Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary ß-glucan-induced inflammatory adaptation.

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal ß-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, ß-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey.

Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.

[Autologous hematopoietic stem cell transplantation for systemic sclerosis : Position statement of the stem cell therapy working party of the German Society of Rheumatology]. / Autologe hämatopoetische Stammzelltransplantation bei systemischer Sklerose : Positionspapier des Arbeitskreises Stammzelltherapie der Deutschen Gesellschaft für Rheumatologie.

There have been three randomized controlled trials on autologous hematopoietic stem cell transplantation (AHSCT) in systemic sclerosis (SSc) that demonstrated significant superiority with respect to survival, improvement of cutaneous fibrosis, lung function and quality of life compared to standard treatment; however, these advantages must be carefully weighed against the transplantation-related risks. For this reason, an expert group from the stem cell therapy working party of the German Society for Rheumatology (DGRh) has now developed recommendations for the use of AHSCT in SSc. Based on the high-quality evidence, AHSCT is considered as the standard option for the treatment of selected SSc patients. Potential candidates for AHSCT are those with early, rapidly progressive, diffuse cutaneous SSc with visceral manifestations who have not yet developed severe damage to internal organs. A close cooperation between rheumatologists and transplantation centers is crucial for optimizing patient selection and treatment outcomes.

[Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany]. / Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland.

BACKGROUND: Raynaud's phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. METHODS: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud's syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. RESULTS: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud's phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaud's phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. CONCLUSION: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaud's phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patients' perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.

[Treatment of systemic sclerosis-associated interstitial lung disease]. / Therapie der systemischen Sklerose-assoziierten interstitiellen Lungenerkrankung.

BACKGROUND: Systemic sclerosis (SSc) is a fibrosing autoimmune disease of the connective tissue. In addition to skin fibrosis, pulmonary involvement and interstitial lung disease (ILD) in particular are the most common and severe manifestations of SSc. The disease is associated with a substantial risk of morbidity and mortality, especially in progressive ILD. In the last 5 years new treatment concepts for SSc-ILD have been investigated in numerous clinical studies. MATERIAL AND METHODS: This review is based on a literature search in PubMed, focusing on the most relevant papers published up to the end of 2018 with the keywords "SSc" and "treatment". RESULTS: The treatment of SSc-ILD has changed over the last few years due to the results of many clinical studies. The updated guidelines of the European League Against Rheumatism (EULAR) recommend the use of cyclophosphamide or hematopoietic stem cell transplantation. Data for a positive influence on SSc-ILD are also available for mycophenolate, tocilizumab and anabasum. Because of the pathophysiological similarities to idiopathic pulmonary fibrosis, the use of the antifibrotic agents nintedanib and pirfenidone is currently being investigated in randomized, multicenter clinical trials and could be a novel and promising therapeutic strategy. CONCLUSION: Current drug studies may provide innovative therapeutic perspectives for SSc-ILD and could significantly improve the prognosis of affected patients in the future.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression.

Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.

[Digital ulcers in systemic sclerosis : A retrospective heath service study analysing treatment with bosentan and other vasoactive therapies]. / Digitale Ulzerationen bei systemischer Sklerose : Eine Versorgungsforschungsstudie über den Einsatz von Bosentan und anderen vasoaktiven Therapien.

BACKGROUND: Digital ulcers (DU) affect up to 60 % of patients with systemic sclerosis (SSc) and have a considerable impact on quality of life and morbidity. It is unclear to what extent authorised medicines are used, and if therapy guidelines are implemented in everyday practice. METHOD: This retrospective health care study examined current standards of treatment for therapy and prevention of SSc-associated DU in an online survey with 83 physicians. Additionally, data from 161 case studies of SSc patients with DU were analysed, and the effect of DU treatment on the course of the disease determined. RESULTS: For treatment and prevention of active DU, physicians predominantly indicated topical therapies, calcium channel blockers, iloprost and endothelin receptor antagonists. According to the case studies, 90 % of episodes with acute DU were treated with bosentan and iloprost in mono- or combination therapy. Preventive treatment was only administered during 50 % of episodes without DU, even after three or more phases with active DU. For the prevention of new DU, bosentan was used in mono- or combination therapy in 57 % of episodes without DU. Bosentan therapy during prevention shortened the following acute phase by 32 %. Additionally, continuous treatment with bosentan in acute and prevention phases reduced the duration of the following acute phase and increased the time to onset of new DU by 16 %. Moreover, bosentan stabilised the number of new DU. CONCLUSION: In summary, these data confirm the efficacy of bosentan in preventing new DU when used in DU-free episodes and possibly also in phases of acute DU. Therapy recommendations for the treatment of DU are currently not fully implemented. In the future, even more attention should be paid to DU therapy.

Effects of In utero environment and maternal behavior on neuroendocrine and behavioral alterations in a mouse model of prenatal trauma.

Maternal posttraumatic stress disorder (PTSD) following trauma exposure during pregnancy is associated with an increased risk of affective disorders in children. To investigate the mechanisms by which prenatal trauma and/or maternal PTSD affect brain development and behavior we established a mouse model of prenatal traumatic (PT) experience based on the application of an electric foot shock to C57Bl/6N female mice on the gestational day 12 during their pregnancy. The model is based on a previously validated animal model of PTSD. We found high anxiety levels and poor maternal care along with reduced serum prolactin and increased corticosterone levels in dams following maternal trauma (MT). PT-pups were born smaller and stayed smaller throughout their life. We show increased time and frequency of ultrasonic calls in PT-pups when separated from the mothers on the postnatal day (PND) 9. Cross-fostering experiments reveal lower anxiety levels in PT pups raised by healthy mothers as compared to trauma-naive pups raised by MT-dams. Importantly, the combination of prenatal trauma and being raised by a traumatized mother leads to: (1) the highest corticosterone levels in pups, (2) longest USV-call time and (3) highest anxiety levels in comparison to other experimental groups. Our data indicates a distinct change in maternal care following MT which is possibly associated with trauma-induced decrease in prolactin levels. Furthermore, we show that maternal behavior is crucial for the development of the offspring anxiety and specific aspects in maternal care overwrite to a significant extend the effects of in utero and postnatal environment. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1254-1265, 2016.

[Common German language nomenclature for systemic sclerosis]. / Gemeinsame deutschsprachige Nomenklatur für die systemische Sklerose.

Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.

Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis.

OBJECTIVE: Fc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis (OA)-related cartilage degradation. METHODS: FcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. RESULTS: Expression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice. CONCLUSION: While FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis.

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype.

OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population.

BACKGROUND: TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported. OBJECTIVE: To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc). METHODS: Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel-Haenszel meta-analysis. RESULTS: The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10⁻7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10⁻8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10⁻9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10⁻6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10⁻5). CONCLUSION: These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.