Screening for rheumatoid arthritis-associated interstitial lung disease-a Delphi-based consensus statement.

OBJECTIVE: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major driver of premature mortality in patients with rheumatoid arthritis (RA). Detection of RA-ILD is crucial but requires awareness among the treating physicians. To date, however, there is no international recommendation concerning screening for ILD in RA patients. METHODS: After a systematic literature review, the modified Delphi technique in combination with the nominal group technique was used to provide a Delphi consensus statement elaborated by an expert panel of pneumonologists, rheumatologists, and a radiologist. Based on the available evidence, several clusters of questions were defined and discussed until consent was reached. RESULTS: A screening algorithm for ILD in patients with RA based on clinical signs, respiratory symptoms, and risk factors has been developed. Further, the recommendations address diagnostic tools for RA-ILD and the follow-up of RA patients qualifying for ILD screening.

Association of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathic changes in limited systemic sclerosis.

Objectives: Pathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy. Methods: Amino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded. Results: No significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p < 0.05). In addition, significant correlations were observed between PTH and 25-hydroxyvitamin D with homoarginine, and between osteocalcin, PTH and P3NP with modified Rodnan skin score and selected periodontal parameters (all with p < 0.05). Vitamin D deficiency defined as 25-hydroxyvitamin D < 20 ng/ml was associated with the presence of puffy finger (p = 0.046) and early pattern (p = 0.040). Conclusion: Selected amino acids may affect endothelial function and may be associated to vasculopathy-related and clinical changes in lcSSc patients, while the association with parameters of bone metabolism seems to be minor.

Periodontal disease and its association to endothelial dysfunction and clinical changes in limited systemic sclerosis: A case-control study.

OBJECTIVES: Periodontal disease occurs frequently in patients with limited cutaneous systemic sclerosis (lcSSc) while data about underlying pathways contributing to periodontal changes are scarce. The aim of this study was to evaluate periodontal disease and to investigate its association with endothelial dysfunction and clinical changes in patients with lcSSc. METHODS: In 38 lcSSc patients and 38 controls, periodontal status was evaluated by disease-specific questionnaire, dental examination including bleeding on probing (BOP), pocket depth, and plaque index, and dental panoramic radiograph. Periodontopathogen bacteria were collected subgingivally using paper points and interleukin-1 (IL-1) gene polymorphisms were evaluated using buccal swabs. Endothelial dysfunction was measured by flow-mediated dilatation, pulse-wave velocity and biochemical analysis, including arginine metabolites and endothelial microparticles. Additionally, lcSSc-specific clinical changes and parameters were recorded. RESULTS: Periodontitis was present in 31 patients with lcSSc (81.6%) and in 27 controls (71.1%) (p = .280). LcSSc patients had a lower teeth number (p = .039) and Eikenella corrodens was to a higher degree detectable in patients with lcSSc (p = .041) while the remaining periodontal parameters revealed no differences between both cohorts. Significant correlations between parameters of arterial stiffness, EUSTAR index, number of teeth and BOP were observed (all p < .05). Detection of Prevotella intermedia was associated with selected IL-1 gene polymorphisms (p = .032) and Porphyromonas gingivalis was associated with severe periodontitis (p = .041). CONCLUSION: Periodontal disease may occur frequently in patients with lcSSc and may be associated with arterial stiffness and with SSc activity.

Altered cellular immune response to vaccination against SARS-CoV-2 in patients suffering from autoimmunity with B-cell depleting therapy.

B-cell depleting therapies result in diminished humoral immunity following vaccination against COVID-19, but our understanding on the impact on cellular immune responses is limited. Here, we performed a detailed analysis of cellular immunity following mRNA vaccination in patients receiving B-cell depleting therapy using ELISpot assay and flow cytometry. Anti-SARS-CoV-2 spike receptor-binding domain antibody assays were performed to elucidate B-cell responses. To complement our cellular analysis, we performed immunophenotyping for T- and B-cell subsets. We show that SARS-CoV-2 vaccination using mRNA vaccines elicits cellular T-cell responses in patients under B-cell depleting therapy. Some facets of this immune response including TNFα production of CD4+ T-cells and granzyme B production of CD8+ T-cells, however, are distinctly diminished in these patients. Consequently, it appears that the finely coordinated process of T-cell activation with a uniform involvement of CD4+ and CD8+ T-cells as seen in HCs is disturbed in autoimmune patients. In addition, we observed that immune cell composition does impact cellular immunity as well as sustainability of anti-spike antibody titers. Our data suggest disturbed cellular immunity following mRNA vaccination in patients treated with B-cell depleting therapy. Immune cell composition may be an important determinant for vaccination efficacy.

[National consensus statement by the Austrian Societies for Rheumatology, Pulmonology, Infectiology, Dermatology and Gastroenterology regarding the management of latent tuberculosis and the associated utilization of biologic and targeted synthetic DMARDS (disease modifying antirheumatic drugs)]. / Consensus Statement der Österreichischen Gesellschaften für Rheumatologie und Rehabilitation, Pneumologie, Infektiologie, Dermatologie und Gastroenterologie zum Umgang mit latenter Tuberkulose bei Therapien mit biologischen oder "targeted synthetic" DMARDs ("disease modifying antirheumatic drugs").

This nationwide Austrian consensus statement summarizes the recommendations on the management of latent tuberculosis by treatment with biologic and targeted synthetic DMARDs. The essential questions with respect to screening and preventive treatment were discussed by experts from the disciplines of rheumatology, pneumology, infectious diseases, dermatology and gastroenterology, based on the available data, and then a joint consensus was formed by agreement. This involved a differentiated discussion on the various forms of treatment, and clear recommendations were formulated.

National consensus statement by the Austrian Societies for Rheumatology, Pulmonology, Infectiology, Dermatology and Gastroenterology regarding the management of latent tuberculosis and the associated utilization of biologic and targeted synthetic disease modifying antirheumatic drugs (DMARDs).

This publication provides a thorough analysis of the most relevant topics concerning the management of latent tuberculosis when using biologic and targeted synthetic Disease Modifying Antirheumatic Drugs (DMARDs) by a multidisciplinary, select committee of Austrian physicians. The committee includes members of the Austrian Societies for Rheumatology and Rehabilitation, Pulmonology, Infectiology, Dermatology and Gastroenterology. Consensus was reached on issues regarding screening and treatment of latent tuberculosis and includes separate recommendations for each biologic and targeted synthetic DMARD.

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.

Evaluation of endothelial dysfunction and clinical events in patients with early-stage vasculopathy in limited systemic sclerosis.

OBJECTIVES: Limited cutaneous systemic sclerosis (lcSSc) is characterised by vasculopathy contributing to vascular apoptosis, structural and functional changes. The aim of this study was to investigate parameters of endothelial dysfunction and their association to clinical events in lcSSc patients with early-stage vasculopathy. METHODS: Patients with lcSSc and early-stage vasculopathy defined as absent pre-existing pulmonary arterial hypertension (PAH), digital ulcers, and symptomatic cardiovascular diseases were recruited together with age-, race- and sex-matched controls with primary Raynaud's phenomenon. All subjects underwent measurements of flow-mediated (FMD) and nitroglycerine-mediated dilation (NMD), pulse-wave analysis, and biochemical analysis, including arginine, homoarginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and endothelial microparticles (EMP). Clinical events, including EUSTAR index, sicca symptoms, microvascular, skin, renal, gastrointestinal, and pulmonary involvement, were recorded by medical history, physical examination, laboratory parameters, disease-specific questionnaire, electrocardiogram, diagnostic imaging and spirometry. RESULTS: 38 patients with lcSSc and 38 controls were included after screening for eligibility. There was no difference in FMD (p=0.775), NMD (p=0.303), aortic pulse-wave velocity (p=0.662) or in augmentation index (p=0.600) between patients with lcSSc and controls. Higher values of ADMA (p=0.030), SDMA (p=0.025) and borderline significantly higher values for CD31+/CD42b- EMP (p=0.062) were observed in lcSSc patients, also with positive correlations between those parameters. ADMA, SDMA and CD31+/CD42b- were correlated with subclinical PAH, nephropathy and capillary changes. CONCLUSIONS: Selected parameters of endothelial dysfunction contribute to clinical events in lcSSc patients with early-stage vasculopathy and endothelial dysfunction seems to be primarily present in microvasculature, while its impact on macrovascular changes in lcSSc is still indistinct.

Successful treatment of severe interstitial pneumonia by removal of circulating autoantibodies: a case series.

BACKGROUND: There is only limited clinical data on the benefit of intense immunosuppression in patients with severe interstitial pneumonia associated with autoimmune features or new-onset connective tissue disease. CASE PRESENTATION: We here report a series of three consecutive patients suffering from severe interstitial lung disease necessitating endotracheal intubation and mechanical ventilation. The first two patients fulfilled many diagnostic criteria for new-onset antisynthetase syndrome, the third patient for systemic lupus erythematosus. We decided to implement aggressive immunosuppressive strategies in these critically-ill patients including therapeutic plasma exchange, immunoadsorption, cyclophosphamide and rituximab. All three patients improved from respiratory failure, were successfully weaned from the respirator, and eventually dismissed from hospital with ongoing immunosuppressive therapy. CONCLUSION: Patients suffering from severe connective tissue disease-associated interstitial lung disease and respiratory failure may benefit from an aggressive immunosuppressive regimen and extracorporeal blood purification with rapid reduction of circulating autoantibodies. The impressive clinical responses in this small case series warrant a controlled clinical trial.

Changes in pulmonary exercise haemodynamics in scleroderma: a 4-year prospective study.

Pulmonary arterial hypertension (PAH) is a feared complication of systemic sclerosis. In this prospective cohort study, we monitored the changes in resting and exercise pulmonary haemodynamics of scleroderma patients without initial PAH over a mean follow-up period of ∼4 years.All patients underwent exercise echocardiography and cardiopulmonary exercise testing at baseline and follow-up. A subgroup underwent exercise right heart catheter (RHC) investigations. The primary end-point was the echocardiographic systolic pulmonary arterial pressure at 50 W exercise (sPAP50).We included 99 patients, of whom 58 had a complete dataset. Three out of 99 patients developed RHC-confirmed PAH (0.75 cases per 100 patient-years). sPAP50 increased (p<0.001) and peak oxygen uptake (secondary end-point) decreased significantly (p=0.001) during follow-up, but there was no significant change in resting sPAP (p=0.38). In the RHC subgroup (n=28), mean (m)PAP and pulmonary vascular resistance at 50 W increased significantly (p=0.02 and p=0.002, respectively), but resting mPAP was unchanged.Scleroderma patients without PAH develop a mild but significant deterioration of pulmonary exercise haemodynamics and exercise capacity over a 4-year follow-up period, indicating a progression of pulmonary vascular disease. The manifestation rate of RHC-confirmed PAH was 0.75 cases per 100 patient-years.

Sphingosine 1-phosphate counteracts the effects of interleukin-1ß in human chondrocytes.

OBJECTIVE: The lipid mediator sphingosine 1-phosphate (S1P) is found in the synovial fluid of osteoarthritis (OA) patients. S1P protects bovine cartilage by counteracting the effects of interleukin-1ß (IL-1ß). This study was undertaken to examine the interaction of S1P and IL-1ß in human OA chondrocytes. METHODS: Human cartilage was obtained from patients undergoing total knee joint replacement. Chondrocytes were cultured in monolayer and treated with IL-1ß and S1P. Expression of S1P receptor subtypes and genes involved in cartilage degradation was evaluated using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. S1P signaling was evaluated using inhibitors of S1P receptors and small interfering RNA (siRNA) knockdown of the S1P2 receptor. Phosphorylation of MAP kinases and NF-κB in response to IL-1ß and S1P was detected by Western blotting. RESULTS: S1P2 was identified as the most prevalent S1P receptor subtype in human OA cartilage and chondrocytes in vitro. S1P reduced expression of inducible nitric oxide synthase (iNOS) in IL-1ß-treated chondrocytes. Reduction of ADAMTS-4 and matrix metalloproteinase 13 expression by S1P correlated with S1P2 expression. Pharmacologic inhibition of the S1P2 receptor, but not the S1P1 and S1P3 receptors, abrogated the inhibition of iNOS expression. Similar results were observed using siRNA knockdown. S1P signaling inhibited IL-1ß-induced phosphorylation of p38 MAPK. CONCLUSION: In human chondrocytes, S1P reduces the induction of catabolic genes in the presence of IL-1ß. Activation of the S1P2 receptor counteracts the detrimental phosphorylation of p38 MAPK by IL-1ß.