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1.
Rheum Dis Clin North Am ; 45(4): 569-581, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31564297

RESUMO

Major advances have been made in the field of idiopathic inflammatory myopathies (IIM), or myositis, that are likely to facilitate development of new therapeutic strategies that have not yet been applied in this group of diseases. These advances include new classification criteria to better identify the patients with IIM, detection of several new myositis-specific autoantibodies that facilitates subgrouping of patients into more specific clinical phenotypes, development of outcome measures for disease activity, and new response criteria. We have learned from clinical studies that exercise is an important part of treatment and that pharmacologic treatment should be combined with exercise.

2.
Ann Rheum Dis ; 78(11): 1472-1479, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31427438

RESUMO

OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (ß=-0.5 (95% CI -0.9 to -0.2) and ß=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.

3.
J Rheumatol ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31416921

RESUMO

OBJECTIVE: In an eHealth setting, to investigate intra- and inter-rater reliability and agreement of joint assessments and disease activity score (DAS28CRP) in patients with rheumatoid arthritis (RA) and test the effect of repeated joint assessment training. METHODS: Patients with DAS28CRP ≤5.1 were included in a prospective cohort study (clinicaltrials.gov: NCT02317939). Intra-rater reliability and agreement of patient-performed joint counts were assessed through completion of five joint assessments over a two-month period. All patients received training on joint assessment at baseline, only half of the patients received repeated training. A subset of patients was included in an appraisal of inter-rater reliability and agreement comparing joint assessments completed by patients, healthcare professionals (HCPs), and ultrasonography. Cohen's Kappa coefficients and intraclass correlation coefficients (ICC) were used for quantifying of reliability of joint assessments and DAS28CRP. Agreement was assessed using Bland-Altman plots. RESULTS: Intra-rater reliability was excellent with ICC of 0.87 (95%CI: 0.83 to 0.90) and minimal detectable change of 1.13. ICCs for inter-rater reliability ranged between 0.69 and 0.90 (good to excellent). Patients tended to rate DAS28CRP slightly higher than HCPs. In patient receiving repeated training, a mean difference in DAS28CRP of -0.08 was observed (limits of agreements of -1.06 and 0.90). After 2 months, reliability between patients and HCPs was similar between groups receiving single or repeated training. CONCLUSION: Patient-performed assessments of joints and DAS28CRP in an eHealth home-monitoring solution were reliable and comparable with HCPs. Patients can acquire the necessary skills to conduct a correct joint assessment after initial and thorough training.

4.
Ann Rheum Dis ; 78(7): 996-1002, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31138531

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

5.
Clin Exp Rheumatol ; 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30963993

RESUMO

OBJECTIVES: Smoking has been shown to influence rheumatoid arthritis (RA) severity and reduce response to some anti-tumour necrosis factor (anti-TNF) therapies. CIMDORA assessed the association between cigarette smoking and clinical effectiveness of certolizumab pegol (CZP) in Hungarian, Slovak, and Czech RA patients. METHODS: CIMDORA was a prospective, non-interventional, 104-week study (Feb 2011-Aug 2015). The primary endpoint was association between change in 28-joint Disease Activity Score (DAS28[ESR]) from baseline to Week 12, and baseline cigarette pack-year history. Secondary endpoints included association between change in DAS28(ESR) and daily number of cigarettes smoked. The full analysis set (FAS) included all patients receiving ≥1 dose of CZP with all necessary assessments for the primary endpoint. Treatment-emergent adverse events (TEAEs) were reported for all patients receiving ≥1 dose of CZP. RESULTS: The FAS included 218/273 enrolled patients: 155 Hungarian, 46 Czech and 17 Slovak. Hungarian and Czech patients completed 104 weeks (n=141); Slovak patients completed 52 weeks. Mean change in DAS28(ESR) [SD] at Week 12 (-2.78 [1.47]) was not significantly associated with baseline cigarette pack-year history (slope estimate [SE]: 0.03, 95% confidence interval [CI]: -0.16, 0.21 [p=0.77]). Mean DAS28(ESR) [SD] reductions to Week 52 (-3.33 [1.33]) were not significantly associated with daily number of cigarettes smoked in the previous month (SE: 0.001, CI: -0.05, 0.05 [p=0.95]). Two deaths were reported but neither of them was related to CZP. No new safety signals were identified and the safety profile was consistent with previous CZP studies. CONCLUSIONS: After 104 weeks of CZP treatment, patients demonstrated similar DAS28(ESR) improvements, irrespective of smoking history.

6.
Rheumatol Int ; 39(6): 1037-1043, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31025138

RESUMO

The purpose of this cross-sectional study was to assess the visfatin levels in patients with axial spondyloarthritis (axSpA) and to investigate the association between visfatin, disease activity and radiographic spinal damage. Serum visfatin levels were determined by enzyme-linked immunosorbent assay in 64 patients with axSpA (46 with radiographic axSpA (r-axSpA) and 18 with non-radiographic axSpA (nr-axSpA)) and 61 age-/sex-matched healthy individuals. Patients with r-axSpA were further divided into two subsets based on radiographic spinal damage using modified Stoke Ankylosing Spondylitis Spine Score (mSASSS = 0 and mSASSS ≥ 1). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to assess disease activity. C-reactive protein (CRP) levels and human leukocyte antigen (HLA)-B27 were determined. Visfatin levels were significantly higher in patients with axSpA and in the subgroup of patients with r-axSpA than in healthy individuals (p = 0.010 and p = 0.005, respectively), with no difference between patients with r-axSpA and with nr-axSpA. In general, disease activity was high (mean BASDAI 5.01) and was moderately correlated with visfatin levels (r = 0.585; p = 0.011) in patients with nr-axSpA. Visfatin levels correlated with mSASSS (r = 0.281; p = 0.026) and were significantly higher in axSpA patients with mSASSS ≥ 1 than in those with mSASSS = 0 (p = 0.025). Our study showed that circulating visfatin levels are elevated in axSpA patients, may be associated with disease activity in early phase of the disease and with the degree of radiographic spinal involvement.

7.
Arthritis Res Ther ; 21(1): 101, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999929

RESUMO

BACKGROUND: Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR). METHODS: Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR. Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo. Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters. Results were analysed using the per-protocol population. RESULTS: One hundred eight patients from Europe and Japan (48.4 ± 12.02 years old; 77.8% female; mean DAS28-CRP 5.60-5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg (n = 27, 28, 25, and 28, respectively). Ninety-two were MTX-IR; 16 were TNF-IR. At week 12, a statistically significant difference in DAS28-CRP (p = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg (p < 0.05), with higher ACR50 and response rates versus placebo at week 12. A dose-response effect was observed across the DAS28-CRP endpoint with separation versus placebo evident from week 2. The most common treatment-emergent AEs were nasopharyngitis (18.5%, 17.9%, 4.0%, 14.3%), dyspnoea (0.0%, 3.6%, 8.0%, 10.7%), bronchitis (7.4%, 3.6%, 4.0%, 3.6%), and headache (3.7%, 3.6%, 12.0%, 0.0%) for placebo and 20, 80, or 150 mg of namilumab, respectively. No serious infections were observed. One serious AE (myocardial infarction) was observed with 150 mg of namilumab. There was no apparent dose relationship for AEs. A biomarker-based disease activity score showed a dose-dependent decrease at week 12. CONCLUSIONS: This phase II study demonstrates the benefit of inhibiting macrophage activity targeting the GM-CSF for RA. The study met its primary endpoint with a clear dose-response effect. An acceptable tolerability profile was demonstrated over the 12-week study. TRIAL REGISTRATION: ClinicalTrials.gov, NEXUS; NCT02379091 , submitted November 28, 2014.

9.
Cytokine ; 116: 13-20, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30684913

RESUMO

BACKGROUND: S100A11 (calgizzarin), a member of the S100 family, is associated with oncogenesis, inflammation and myocardial damage. Our aim was to analyse S100A11 in idiopathic inflammatory myopathies (IIMs) and its association with disease activity features and cancer development. METHODS: S100A11 in muscle was determined by immunohistochemistry in polymyositis (PM), dermatomyositis (DM), myasthenia gravis (MG) and in subjects without autoimmune inflammatory disease (HC). S100A11 in plasma was measured in 110 patients with IIMs (PM, DM, and cancer associated myositis (CAM) patients) and in 42 HC. Disease activity was assessed by myositis disease activity assessment (MYOACT), muscle enzymes and C-reactive protein (CRP) were measured by routine laboratory techniques; autoantibodies by immunoprecipitation or by immunoblot. RESULTS: We observed an accumulation of S100A11 in the cytoplasm of regenerating and necrotizing muscle fibres of PM and DM patients. S100A11 was increased in plasma of all myositis patients compared to HC (3.8 (1.5-16.8) vs 2.8 (1.7-11.2) ng/ml, p = 0.011) and in DM and CAM patients compared to HC (4.0 (2.2-14.9) and 4.5 (1.5-9.1) vs 2.8 (1.7-11.2) ng/ml, p < 0.001 and p = 0.022, respectively). In all myositis patients, S100A11 correlated with the levels of lactate dehydrogenase (r = 0.256, p = 0.011), aspartate aminotransferase (AST) (r = 0.312, p = 0.002), CRP (r = 0.254, p = 0.022) and MYOACT (r = 0.245, p = 0.022). S100A11 was associated with MYOACT (r = 0.377, p = 0.030) and pulmonary and cutaneous disease activity in DM patients (r = 0.408, p = 0.017 and r = 0.417, p = 0.01, respectively). S100A11 was related to the levels of AST (r = 0.412, p = 0.027) in PM and to the levels of creatine phosphokinase (r = 0.432, p = 0.028) in CAM patients. CONCLUSIONS: We show for a first time a potential implication of S100A11 in the local inflammatory and tissue remodelling processes in myositis and an association of circulating S100A11 with disease activity and extra muscular manifestations in DM.

11.
Rheumatol Int ; 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30392117

RESUMO

S100 proteins are currently being investigated as potential diagnostic and prognostic biomarkers of several cancers and inflammatory diseases. The aims of this study were to analyse the plasma levels of S100A4, S100A8/9 and S100A12 in patients with incomplete systemic lupus erythematosus (iSLE), in patients with established SLE and in healthy controls (HCs) and to investigate the potential utility of the S100 proteins as diagnostic or activity-specific biomarkers in SLE. Plasma levels were measured by ELISA in a cross-sectional cohort study of 44 patients with SLE, 8 patients with iSLE and 43 HCs. Disease activity was assessed using the SLEDAI-2K. The mean levels of all S100 proteins were significantly higher in SLE patients compared to HCs. In iSLE patients, the levels of S100A4 and S100A12 but not S100A8/9 were also significantly higher compared to HCs. There were no significant differences in S100 levels between the iSLE and SLE patients. Plasma S100 proteins levels effectively discriminated between SLE patients and HCs. The area under the curve (AUC) for S100A4, S100A8/9 and S100A12 plasma levels was 0.989 (95% CI 0.976-1.000), 0.678 (95% CI 0.563-0.792) and 0.807 (95% CI 0.715-0.899), respectively. S100 levels did not differentiate between patients with high and low disease activity. Only the S100A12 levels were significantly associated with SLEDAI-2K and with cSLEDAI-2K. S100 proteins were significantly higher in SLE patients compared HCs and particularly S100A4 could be proposed as a potential diagnostic biomarker for SLE.

12.
Scand J Immunol ; : e12732, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451307

RESUMO

We aimed to evaluate in vivo effects of abatacept on phenotypes of T and B cells in the circulation of myositis patients in a sub-study of the ARTEMIS trial. Twelve patients with paired frozen PBMCs before and after 6-month abatacept treatment were included in this sub-study where mass cytometry (CyTOF) was chosen as a technology to be tested for its utility in a real life clinical immune-monitoring setting. Using CyTOF, the peripheral T cell phenotypes demonstrated considerable variation over time and between individuals precluding the identification of treatment-specific changes. We therefore conclude that studies of patient cohorts displaying wide clinical heterogeneity using mass cytometry must be relatively large in order to be suited for discovery research and immune-monitoring. Still, we did find some correlations with functional muscle outcome, namely positive correlations between the ratio of CD4+ T cells and CD8+ T cells (CD4/CD8) in peripheral blood samples both at baseline and after treatment with muscle endurance improvement as assessed by the functional index (FI-2) test. Our data suggests that the CD4/CD8 ratio in circulation at time of active disease may be a predictor of treatment efficacy in myositis patients. This article is protected by copyright. All rights reserved.

13.
Clin Exp Rheumatol ; 36 Suppl 114(5): 74-81, 2018 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30296982

RESUMO

OBJECTIVES: To describe imaging modalities for diagnosing and monitoring of patients with idiopathic inflammatory myopathies. METHODS: A detailed literature search summarising recent data documenting the contribution of different imaging techniques to current management of idiopathic inflammatory myopathies was performed. RESULTS: An overview of methods most frequently used for evaluation of inflammatory myopathies and the description of their role in the diagnostic and monitoring process is presented. CONCLUSIONS: MRI is currently the most useful method capable of demonstrating both inflammatory and post-inflammatory changes in the muscles and surrounding soft tissue. Several studies have documented potential usefulness of other imaging techniques, such as ultrasonography, positron emission tomography, scintigraphy, and dual-energy x-ray absorptiometry.

14.
BMC Musculoskelet Disord ; 19(1): 264, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053814

RESUMO

BACKGROUND: The aims of this study were to analyse the serum concentrations of clusterin (CLU) in patients with hand osteoarthritis (OA) and in healthy controls, to compare CLU levels between patients with erosive and non-erosive disease, and to examine the association of CLU levels with clinical and laboratory parameters. METHODS: A total of 135 patients with hand OA (81 with erosive and 54 with non-erosive disease) and 53 healthy individuals were included in this study. All patients underwent clinical and hand joint ultrasound examination. The Australian/Canadian (AUSCAN) hand osteoarthritis index, algofunctional index and a visual analogue scale (VAS) for the measurement of pain were assessed. Serum levels of CLU were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum levels of CLU were significantly lower in patients with hand OA than in control subjects (p < 0.0001). In addition, patients with erosive hand OA had significantly lower CLU levels than those with non-erosive disease (p = 0.044). Negative correlations between CLU levels and pain as assessed by the AUSCAN score and the VAS were found in patients with erosive hand OA (r = - 0.275; p = 0.013 and r = - 0.220; p = 0.049, respectively). CONCLUSION: The present study demonstrates that lower concentrations of CLU are found in hand OA patients than in healthy individuals, especially in those with erosive disease, and that CLU concentrations have a negative association with hand pain.

15.
Arthritis Res Ther ; 20(1): 158, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053824

RESUMO

BACKGROUND: B-cell activating factor of the tumour necrosis factor family (BAFF) plays a role in autoantibody production and is elevated in dermatomyositis (DM) and anti-Jo-1-positive polymyositis (PM). We investigated the inter-relationships between serum levels of BAFF, anti-Jo-1 autoantibodies, and disease activity. METHODS: Serum levels of BAFF and anti-Jo-1 antibodies measured by enzyme-linked immunosorbent assay (ELISA) were compared to levels of myoglobin, creatine kinase (CK), aminotransferases (alanine (ALT) and aspartate (AST)), C-reactive protein (CRP), and disease activity assessed by the Myositis Disease Activity Assessment Tool in 63 anti-Jo-1 antibody-positive DM/PM patients. Serial serum samples collected at 2 (46 cases) and 3-5 time points (23 cases) were included. Relationships between BAFF, anti-Jo-1, disease activity, CRP, and their longitudinal changes were evaluated using correlation analysis, multiple regression (MR), path analysis (PA), and hierarchical linear models (HLM). RESULTS: Cross-sectional assessment demonstrated significant correlations between the levels of BAFF and anti-Jo-1 antibodies which were associated with levels of CK, myoglobin, AST, and CRP, as well as multivariate associations between BAFF, anti-Jo-1 antibodies, and CK levels. PA revealed direct effects of anti-Jo-1 antibodies on CK (ß = 0.41) and both direct (ß = 0.42) and indirect (through anti-Jo-1 antibodies; ß = 0.17) effects of BAFF on CK. Changes in levels of both BAFF and anti-Jo-1 between two time points (Δ) were associated with Δmyoglobin and Δaminotransferases and changes of BAFF correlated with ΔCK, Δcutaneous, Δmuscle, Δglobal, and Δskeletal disease activities. The longitudinal analysis showed a high intra-individual variability of serum levels of BAFF over time (97%) which could predict 79% of the variance in anti-Jo-1 levels. The anti-Jo-1 variability was explained by inter-individual differences (68%). The close longitudinal relationship between levels of BAFF, anti-Jo-1, and disease activity was supported by high proportions of their variance explained with serum levels of CK and CRP or pulmonary and muscle activities. CONCLUSION: Our findings of associations between levels of BAFF and anti-Jo-1 antibodies in serum and myositis activity suggest a role of this cytokine in disease-specific autoantibody production as part of disease mechanisms, and support BAFF as a potential target for intervention in anti-Jo-1-positive myositis patients.

16.
Clin Rheumatol ; 37(8): 2055-2062, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29656372

RESUMO

Approximately half of patients with rheumatoid arthritis (RA) have normal C-reactive protein (CRP) levels. Calprotectin is a promising and likely more specific biomarker of disease activity than conventionally used acute phase reactants. We aimed to analyse the levels of serum calprotectin in RA patients with clinically active disease and with normal/low CRP. A total of 160 RA patients underwent clinical examination (DAS28-ESR and CDAI). The levels of calprotectin were analysed in patients with moderate to high disease activity with normal/low CRP levels and in 32 healthy subjects. The discriminatory capacity of calprotectin to identify clinically active patients in spite of normal/low CRP was assessed using ROC curves. Out of all RA patients, 74/160 (46.3%) were in remission or had low disease activity according to DAS28 and had normal/low CRP levels. However, 51/160 (32%) had normal/low CRP levels despite having moderate to high disease activity. In these patients, calprotectin levels were significantly higher than those in patients who had normal/low CRP and were in remission or showed low disease activity (2.7 ± 1.5 vs. 2.1 ± 1.2 µg/mL, p = 0.043), which differed from those in healthy subjects (2.7 ± 1.5 vs. 1.9 ± 1.2 µg/mL, p = 0.011). The discriminatory capacity for calprotectin to distinguish clinically active vs. inactive disease despite normal/low CRP using AUC of the DAS28 was 0.607 (95% CI 0.503 to 0.711, p = 0.043). The present study demonstrates that calprotectin may reflect inflammatory activity in RA patients where CRP fails to do so.

17.
Vnitr Lek ; 64(2): 155-163, 2018.
Artigo em Tcheco | MEDLINE | ID: mdl-29595280

RESUMO

Idiopathic inflammatory myopathies form a heterogeneous group of acquired inflammatory diseases afflicting striated muscles. The disease is frequently accompanied by systemic and organ involvement. Dermatomyositis, polymyositis, cancer associated myositis, immune mediated necrotizing myopathy, myositis in overlap syndromes, juvenile myositis and inclusion body myositis are the most frequently encountered subtypes. The basic manifestation is usually painless muscle weakness brought about by inflammation and by other immune changes at the impacted muscles. Enzymes of muscle origin and myoglobin are found elevated in the circulation. There are changes in electrical properties of muscle fibers detected by EMG. A majority of patients have autoantibodies against nuclear or cytoplasmic antigens in their serum. They are often very specific for these diseases and frequently found in association with particular clinical presentations. For some patients with dermatomyositis the increased incidence of cancer is significantly associated with anti-TIF1γ and anti-NXP2 autoantibodies. Differential diagnostics of inflammatory myopathies is often difficult. Misdiagnosis for a non-inflammatory myopathy is not rare and therefore a very thorough diagnostic approach is necessary. Therapy aims to suppression of autoimmune response using glucocorticoids and immunosuppressive drugs. In large part of patients the response to standard treatment is not sufficient and less common synthetic compounds, biological drugs or intravenous immunoglobulins need to be used. Most patients with inclusion body myositis has limited or no effect of any treatment.Key words: autoantibodies - autoimmunity - inflammation - myopathy - myositis - systemic disease.

18.
Arthritis Rheumatol ; 70(5): 679-689, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29361199

RESUMO

OBJECTIVE: Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor α. We undertook to determine the long-term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open-label extension study (ClinicalTrials.gov identifier: NCT01712399). METHODS: In study 1071, patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open-label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long-term safety and efficacy of mavrilimumab were assessed. RESULTS: A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open-label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years). The most common treatment-emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient-years) and bronchitis (n = 51; 5.68 per 100 patient-years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <3.2, and 40.6% of patients achieved a DAS28-CRP of <2.6. CONCLUSION: Long-term treatment with mavrilimumab maintained response and was well-tolerated with no increased incidence of treatment-emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.

19.
Ann Rheum Dis ; 77(4): 495-499, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29343509

RESUMO

OBJECTIVE: To evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). METHODS: 321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48. RESULTS: At week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation. CONCLUSION: Treatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified. TRIAL REGISTRATION NUMBER: NCT01999192; Results.

20.
Ann Rheum Dis ; 77(4): 602-611, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29331962

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

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