systemic sclerosis or mixed connective tissue disease. Qualitative and quantitative assessment of the nail-fold dermal capillaries and of their organization can readily distinguish between a normal capillaroscopic pattern in primary Raynaud phenomenon and a specific sclerodermic pattern in secondary Raynaud phenomenon carrying a very high risk of systemic sclerosis. Apart from its important role as a diagnostic tool for distinguishing between primary and secondary Raynaud phenomenon, capillaroscopy is now used to predict the risk of development of digital ulcers and of future visceral complications in patients with systemic sclerosis. Moreover, nail-fold capillaroscopy is essential for differential diagnosis between connective tissue diseases, for the etiologic diagnosis of digital necrosis and diffuse interstitial lung disease, and in sclerodermiform syndromes.

Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud’s phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud’s-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as “uncertain” for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists “agreed” were “appropriate” diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were “appropriate,” 12 items had “uncertain” appropriateness, and 13 items were “inappropriate” to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were “appropriate and accurate” for use by physicians to diagnose patients with RP.

The term "mixed connective tissue disease" (MCTD) concerns a systemic autoimmune disease typified by overlapping features between two or more systemic autoimmune diseases and the presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP). Since the first description of this condition in 1972, the understanding of clinical manifestations and long-term outcome of MCTD have significantly advanced. Polyarthritis, Raynaud's phenomenon, puffy fingers, lung involvement and esophageal dysmotility are the most frequently reported symptoms among the different cohorts during the course of the disease. Moreover, in recent years a growing interest has been focused on severe organ involvement such as pulmonary arterial hypertension and interstitial lung disease which can accrue during the long-term follow-up and can still significantly influence disease prognosis. Over the last years, significant advances have been made also in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Although controversies on disease definition and classification still persist, MCTD identifies a group of patients in whom increased surveillance for specific manifestations and prognostic stratification became mandatory to improve patient's outcomes.

Skin lesions occur, often at very early stages, in many of the most frequent inflammatory rheumatic diseases such as in systemic lupus erythematosus (SLE), dermatomyositis (DM), systemic sclerosis (SSc), Sjogren's syndrome, rheumatoid arthritis (RA), and psoriatic arthritis. It is important to recognize the different specific cutaneous lesions in SLE (e.g., “butterfly” rash in acute, annular or psoriasiform photosensitive lesions in the subacute form, and discoid lesions in the chronic form) for an early diagnosis and to estimate the associated risks of internal disease, whereas nonspecific lesions (exanthema, vasculitis, and alopecia) can be part of SLE flares. Cutaneous lesions in DM (Gottron's papules and sign, heliotrope rash, dystrophic cuticles, and nailfold capillary abnormalities) may occur before any clinically evident muscular or systemic organ involvement and are of utmost importance for early diagnosis. The pattern of cutaneous lesions and associated autoantibodies also allow the distinction of different phenotypes, either more prone to life-threatening interstitial lung disease (MDA-5) or with higher risk for neoplasia (TIF1-γ). Many other skin lesions, although not specific, require further investigation to look for a possible underlying inflammatory rheumatic disease: non-pruritic urticarial lesions in anti-C1q-associated urticarial vasculitis, Still's disease or hereditary auto-inflammatory syndromes, transient macular purpura of vasculitis in Sjogren's syndrome, Behcet's disease, or RA, Raynaud's phenomenon in SSc and mixed connective tissue disease, erythema nodosum or other panniculitis in RA, Behcet's disease and SLE, pustular eruptions in Behcet's disease, psoriasis, and hereditary auto-inflammatory syndromes. After reviewing in detail the cutaneous manifestations of the most frequent inflammatory rheumatic diseases, we describe a topographic and morphological approach to skin rashes, calling attention to facial rashes, hand involvement, scalp, nail, or leg lesions or to some morphological aspects of skin lesions (annular, pustular, urticarial, or exanthematous) that may be the initial manifestations of inflammatory rheumatic diseases. The importance of skin lesions is confirmed by their presence as part of the classification criteria of many inflammatory rheumatic diseases. They also contribute to early diagnosis, to characterize disease phenotypes, to aid in effective patient management, and, ultimately, to impact on disease prognosis.

Mitral valve repair with the transapical Neochord implantation is a safe and effective new method to treat patients with degenerative severe mitral regurgitation. Mixed connective tissue disease is a systemic autoimmune disorder that can affect the heart. Subendocardial and interstitial myocardial

Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren’s syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers.

Introduction Idiopathic angioedema without urticaria presents infrequently and warrants investigation for an underlying etiology. Autoimmune conditions are a rare cause of acquired angioedema (AAE). The identification of an underlying cause has significant potential implications for treatment and thus resolution of AAE. We present a patient who was diagnosed with mixed connective tissue disease (MCTD) after initially presenting with recurrent angioedema. Case Description A 17-year-old female with a six-month history of recurrent angioedema without urticaria presented for evaluation to an outpatient pediatric allergy clinic. At initial presentation, she denied musculoskeletal complaints. Laboratory evaluation revealed a significantly elevated sedimentation rate with a normal C-reactive protein. Over the next several months she developed pain and stiffness, particularly in her wrist and elbow joints. These findings triggered rheumatologic referral for further evaluation. She was ultimately diagnosed with MCTD with corresponding U1-ribonucleoprotein antibodies and high titer anti-nuclear antibodies. She was started on mycophenolate mofetil and hydroxychloroquine for MCTD treatment with resolution of her arthritis and no further episodes of angioedema. Discussion The pathophysiology of nonhistaminergic idiopathic angioedema remains unknown. This case highlights the need to asses for concurrent rheumatologic and autoimmune symptoms while evaluating AAE in the absence of urticaria, especially in the pediatric population. To our knowledge, this is the first report of MCTD presenting as acquired angioedema in published literature.

Calcinosis cutis (CC) is a rare disorder known to occur commonly in association with underlying autoimmune connective tissue diseases. CC primarily occurs in patients with dermatomyositis, systemic scleroderma, and mixed connective tissue disease. It is only rarely associated with systemic lupus erythematosus (SLE) and even more rarely with discoid lupus erythematosus (DLE).

Collagen diseases are a large group of systemic inflammatory diseases of autoimmune etiology. The etiopathogenesis of collagen diseases is multifactorial. There is genetic susceptibility, as many connective tissue disorders show family history, and environmental factors may trigger the disease. Collagen diseases can affect almost all the organs of the body. The respiratory system is one of the most frequently affected, although the prevalence of pulmonary disease is not precisely known for the different collagen disorders. Any structure of the respiratory tract can be affected, but perhaps the most frequent is pulmonary parenchymal disease in the form of pneumonitis, which can be produced in any of the idiopathic interstitial pneumonitis patterns. The pleura, pulmonary vessels, airways and respiratory muscles may also be affected. The frequency of lung disease associated with collagen diseases is on the rise. This due in part to the better diagnostic methods that are available to us today (such as high-resolution computed tomography) and also to the appearance of new forms of pneumonitis associated with the new treatments that are currently used. The objective of this article is to offer a global vision of how collagen diseases can affect the lungs according to the latest scientific evidence.

Systemic inflammatory disorders of the connective tissue, also known as connective tissue diseases are characterized by the production of antibodies directed against one's own cellular structures. These autoantibodies which usually recognize nuclear components are called generically antinuclear antibodies (ANAs). However, they can also recognize either cytoplasmic antigens or cell membrane antigens and extracellular proteins. The following ANAs are considered disease classification criteria: anti-native double-stranded (ds)DNA, anti-Sm, and antiphospholipid for systemic lupus erythematosus; anti-topoisomerase 1 and anticentromere for scleroderma; antisynthetases, which are characteristic of polymyositis, for antisynthetase syndrome; anti-U1 ribonucleoproteins (RNP) in mixed connective tissue disease; ANAs, rheumatoid factor (RF), and anti-Ro/SS-A and anti-La/SS-B in Sjogren's syndrome; RF in rheumatoid arthritis; antiphospholipid in antiphospholipid syndrome; and antineutrophil cytoplasmic (ANCA) for small vessel vasculitis and necrotizing glomerulonephritis.

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4(pos)CD25(pos) cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4(pos)CD25(pos)CD25(high) T-regs were reduced in number and contained an increased proportion of activated CD127(pos) and IFNγ(pos) cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4(pos)CD25(neg) responder cells. Impairment in suppressor function both of CD4(pos)CD25(pos) cells and CD4(pos)CD25(pos)CD127(neg) T-regs was observed in all three autoimmune conditions, but while addition of CD4(pos)CD25(pos)CD127(neg) T-regs decreased CD4(pos)CD25(neg) responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients. In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.