EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). METHODS: A task force comprising 7 rheumatologists, 15 other healthcare professionals and 3 patients was established. Following a systematic literature review performed to inform the recommendations, statements were formulated, discussed during online meetings and graded based on risk of bias assessment, level of evidence (LoE) and strength of recommendation (SoR; scale A-D, A comprising consistent LoE 1 studies, D comprising LoE 4 or inconsistent studies), following the European Alliance of Associations for Rheumatology standard operating procedure. Level of agreement (LoA; scale 0-10, 0 denoting complete disagreement, 10 denoting complete agreement) was determined for each statement through online voting. RESULTS: Four overarching principles and 12 recommendations were developed. These concerned common and disease-specific aspects of non-pharmacological management. SoR ranged from A to D. The mean LoA with the overarching principles and recommendations ranged from 8.4 to 9.7. Briefly, non-pharmacological management of SLE and SSc should be tailored, person-centred and participatory. It is not intended to preclude but rather complement pharmacotherapy. Patients should be offered education and support for physical exercise, smoking cessation and avoidance of cold exposure. Photoprotection and psychosocial interventions are important for SLE patients, while mouth and hand exercises are important in SSc. CONCLUSIONS: The recommendations will guide healthcare professionals and patients towards a holistic and personalised management of SLE and SSc. Research and educational agendas were developed to address needs towards a higher evidence level, enhancement of clinician-patient communication and improved outcomes.

The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance.

Synovial fibroblasts (SF) drive inflammation and joint destruction in chronic arthritis. Here we show that SF possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In SF and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable. Repeated stimulation of SF with LPS resulted in loss of activating histone marks only in promoters of tolerizable genes. The epigenetic landscape at promoters of tolerizable genes was similar in unstimulated SF and monocytes, whereas the basal configuration of histone marks profoundly differed in genes that were non-tolerizable in SF only. Our data suggest that the epigenetic configuration at gene promoters regulates cell-specific LPS-induced responses and primes SF to sustain their inflammatory response in chronic arthritis.

Characteristics of ScleroID highlighting musculoskeletal and internal organ implications in patients afflicted with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ disease with impaired health-related quality of life (HRQoL). The EULAR SSc Impact of Disease (ScleroID) is a newly introduced SSc-specific patient-reported outcome to evaluate HRQoL in SSc. OBJECTIVE: To investigate the correlation between the ScleroID and the involvement of organ systems as well as disease activity/damage in a SSc cohort from a large tertiary care centre. PATIENTS AND METHODS: The ScleroID and clinical characteristics including internal organ involvement and hand function were investigated in 160 consecutive patients with SSc (median age 46 (43;56) years; diffuse cutaneous SSc 55%). RESULTS: A strong correlation was found between the ScleroID and articular disease activity scores (DAS28-CRP, DAS28-ESR, CDAI, SDAI), a hand function performance test, the Hand Anatomy Index and muscle strength tests. Additionally, a strong significant correlation was discovered using instruments representing hand function and musculoskeletal disability including the Cochin Hand Function Scale, the Quick Questionnaire of the Disability of the Hands, Arms and the Shoulders and the Health Assessment Questionnaire Disability Index. A significant negative correlation was found between the ScleroID score and the 6-min walking test (6MWT) (rho - 0.444, p < 0.001). Clinically mild lung/heart disease did not show increased ScleroID values. The Mouth Handicap in the Scleroderma Scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 also showed significant positive correlations to the ScleroID score (rho: 0.626, p < 0.001; rho: 0.646, p < 0.001, respectively). Patients experiencing oesophageal difficulties bore a significantly higher score compared to individuals with a normal functioning oesophagus (3.2/1.5;4.5/ vs. 2.2/1.0;3.2/, p = 0.011). Moreover, the ScleroID showed a significant positive correlation to the revised EUSTAR disease activity index and modified activity index. CONCLUSION: In a large single-centre cohort, the previously described ScleroID-related findings were confirmed. Furthermore, several organ involvement-related functional and performance tests showed a good correlation to the ScleroID including the 6MWT and gastrointestinal-related complaints. Many aspects of musculoskeletal damage, overall disease activity, pain and fatigue were also well represented in the ScleroID, which efficiently reflects the impact of organ involvement, disease activity and functional damage.

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction.

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology.

[Primary Sjögren's Syndrome - News on Diagnostics and Therapy]. / Primäres Sjögren-Syndrom ­ Neues zu Diagnostik und Therapie.

Primary Sjögren's Syndrome - News on Diagnostics and Therapy Abstract. Primary Sjögren's syndrome is an autoimmune disease that affects primarily the exocrine glands and is mainly characterized by sicca symptoms of the eyes and mouth, but also nose, throat, vagina and skin can be affected. Fatigue and pain are also very characteristic. Systemic manifestations can occur, e.g. in joints, muscles, lungs, kidneys, skin or the nervous system. A feared complication is the development of a lymphoma, the risk being especially high in case of positive anti-SSA-(Ro) antibodies, but also in case of a high ESSDAI score, hypocomplementemia, cytopenia or evidence of ectopic germinal centers in salivary gland biopsies. Diagnosis is principally made by verification of sicca symptoms (e.g. Schirmer's test) and detection of typical antibodies or a typical gland biopsy. Sicca symptoms are primarily treated symptomatically (e.g. artificial tears or saliva). In case of systemic manifestations glucocorticoids, conventional DMARDs or biologics (mostly rituximab) are treatment options. In severe cases, intravenous immunoglobulins or plasma exchange may be required.

Location-specific mechanical response and morphology of facial soft tissues.

The facial tissue of 9 healthy volunteers (m/f; age: 23-60y) is characterized at three different locations using a procedure combining suction measurements and 18MHz ultrasound imaging. The time-dependent and multilayered nature of skin is accounted for by adopting multiple loading protocols which differ with respect to suction probe opening size and rate of tissue deformation. Over 700 suction measurements were conducted and analyzed according to location-specific mechanical and morphological characteristics. All corresponding data are reported and made available for facial tissue analysis and biomechanical modeling. Higher skin stiffness is measured at the forehead in comparison to jaw and parotid; these two regions are further characterized by lower creep deformation. Thicker tissue regions display a tendency towards a more compliant and less dissipative response. Comparison of superficial layer thickness and corresponding mechanical measurements suggests that connective tissue density determines the resistance to deformation in suction experiments.

Nucleofection: a new, highly efficient transfection method for primary human keratinocytes*.

Transfection is an essential tool for numerous in vitro applications including studies of gene expression, promoter analysis, and intracellular signaling pathways and also for therapeutic strategies such as tissue engineering and gene therapy. However, transfection of primary cells including keratinocytes with common methods such as calcium phosphate, DEAE-dextran, liposome-mediated transfer, electroporation or viral vectors is problematic because of low transfection efficiency and the induction of terminal differentiation. Here we analyzed the use of nucleofection, a new, electroporation-based transfection method that enables the DNA to enter directly the nucleus, for the transfection of keratinocytes. Several different conditions were tested and optimized, resulting in a final transfection efficiency of 56% in primary human epidermal keratinocytes. This efficiency is superior to all non-viral transfection methods reported so far. The number of non-viable keratinocytes after nucleofection was low, varying between 14 and 16%. In contrast to other transfection protocols, nucleofection did not induce terminal differentiation in the transfected keratinocytes. In addition, nucleofection is a fast method, because the results can be analyzed within 7 h. In summary, nucleofection is a fast, easy and highly effective alternative for the transfection of primary human keratinocytes, which offers new opportunities for various research applications.