Az aktivitás felmérése és a klinikai paraméterek és biomarkerek vizsgálata szisztémás sclerosisban

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SURVIVAL AND SUBSET CLASSIFICATION ANALYSIS OF 82 PATIENTS WITH INFLAMMATORY MYOPATHY

Background: Idiopathic inflammatory myopathies (IIM) are characterised by chronic muscle inflammation, various organ involvements and the presence of certain specific autoantibodies. Objectives: We assessed survival and characterized subsets based on muscle biopsy and myositis specific autoantibodies (MSAs). Methods: Eighty-two patients with muscle biopsy proven IIM were included in the study. All cases had MSA and myositis associated antibody (MAA) tests (Jo-1, PL-7, PL-12, Mi-2, SRP, Pm-Scl, Ku, ribosomal, AMA-M2) using Western-blot kits. Survival analysis was performed by Kaplan Meier test. Results: Fift y-nine women and 23 men with a mean age of 49.3 ± 14.6 years and with 7.5 ± 4.5 years of mean follow-up time were included. Interstitial lung disease (ILD) (51.2%), arthritis (51.2%), Raynaud’s phenomenon (42.7%), skin symptoms (45.1%), dysphagia (24.4%) and significant cardiac involvement (15.9%) were the most prevalent disease manifestations. 15 cases were associated with malignancies. Myositis subsets were as follow: 26.8% (n=22) polymyositis /PM/, 30.5% (n=25) dermatomyositis/DM/, 1.2% (n=1) juvenile PM/DM, 8.5% (n=7) inclusion body myositis /IBM/, 22% (n=18) overlap myositis /OM/, and 11% (n=9) immune mediated necrotizing myopathy /IMNM/. Malignancy was most frequently associated with IMNM (7 out of 9 patients). Altogether 18 patients died from which 15 deaths can be connected to myositis related events. Eight patients died of malignancies, 5 patients due to cardiac events (heart failure, arrythmia), 2 due to lung fibrosis and 3 by unknown causes. The worst prognosis with a 10-year survival of 31 % was in the IMNM subgroup (p<0.01), followed by patients with PM (68%), IBM (84%) OM (85.1%) and DM (85.3%). Mi-2 positive patients had a favourable prognosis with a 10-year survival of 100%. Patients with IMNM had the worst prognosis (10-year survival of 31.1%), followed by PM (76%), DM and IBM (85.7% each). Patients with antisynthetase antibody-positivity had worse prognosis compared to patients with other antibodies or no identifiable antibodies (10-year survival of 55%, n=16) (p<0.05). Conclusions: Th e worst survivals were seen in the IMNM and PM groups, due to the high frequency of the underlying malignancies and cardiac manifestations. Although ILD was the most frequent involvement, it was not the main cause of death

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

Ligation of TLR Homologue CD180 of B Cells Activates the PI3K/Akt/mTOR Pathway in Systemic Sclerosis and Induces a Pathological Shift in the Expression of BAFF Receptors

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) pathways are known to play a key role in B-cell activation and fibrosis in systemic sclerosis (SSc). Receptors of B-cell activator factor (BAFF) utilize these pathways, which can be influenced by Toll-like receptors (TLRs), as TLRs can alter the expression of BAFF-binding receptors. Our results show that B-cell stimulation via TLR homologue CD180 phosphorylates Akt in diffuse cutaneous SSc (dcSSc) to a lower extent than in healthy controls (HCs). We found basal downregulated BAFF receptor (BAFF-R) and enhanced transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) expression in dcSSc B cells, which might enhance the formation of autoantibody-secreting plasma cells. Moreover, this pathological shift was observed in naive B cells, emphasizing the importance of their increase in SSc. Additionally, we measured higher serum levels of autoantibodies to BAFF in dcSSc patients, suggesting that an imbalance in the complex system of BAFF/anti-BAFF autoantibodies/BAFF-binding receptors may contribute to the development of SSc. Anti-CD180 antibody treatment had opposite effects on the expression of BAFF-R and TACI in HC B cells, resulting in similar levels as observed in SSc B cells without stimulation, which argues against the usefulness of such therapy in SSc

Minimal Clinically Important Differences (MCID) for the Functional Assessment of Chronic Illness Therapy Fatigue Scale in Patients with Systemic Sclerosis

(1) Background: Systemic sclerosis (SSc) is characterized by significant fatigue, causing diminished quality of life (QoL). The aim of this study was to examine fatigue levels and their associations with clinical factors and determine the minimal clinically important difference (MCID) value for the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-FS). (2) Methods: A total of 160 SSc patients and 62 individuals without SSc were followed-up over a 12-month period by measuring the FACIT-FS and the Visual Analogue Scale and the Short Form 36 Vitality Score analyzing changes in exhaustion. (3) Results: Fatigue was strongly correlated with HRQoL, level of pain, emotional disorders, physical capability and functionality. The MCID values for FACIT-FS were calculated as &minus;3 for deterioration and +4 for improvement after a 12-month follow-up. The predictors of improvement of fatigue from baseline parameters were the significant disease activity, the patients&rsquo; poorer functionality and the short disease duration. Patients with scleroderma-related interstitial lung disease at baseline had approximately tripled risks for worsening fatigue. The independent influential factors regarding the changing of FACIT-FS were improving or worsening in the same direction in reference to physical condition, gastrointestinal and emotional factors. (4) Conclusions: Fatigue is a multi-dimensional symptom, which is strongly correlated to HRQoL. MCID values of FACIT-FS can be useful tools in monitoring the changes of HRQoL in clinical trials and in daily practice among patients with SSc

Reduced non-switched memory B cell subsets cause imbalance in B cell repertoire in systemic sclerosis

OBJECTIVES: Analysis of peripheral blood B lymphocytes in patients with systemic sclerosis (SSc) has provided evidence for specific alterations in naive and memory B cell balance. However, memory B cell subsets in SSc have not been thoroughly investigated. This study sought to identify phenotypic abnormalities and activation markers in peripheral blood memory B cells in SSc subtypes. METHODS: Blood samples were obtained from 28 SSc patients with early form of disease (9 limited (lcSSc), 19 diffuse cutaneous SSc (dcSSc)) and 15 healthy controls. After magnetic bead separation of CD19+ B cells, multiparametric flow cytometry was performed and CD19+CD27- IgD+ naive, CD19+CD27+ memory, CD19+CD27+IgD+ non-switched memory CD19+CD27+IgD- switched memory, CD19+CD27-IgD- double negative (DN) memory, CD80+ or CD95+ activated cells were identified. RESULTS: The proportion of naive B cells was higher (p=0.046) in SSc than in controls, with a decreased percentage of memory (p=0.018), especially non-switched memory B cells (p=0.015). The dcSSc patients had a significantly higher frequency of switched memory and DN memory B cells compared to lcSSc patients (p=0.025 and p=0.031). Percentage of CD95+CD27+ memory and CD95+ DN memory B cells was also significantly elevated in dcSSc compared to lcSSc patients (p=0.038 and p=0.045). CONCLUSIONS: We conclude that the decreased proportion of memory B cells in SSc is due to reduction of non- switched memory B cells, resulting in an imbalance between the tolerogenic and activated memory B cell types. Elevated switched and activated CD95+ DN memory B cells may serve as a biomarker for dcSSc and can have a pathogenic potential by cytokine and autoantibody production

The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis:Derivation and validation of a preliminarily revised EUSTAR activity index

BACKGROUND Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. METHODS Three investigators assigned an activity score on a 0-10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate-multivariate linear regression analyses were used to define variables predicting the 'gold standard', their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0-10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). RESULTS A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). CONCLUSIONS A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies