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- Demirdal, D, et al.
(författare)
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CHARACTERISATION OF SWEDISH MYOSITIS PATIENTS WITH ANTI-MDA5 AUTOANTIBODIES AND CORRELATION OF CLINICAL FEATURES WITH AUTOANTIBODY LEVELS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 751-752
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The association between anti-melanoma differentiation association protein 5 autoantibodies (aMDA5) and rapidly progressive interstitial lung disease (RP-ILD) in clinically amyopathic dermatomyositis is well established in Asian population cohorts. In western cohorts, ILD has been strongly associated with aMDA5 but data regarding RP-ILD have been more conflicting. It is also suggested that western cohorts have more pronounced myopathic features than Asian.ObjectivesTo characterise the disease manifestations of a Swedish aMDA5 positive idiopathic inflammatory myositis (IIM) cohort and to explore antigen reactivity of the MDA5 protein.MethodsFirst available serum samples collected from 28 consecutive patients with IIM and positive aMDA5 ever tested by ELISA, Line Blot (LB) or Immunoprecipitation, attending Karolinska University Hospital between 1999 and 2021, were included. Clinical data including presence of anti-SSA autoantibodies by ELISA or LB was retrieved retrospectively. An in-house ELISA was used to screen serum samples for reactivity against a recombinant MDA5 protein (rMDA5, aa A110-D1025, UniProt ID Q9BYX4) and seven MDA5-derived constructs containing different domains. Correlations between aMDA5 reactivity levels and clinical data were explored.ResultsNine patients showed no reactivity to any of the rMDA5 constructs by ELISA and were excluded from further analysis.Reactivity against rMDA5 was confirmed by ELISA in 19 patients (median 184.7 µg/mL (interquartile range (IQR) 277.07). The cohort included 13 male and 6 female patients, 94% Caucasian, with mean age at diagnosis of 41.05 years (standard deviation (SD) 10.5). Median disease duration at time of sampling was 0 months (IQR 1). All patients except one had signs of muscle involvement (muscle weakness, elevated muscle enzymes, muscle oedema or muscle biopsy consistent with myositis). At diagnosis 63.2% of patients reported muscle weakness (21.1 % had a manual muscle test 8 score <75). Dermatological findings were observed in 17/19 (89.7 %). During disease course nine patients (47.4%) had confirmed arthritis.ILD was diagnosed in 16/19 patients (84.2%), four of these (25%) developed a RP-ILD. One patient passed away due to RP-ILD and one required a lung transplant. Patients with ILD had a statistically significant higher mean age at diagnosis than those without (42.8.5 (SD 10.3) vs 31.3 (SD 4.7) years, p=0.02). Patients developing RP-ILD were not significantly older than patients with chronic ILD. Respiratory symptoms were reported by 75% of patients with ILD at time of diagnosis. The mean total lung capacity (TLC) of the ILD cohort was 68% (SD 17), mean diffusion capacity of carbon monoxide (DLCO) was 59% (SD 15) and mean forced vital capacity (FVC) was 62% (SD 19). There was a higher proportion of patients with CRP ≥ 3 times the reference range at diagnosis amongst patients with FVC <70 % than patients with FVC >70 % (88.9 % vs 16.7 %, p= 0.01).Ten patients (52.6%) had anti-SSA autoantibodies, all had ILD. Anti-SSA positive patients had a statistically significant lower TLC than those without (62% vs 79% respectively, p=0.04) and a lower FVC (57% vs 76% respectively, p=0.05).We found a weak non-statistically significant negative correlation between titres of aMDA5 and TLC, DLCO and FVC (Pearson coefficients -0.187, -0.289, -0.130 respectively). Frequency of ILD was higher in patients with aMDA5 titres >100 µg/mL than those with titers <100, but not statistically significant (81.3% vs 18.8%, respectively).ConclusionIn this Caucasian cohort of aMDA5 positive IIM patients, ILD was present in over 80% of patients, of these, one quarter had RP-ILD. Older patients were more likely to present with ILD. Anti-SSA positivity and higher CRP levels were associated with worse lung function. We found a weak negative correlation between aMDA5 titres and lung function tests, as well as a trend of higher frequency of ILD in patients with higher aMDA5 titres. Muscle and skin involvement were found in a high proportion of patients.AcknowledgementsD. Demirdal & E. Van Gompel contributed equally to this abstract.Disclosure of InterestsDeniz Demirdal: None declared, Eveline Van Gompel: None declared, Edvard Wigren: None declared, Maryam Dastmalchi: None declared, Begum Horuluoglu: None declared, Angeles Shunashy Galindo-Feria: None declared, Susanne Gräslund: None declared, Karine Chemin: None declared, Ingrid E. Lundberg Shareholder of: Roche and Novartis., Consultant of: Consulting fees from Corbus Pharmaceuticals Inc, Astra Zeneca, Bristol Myer´s Squibb, Corbus Pharmaceutical, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, and Janssen, Grant/research support from: Research grants from Astra Zeneca, Antonella Notarnicola Speakers bureau: compensation for lecture at conference sponsored by Boehringer Ingelheim.
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- Jacob, Alexander W., et al.
(författare)
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Sentinel-1 InSAR Coherence for Land Cover Mapping : A Comparison of Multiple Feature-Based Classifiers
- 2020
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Ingår i: IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing. - : IEEE. - 1939-1404 .- 2151-1535. ; 13, s. 535-552
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Tidskriftsartikel (refereegranskat)abstract
- This article investigates and demonstrates the suitability of the Sentinel-1 interferometric coherence for land cover and vegetation mapping. In addition, this study analyzes the performance of this feature along with polarization and intensity products according to different classification strategies and algorithms. Seven different classification workflows were evaluated, covering pixel- and object-based analyses, unsupervised and supervised classification, different machine-learning classifiers, and the various effects of distinct input features in the SAR domain-interferometric coherence, backscattered intensities, and polarization. All classifications followed the Corine land cover nomenclature. Three different study areas in Europe were selected during 2015 and 2016 campaigns to maximize diversity of land cover. Overall accuracies (OA), ranging from 70% to 90%, were achieved depending on the study area and methodology, considering between 9 and 15 classes. The best results were achieved in the rather flat area of Donana wetlands National Park in Spain (OA 90%), but even the challenging alpine terrain around the city of Merano in northern Italy (OA 77%) obtained promising results. The overall potential of Sentinel-1 interferometric coherence for land cover mapping was evaluated as very good. In all cases, coherence-based results provided higher accuracies than intensity-based strategies, considering 12 days of temporal sampling of the Sentinel-1 A stack. Both coherence and intensity prove to be complementary observables, increasing the overall accuracies in a combined strategy. The accuracy is expected to increase when Sentinel-1 A/B stacks, i.e., six-day sampling, are considered.
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- Lundtoft, Christian, et al.
(författare)
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Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
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- Notarnicola, A., et al.
(författare)
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Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82, s. 574-574
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Tidskriftsartikel (refereegranskat)abstract
- Background Autoantibodies are found in up to 80% of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes [1]. Autoantibodies targeting cytosolic 5´-nucleotidase 1A (anti-cN1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM) (2), although detected even in other autoimmune diseases.Objectives To identify new autoimmune targets in IIM by antigen bead array assay.Methods In a first cross-sectional exploratory study, 357 antigens representing 268 proteins were incubated with plasma samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls for screening of IgG reactivity by antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Interesting results obtained for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by western blot. As controls, serum samples from 30 patients with PM and 30 with DM, HLA-matched with the IBM Swedish cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.Results In the exploratory study IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9,7%) than PM (2,8%) and DM samples (2,5%), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 2,3% of SLE and 2,6% of population control samples. In the validation study anti-NDUFA11 autoantibodies were detected in 11/287 IBM patients (3,8%), 0/30 PM and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by western blot (Table 1, Figure 1). The eleven anti-NDUFA11 positive patients showed a trend of lower frequency of wheelchair/walker ever use and higher creatine kinase levels at time of IBM diagnosis compared to the anti-NDUFA11 negative group. Ragged red fibers were significantly more prevalent in anti-NDUFA11 positive than negative patients (p=0.04). Anti-cN1A autoantibodies were detected in 98/287 (34,1%) of IBM, 3/30 (10%) DM and 9/29 (31%) PM patients, p=0.03. Coexistence of anti NDUFA11 and anti-cN1A antibodies was observed in 3 IBM patients.Conclusion Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.References [1]Galindo-Feria AS, Wang G, Lundberg IE. Autoantibodies: Pathogenic or epiphenomenon. Best Pract Res Clin Rheumatol. 2022;36(2):101767.[2]Herbert MK,et al. Disease specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis. 2016;75(4):696-701.
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- Notarnicola, A., et al.
(författare)
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Serum and balf-derived anti-JO1 autoantibodies exhibit high reactivity to distinct HISRS domains and associate with lung and joint involvement in patients with IIM/ASS
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 79, s. 1109-1110
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Autoantibodies that target aminoacyl transfer(t) RNA synthetases (aaRS) represent the serological marker of the anti-synthetase syndrome (ASS), a major subgroup of the idiopathic inflammatory myopathies (IIM) (1). Among the anti-aaRS, anti-histidyl tRNA synthetase (HisRS) autoantibodies (anti-Jo1) are the most common. Up to 90% of IIM/ASS patients diagnosed with interstitial lung disease (ILD) harbor anti-Jo1 autoantibodies (2).Objectives:Reactivity and affinity of anti-Jo1 autoantibodies from serum and broncheoalveolar lavage fluid (BALF) were investigated against HisRS autoantigen. Associations with clinical data from patients IIM/ASS were addressed.Methods:Total IgGs were purified by affinity chromatography. Samples and clinical data were obtained from: i) 26 anti-Jo1+patients (19 at diagnosis, 16/19 at follow-up, 7 BALF/matching serum at baseline; ii) 29 anti-Jo1-(25 serum at diagnosis, 4 BALF/matching serum at baseline); iii) 24 age/gender matched healthy controls. Anti-Jo1 IgG and IgA response against HisRS was evaluated by ELISA and western blot. Affinity was measured by surface plasmon resonance. HisRS full-length (HisRS-FL), two HisRS domains (ABD and CD), and two HisRS splice variants (WHEP and WHEP + ABD splice variant (SV)) were tested. Correlations between autoantibody reactivity and clinical data, at baseline and over disease course, were evaluated.Results:Anti-Jo1 autoantibodies from serum and lung bound HisRS-FL, WHEP and SV with high reactivity and affinity already at diagnosis and recognized both conformational and linear HisRS epitopes (Fig. 1). Levels of autoantibodies (against HisRS-FL, -domains and -splice variants) varied among patients and overtime. Patients with ILD, arthritis and less skin involvement presented higher anti-Jo1 titers compared to those with lower anti-Jo1 titers and to the anti-Jo1 negative group (Fig. 2). Anti-WHEP reactivity in BALF strongly correlated with poor pulmonary function.Conclusion:High reactivity and affinity at time of diagnosis indicates that autoimmunity against HisRS is most likely initiated before IIM/ASS diagnosis. Reactivity to specific splice variants of HisRS may be employed as diagnostic and prognostic markers.References:[1]Marguerie C, Bunn CC, Beynon HL, Bernstein RM, Hughes JM, So AK, Walport MJ: Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. Q J Med 1990, 77(282):1019-1038[2]Richards TJ, Eggebeen A, Gibson K, Yousem S, Fuhrman C, Gochuico BR, Fertig N, Oddis CV, Kaminski N, Rosas IO et al: Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum 2009, 60(7):2183-2192.Fig. 1.Anti-Jo1 reactivity in total IgG purified from the first available serum sampleFig. 2.Reactivity of total anti-Jo1+ IgG purified from the first available serum close to IIM/ASS diagnosis in relation to clinical dataDisclosure of Interests:Antonella Notarnicola: None declared, Charlotta Preger: None declared, Susanna Lundström: None declared, Nuria Renard: None declared, Edvard Wigren: None declared, Eveline Van Gompel: None declared, Angeles Shunashy Galindo-Feria: None declared, Helena Persson: None declared, Maryam Fathi: None declared, Johan Grunewald: None declared, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Susanne Gräslund: None declared, Ingrid E. Lundberg Grant/research support from: Bristol Meyer Squibb, Corbus Pharmaceuticals, Inc and Astra Zeneca, Catia Cerqueira: None declared
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