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ZUSAMMENFASSUNGDie RA-ILD ist eine schwerwiegende extraartikuläre Manifestation der RA, welche mit einer gesteigerten Mortalität einhergeht. Dieser Beitrag verschafft einen Überblick und greift neue Erkenntnisse zu diesem wichtigen Thema auf. Eingegangen wird auf Epidemiologie, Risikofaktoren, Prognose sowie auf Diagnostik und Therapie. Besonders wichtig sind die frühe Diagnose und die Evaluation der Risikofaktoren. Diese ermöglichen eine Prognoseabschätzung. Dabei spielt die HRCT-Morphologie der Lungen wie auch eine Mutation in MUC5B eine besondere Rolle. In der täglichen Praxis sollte Augenmerk auf Anamnese, körperliche Untersuchung und die regelmäßige Lungenfunktion gerichtet werden, um progredient fibrosierende Verläufe der RA-ILD frühzeitig zu entdecken. Für diese Verlaufsformen gibt es neben der Therapie mittlerweile auch die Option einer antifibrotischen Therapie.

Objectives Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). Methods We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan–Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. Results It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9–93.8); n = 290] and after 5 years [91.4% (89.2–93.8); n = 357 vs 70.9% (65.2–77.1); n = 106; P Conclusion GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Zusammenfassung Hintergrund Chronische Entzündungserkrankungen (engl. „immune-mediated inflammatory diseases“ [IMID]) sind mit einer erheblichen Krankheitslast verbunden. Diese ist umso ausgeprägter, sofern diese gleichzeitig bei Patienten auftreten oder z. B. weitere Komorbiditäten bestehen. Die Versorgung der IMID ist komplex und involviert diverse medizinische Fachdisziplinen. Ziel der Arbeit Die Beschreibung der Krankheitslast und der aktuellen Arzneimittelversorgung der Patienten mit IMID. Material und Methoden Die retrospektive Querschnittanalyse erfolgte unter Nutzung von Abrechnungsdaten der gesetzlichen Krankenversicherung der InGef-Datenbank. Unter 3.988.695 Versicherten wurden im Jahr 2018 anhand dokumentierter Diagnosen (ICD-10-GM) prävalente Patienten mit Psoriasis (Pso), Psoriasisarthritis (PsA), Spondyloarthritiden (SpA), rheumatoider Arthritis (RA), Morbus Crohn (MC), Colitis ulcerosa (CU) oder Kollagenosen identifiziert. Das gemeinsame Auftreten verschiedener IMID sowie weiterer Begleiterkrankungen wurde im Vergleich zur Referenzpopulation untersucht. Die medikamentöse Versorgung wurde basierend auf vordefinierten Therapieformen beschrieben. Ergebnisse Im Jahr 2018 wurden 188.440 Patienten mit IMID (4,7 %) identifiziert. Im Vergleich zur Referenzpopulation war die Prävalenz von depressiven Episoden und kardiovaskulären Risikoerkrankungen bei Patienten mit IMID höher. Bei MC, CU, RA, und PsA wurden DMARDs (engl. „disease-modifying antirheumatic drugs“) und klassische systemische Therapien am häufigsten eingesetzt. Bei Pso, SpA und Kollagenosen waren NSAR (nichtsteroidale Antirheumatika) die häufigsten Therapieformen oft in Kombination mit anderen Wirkstoffen. Diskussion Ein beträchtlicher Anteil der Patienten mit IMIDs (16,9–27,5 %) leidet an unterschiedlichen Erkrankungen des IMID-Formenkreises. Sie sind häufig von Begleiterkrankungen betroffen und bedürfen einer interdisziplinären medizinischen Versorgung.

Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

ZusammenfassungDas familiäre Mittelmeerfieber (FMF) ist die häufigste autoinflammatorische Erkrankung und gehört zu den monogenetischen Fiebersyndromen. Die Erkrankung beruht auf einer Mutation desMEFV-Gens; dieses ist auf dem kurzen Arm von Chromosom 16 lokalisiert und kodiert für das Protein Pyrin. Pyrin aktiviert über mehrere Schritte eine erhöhte Ausschüttung der proinflammatorischen Zytokine Interleukin (IL)‑1β und IL‑18. Die wichtigsten Symptome sind neben dem Fieber wiederkehrende abdominelle und pleuritische Schmerzen, Gelenkschmerzen und Myalgien, Orchitiden oder auch ein erysipelartiges Exanthem. Die Standardtherapie ist bis heute Colchizin. Ca. 10–15 % der Patienten sprechen jedoch nicht ausreichend auf diese Therapie an oder vertragen die notwendige Dosierung nicht. Bei diesen Patienten und auch bei Patienten mit anhaltend hohen SAA-Werten trotz klinischer Kontrolle stehen uns heute mit den IL‑1 Inhibitoren Anakinra und Canakinumab hocheffektive Alternativen zur Verfügung.

Background: An effective and well-tolerated topical treatment of Raynaud’s phenomenon is needed. The aim of this pilot study was to determine change in skin temperature and self-reported warmth perception from topical rosemary essential oil in patients with systemic sclerosis and secondary Raynaud’s phenomenon. Patients and Methods: Twelve patients with progressive systemic sclerosis and Raynaud’s phenomenon were consecutively enrolled in an open-label pilot study at a university outpatient rheumatology clinic. Each patient received an application of olive oil to both hands as a control and 3 h later an application of a 10% essential oil of Rosmarinus officinalis L. Clinical severity and subjective warmth perception were assessed; skin temperature was measured by infrared thermography. Results: Skin temperature increased significantly after both olive oil and rosemary oil but differences between oils did not reach significance. Self-reported warmth perception increased after rosemary oil but not after olive oil. No adverse effects were observed. Conclusion: Topical rosemary essential oil increased warmth perception in patients with systemic sclerosis-related Raynaud’s phenomenon but did not increase finger skin temperature more than the olive oil control.

We here report on a 60-year-old woman with familial Mediterranean fever (FMF) who developed cognitive impairment 16 years after initial diagnosis. On MRI, a new extensive white matter lesion in the right frontal lobe with mild local mass effect but without contrast enhancement was detectable and classified as a tumefactive lesion. Additional MR spectroscopy showed markedly increased choline levels accompanied by a significant lactate peak, highly suggestive of a low-florid demyelinating process. Although diffuse central nervous system (CNS) lesions have been described in single FMF cases, tumefactive lesions have not been observed in FMF patients without concomitant multiple sclerosis. In summary, this case highlights rare differential diagnoses of atypical, inflammatory CNS lesions and the clinical utility of MR spectroscopy.Die Autoren berichten in dem vorgestellten Fall von einer 60-jährigen Frau mit vorbekanntem familiärem Mittelmeerfieber (FMF), die 16 Jahre nach Diagnosestellung subakut kognitive Defizite entwickelt hatte. In der Bildgebung mittels Magnetresonanztomographie (MRT) zeigte sich als mögliche Erklärung dafür eine neue, frontal rechts gelegene Läsion mit leichtem Masseneffekt, aber ohne Kontrastmittelaufnahme, die als tumefaktive Läsion eingestuft wurde. Eine ergänzende MR-Spektroskopie zeigte einen deutlich erhöhten Cholin-Peak zusammen mit einem Laktat-Peak, was einen niedrigfloriden demyelinisierenden Prozess nahelegte. Auch wenn diffuse Läsionen des zentralen Nervensystems (ZNS) bei FMF vorbekannt sind, so wurden bislang tumefaktive Läsionen bei FMF ohne begleitende Multiple Sklerose nicht beschrieben. Zusammenfassend werden anhand dieses Falls seltene Differenzialdiagnosen von atypischen ZNS-Läsionen und der klinische Nutzen der MR-Spektroskopie hervorgehoben.

Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines.To describe the burden of disease and the current routine drug treatment of patients with IMID.The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment.In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs.A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.HINTERGRUND: Chronische Entzündungserkrankungen (engl. „immune-mediated inflammatory diseases“ [IMID]) sind mit einer erheblichen Krankheitslast verbunden. Diese ist umso ausgeprägter, sofern diese gleichzeitig bei Patienten auftreten oder z. B. weitere Komorbiditäten bestehen. Die Versorgung der IMID ist komplex und involviert diverse medizinische Fachdisziplinen.Die Beschreibung der Krankheitslast und der aktuellen Arzneimittelversorgung der Patienten mit IMID.Die retrospektive Querschnittanalyse erfolgte unter Nutzung von Abrechnungsdaten der gesetzlichen Krankenversicherung der InGef-Datenbank. Unter 3.988.695 Versicherten wurden im Jahr 2018 anhand dokumentierter Diagnosen (ICD-10-GM) prävalente Patienten mit Psoriasis (Pso), Psoriasisarthritis (PsA), Spondyloarthritiden (SpA), rheumatoider Arthritis (RA), Morbus Crohn (MC), Colitis ulcerosa (CU) oder Kollagenosen identifiziert. Das gemeinsame Auftreten verschiedener IMID sowie weiterer Begleiterkrankungen wurde im Vergleich zur Referenzpopulation untersucht. Die medikamentöse Versorgung wurde basierend auf vordefinierten Therapieformen beschrieben.Im Jahr 2018 wurden 188.440 Patienten mit IMID (4,7 %) identifiziert. Im Vergleich zur Referenzpopulation war die Prävalenz von depressiven Episoden und kardiovaskulären Risikoerkrankungen bei Patienten mit IMID höher. Bei MC, CU, RA, und PsA wurden DMARDs (engl. „disease-modifying antirheumatic drugs“) und klassische systemische Therapien am häufigsten eingesetzt. Bei Pso, SpA und Kollagenosen waren NSAR (nichtsteroidale Antirheumatika) die häufigsten Therapieformen oft in Kombination mit anderen Wirkstoffen.Ein beträchtlicher Anteil der Patienten mit IMIDs (16,9–27,5 %) leidet an unterschiedlichen Erkrankungen des IMID-Formenkreises. Sie sind häufig von Begleiterkrankungen betroffen und bedürfen einer interdisziplinären medizinischen Versorgung.

Behçet’s disease (BD) can affect the genital system and is more common in Middle Eastern countries and Asia but also occurs in Caucasian people. Aim of this study was to evaluate the prevalence of sexual dysfunction (SD) and depression in patients with BD compared to a healthy control group (HCG). In addition, differences with regard to depression and patients’ origin were evaluated. This prospective, monocentric study included 106 consecutive patients from our specialized BD outpatient clinic. Patients were asked to fill out the paper based standardized and validated questionnaires International Index of Erectile Function (IIEF), the Female Sexual Function Index (FSFI) and the Beck Depression Inventory (BDI). In addition, 206 healthy controls were asked to fill out the questionnaires. 106 patients with BD were evaluated and 206 participants in the HCG. The mean age in BD group was 40.5 years as compared to 44.4 years in the HCG. Half of the patients had Middle Eastern and half Caucasian origin. SD was found in 24.5% of all subjects. Only 6.9% of male patients showed signs of SD, while half of the women’s group was suffering from SD. The prevalence for SD was significantly higher in women with Middle Eastern ethnic origin compared to women with Caucasian origin (75 vs. 33.3%, p = 0.024). Erectile Dysfunction occurred in 55% of all male patients which was not statistical different from the HCG. Genital ulcers affected 73.6% of all patients. Depression was found in 36.7% of all subjects as compared to 6.25% in the HCG (p p = 0.017) and females (p = 0.013). SD and depression are very common problems in BD and should be addressed by the treating physician. Both manifestations are intensifying each other. Depression especially is more prevalent compared to the healthy population.

For some rare rheumatic diseases the data situation on fertility and pregnancy is still scant. This article attempts to present the data known so far and to derive and supplement some treatment recommendations from the data. A stable disease situation before the pregnancy drastically reduces the risk of complications for mother and child; therefore, an appropriate and timely adjustment of treatment in consultation with patients and gynecologists is important.

To assess muscular abnormalities related to systemic sclerosis (SSc) using shear wave elastography and correlate results with those of clinical tests.We evaluated 55 patients (mean age: 50.4 years; range: 18-88; 34 female) with SSc before treatment and choose muscle groups based on cutaneous involvement and functional impairment [forearms (9); thighs (41); thenar/hypothenar (5)]. We performed shear wave elastography in two orientations to access heterogeneity using virtual touch IQ and mean shear wave velocity values (SWV) and measured skin and fascia thickness. We compared SWVs to the modified Rodnan skin score (mRSS). Twenty-two healthy controls (mean age: 52.0; range: 19-88; 7 female) underwent the same protocol.SWV pattern analysis (homogeneous vs heterogeneous) detected SSc with sensitivity/specificity/negative predictive value/positive predictive value0.79/0.81/0.91/0.62 in transverse and 0.75/0.18/0.91/0.56 in longitudinal orientation. In patients we found poor correlation between SWVs and mRSS but a cutoff of mRSSE = 20 separated them significantly (p0.01). Skin and muscle fascia were significantly thicker in patients vs. controls (p0.001).SSc involves more than increased skin and fascial thickness which is not fully represented by mRSS. Elasticity differs in muscles with and without SSc. The former shows higher SWV and increased heterogeneity in transversal planes of muscular fibers.

Objective Behcet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behcet's disease in a diverse multiethnic population. Methods A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. Results We identified 2 novel genetic susceptibility loci for Behcet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 x 10(-9)) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 x 10(-8)). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 x 10(-8)) of 6 previously identified susceptibility loci in Behcet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behcet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 x 10(-5)), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behcet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. Conclusion We performed the largest genetic association study in Behcet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries., National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [R01AR070148]; NIH [U54GM104938, U19AI082714, UM1AI144292, P30AR053483, P30AR073750], Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) grant number R01AR070148 to Dr. Sawalha. Recruitment and genotyping of the EuropeanAmerican controls was supported by NIH grants number U54GM104938, U19AI082714, UM1AI144292, P30AR053483, and P30AR073750 to Drs. Guthridge and James. This work was supported by the use of study data downloaded from the dbGaP web site, under dbGaP accession phs000272. v1.p1.

Objective Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or ‘never’ DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud’s duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51–24.87), active digital ischaemia: 6.30 (5.34–7.42) and death: 1.86 (1.48–2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.

Regarding scarce capacities an early detection consultation (EDC) was established to discriminate patients in an outpatient setting with inflammatory from non-inflammatory rheumatic diseases. A total of 500 patients suspected of having a rheumatic disease received an appointment within 2 weeks. They were interviewed with the help of a digital questionnaire (RhePort), briefly physically examined followed by a determination of CRP. The questionnaire answers were scored using an algorithm within RhePort (from 0 = non-inflammatory to 4 = highly probably inflammatory). Likewise, after completion of the EDC, the rheumatologists scored the overall assessment. The RhePort score and EDC score were compared with the "true" diagnosis made in a detailed second examination after an average of 10 weeks. In 490 evaluable patients 133 inflammatory (27%) and 357 noninflammatory rheumatic diseases (73%) were diagnosed. A classification based solely on the RhePort questionnaire (score 1) identified 103 out of 129 as inflammatory (sens. 80%) and 125 out of 355 as non-inflammatory (spec. 35%) resulting in an AUC of 0.62 after ROC analysis. With a score 1, the rheumatological assessment after EDC classified 130 out of 133 patients as inflammatory (sensitivity 98%) and 261 out of 357 as non-inflammatory (specificity 73%). The combined EDC can decisively increase the sensitivity and specificity compared to an "automated" survey by means of a digital questionnaire alone. In addition to the early identification and treatment of inflammatory patients, rapid identification of patients who are not in need of rheumatological treatment can create capacities for care.Angesichts knapper rheumatologischer Ressourcen wurde eine digital unterstützte Früherkennungssprechstunde (FS) etabliert zur frühen und sicheren Unterscheidung von Patienten mit entzündlich rheumatischen vs. nichtentzündlichen Erkrankungen. Es erhielten 500 Patienten mit Verdacht auf eine rheumatische Erkrankung einen Termin innerhalb von 2 Wochen. Sie wurden mithilfe eines digitalen Fragebogens (RhePort) befragt, kurz symptomorientiert untersucht, rheumatologische Basislaborwerte wurden bestimmt. Die Antworten wurden mit einem in RhePort hinterlegten Algorithmus gescort (von 0 = nichtentzündlich bis 4 = hochwahrscheinlich entzündlich), ebenso die Gesamteinschätzung der Rheumatologen nach Abschluss der FS. RhePort-Score und FS-Score wurden verglichen mit der Referenzdiagnose, die bei einer ausführlichen Zweituntersuchung nach im Mittel 10 Wochen erfolgte. Bei 490 auswertbaren Patienten wurden 133 entzündlich rheumatische (27 %) und 357 nichtentzündliche Erkrankungen (73 %) diagnostiziert. Eine Klassifikation allein aufgrund des RhePort-Fragebogens (Score 1) erkannte 103 von 129 als entzündlich (Sens. 80 %) und 125 von 355 als nichtentzündlich (Spez. 35 %), was in einer AUC von 0,62 nach ROC-Analyse resultierte. Bei einem Score 1 klassifizierte die rheumatologische Einschätzung nach FS 130 von 133 Patienten als entzündlich (Sensitivität 98 %), 261 von 357 nichtentzündlich (Spezifität 73 %). Die kombinierte FS kann Sensitivität und Spezifität entscheidend steigern im Vergleich zu einer alleinigen „automatisierten“ Befragung mittels Fragebogen. Neben früher Identifikation und Behandlung von entzündlich rheumatischen Patienten können durch schnelle Identifikation nicht rheumatologisch behandlungsbedürftiger Patienten Kapazitäten für die Versorgung geschaffen werden.

Objectives To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I (topo-I) in SSc-patients and to analyse their prognostic relevance. Material and methods Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients’ sera were tested for anti-AT1R and anti-topo-I antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4–217 months, median 28 months). Anti-topo-I antibodies were also analysed for their capacity to inhibit enzyme function. Results A total of 70% of the SSc patients had anti-topo-I- and 51% anti-AT1R antibodies in the ELISA before aSCT. In all instances, anti-topo-I antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2 patients than in group 1 patients (P Conclusions Reactivity of functionally active anti-AT1R antibodies was not influenced by aSCT, while anti-topo-I antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

Die Einfuhrung biologischer und zielgerichteter synthetischer („targeted-synthetic“) krankheitsmodifizierender Basistherapeutika hat zu mehr Spezifitat in der Behandlung von Autoimmunerkrankungen gefuhrt. Sie erfordern allerdings eine kontinuierliche oder intermittierende Verabreichung, sind mit kumulativen Risiken fur Nebenwirkungen verbunden, verursachen hohe Kosten und bieten keine Heilung. Im Gegensatz dazu kann eine hoch dosierte Chemotherapie mit anschliesender Transplantation autologer hamatopoetischer Stammzellen (AHSZT) lang anhaltende und therapiefreie Remissionen bei verschiedenen Autoimmunerkrankungen induzieren. Das Prinzip der AHSZT beruht auf einer Eliminierung wichtiger Komponenten des autoreaktiven immunologischen Gedachtnisses mit anschliesender Neubildung des gesamten Immunsystems. Dieser sog. „Immun-Reset“ ist mit fundamentalen Veranderungen des Immunrepertoires verbunden, die zu einer Toleranzinduktion gegenuber Selbst fuhren. In diesem Beitrag prasentieren wir aktuelle Indikationen der AHSZT fur Autoimmunerkrankungen, basierend auf Registerdaten der Europaischen Gesellschaft fur Blut- und Knochenmarktransplantation (EBMT), und diskutieren Ergebnisse aus mechanistischen Studien, die detaillierte Einblicke in die Wirkungsweise der Therapie bieten.

ObjectivesSystemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).MethodsClinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (60 years).ResultsAmong all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age 60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.ConclusionIn this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.

[Objectives] Behçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease., [Methods] A total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients., [Results] Genetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10−8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10−8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10−7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients., [Conclusions] Male patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease., This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant number R01AR070148.

Purpose of the Review Elevated levels of anti-phospholipid (aPL) antibodies are the most important criterion in the diagnosis of anti-phospholipid syndrome (APS) and are usually responsible for promoting the risk of thrombotic complications. Now, in the course of the global coronavirus disease 2019 (COVID-19) pandemic, measurable aPL antibodies have also been detected in a noticeable number of patients showing a variety ranging from studies with only isolated positive tests to cohorts with very high positivity. Thus, the question arises as to whether these two different clinical pictures may be linked. Recent Findings The ambivalent results showed a frequent occurrence of the investigated aPL antibodies in COVID-19 patients to an individually varying degree. While some question a substantial correlation according to their results, a number of studies raise questions about the significance of a correlation of aPL antibodies in COVID-19 patients. Within the scope of this review, these have now been described and compared with each other. Summary Ultimately, it is necessary to conduct further studies that specifically test aPL antibodies in a larger context in order to make subsequent important statements about the role of APS in COVID-19 and to further strengthen the significance of the described comparisons.

For some rare rheumatic diseases the data situation on fertility and pregnancy is still scant. This article attempts to present the data known so far and to derive and supplement some treatment recommendations from the data. A stable disease situation before the pregnancy drastically reduces the risk of complications for mother and child; therefore, an appropriate and timely adjustment of treatment in consultation with patients and gynecologists is important.Für einige seltenere rheumatische Erkrankungen ist die Datenlage zu Fertilität und Schwangerschaft immer noch gering. Dieser Beitrag versucht die bis dato bekannten Daten wiederzugeben und auch einige Therapieempfehlungen daraus abzuleiten und zu ergänzen. Eine stabile Krankheitseinstellung vor der Schwangerschaft reduziert das Komplikationsrisiko für Mutter und Kind drastisch, daher ist eine entsprechende Therapieanpassung rechtzeitig in Absprache mit Patienten und Gynäkologen wichtig.

ZUSAMMENFASSUNGCheckpoint-Inhibitoren besitzen einen anderen Wirkmechanismus als Chemotherapeutika und können daher auch bei fortgeschrittenen und metastasierten Tumoren noch Teilremissionen, in manchen Fällen sogar komplette Remissionen bewirken. Checkpoint-Inhibitoren blockieren inhibitorische Signale, welche die Krebszelle sich zu Nutzen macht, um einer Erkennung durch das Immunsystem zu entkommen. Hierbei kommt es zu einer erneuten Aktivierung des Immunsystems, die als Nebeneffekt auch die Toleranz des Immunsystems gegenüber normalen Körperzellen verringert und dadurch Autoimmunerkrankungen auslösen oder bereits bestehende verschlechtern kann. Im Rahmen früher Pilotstudien und nachfolgender Zulassungsstudien ergaben sich eine Vielzahl von Nebenwirkungen, die man als immune-related adverse events (irAE) bezeichnet. Die meisten Nebenwirkungen aller Checkpoint-Inhibitoren treten in der Regel erst nach einigen Wochen oder Monaten auf, sind leicht- bis mäßiggradig einzustufen und zumeist reversibel.

ZUSAMMENFASSUNGDie Stammzelltransplantation von hämatopoetischen Stammzellen (HSCT) kann den autoaggressiven Teil des Immunsystems ersetzen. Daher stellt diese Therapie eine Option auch für schwere Autoimmunerkrankungen dar. Vor allem bei der Systemischen Sklerose und der Multiplen Sklerose konnte durch prospektive, randomisierte Studien die Effektivität der Therapie gezeigt werden. Die hämatopoetische Stammzelltransplantation ist eine aggressive Therapie mit vielen möglichen Komplikationen, daher darf die Indikation nur durch erfahrene Zentren und bei gut ausgewählten Patienten erfolgen. Einige Studien laufen derzeit auch in Deutschland.

To prevent serious complications such as permanent loss of vision and structural vascular damage, treatment must be initiated quickly in patients with giant-cell arteritis (GCA). So far, usually long-term corticosteroids in cumulative high dosages have been the standard therapy option. However, steroids are often insufficient to achieve adequate disease control and are associated with serious adverse events. Therefore, steroid-sparing therapy options are the focus of interest.

Objective.Scleroderma renal crisis (SRC) is a severe life-threatening manifestation in patients with systemic sclerosis (SSc). However, the knowledge about risk factors for SRC is limited. We determined here the frequency of SRC and identified risk factors for the prediction of SRC.Methods.Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC.Results.Data of 2873 patients with 10,425 visits were available for analysis with a mean number of registry visits of 3.6 ± 2.8 and a mean time of followup of 3.6 ± 3.8 years. In total, 70 patients developed SRC (70/2873, 2.4%). Of these patients, 57.1% (40/70) were diagnosed with diffuse cutaneous SSc, 31.4% (22/70) with limited cutaneous SSc, and 11.4% (8/70) with SSc-overlap syndromes. Predictive independent factors with the highest probability for SRC were positive anti-RNA polymerase antibodies (RNAP), a history of proteinuria prior to SRC onset, diminished DLCO, and a history of hypertension. Interestingly, positive antitopoisomerase autoantibodies did not predict a higher risk for SRC. Further, patients with SRC were significantly more frequently treated with ACEi and corticosteroids without being independently associated with SRC.Conclusion.In this cohort, SRC has become a rare complication. By far the highest risk for SRC was associated with the detection of anti-RNAP and proteinuria.

Als Eosinophilie bezeichnet man eine Erhohung der absoluten Eosinophilenzahl und unterscheidet hieruber auch bezuglich der Schwere. Die haufigsten Ursachen sind allergische (auch Medikamentennebenwirkungen) und infektiose Ausloser, aber auch maligne und autoimmune Erkrankungen konnen mit einer Eosinophilie einhergehen. Ausgepragte Eosinophilien mit Eosinophilenzahlen >5000/µl finden sich meist bei myeloproliferativen Erkrankungen, der eosinophilen Granulomatose mit Polyangiitis (EGPA) und bei Gewebsmigration von Gewebeparasiten. Als hypereosinophiles Syndrom bezeichnet man eine uber 6 Monate bestehende Eosinophilie mit >1500 Eosinophilen/µl bei Ausschluss einer Parasitose, Allergie oder anderer Ursache und Zeichen einer Gewebeeosinophilie mit Endorganschadigung. Zur Abklarung sollten bei persistierender Eosinophilie neben einer genauen Anamnese und korperlichen Untersuchung auch fruh ein Organscreening, eine Wurmdiagnostik sowie eine hamatologische Labordiagnostik inklusive Knochenmarkuntersuchung erwogen werden.

Objective.To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)–tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission.Methods.The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates.Results.RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83.Conclusion.Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

Introduction Raynaud’s phenomenon is the earliest manifestation of systemic sclerosis. Nitroglycerin gel is the only proven topical therapy. Methods A 53-year-old woman with systemic sclerosis had topical Rosamarinus officinalis (rosemary) oil, often used in anthroposophic medicine, applied to her hands over 3 days and then, separately, olive oil. Results Thermography images showed significant warming of fingers after rosemary oil, but not after olive oil, coinciding with the patient’s subjective experience. Conclusions Topical Rosamarinus officinalis oil had a vasodilator and warming effect in a patient with systemic sclerosis and Raynaud’s phenomenon.

An effective and well-tolerated topical treatment of Raynaud's phenomenon is needed. The aim of this pilot study was to determine change in skin temperature and self-reported warmth perception from topical rosemary essential oil in patients with systemic sclerosis and secondary Raynaud's phenomenon.Twelve patients with progressive systemic sclerosis and Raynaud's phenomenon were consecutively enrolled in an open-label pilot study at a university outpatient rheumatology clinic. Each patient received an application of olive oil to both hands as a control and 3 h later an application of a 10% essential oil of Rosmarinus officinalis L. Clinical severity and subjective warmth perception were assessed; skin temperature was measured by infrared thermography.Skin temperature increased significantly after both olive oil and rosemary oil but differences between oils did not reach significance. Self-reported warmth perception increased after rosemary oil but not after olive oil. No adverse effects were observed.Topical rosemary essential oil increased warmth perception in patients with systemic sclerosis-related Raynaud's phenomenon but did not increase finger skin temperature more than the olive oil control.Hintergrund: Wirksame und gut verträgliche topische Behandlungen des Raynaud-Phänomens werden ge­braucht. Ziel dieser Pilotstudie war es, bei Patienten mit systemischer Sklerose und sekundärem Raynaud-Phänomen die Veränderung der Hauttemperatur und die selbstberichtete Wärmeempfindung nach topischer Anwendung von Rosmarinöl zu erfassen. Patienten und Methoden: In einer rheumatologischen Universitätsklinik wurden nacheinander zwölf Patienten mit progressiver systemischer Sklerose und Raynaud-Phänomen in eine offene Pilotstudie aufgenommen. Jeder Patient erhielt an beiden Händen eine Einreibung mit Olivenöl als Kontrolle und drei Stunden später eine Einreibung mit 10%igem Rosmarinöl (Rosmarinus officinalis L.). Der klinische Schweregrad und die subjektive Wärmeempfindung wurden bestimmt; die Hauttemperatur wurde mittels Infra­rot-Thermografie gemessen. Ergebnisse: Die Hauttemperatur stieg sowohl nach Olivenöl als auch nach Rosmarinöl signifikant an, aber die Unterschiede zwischen den Ölen erreichten keine Signifikanz. Die selbstberichtete Wärmeempfindung stieg nach der Anwendung von Rosmarinöl, nicht aber nach der Anwendung von Olivenöl. Es wurden keine unerwünschten Wirkungen beobachtet. Schlussfolgerung: Ätherisches Rosmarinöl zur äußerlichen Anwendung steigerte die Wärmeempfindung bei Patienten mit systemischer Sklerose und Raynaud-Phänomen, erhöhte aber die Hauttemperatur an den Fingern nicht stärker als die Olivenöl-Kontrolle.