[Inflammation in the blood: what's behind it?] / Entzündung im Blut ­ was steckt dahinter?

Inflammation is the body's defensive response to mostly harmful stimuli, usually in response to pathogens or toxic substances. However, the immune response in chronic inflammation is usually directed against harmless antigens, such as allergens, or commensal pathogens, such as herpes viruses, or against the body's own structures, as in autoimmune diseases. The body reacts to the respective stimulating factors with a relatively uniform inflammatory response. Besides the initial reaction of the innate immune system, the activation of immune cells and the release of pro-inflammatory cytokines are in the foreground. Accordingly, inflammatory changes that can be detected in the blood usually do not arise in the blood itself, but in a specific tissue or organ system. In the case of long-term or chronic inflammation, the inflammatory response can be detected in the blood by means of various factors, and both general inflammatory parameters as well as specific parameters can be used for diagnostic purposes. However, the long-term systemic inflammatory response itself also affects the patients suffering from chronic inflammation. This article provides an overview of systemic inflammatory factors relevant for laboratory diagnostics, of how they contribute to specific diseases, and of the systemic effects induced by chronic inflammation.

Microangiopathy in Inflammatory Diseases-Strategies in Surgery of the Lower Extremity.

BACKGROUND: Patients with an inflammatory disease frequently develop chronic angiopathy of the capillaries. Due to this pathology, there is an increased rate of complications in lower extremity surgical procedures. It is not uncommon for microangiopathic wound healing disorders to cause deep infections and fistulas, which lead to prolonged courses and hospitalizations. In addition, adhesions and ossifications of the contractile elements occur regularly. This sometimes results in serious limitations of the mobility of the patients. The study aims to present the results of a combination of vacuum and physical therapy. PATIENT AND METHODS: A retrospective study of six patients with systemic sclerosis undergoing joint-related procedures of the lower extremity between 2015 and 2020 was performed. In addition to characterization of the patients and therapy, special attention was paid to cutaneous wound healing, affection of the fascia and displacement layers, and sclerosis of the muscle and tendon insertion. RESULTS: The characterized structures (skin, tendon, fascia) show pathological changes at the microangiopathic level, which are associated with delayed healing and less physical capacity. Early suture removal regularly results in secondary scar dehiscence. With a stage-adapted vacuum therapy with sanitation of the deep structures and later on a dermal vacuum system, healing with simultaneous mobilization of the patients could be achieved in our patient cohort. CONCLUSION: In the case of necessary interventions on the lower extremity, such as trauma surgery, additional decongestive measures in the sense of regular and sustained lymphatic therapy and adapted physiotherapy are indispensable.

Effects of multimodal rheumatologic complex treatment in patients with rheumatoid arthritis: a monocentric prospective study.

OBJECTIVES: To prospectively evaluate the effects of multimodal rheumatologic complex treatment (MRCT), a special concept of in-patient physical treatment (PT), in patients with rheumatoid arthritis (RA). METHODS: RA patients receiving a 16-day MRCT were eligible. MRCT was delivered to participants in 64 PT sessions of various modalities with a minimum of 1.400 Minutes of treatment. The primary outcome was the change in pain levels measured on a numeric rating scale (0-10) between baseline and discharge. Secondary outcomes were assessments of i) disease activity, ii) functional disabilities, iii) serum cytokine levels, iv) analgesic usage, v) patient global health and vi) patient's satisfaction with their therapeutic response to MRCT from baseline to discharge and over a 12-week follow-up. RESULTS: 53 RA patients completed the study and were analysed. Pain levels were reduced significantly and clinically meaningfully (mean ± standard error: -2.1 ± 0.3, p<0.001). Effects of MRCT lasted up to 12 weeks after discharge. After MRCT and during the 12-week follow-up use of analgesics was reduced compared to baseline. Regression analyses revealed no influencing factors on change in pain levels. Patient global health assessment remained improved throughout the entire follow-up period. No MRCT-related side effects were recorded. CONCLUSIONS: MRCT as a multimodal treatment concept with a strong emphasis on PT reduces pain significantly and in a clinically meaningful manner allowing for reduced analgesic usage.

Multimodal rheumatologic complex treatment in patients with spondyloarthritis - a prospective study.

INTRODUCTION: Aim of this study was to prospectively assess the effects of multimodal rheumatologic complex treatment (MRCT), a special concept of in-patient physical treatment (PT) for treating spondyloarthritis (SpA), namely radiographic (r-) and non-radiographic (nr-) axial (ax-) SpA and psoriatic arthritis (PsA). METHODS: r-, nr-axSpA and PsA patients receiving a 16-day MRCT were eligible. MRCT was delivered to participants over 64 PT sessions of various modalities with a minimum of 1,400 min of treatment. Primary outcome was a change in pain levels measured on a numeric rating scale (NRS, 0 - 10) between baseline and discharge. Secondary outcomes were assessments of i) disease activity ii) functional disabilities iii) serum cytokine levels iv) analgesic usage v) patient global health assessment and patients' satisfaction with their therapeutic response to MRCT from baseline to discharge and over a 12-week follow-up. RESULTS: 50 patients completed the study and were analysed. Pain levels were improved significantly (p < 0.001, 95% confidence interval -2.25 to -0.8,). Further analyses revealed no influencing factors or relevant inter-group differences. Positive effects of MRCT lasted up to 12 weeks after discharge. Analgesic usage was reduced compared to baseline. Patient global health assessment continued to be improved throughout the whole follow-up. No MRCT-related harms were recorded. CONCLUSION: MRCT as a multimodal treatment concept with a strong emphasis on PT reduces pain in SpA meaningfully and facilitates reduced analgesic usage.

Sensitivity to change of joint count composite indices in 72 patients with systemic sclerosis.

OBJECTIVES: We validated the responsiveness of joint count composite indices (JCCIs) in 72 patients with systemic sclerosis (SSc). METHODS: Changes in Disease Activity Score of 28 Joints using ESR and CRP (DAS28-ESR, DAS28-CRP), Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) were evaluated in a one-year follow-up study. Charts of patients including swollen/tender joint counts, laboratory signs of inflammation, and visual analogue scales referring to disease activity, severity and pain were also blindly categorized by two rheumatologists as improved, unchanged or deteriorated. These categories were used as references for the determination of effect size (ES) and standardised response mean (SRM). RESULTS: Articular inflammation improved in 15, deteriorated in 12, and remained unchanged in 45 (63%) patients with SSc based on the concordant opinion of two clinical investigators. All four JCCIs were sensitive to changes (ES>1; SRM>1). The correlation between changes in JCCIs and the physicians' evaluation was high (r >0.68; p<0.001). Arthritis was predominantly prone to change in patients with high JCCIs, impaired functional status, anti-RNA polymerase III antibodies and patients on DMARD therapy. Synovitis was more prevalent in patients with early diffuse SSc, and tended to improve during the follow-up. CONCLUSIONS: All four JCCIs were sensitive to changes, if tender/swollen joints were present at baseline. Articular inflammation was most prone to change in patients with high JCCIs, impaired functional status and already decreased health-related quality of life at baseline.

Adipokines and Inflammation Alter the Interaction Between Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells.

Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 µg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm2: 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm2: -40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (-6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids.

Evaluation of a special concept of physical therapy in spondyloarthritis: German multimodal rheumatologic complex treatment for spondyloarthritis.

OBJECTIVES: Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment. As physical therapy is a key concept in the treatment of spondyloarthritis (SpA), we conducted a monocentric retrospective analysis of the effects of MRCT on pain and functional status in patients with SpA including patients with axial spondyloarthritis (axSpA), non-radiographic axial spondyloarthritis (nr-axSpA) and psoriatic arthritis with axial involvement (axPsA). METHODS: 134 treatment episodes provided to 100 patients with SpA between 2014 and 2017 were analysed. We evaluated changes in pain intensity, in functional status and in disease activity before and after a treatment episode. In addition, we assessed potential influences of various patient characteristics, the course of the disease and comorbidities. RESULTS: Overall, MRCT resulted in significant amelioration of pain (NRS: p < 0.001), significant improvement of functional capacity (FFbH: p = 0.03; HAQ: p = 0.02; BASFI: p < 0.001) and significant reduction of disease activity (BASDAI p < 0.001; DAS28: p = 0.009). In general, treatment effects on axSpA, nr-axSpA and axPsA were comparable. Different aspects of the disease and its previous course did not have a significant effect on the outcome parameters. Comorbidities (e.g. fibromyalgia) did not significantly influence treatment response. CONCLUSION: MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia), thus underlining the importance of non-pharmacological and physical treatment in the treatment of SpA.Key Points• Physical treatment is a key component in treating SpA.• Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment.• MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia).• MRCT could be a role model of treating SpA by means of physical therapy as its effects are not influenced by therapy, disease duration or comorbidities and as it has no side effects.

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study.

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

The activin-follistatin anti-inflammatory cycle is deregulated in synovial fibroblasts.

BACKGROUND: Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown. METHODS: Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1ß or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot. RESULTS: In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1ß and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin. CONCLUSION: The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment.

The effects of a single carbon dioxide and hot water hand bath on acral perfusion in systemic sclerosis: A randomized, clinical study.

Secondary Raynaud's phenomenon is the most common manifestation of systemic sclerosis, affecting more than 99% of systemic sclerosis patients, and a major cause of morbidity. Frequent and prolonged secondary Raynaud's phenomenon attacks not only cause severe discomfort and pain but also ischemic acral tissue damage. In addition to vasoactive drugs, carbon dioxide (CO2) hand bath and hot water bath are potential non-pharmacological treatment options which can be self-administered by affected patients at any time. In order to compare the efficacy of these two physical measures, this randomized, clinical study evaluated the effects of a single CO2 hand bath in patients with systemic sclerosis and secondary Raynaud's phenomenon and a healthy control group versus a single hot water hand bath on acral perfusion in systemic sclerosis by Doppler ultrasonography. None of the patients had currently digital ulcers, a vasoactive medication or a concomitant vascular disease. CO2 immersion induced an acute hemodynamic response, whereas hot water immersion had no significant effect on acral perfusion in systemic sclerosis.

Intravenous sildenafil acutely improves hemodynamic response to exercise in patients with connective tissue disease.

BACKGROUND: Hemodynamic assessment during exercise may unmask an impaired functional reserve of the right ventricle and the pulmonary vasculature in patients with connective tissue disease. We assessed the effect of intravenous sildenafil on the hemodynamic response to exercise in patients with connective tissue disease. METHODS: In this proof-of-concept study, patients with connective tissue disease and mean pulmonary arterial pressure (mPAP) >20 mm Hg were subjected to a supine exercise hemodynamic evaluation before and after administration of intravenous sildenafil 10 mg. RESULTS: Ten patients (four with moderately elevated mPAP 21-24 mm Hg; six with mPAP >25 mm Hg) underwent hemodynamic assessment. All of them showed markedly abnormal exercise hemodynamics. Intravenous sildenafil was well tolerated and had significant hemodynamic effects at rest and during exercise, although without pulmonary selectivity. Sildenafil reduced median total pulmonary resistance during exercise from 6.22 (IQR 4.61-8.54) to 5.24 (3.95-6.96) mm Hg·min·L-1 (p = 0.005) and increased median pulmonary arterial capacitance during exercise from 1.59 (0.93-2.28) to 1.74 (1.12-2.69) mL/mm Hg (p = 0.005). CONCLUSIONS: In patients with connective tissue disease who have an abnormal hemodynamic response to exercise, intravenous sildenafil improved adaption of the right ventricular-pulmonary vascular unit to exercise independent of resting mPAP. The impact of acute pharmacological interventions on exercise hemodynamics in patients with pulmonary vascular disease warrants further investigation. TRIAL REGISTRATION: Clinicaltrials.gov NCT01889966.

Systemic sclerosis associated interstitial lung disease - individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group.

BACKGROUND: Interstitial lung disease in systemic sclerosis (SSc-ILD) is a major cause of SSc-related death. Imunosuppressive treatment (IS) is used in patients with SSc for various organ manifestations mainly to ameliorate progression of SSc-ILD. Data on everyday IS prescription patterns and clinical courses of lung function during and after therapy are scarce. METHODS: We analysed patients fulfilling American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2013 criteria for SSc-ILD and at least one report of IS. Types of IS, pulmonary function tests (PFT) and PFT courses during IS treatment were evaluated. RESULTS: EUSTAR contains 3778/11,496 patients with SSc-ILD (33%), with IS in 2681/3,778 (71%). Glucocorticoid (GC) monotherapy was prescribed in 30.6% patients with GC combinations plus cyclophosphamide (CYC) (11.9%), azathioprine (AZA) (9.2%), methotrexate (MTX) (8.7%), or mycophenolate mofetil (MMF) (7.3%). Intensive IS (MMF + GC, CYC or CYC + GC) was started in patients with the worst PFTs and ground glass opacifications on imaging. Patients without IS showed slightly less worsening in forced vital capacity (FVC) when starting with FVC 50-75% or >75%. GC showed negative trends when starting with FVC <50%. Regarding diffusing capacity for carbon monoxide (DLCO), negative DLCO trends were found in patients with MMF. CONCLUSIONS: IS is broadly prescribed in SSc-ILD. Clusters of clinical and functional characteristics guide individualised treatment. Data favour distinguished decision-making, pointing to either watchful waiting and close monitoring in the early stages or start of immunosuppressive treatment in moderately impaired lung function. Advantages of specific IS are difficult to depict due to confounding by indication. Data do not support liberal use of GC in SSc-ILD.

Functional disability and its predictors in systemic sclerosis: a study from the DeSScipher project within the EUSTAR group.

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.

Disease-Specific Effects of Matrix and Growth Factors on Adhesion and Migration of Rheumatoid Synovial Fibroblasts.

In rheumatoid arthritis (RA), cartilage and bone matrix are degraded, and extracellular matrix (ECM) proteins, acting as cellular activators, are liberated. Similar to ECM proteins, matrix-bound chemokines, cytokines, and growth factors (GFs) influence functional properties of key cells in RA, especially synovial fibroblasts. The role of these molecules on attachment, migration, and proinflammatory and prodestructive activation of RASFs was analyzed. Adhesion/migration of RASFs were examined under GF-enriched (GF+) or -reduced (GF-) conditions with or without addition of matrix-associated GFs, TGF-ß, and platelet-derived GF to GF- or culture supernatants. Fibroblast adhesion and alterations in proinflammatory/prodestructive properties (e.g., IL-6/matrix metalloproteinase 3-release) in response to matrix-associated molecules were compared. Effects of GF+, GF-, and other ECM components on human RASF-mediated cartilage invasion were examined in the SCID mouse model. RASF adhesion under GF- conditions was significantly lower compared with GF+ conditions (6.8- versus 8.3-fold). This effect was specific for RA because control cells showed opposite effects (e.g., osteoarthritis synovial fibroblasts [SF]; GF- versus GF+: 10.7- versus 8-fold). Addition of TGF-ß to GF- increased RASF attachment (12.7-fold) compared with other matrices and components. RASF adhesion to GF+ matrix resulted in the strongest IL-6 and matrix metalloproteinase-3 release, and was even more pronounced compared with supplementation of single GFs. In vivo, GF- matrix decreased RASF-mediated cartilage invasion compared with GF+ matrix. ECM components and especially GFs when bound within ECM actively enhance RASF attraction and cartilage adhesion. This observation was specific for RASFs as a reverse behavior was observed for controls.

Adoptive Cellular Gene Therapy for the Treatment of Experimental Autoimmune Polychondritis Ear Disease.

In the past, the clinical therapy for autoimmune diseases, such as autoimmune polychondritis ear disease, was mostly limited to nonspecific immunosuppressive agents, which could lead to variable responses. Currently, gene therapy aims at achieving higher specificity and less adverse effects. This concept utilizes the adoptive transfer of autologous T cells that have been retrovirally transduced ex vivo to express and deliver immunoregulatory gene products to sites of autoimmune inflammation. In the animal model of collagen-induced autoimmune polychondritis ear disease (CIAPED), the adoptive transfer of IL-12p40-expressing collagen type II (CII)-specific CD4+ T-cell hybridomas resulted in a significantly lower disease incidence and severity compared with untreated or vector-only-treated animals. In vivo cell detection using bioluminescent labels showed that transferred CII-reactive T-cell hybridomas accumulated in the inflamed earlobes of the mice with CIAPED. In vitro analysis demonstrated that IL-12p40-transduced T cells did not affect antigen-specific T-cell activation or systemic anti-CII Ab responses. However, IL-12p40-transduced T cells suppressed IFN-γ and augmented IL-4 production, indicating their potential to act therapeutically by interrupting Th1-mediated inflammatory responses via augmenting Th2 responses. These results indicate that the local delivery of IL-12p40 by T cells could inhibit CIAPED by suppressing autoimmune responses at the site of inflammation.

Update of EULAR recommendations for the treatment of systemic sclerosis.

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

The impact of serial radon and hyperthermia exposure in a therapeutic adit on pivotal cytokines of bone metabolism in rheumatoid arthritis and osteoarthritis.

Secondary osteoporosis is a frequent complication of rheumatoid arthritis (RA) and the result of an imbalance of catabolic and anabolic mechanisms of bone metabolism. The effects of serial low-dose radon and hyperthermia (LDRnHT) exposure in a therapeutic adit (12 applications in 3 weeks) on the serum levels of the cytokines osteoprotegerin (OPG), receptor activator of NF kappa-B ligand (RANKL), tumor necrosis factor-α (TNF-α), and also on the RANKL/OPG ratio were investigated in 25 RA patients and an age-matched control of 24 patients with osteoarthritis (OA). Cytokine measurements were performed at baseline and after completion of LDRnHT. Anti-CCP antibodies (ACPA) were measured in RA patients in parallel. Medication in both groups was limited to non-steroidal anti-inflammatory drugs, and low-dose prednisolone (16 of 24 RA patients) as needed. RA and OA patients showed a significant decrease of TNF-α levels (p < 0.001). Both groups showed significantly decreased levels of RANKL (RA: p < 0.001, OA: p < 0.01). Only the RA patients presented a significant increase of OPG (p < 0.01) and decrease of the RANKL/OPG ratio (p < 0.01), and the ACPA levels (p < 0.001). LDRnHT results in a reduction of osteocatabolic and an increase of osteoanabolic cytokines, which represents the molecular basis for inhibiting osteoclastic activity in secondary osteoporosis and explains in part the effect of LDRnHT this physical therapy modality in a key inflammatory disease. Although reduced ACPA levels were observed under the therapy and although this could potentially contribute to an osteoprotective effect, in this case, it is rather uncertain as the reduction was only minor in magnitude.

Is osteonecrosis of the lunate bone an underestimated feature of systemic sclerosis? A case series of nine patients and review of literature.

Osteonecrosis of the lunate bone, also known as Kienböck's disease, is a very rare disease of unknown cause. Until today, only six cases of osteonecrosis of the lunate bone in patients with systemic sclerosis (SSc) have been reported in the literature. It is unknown whether these few cases reflect only a coincidence of two rare diseases or whether osteonecrosis of the lunate bone is a potential currently underestimated disease-associated feature of SSc. In this study, we report the clinical course of nine SSc patients with magnetic resonance imaging proven osteonecrosis of the lunate bone and discuss associated disease characteristics and potential underlying pathophysiological mechanisms. Overall, our observations suggest that osteonecrosis of the lunate bone is a frequent and so far under-recognized manifestation of SSc which might be linked to SSc-related vasculopathy. It is important to distinguish osteonecrosis of the lunate bone from wrist arthritis in SSc patients because the clinical treatment is different. In general, the clinical progression of osteonecrosis of the lunate bone seems to be slow in SSc patients. As most of the patients have only minor complaints, watchful waiting in combination with analgesic therapy seems to be a feasible treatment approach in most patients whether an operative intervention might be necessary in rapid progressive cases.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.