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  • 1.
    Lindelof, Linnea
    et al.
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Lundtoft, Christian
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Sayadi, Ahmed
    Uppsala Univ, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Enocsson, Helena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Hong, Mun-Gwan
    Stockholm Univ, Sweden.
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard, MA USA.
    Ekdahl, Kristina Nilsson
    Uppsala Univ, Sweden; Linnaeus Univ, Sweden.
    Nilsson, Bo
    Uppsala Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Eriksson, Oskar
    Uppsala Univ, Sweden.
    A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile2024Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 143, artikel-id 103166Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.

  • 2.
    Walhelm, Tomas
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Wirestam, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Enman, Yvonne
    Karolinska Inst, Sweden.
    Parodis, Ioannis
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Factors Associated with Survival and Discontinuation of Anti-Malarial Agents in Systemic Lupus Erythematosus: Results from a Tertiary Swedish Referral Centre2024Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 13, nr 5, artikel-id 1485Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Antimalarial agents (AMAs) are cornerstone drugs in the treatment of systemic lupus erythematosus (SLE), and their use has established benefits, such as improved prognosis and decelerated accrual of organ damage. The aim of this study was to investigate the frequency of discontinuation of AMAs and associated factors in a Swedish SLE population. Methods: We retrieved data from a regional SLE register where all patients fulfilled the 1982 ACR and/or the 2012 SLICC classification criteria. A total of 328 subjects were included in the analysis. Results: Altogether, 92.4% (303/328) had been prescribed AMAs at some point during their disease. At the last available visit, 67.7% (222/328) were currently prescribed AMAs. Among individuals who had discontinued use, 24.7% (20/81) had developed a contraindication. Side effects were also common reasons for discontinuation (n = 38); gastrointestinal symptoms (52.6%, 20/38) were most common. Patients who discontinued had accrued more organ damage at the last visit (mean SDI: 2.9; SD: 2.8) compared with those still on AMAs (mean SDI: 1.4; SD: 1.8; p = 0.001). Conclusions: Most patients had been exposed to AMAs, but 25% discontinued therapy. Among side effects leading to discontinuation, >50% were gastrointestinal, calling for adequate gastroprotection towards drug retention and prevention of organ damage progression.

  • 3.
    Torell, Agnes
    et al.
    Univ Gothenburg, Sweden.
    Stockfelt, Marit
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Blennow, Kaj
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Sorbonne Univ, France; Univ Sci & Technol China, Peoples R China; Univ Sci & Technol China, Peoples R China; USTC, Peoples R China.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; UCL, England; UCL, England; Hong Kong Ctr Neurodegenerat Dis, Peoples R China; Univ Wisconsin, WI USA.
    Akhter, Tansim
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Roennblom, Lars
    Uppsala Univ, Sweden.
    Pihl, Sofia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken US.
    Saleh, Muna Atallah
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Strevens, Helena
    Skane Univ Hosp, Sweden.
    Joensen, Andreas
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Trysberg, Estelle
    Sahlgrens Univ Hosp, Sweden.
    Majczuk Sennstroem, Maria
    Karolinska Univ Hosp, Sweden.
    Zickert, Agneta
    Karolinska Univ Hosp, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden.
    Bylund, Johan
    Univ Gothenburg, Sweden.
    Jacobsson, Bo
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden; Inst Publ Hlth, Norway.
    Rudin, Anna
    Univ Gothenburg, Sweden.
    Lundell, Anna-Carin
    Univ Gothenburg, Sweden.
    Low CD4+T cell count is related to specific anti-nuclear antibodies, IFNa protein positivity and disease activity in systemic lupus erythematosus pregnancy2024Ingår i: ARTHRITIS RESEARCH & THERAPY, ISSN 1478-6354, Vol. 26, nr 1, artikel-id 65Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundLymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFN alpha protein in SLE pregnancy.MethodsRepeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjogren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and beta 2 glycoprotein I [beta 2GPI]) was assessed with multiplexed bead assay. IFN alpha protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records.ResultsWomen with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-beta 2GPI), IFN alpha protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFN alpha protein positive relative to negative women. Finally, CD4 + T cell count was unrelated to treatment.ConclusionLymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFN alpha protein levels and disease activity, which could be due to divergent disease pathways.

  • 4.
    Gomez, Alvaro
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Parodis, Ioannis
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Obesity and tobacco smoking are independently associated with poor patient-reported outcomes in SLE: a cross-sectional study2024Ingår i: Rheumatology International, ISSN 0172-8172, E-ISSN 1437-160XArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigated associations of obesity and tobacco smoking with health-related quality of life (HRQoL), pain, fatigue, and functional impairment in systemic lupus erythematosus (SLE). Furthermore, we explored whether there was an effect modification between these two factors. We included adult SLE patients from the Linkoping University Hospital (n = 325) in the present cross-sectional analysis. We further included population-based controls and performed cardinality matching to balance age and sex distributions with cases (n = 224). HRQoL was assessed with the EQ-5D index score; pain, fatigue, and overall SLE-related health state with visual analogue scales (VAS; 0 [best] to 100 [worst]); and functional impairment with the HAQ-DI. Unacceptable outcomes were defined as VAS scores corresponding to the 90th percentile derived from the matched controls. SLE patients reported worse scores than controls in all measures, and approximately 30% experienced unacceptable outcomes. When compared with normal-weight, obese SLE patients reported lower HRQoL, and greater functional impairment and risk of unacceptable pain (OR: 3.2; 95% CI 1.6-6.7) and fatigue (OR: 2.1; 95% CI 1.0-4.3). Similarly, the current smokers reported higher levels of functional impairment and a greater risk of unacceptable pain (OR: 3.8; 95% CI 1.8-8.2) and fatigue (OR: 2.8; 95% CI 1.3-5.9) than never smokers. The associations were independent of age, sex, disease duration, disease activity, and organ damage. There was no evidence of a synergistic effect between increased BMI and smoking on any outcome. In summary, obesity and smoking are risk factors for unacceptable patient-reported outcomes in SLE, regardless of clinical activity.

  • 5.
    Saleh, Muna Atallah
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Johanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Infektionskliniken i Östergötland.
    Bendtsen, Marcus
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för samhälle och hälsa. Linköpings universitet, Medicinska fakulteten.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    The prevalence of neutropenia and association with infections in patients with systemic lupus erythematosus: a Swedish single-center study conducted over 14 years2024Ingår i: Rheumatology International, ISSN 0172-8172, E-ISSN 1437-160XArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hematologic abnormalities are common manifestations of SLE, although neutropenia is observed less frequently and is not included in the classification criteria. Nonetheless, neutropenia is a risk factor for infections, especially those caused by bacteria or fungi. We aimed to evaluate the impact of neutropenia in SLE through a systematic investigation of all infections in a large cohort of well-characterized patients, focusing on neutropenia, lymphopenia, and hypocomplementemia. Longitudinal clinical and laboratory parameters obtained at visits to the Rheumatology Unit, Link & ouml;ping University Hospital, and linked data on all forms of healthcare utilization for all the subjects included in our regional SLE register during 2008-2022 were assessed. Data regarding confirmed infections were retrieved from the medical records. Overall, 333 patients were included and monitored during 3,088 visits to a rheumatologist during the study period. In total, 918 infections were identified, and 94 occasions of neutropenia (ANC < 1.5 x 10(9)/L) were detected in 40 subjects (12%). Thirty neutropenic episodes in 15 patients occurred in association with infections, of which 13 (43%) required in-hospital care, 4 (13%) needed intensive care, and 1 (3%) resulted in death. Bayesian analysis showed that patients with >= 1 occasion of neutropenia were more likely to experience one or more infections (OR = 2.05; probability of association [POA] = 96%). Both invasiveness (OR = 7.08; POA = 98%) and severity (OR = 2.85; POA = 96%) of the infections were significantly associated with the present neutropenia. Infections are common among Swedish SLE patients, 12% of whom show neutropenia over time. Importantly, neutropenia is linked to both the invasiveness and severity of infections. Awareness of the risks of severe infections in neutropenic patients is crucial to tailor therapies to prevent severe illness and death.

  • 6.
    Aoun, Mike
    et al.
    Karolinska Inst, Sweden.
    Coelho, Ana
    Karolinska Inst, Sweden.
    Kraemer, Alexander
    Karolinska Inst, Sweden.
    Saxena, Amit
    Karolinska Inst, Sweden.
    Sabatier, Pierre
    Karolinska Inst, Sweden.
    Beusch, Christian Michel
    Karolinska Inst, Sweden.
    Loennblom, Erik
    Karolinska Inst, Sweden.
    Geng, Manman
    Xian JiaotongUniv, Peoples R China.
    Do, Nhu-Nguyen
    Karolinska Inst, Sweden; Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany.
    Xu, Zhongwei
    Karolinska Inst, Sweden.
    Zhang, Jingdian
    Karolinska Inst, Sweden.
    He, Yibo
    Karolinska Inst, Sweden.
    Romero Castillo, Laura
    Karolinska Inst, Sweden.
    Abolhassani, Hassan
    Karolinska Univ Hosp, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Viljanen, Johan
    Uppsala Univ, Sweden.
    Rorbach, Joanna
    Karolinska Inst, Sweden.
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Sweden.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kihlberg, Jan
    Uppsala Univ, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden; IM Sechenov First Moscow State Med Univ, Russia.
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany; Goethe Univ, Germany.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Xian JiaotongUniv, Peoples R China.
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, nr 11, artikel-id e20230101Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

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  • 7.
    Lönnblom, Erik
    et al.
    Karolinska Inst, Sweden.
    Leu Agelii, Monica
    Univ Gothenburg, Sweden.
    Sareila, Outi
    Karolinska Inst, Sweden; Univ Gothenburg, Sweden.
    Cheng, Lei
    Karolinska Inst, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Viljanen, Johan
    Uppsala Univ, Sweden.
    Hafström, Ingiäld
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Andersson, Maria L. E.
    Spenshult Res & Dev Ctr, Sweden; Lund Univ, Sweden.
    Bergström, Göran
    Reg Vastra Gotaland, Sweden.
    Ekwall, Anna-Karin Hultgard
    Univ Gothenburg, Sweden.
    Rudin, Anna
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jacobsson, Lennart T. H.
    Univ Gothenburg, Sweden.
    Kihlberg, Jan
    Uppsala Univ, Sweden.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Holmdahl, Rikard
    Karolinska Inst, Sweden.
    Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis2023Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 75, nr 7, s. 1110-1119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.Methods. We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE).Results. Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE.Conclusion. A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.

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  • 8.
    Hedenstedt, Anna
    et al.
    Uppsala Univ, Sweden.
    Reid, Sarah
    Uppsala Univ, Sweden.
    Sayadi, Ahmed
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Skoglund, Elisabeth
    Uppsala Univ, Sweden.
    Bolin, Karin
    Uppsala Univ, Sweden.
    Frodlund, Martina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Lerang, Karoline
    Oslo Univ Hosp, Norway.
    Joensen, Andreas
    Lund Univ, Sweden.
    Rantapaeae-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Rudin, Anna
    Univ Gothenburg, Sweden.
    Molberg, Oyvind
    Oslo Univ Hosp, Norway.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus2023Ingår i: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 10, nr 2, artikel-id e000926Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectiveB cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.MethodsFemale patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illuminas Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.ResultsDouble-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).ConclusionsHigh genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.

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  • 9.
    Gomez, Alvaro
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jagerback, Sandra
    Karolinska Inst, Sweden; Danderyd Hosp, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Parodis, Ioannis
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Belimumab and antimalarials combined against renal flares in patients treated for extra-renal systemic lupus erythematosus: results from 4 phase III clinical trials2023Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives To determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with SLE treated for extra-renal disease. Methods We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia trials of belimumab (n = 3225), that included patients with active SLE yet no severe ongoing nephritis. Participants were allocated to receive intravenous belimumab 1 mg/kg, intravenous belimumab 10 mg/kg, subcutaneous belimumab 200 mg, or placebo in addition to standard therapy. We estimated hazards of renal flare development throughout the study follow-up (52-76 weeks) using Cox regression analysis. Results In total, 192 patients developed a renal flare after a median of 197 days. Compared with placebo, the risk of renal flares was lower among patients receiving intravenous belimumab 10 mg/kg (HR: 0.62; 95% CI: 0.41, 0.92; P = 0.018) and intravenous belimumab 1 mg/kg (HR: 0.42; 95% CI: 0.22, 0.79; P = 0.007), while no significant association was found for subcutaneous belimumab 200 mg. AMA use yielded a lower hazard of renal flares (HR: 0.66; 95% CI: 0.55, 0.78; P < 0.001). The protection conferred was enhanced when belimumab and AMA were co-administered; the lowest flare rate was observed for the combination intravenous belimumab 1 mg/kg and AMA (18.5 cases per 1000 person-years). Conclusions The protection conferred from belimumab against renal flare development in patients treated for extra-renal SLE appears enhanced when belimumab was administered along with AMA. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate belimumab doses.

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  • 10.
    Eriksson, Per
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Skoglund, Oliver
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Hemgren, Cecilia
    Cty Hosp Ryhov, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Clinical experience and safety of Janus kinase inhibitors in giant cell arteritis: a retrospective case series from Sweden2023Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikel-id 1187584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Janus kinase (JAK)-STAT signaling pathway is relevant in both Takayasu and giant cell arteritis (GCA), and the use of JAK inhibitors (JAKi) in arthritis, psoriasis, and inflammatory bowel disease is nowadays common. Some evidence of the clinical efficacy of JAKi in GCA exists and a phase III randomized controlled trial (RCT) of upadacitinib is currently recruiting. In 2017, we started using barcitinib in a GCA patient with inadequate response to corticosteroids, and later on, we treated other 14 GCA patients with baricitinib/tofacitinib during intense follow-up. The retrospective data of these 15 individuals are here summarized. GCA was diagnosed based on the ACR criteria and/or imaging techniques combined with increased C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) followed by a good initial response to corticosteroids. JAKi was initiated based on inflammatory activity, with increased CRP, presumably dependent on GCA with clinical symptoms, despite unsatisfying high doses of prednisolone. The mean age at JAKi initiation was 70.1 years and the mean exposure to JAKi was 19 months. From initiation, significant reductions in CRP were seen already at 3 (p = 0.02) and 6 (p = 0.02) months. A slower decrease was observed regarding ESR at 3 (p = 0.12) and 6 (p = 0.02) months. Furthermore, the daily prednisolone doses were reduced at 3 (p = 0.02) and 6 (p = 0.004) months. No GCA relapses were observed. Two patients were affected by serious infections, but JAKi therapy was retained or reintroduced after recovery. We present encouraging observational data on JAKi in GCA in one of the hitherto largest case series with long-term follow-up. Our clinical experiences will complement the results from the awaited RCT.

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  • 11.
    Svanberg, Cecilia
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Enocsson, Helena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Govender, Melissa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Martinsson, Klara
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Potempa, Lawrence A.
    Roosevelt Univ, IL USA.
    Rajab, Ibraheem M.
    Roosevelt Univ, IL USA.
    Fernandez-Botran, Rafael
    Univ Louisville, KY USA.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Larsson, Marie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation2023Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 135, artikel-id 102998Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Presence of autoantibodies targeting nuclear constituents, i.e., double-stranded DNA and small nuclear ribonu-cleoproteins (snRNPs), remain a cornerstone in systemic lupus erythematosus (SLE). Fc gamma receptor IIa (Fc gamma RIIa) dependent uptake of nucleic acid containing immune complexes (ICs) by plasmacytoid dendritic cells (PDCs) can activate toll-like receptors (TLRs) such as TLR7 and TLR9 resulting in type I interferon (IFN) production. Pre-viously, the classical liver-derived acute-phase reactant C-reactive protein (CRP) has been suggested to reduce IC -induced type I IFN production, whereas monomeric (mCRP) vs. pentameric (pCRP) mediated effects have not yet been unraveled. Herein, peripheral blood mononuclear cells (PBMCs) or enriched blood DCs from healthy vol-unteers were stimulated with SLE sera, snRNP-IgG (ICs), or TLR ligands with or without pCRP, mCRP, or anti- Fc gamma RIIa antibody. Type I IFNs and cytokine responses were investigated using quantitative PCR, ELISA, and flow cytometry. pCRP inhibited IFN gene expression in PBMCs and enriched DCs after incubation with ICs, compared to ICs alone, whereas mCRP had significantly less inhibitory effect. The effect was independent on the order in which IC or CRP was added to the cells. In addition, pCRP inhibited IFN induced by other TLR stimulators, implicating broader inhibitory effects induced by pCRP. We demonstrate pronounced immunoregulatory functions of CRP whereas the inhibitory properties were evidently dependent on CRPs intact conformational state. The inhibition of type I IFNs was not due to competition of Fc gamma Rs, or binding of CRP to the ICs. Our findings have implications for autoimmune IC-mediated conditions imprinted by type I IFN gene dysregulation.

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  • 12.
    Roennelid, Johan
    et al.
    Uppsala Univ, Sweden.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Correspondence on Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities2023Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 82, nr 1Artikel i tidskrift (Övrigt vetenskapligt)
  • 13.
    Ahmad, Awais
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Brylid, Andre
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Saleh, Muna Atallah
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Enocsson, Helena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus2023Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, nr 12, artikel-id 10398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjogrens syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

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  • 14.
    Parodis, Ioannis
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Lindblom, Julius
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Cetrez, Nursen
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Palazzo, Leonardo
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Ala, Henri
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Houssiau, Frederic A.
    Univ Catholic Louvain, Belgium; Clin Univ St Luc, Belgium.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Rovin, Brad H.
    Ohio State Univ, OH USA.
    Effect of Belimumab on Preventing de novo Renal Lupus Flares2023Ingår i: KIDNEY INTERNATIONAL REPORTS, ISSN 2468-0249, Vol. 8, nr 9, s. 1822-1830Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Belimumab was recently approved for treating lupus nephritis (LN), yet de novo LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative.Methods: We evaluated belimumab efficacy in preventing de novo renal flares and factors associated with renal flare occurrence in nephritis-naive patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis.Results: Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HRadj]: 1.97; 95% confidence interval [CI]: 1.32-2.94; P = 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HRadj: 1.32; 95% CI: 1.07-1.63; P = 0.008), and increasing mean prednisone dose during follow-up (HRadj: 1.03; 95% CI: 1.02-1.04; P < 0.001) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of de novo renal flare (HRadj: 0.38; 95% CI: 0.20-0.73; P = 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HRadj.: 0.69; 95% CI: 0.54-0.88; P = 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HRadj.: 0.74; 95% CI: 0.50-1.09; P = 0.127).Conclusion: We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naive patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.

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  • 15.
    Arkema, Elizabeth V. V.
    et al.
    Karolinska Inst, Sweden.
    Saleh, Muna Atallah
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Simard, Julia F. F.
    Karolinska Inst, Sweden; Stanford Univ, CA USA.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Epidemiology and Damage Accrual of Systemic Lupus Erythematosus in Central Sweden: A Single-Center Population-Based Cohort Study Over 14 Years From ostergotland County2023Ingår i: ACR Open Rheumatology, E-ISSN 2578-5745, Vol. 5, nr 8, s. 426-432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectiveVariations in prevalence and incidence of systemic lupus erythematosus (SLE) within a geographically defined area of central Sweden over a time period of 14 years were examined. Longitudinal differences in disease activity, laboratory test results, and damage accrual were investigated. MethodsAdults (aged & GE;18 years) residing in ostergotland County between 2008 and 2021 (mean adult population: 357,000 citizens) with confirmed SLE were identified and followed prospectively until death, December 31, 2021, or emigration. We estimated annual incidence per 100,000 inhabitants stratified by sex and age. Linear regression with year of diagnosis as the outcome assessed whether each clinical measurement at diagnosis varied over time. ResultsPrevalence on December 31, 2021, was 71.5 of 100,000 (87% female). One hundred twenty-six new cases were identified during the study period, yielding a mean annual incidence of 3.0 of 100,000 inhabitants; this was higher in females (4.8/100,000) than in males (1.2/100,000). Mean age at diagnosis was 43.7 years (SD 17.3). Age at diagnosis and disease activity measures increased over the calendar year of diagnosis (P < 0.05) whereas disease manifestations, including lupus nephritis, did not vary significantly. Accrual of organ damage was demonstrated over time since diagnosis and stratified by sex, lupus nephritis, and corticosteroid-related damage. Approximately 40% developed damage within 5 years. ConclusionSLE prevalence and incidence estimates remained constant over 14 years, and disease phenotypes at SLE onset were similar. SLE was diagnosed also among older individuals with a smaller female-to-male ratio. Estimates of prevalence and incidence were comparable to previous Scandinavian reports but lower than observed in registry data from the US and the UK.

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  • 16.
    Karlsson, Jesper
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Potempa, Lawrence A.
    Roosevelt Univ, IL USA.
    Fernandez-Botran, Rafael
    Univ Louisville, KY USA.
    ONeill, Yasmine
    Uppsala Univ, Sweden.
    Wirestam, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Mobarrez, Fariborz
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Extracellular vesicles opsonized by monomeric C-reactive protein (CRP) are accessible as autoantigens in patients with systemic lupus erythematosus and associate with autoantibodies against CRP2023Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 139, artikel-id 103073Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

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  • 17.
    Wirestam, Lina
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Jönsson, Frida
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Enocsson, Helena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Svensson, Christina
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Weiner, Maria
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Njurmedicinska kliniken US.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Zachrisson, Helene
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Limited Association between Antibodies to Oxidized Low-Density Lipoprotein and Vascular Affection in Patients with Established Systemic Lupus Erythematosus2023Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, nr 10, artikel-id 8987Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with systemic lupus erythematosus (SLE) are at an increased risk of cardiovascular disease. We aimed to evaluate whether antibodies to oxidized low-density lipoprotein (anti-oxLDL) were associated with subclinical atherosclerosis in patients with different SLE phenotypes (lupus nephritis, antiphospholipid syndrome, and skin and joint involvement). Anti-oxLDL was measured by enzyme-linked immunosorbent assay in 60 patients with SLE, 60 healthy controls (HCs) and 30 subjects with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Intima-media thickness (IMT) assessment of vessel walls and plaque occurrence were recorded using high-frequency ultrasound. In the SLE cohort, anti-oxLDL was again assessed in 57 of the 60 individuals approximately 3 years later. The levels of anti-oxLDL in the SLE group (median 5829 U/mL) were not significantly different from those in the HCs group (median 4568 U/mL), while patients with AAV showed significantly higher levels (median 7817 U/mL). The levels did not differ between the SLE subgroups. A significant correlation was found with IMT in the common femoral artery in the SLE cohort, but no association with plaque occurrence was observed. The levels of anti-oxLDL antibodies in the SLE group were significantly higher at inclusion compared to 3 years later (median 5707 versus 1503 U/mL, p < 0.0001). Overall, we found no convincing support for strong associations between vascular affection and anti-oxLDL antibodies in SLE.

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  • 18.
    Torell, Agnes
    et al.
    Univ Gothenburg, Sweden.
    Stockfelt, Marit
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Larsson, Gunilla
    Univ Gothenburg, Sweden.
    Blennow, Kaj
    Univ Gothenburg, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; UCL Inst Neurol, England; UCL, England; Hong Kong Ctr Neurodegenerat Dis, Peoples R China; Univ Wisconsin, WI USA.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Roennblom, Lars
    Uppsala Univ, Sweden.
    Saleh, Muna Atallah
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Strevens, Helena
    Skane Univ Hosp, Sweden.
    Joensen, Andreas
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Trysberg, Estelle
    Sahlgrens Univ Hosp, Sweden.
    Sennstroem, Maria Majcuk
    Karolinska Inst, Sweden.
    Zickert, Agneta
    Karolinska Inst, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Christenson, Karin
    Univ Gothenburg, Sweden.
    Bylund, Johan
    Univ Gothenburg, Sweden.
    Jacobsson, Bo
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Inst Publ Hlth, Norway.
    Rudin, Anna
    Univ Gothenburg, Sweden.
    Lundell, Anna-Carin
    Univ Gothenburg, Sweden.
    Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus2023Ingår i: Arthritis Research & Therapy , E-ISSN 1478-6362, Vol. 25, nr 1, artikel-id 107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundAn increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFN alpha protein levels, autoantibody profile, and gestational age at birth.MethodsRepeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFN alpha protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records.ResultsWomen with SLE had higher LDG proportions and increased IFN alpha protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFN alpha levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFN alpha protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE.ConclusionOur results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFN alpha blood levels in SLE.

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  • 19.
    Lilja, Sandra
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Mavatar Inc, Sweden.
    Li, Xinxiu
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Smelik, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Lee, Eun Jung
    Yonsei Univ, South Korea.
    Loscalzo, Joseph
    Brigham & Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA.
    Marthanda, Pratheek Bellur
    Icahn Sch Med Mt Sinai, NY 10029 USA.
    Hu, Lang
    Xuzhou Med Univ, Peoples R China.
    Magnusson, Mattias
    Natl Board Hlth & Welf, Sweden.
    Sysoev, Oleg
    Linköpings universitet, Institutionen för datavetenskap, Statistik och maskininlärning. Linköpings universitet, Filosofiska fakulteten.
    Zhang, Huan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Zhao, Yelin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Gawel, Danuta
    Mavatar Inc, Sweden.
    Wang, Hui
    Xuzhou Med Univ, Peoples R China.
    Benson, Mikael
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Karolinska Inst, Sweden.
    Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases2023Ingår i: Cell Reports Medicine, E-ISSN 2666-3791 , Vol. 4, nr 3, artikel-id 100956Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prioritization of disease mechanisms, biomarkers, and drug targets in immune-mediated inflammatory dis-eases (IMIDs) is complicated by altered interactions between thousands of genes. Our multi-organ single -cell RNA sequencing of a mouse IMID model, namely collagen-induced arthritis, shows highly complex and heterogeneous expression changes in all analyzed organs, even though only joints showed signs of inflammation. We organized those into a multi-organ multicellular disease model, which shows predicted mo-lecular interactions within and between organs. That model supports that inflammation is switched on or off by altered balance between pro-and anti-inflammatory upstream regulators (URs) and downstream path-ways. Meta-analyses of human IMIDs show a similar, but graded, on/off switch system. This system has the potential to prioritize, diagnose, and treat optimal combinations of URs on the levels of IMIDs, subgroups, and individual patients. That potential is supported by UR analyses in more than 600 sera from patients with systemic lupus erythematosus.

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  • 20.
    Hopkins, Francis
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Nordgren, Johan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Fernandez-Botran, Rafael
    Univ Louisville, KY USA.
    Enocsson, Helena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Govender, Melissa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Svanberg, Cecilia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Svensson, Lennart
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Hagbom, Marie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Nilsdotter-Augustinsson, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Infektionskliniken i Östergötland.
    Nyström, Sofia
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Johanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Infektionskliniken i Östergötland.
    Larsson, Marie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Pentameric C-reactive protein is a better prognostic biomarker and remains elevated for longer than monomeric CRP in hospitalized patients with COVID-192023Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikel-id 1259005Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The differing roles of the pentameric (p) and monomeric (m) C-reactive protein (CRP) isoforms in viral diseases are not fully understood, which was apparent during the COVID-19 pandemic regarding the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Herein, we investigated the predictive value of the pCRP and mCRP isoforms for COVID-19 severity in hospitalized patients and evaluated how the levels of the protein isoforms changed over time during and after acute illness. This study utilized samples from a well-characterized cohort of Swedish patients with SARS-CoV-2 infection, the majority of whom had known risk factors for severe COVID-19 and required hospitalization. The levels of pCRP were significantly raised in patients with severe COVID-19 and in contrast to mCRP the levels were significantly associated with disease severity. Additionally, the pCRP levels remained elevated for at least six weeks post inclusion, which was longer compared to the two weeks for mCRP. Our data indicates a low level of inflammation lasting for at least six weeks following COVID-19, which might indicate that the disease has an adverse effect on the immune system even after the viral infection is resolved. It is also clear that the current standard method of testing pCRP levels upon hospitalization is a useful marker for predicting disease severity and mCRP testing would not add any clinical relevance for patients with COVID-19.

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  • 21.
    Wirestam, Lina
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Benjaminsson Nyberg, Pernilla
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Dzhendov, Todor
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Gasslander, Thomas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Sandström, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Björnsson, Bergthor
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Plasma Osteopontin Reflects Tissue Damage in Acute Pancreatitis2023Ingår i: Biomedicines, E-ISSN 2227-9059, Vol. 11, nr 6, artikel-id 1627Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several scoring systems for clinical prediction of the severity of acute pancreatitis (AP) have been proposed. Yet, there is still a need for an easy-to-measure biomarker. Osteopontin (OPN) may be released to the circulation early during tissue injury, but the significance of OPN in AP has not yet been established. We aimed to evaluate plasma levels of OPN in relation to the severity of AP. In 39 individuals with confirmed AP, plasma was collected on the day of admission and consecutively for three days thereafter. Sex- and age-matched healthy blood donors (n = 39) served as controls. Plasma OPN was measured by a commercial enzyme-linked immunosorbent assay. At admission, patients with AP displayed higher OPN, 156.4 ng/mL (IQR 111.8-196.2) compared to controls, 37.4 ng/mL (IQR 11.7-65.7) (p < 0.0001). However, OPN levels on admission could not discriminate between mild and moderate-to-severe disease (132.6 ng/mL vs. 163.4 ng/mL). Nevertheless, the changes in OPN within 24 h of admission and Day 2/3 were higher among patients with moderate/severe AP (33.7%) compared to mild AP (-8.1%) (p = 0.01). This indicates that OPN is a relevant biomarker reflecting tissue injury in AP. The increase in OPN over time suggests that serial OPN measurements could contribute to the early detection of at-risk patients. Prospective studies assessing OPN in relation to outcome in AP are warranted.

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  • 22.
    Lewander, Per
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Norrköping.
    Wirestam, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Serum levels of soluble urokinase plasminogen activator receptor in juvenile idiopathic arthritis: a single-center Swedish case-control study2023Ingår i: Pediatric Rheumatology, E-ISSN 1546-0096, Vol. 21, nr 1, artikel-id 49Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectivesReliable biomarkers in the early stages of idiopathic arthritis (JIA) are scarce and the disease heterogeneity makes it clinically challenging to predict the risk of joint damage. Biomarkers with prognostic potential are warranted in order to individualize treatment and follow-up in JIA. The soluble urokinase plasminogen activator receptor (suPAR) has been reported as an easily measurable biomarker for prognosis and severity in several rheumatic diseases but it has never been studied in JIA.MethodsSera from 51 well-characterized patients with JIA and 50 age- and sex-matched control subjects were collected and stored for later analysis of suPAR. Patients were carefully followed clinically over 3 years and analysis of erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed as part of clinical routine. Signs of joint erosions were evaluated by radiography.ResultsOverall, the levels of suPAR did not differ significantly between JIA patients and controls but those with polyarticular involvement showed higher suPAR (p = 0.013). In addition, elevated suPAR were associated with joint erosions (p = 0.026). Two RF/anti-CCP negative individuals with erosions showed high levels of suPAR.ConclusionsWe present new data on the biomarker suPAR in JIA. Our results indicate that, apart from RF and anti-CCP, analysis of suPAR could be of additional value in assessing the risk of erosions. Analysis of suPAR early could potentially guide treatment decision-making in JIA, but our observations should be confirmed in prospective studies.

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  • 23.
    Saleh, Muna Atallah
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    A rare case of idiopathic multicentric Castleman disease in a patient with long-standing systemic autoimmunity2022Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 51, nr 2, s. 161-163Artikel i tidskrift (Övrigt vetenskapligt)
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  • 24.
    Svensson, Christina
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Bjarnegård, Niclas
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jonasson, Hanna
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Strömberg, Tomas
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Zachrisson, Helene
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Affected Microcirculation and Vascular Hemodynamics in Takayasu Arteritis2022Ingår i: Frontiers in Physiology, E-ISSN 1664-042X, Vol. 13, artikel-id 926940Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Takayasu arteritis (TAK) is a rare inflammatory disease affecting aorta and its major branches. Ultrasound (US) can detect inflammatory features in the arterial wall, but less is known regarding skin microcirculation and vascular hemodynamics. The aim was to study if assessment of these variables could add valuable information regarding vascular affection in TAK.Methods: 17 patients diagnosed with TAK and 17 age- and sex-matched healthy controls were included. Microcirculatory peak oxygen saturation (OxyP) in the skin after induced ischemia was evaluated with laser Doppler flowmetry/diffuse reflectance spectroscopy. Cerebrovascular reserve capacity (CVR) in the brain was assessed with transcranial Doppler (TCD). Pulse waves were recorded in the radial artery by the aid of applanation tonometry, for calculation of central augmentation index (AIx75). Intima-media thickness (IMT) and stenosis/occlusions were evaluated using US in carotid and central arteries.Results: Reduced OxyP (79 +/- 8% vs. 87 +/- 4%, p < 0.001) was seen in patients with TAK regardless of significant arterial stenosis/occlusion or not. Increased AIx75 (22.3 +/- 13.6 vs. 9.2 +/- 16.3, p = 0.01) was seen in TAK patients without significant stenosis/occlusions. No differences were found in CVR, regardless of proximal stenosis. However, signs of a more high-resistance flow profile were seen in arteria cerebri media.Conclusion: Regardless of arterial stenosis or not, impaired microcirculation of the skin and preserved CVR in the brain were found in subjects with TAK. Signs of increased arterial stiffness in the brain and central arteries were observed. The value of these findings for prediction of future cardiovascular events needs to be clarified in further studies.

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  • 25.
    Karlsson, Jesper
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Weiner, Maria
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Njurmedicinska kliniken US.
    Rönnelid, Johan
    Uppsala Univ, Sweden.
    Fernandez-Botran, Rafael
    Univ Louisville, KY 40292 USA.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Associations of C-reactive protein isoforms with systemic lupus erythematosus phenotypes and disease activity2022Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 24, nr 1, artikel-id 139Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a large production of autoantibodies and deficient clearance of cellular waste. The disease typically oscillates between episodes of elevated disease activity and quiescent disease. C-reactive protein (CRP) is a pentameric acute-phase protein usually reflecting inflammation and tissue damage. However, despite increased inflammation and elevated interleukin-6, the levels of CRP typically remain low or only slightly raised in SLE. Under certain conditions, pentameric CRP (pCRP) can dissociate into its monomeric isoform (mCRP), which mainly has been ascribed pro-inflammatory properties. The present study aims to investigate the potential relationship between pCRP and mCRP, respectively, with disease activity and clinical features of SLE. Methods The levels of pCRP and mCRP were measured, by turbidimetry (high-sensitive) and sandwich enzyme-linked immunosorbent assay (ELISA) respectively, in serum samples from 160 patients with SLE and 30 patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Twenty-two of the SLE cases were selected for analysis at two time-points; quiescent disease and active disease. The two CRP isoforms were evaluated in relation to disease activity and clinical features in the two diseases. Results Levels of pCRP and mCRP were significantly lower in SLE than AAV (p < 0.001) and the ratio of mCRP/pCRP was higher in SLE compared to AAV. The mCRP/pCRP ratio was higher for patients in remission and able to significantly separate between active/quiescent disease in paired, but not in non-paired, samples from patients with SLE. Significant correlations were observed with SLICC/ACR damage index for pCRP levels as well as inversely with the mCRP/pCRP ratio. Lower mCRP levels associated with malar rash. Conclusion As the interrelationship between the two isoforms appear to (a) discriminate between quiescent and active SLE and (b) differ between SLE and AAV, our data indicates that the two CRP isoforms could exert contrasting immunological effects and/or reflect different milieus. Given the biological effects of mCRP, it is possible that altered levels may indicate increased opsonization of immune complexes and apoptotic debris, and thereby prevent their deposition outside the reticuloendothelial system and manifestations such as lupus nephritis and lupus-related skin disease.

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  • 26.
    Ahmad, Awais
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Rönnelid, Johan
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test2022Ingår i: Diagnostics, ISSN 2075-4418, Vol. 12, nr 7, artikel-id 1572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturers recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

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  • 27.
    Andraos, Rama
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Ahmad, Awais
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Wirestam, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Hesselstrand, Roger
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Andreasson, Kristofer
    Lund Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis2022Ingår i: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, nr 1, artikel-id e000732Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

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  • 28.
    Parodis, Ioannis
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Gomez, Alvaro
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lindblom, Julius
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Chow, Jun Weng
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sciascia, Savino
    Univ Turin, Italy.
    Gatto, Mariele
    Univ Padua, Italy.
    B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab2022Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, nr 22, artikel-id 13941Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19(+) B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19(+)CD20(+)CD138(+) short-lived plasma cells (-50.4% vs. -16.7%; p = 0.019) and CD19(+)CD20(-)CD27(bright) plasmablasts (-50.0% vs. -29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19(+)CD27(-)CD24(bright)CD38(bright) transitional B cells (-42.9% vs. -75.0%; p = 0.038) and CD19(+)CD20(-)CD138(+) peripheral long-lived plasma cells (-11.3% vs. -29.2%; p = 0.019) were seen in belimumab-treated-but not placebo-treated-patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.

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  • 29.
    Parodis, Ioannis
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Gatto, Mariele
    Univ Padua, Italy.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools2022Ingår i: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 9, artikel-id 952304Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

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  • 30.
    Sjöwall, Christopher
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Parodis, Ioannis
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Orebro Univ, Sweden.
    Clinical Heterogeneity, Unmet Needs and Long-Term Outcomes in Patients with Systemic Lupus Erythematosus2022Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, nr 22, artikel-id 6869Artikel i tidskrift (Övrigt vetenskapligt)
  • 31.
    Saleh, Muna Atallah
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Comment on Systemic autoimmunity with Castleman-like lymphadenopathy: a diagnostic and therapeutic challenge: reply2022Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 51, nr 3, s. 250-251Artikel i tidskrift (Övrigt vetenskapligt)
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  • 32.
    Heijke, Rebecca
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Björk, Mathilda
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för prevention, rehabilitering och nära vård. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Thyberg, Ingrid
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    McDonald, Laura
    Bristol Myers Squibb, England.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Comparing longitudinal patient-reported outcome measures between Swedish patients with recent-onset systemic lupus erythematosus and early rheumatoid arthritis2022Ingår i: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 41, nr 5, s. 1561-1568Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The onset of rheumatic disease affects each patient differently and may impact quality of life with progression. We investigated the relationship between patient-reported outcome measure (PROM) scores and organ damage in patients with recent-onset systemic lupus erythematosus (SLE) and those with early rheumatoid arthritis (RA). Patients with recent-onset SLE without prior organ damage from the Clinical Lupus Register in Northeastern Gothia and patients with early RA from the observational 2nd Timely Interventions in Early RA study, Sweden, were included. Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) was used to assess organ damage. PROM (visual analog scale [VAS]: pain, fatigue, well-being, Health Assessment Questionnaire, and EQ-5D-3L) scores were captured at months 0, 6, 12, 24, 36, 48, and 60 after diagnosis. Statistical tests included Pearson correlation coefficients and t-tests. Forty-one patients with recent-onset SLE and 522 with early RA were included. Numerical differences were seen in age and sex. PROMs were worse for patients with RA versus SLE but improved by month 6 following diagnosis, while SLE PROMs remained stable. The incidence of organ damage in SLE was 13.6 per 100 patient-years. SDI significantly correlated with EQ-5D-3L (- 0.48, P = 0.003), VAS fatigue (0.44, P = 0.009), and well-being (0.41, P = 0.01) at month 24. As illustrated, the complexity of disease burden in patients with SLE is clear and may result from disease-related multiorgan system effects and slower symptom resolution compared with RA. This underscores the need for improved multiprofessional interventions to manage all aspects of SLE.

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  • 33.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Lindström, Ulf
    Univ Gothenburg, Sweden.
    Bower, Hannah
    Karolinska Inst, Sweden.
    Delcoigne, Benedicte
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Lindqvist, Elisabet
    Lund Univ, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden.
    Comparison of treatment retention of originator vs biosimilar products in clinical rheumatology practice in Sweden2022Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, nr 9, s. 3596-3605Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives To compare treatment retention between biosimilars and their originator products among first starters (etanercept, infliximab, adalimumab and rituximab), as well as after non-medical switch. Methods Patients with rheumatic diseases starting, for the first time, an originator or biosimilar etanercept, infliximab, adalimumab or rituximab were identified in the national Swedish Rheumatology Quality Register. Moreover, patients switching from an originator to its biosimilar were identified and individually matched to patients continuing on the originator. One-year treatment retention was calculated and hazard ratios (HR) for discontinuation with 95% CIs were estimated, adjusting for comorbidities and socio-economic factors. Results In total, 21 443 first treatment courses were identified. The proportion of patients still on the drug at 1 year and the HR for discontinuation revealed no differences across adalimumab (Humira, Imraldi, Amgevita and Hyrimoz) nor across rituximab products (Mabthera, Ritemvia/Truxima and Rixathon). The proportions on the drug at 1 year were similar for Benepali (77%) and Enbrel (75%) and the adjusted HR for Benepali compared with Enbrel was 0.91 (95% CI 0.83, 0.99). For infliximab, the proportion still on the drug at 1 year was 67% for Remicade and 66% for Remsima/Inflectra and the HR compared with Remicade was 1.16 (95% CI 1.02, 1.33). Among 2925 patients switching from an originator drug to one of its biosimilars, we noted no statistically significant or clinically relevant differences in drug survival compared with those who remained on originator therapy. Conclusion This large observational study supports the equivalence of biologic DMARD biosimilar products and originators when used in routine rheumatology care.

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  • 34.
    Lundtoft, Christian
    et al.
    Uppsala Univ, Sweden.
    Pucholt, Pascal
    Uppsala Univ, Sweden.
    Martin, Myriam
    Lund Univ, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden; Sci Life Lab, Sweden.
    Lundstrom, Emeli
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jonsen, Andreas
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Jonsson, Roland
    Univ Bergen, Norway.
    Hammenfors, Daniel
    Haukeland Hosp, Norway.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Mandl, Thomas
    Lund Univ, Sweden.
    Bucher, Sara Magnusson
    Orebro Univ, Sweden.
    Norheim, Katrine B.
    Stavanger Univ Hosp, Norway.
    Johnsen, Svein Joar Auglaend
    Stavanger Univ Hosp, Norway.
    Omdal, Roald
    Stavanger Univ Hosp, Norway.
    Kvarnstrom, Marika
    Karolinska Univ Hosp, Sweden; Reg Stockholm, Sweden.
    Wahren-Herlenius, Marie
    Univ Bergen, Norway; Karolinska Inst, Sweden; Karolinska Univ Hosp Stockholm, Sweden.
    Notarnicola, Antonella
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Andersson, Helena
    Oslo Univ Hosp, Norway.
    Molberg, Oyvind
    Oslo Univ Hosp, Norway.
    Diederichsen, Louise Pyndt
    Copenhagen Univ Hosp, Denmark; Odense Univ Hosp, Denmark.
    Almlof, Jonas
    Uppsala Univ, Sweden; Sci Life Lab, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden; Sci Life Lab, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden; Sci Life Lab, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Sci Life Lab, Sweden; Broad Inst MIT & Harvard, MA 02142 USA.
    Nilsson, Bo
    Uppsala Univ, Sweden.
    Blom, Anna M.
    Lund Univ, Sweden.
    Lundberg, Ingrid E.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Diaz-Gallo, Lina Marcela
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases2022Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 74, nr 8, s. 1440-1450Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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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  • 35.
    Skoglund, Oliver
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Walhelm, Tomas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Thyberg, Ingrid
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Fighting Fatigue in Systemic Lupus Erythematosus: Experience of Dehydroepiandrosterone on Clinical Parameters and Patient-Reported Outcomes2022Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, nr 18, artikel-id 5300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Manifestations related to ongoing inflammation in systemic lupus erythematosus (SLE) are often adequately managed, but patient-reported outcome measures (PROMs) support that fatigue and low quality of life (QoL) in the absence of raised disease activity remain major burdens. The adrenal hormone dehydroepiandrosterone (DHEA) has shown potential as a pharmacological agent for managing fatigue in mild SLE. We retrospectively evaluated data on dosage, disease activity, corticosteroid doses, concomitant antirheumatic drugs, and PROMs regarding pain intensity, fatigue, and well-being (visual analogue scales), QoL (EQ-5D-3L) and functional disability. A total of 15 patients with SLE were exposed to DHEA and 15 sex- and age-matched non-exposed SLE patients served as comparators. At baseline, 83% of the DHEA-exposed patients had subnormal DHEA concentration. The 15 subjects prescribed DHEA were exposed during a median time of 12 months (IQR 16.5) [range 3-81] and used a median daily dose of 50 mg of DHEA (IQR 25.0) [range 25-200]. Neither disease activity, nor damage accrual, changed significantly over time among patients using DHEA, and no severe adverse events were observed. Numerical improvements of all evaluated PROMs were seen in the DHEA-treated group, but none reached statistical significance. For DHEA-exposed patients, a non-significant trend was found regarding fatigue comparing baseline and 36 months (p = 0.068). In relation to SLE controls, the DHEA-exposed group initially reported significantly worse fatigue, pain, and well-being, but the differences diminished over time. In conclusion, DHEA was safe, but evidence for efficacy of DHEA supplementation in relation to PROMs were not found. Still, certain individuals with mild SLE, plagued by fatigue and absence of increased disease activity, appear to benefit from DHEA in terms of improved fatigue and QoL. Testing of DHEA concentration in blood should be performed before initiation, and investigation of other conditions, or reasons responsible for fatigue, must always be considered first.

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  • 36.
    Van Hoovels, Lieve
    et al.
    Katholieke Univ Leuven, Belgium; Onze Lieve Vrouw Hosp, Belgium.
    Vander Cruyssen, Bert
    Onze Lieve Vrouw Hosp, Belgium.
    Sieghart, Daniela
    Med Univ Vienna, Austria.
    Bonroy, Carolien
    Univ Ghent, Belgium; Univ Ghent, Belgium.
    Nagy, Eszter
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Pullerits, Rille
    Sahlgrenska Univ Hosp Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Cucnik, Sasa
    Univ Med Ctr Ljubljana, Slovenia.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Heijnen, Ingmar
    Univ Hosp Basel, Switzerland.
    Bernasconi, Luca
    Kantonsspital Aarau, Switzerland.
    Benkhadra, Farid
    Ctr Hosp Luxembourg, Luxembourg.
    Bogaert, Laura
    Onze Lieve Vrouw Hosp, Belgium.
    Van den Bremt, Stefanie
    Onze Lieve Vrouw Hosp, Belgium.
    Van Liedekerke, Ann
    AZ Sint Elisabeth, Belgium.
    Vanheule, Geert
    AZ Rivierenland, Belgium.
    Robbrecht, Johan
    AZ Sint Lucas, Belgium.
    Studholme, Lucy
    Natl Inst Biol Stand & Control NIBSC, England.
    Wirth, Claudine
    Ctr Hosp Luxembourg, Luxembourg.
    Mueller, Ruediger
    Rheumazentrum Ostschweiz, Switzerland.
    Kyburz, Diego
    Univ Hosp Basel, Switzerland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jese, Rok
    Univ Med Ctr Ljubljana, Slovenia.
    Jovancevic, Boja
    Univ Gothenburg, Sweden.
    Kiss, Emese
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Jacques, Peggy
    Univ Hosp Ghent, Belgium; Univ Hosp Ghent, Belgium.
    Aletaha, Daniel
    Med Univ Vienna, Austria.
    Steiner, Guenter
    Med Univ Vienna, Austria; Ludwig Boltzmann Inst Arthrit & Rehabil, Austria.
    Verschueren, Patrick
    Univ Hosp Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Bossuyt, Xavier
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    IgA rheumatoid factor in rheumatoid arthritis2022Ingår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 60, nr 10, s. 1617-1626Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context. Methods An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available. Results The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjogrens syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies. Conclusions IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity.

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  • 37.
    Yavuz, Sule
    et al.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Pucholt, Pascal
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Bolin, Karin
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden.
    Lanata, Cristina M.
    Nat Human Genome Res Inst, MD USA.
    Jönsen, Andreas
    Lund Univ, Sweden; Skane Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden; Skane Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Nititham, Joanne
    Nat Human Genome Res Inst, MD USA.
    Criswell, Lindsey A.
    NIAMSD, MD USA.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst, MA USA.
    Rönnblom, Lars
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Mer-tyrosine kinase: a novel susceptibility gene for SLE related end-stage renal disease2022Ingår i: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, nr 1, artikel-id e000752Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Lupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD. Methods We analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants. Results A genetic variant (rs56097910) within the MERTK gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0x10(-6). We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7x10(-4)), at one CpG site (cg16333401) in close vicinity to the transcription start site of MERTK and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered MERTK expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: PRDM1 (rs6924535, p(meta)=1.6x10(-5), OR=0.58) and APOA1BP (NAXE) (rs942960, p(meta)=1.2x10(-5), OR=2.64). Conclusion We identified a novel genetic risk locus, MERTK, associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in the MERTK gene are important for the risk of developing SLE-ESRD and suggest a role for PRDM1 and APOA1BP in proliferative LN.

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  • 38.
    Van Hoovels, Lieve
    et al.
    Katholieke Univ Leuven, Belgium; Onze Lieve Vrouw Hosp, Belgium.
    Vander Cruyssen, Bert
    Onze Lieve Vrouw Hosp, Belgium.
    Sieghart, Daniela
    Med Univ Vienna, Austria.
    Bonroy, Carolien
    Univ Ghent, Belgium; Univ Ghent, Belgium.
    Nagy, Eszter
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Pullerits, Rille
    Sahlgrens Univ Hosp, Sweden; Sahlgrens Acad, Sweden.
    Cucnik, Sasa
    Katholieke Univ Leuven, Belgium.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Heijnen, Ingmar
    Univ Hosp Basel, Switzerland.
    Bernasconi, Luca
    Kantonsspital Aarau AG, Switzerland.
    Benkhadra, Farid
    Ctr Hosp Luxembourg, Luxembourg.
    Bogaert, Laura
    Onze Lieve Vrouw Hosp, Belgium.
    Van den Bremt, Stefanie
    Onze Lieve Vrouw Hosp, Belgium.
    Van Liedekerke, Ann
    AZ Sint Elisabeth Ziekenhuis Zottegem, Belgium.
    Vanheule, Geert
    AZ Rivierenland Campus Bornem, Belgium.
    Robbrecht, Johan
    AZ Sint Lucas Brugge, Belgium.
    Studholme, Lucy
    Natl Inst Biol Stand & Controls, England.
    Wirth, Claudine
    Ctr Hosp Luxembourg, Luxembourg.
    Müller, Rüdiger
    Rheumazentrum Ostschweiz, Switzerland.
    Kyburz, Diego
    Univ Hosp Basel, Switzerland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jese, Rok
    Univ Med Ctr Ljubljana, Slovenia.
    Jovancevic, Boja
    Sahlgrens Acad, Sweden.
    Kiss, Emese
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Jacques, Peggy
    Univ Hosp Ghent, Belgium; VIB Inflammat Res Ctr, Belgium.
    Aletaha, Daniel
    Med Univ Vienna, Austria.
    Steiner, Guenter
    Med Univ Vienna, Austria; Ludwig Boltzmann Inst Arthrit & Rehabil, Austria.
    Verschueren, Patrick
    KU Leuven Univ Hosp Leuven, Belgium; Katholieke Univ Leuven, Belgium.
    Bossuyt, Xavier
    Katholieke Univ Leuven, Belgium; Katholieke Univ Leuven, Belgium.
    Multicentre study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results2022Ingår i: RMD Open, E-ISSN 2056-5933, Vol. 8, nr 1, artikel-id e002099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are important biomarkers for diagnosis of rheumatoid arthritis (RA). However, there is poor harmonisation of RF and ACPA assays. The aim of this study was to refine RF and ACPA interpretation across commercial assays. Materials and methods Six total RF isotype-non-specific assays, 3 RF IgM isotype-specific assays and 9 ACPA immunoglobulin G assays of 13 different companies were evaluated using 398 diagnostic samples from patients with RA and 1073 disease controls. Results Using cut-offs proposed by the manufacturer, there was a large variability in diagnostic sensitivity and specificity between assays. Thresholds of antibody levels were determined based on predefined specificities and used to define test result intervals. Test result interval-specific likelihood ratios (LRs) were concordant across the different RF and ACPA assays. For all assays, the LR for RA increased with increasing antibody level. Higher LRs were found for ACPA than for RF. ACPA levels associated with LRs >80 were found in a substantial fraction (>22%) of patients with RA. Conclusion Defining thresholds for antibody levels and assigning test result interval-specific LRs allows alignment of clinical interpretation for all RF and ACPA assays.

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  • 39.
    Knopf, Jasmin
    et al.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Sjöwall, Johanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Infektionskliniken i Östergötland.
    Frodlund, Martina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Hinkula, Jorma
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Herrmann, Martin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany; Univ Klinikum Erlangen, Germany; Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    NET Formation in Systemic Lupus Erythematosus: Changes during the COVID-19 Pandemic2022Ingår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 17, artikel-id 2619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2.

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  • 40.
    Van Hoovels, Lieve
    et al.
    Katholieke Univ Leuven, Belgium; Onze Lieve Vrouwziekenhuis Aalst, Belgium.
    Studholme, Lucy
    Natl Inst Biol Stand & Controls, England.
    Vander Cruyssen, Bert
    Onze Lieve Vrouwziekenhuis Aalst, Belgium.
    Sieghart, Daniela
    Med Univ Vienna, Austria.
    Bonroy, Carolien
    Univ Ghent, Belgium; Univ Ghent, Belgium.
    Nagy, Eszter
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Pullerits, Rille
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Cucnik, Sasa
    Univ Med Ctr Ljubljana, Slovenia.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Heijnen, Ingmar
    Univ Hosp Basel, Switzerland.
    Bernasconi, Luca
    Kantonsspital Aarau, Switzerland.
    Benkhadra, Farid
    Ctr Hosp Luxembourg, Luxembourg.
    Bogaert, Laura
    Onze Lieve Vrouwziekenhuis Aalst, Belgium.
    Van den Bremt, Stefanie
    Onze Lieve Vrouwziekenhuis Aalst, Belgium.
    Van Liedekerke, Ann
    AZ Sint Elisabeth Ziekenhuis Zottegem Vzw, Belgium.
    Vanheule, Geert
    AZ Rivierenland, Belgium.
    Robbrecht, Johan
    AZ Sint Lucas Bruges, Belgium.
    Wirth, Claudine
    Ctr Hosp Luxembourg, Luxembourg.
    Mueller, Ruediger
    Rheumazentrum Ostschweiz, Switzerland.
    Kyburz, Diego
    Univ Hosp Basel, Switzerland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Jese, Rok
    Univ Med Ctr Ljubljana, Slovenia.
    Jovancevic, Boja
    Univ Gothenburg, Sweden.
    Kiss, Emese
    Natl Inst Locomotor Dis & Disabil, Hungary.
    Jacques, Peggy
    Univ Hosp Ghent, Belgium; Univ Hosp Ghent, Belgium.
    Aletaha, Daniel
    Med Univ Vienna, Austria.
    Steiner, Guenter
    Med Univ Vienna, Austria; Ludwig Boltzmann Inst Arthrit & Rehabil, Austria.
    Verschueren, Patrick
    Univ Hosp Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Bossuyt, Xavier
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Standardisation of ACPA tests: evaluation of a new candidate reference preparation2022Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 81, nr 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays. Materials and methods This is an international study in which the NIBSC candidate ACPA standard and the IUIS-CDC ACPA reference material were analysed together with 398 diagnostic samples from individuals with rheumatoid arthritis (RA) and in 1073 individuals who did not have RA using nine commercial ACPA assays. Results For both reference materials and samples from individuals with RA and individuals who did not have RA, there were large differences in quantitative ACPA results between assays. For most assays, values for the IUIS-CDC standard were lower than values for NIBSC 18/204 and the IUIS-CDC/NIBSC ratio was comparable for several, but not all assays. When NIBSC 18/204 was used as a calibrator, an improvement in alignment of ACPA results across several of the evaluated assays was obtained. Moreover, NIBSC 18/204 could align clinical interpretation for some but not all assays. Conclusion Adoption of an international standard for ACPA determination is highly desirable. The candidate NIBSC 18/204 standard improved the standardisation and alignment of most ACPA assays and might therefore be recommended to be used as reference in commercial assays.

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  • 41.
    Lundtoft, Christian
    et al.
    Olink Proteo, Sweden; Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Jönsen, Andreas
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Pucholt, Pascal
    Uppsala Univ, Sweden.
    Wu, Yee Ling
    Nationwide Childrens Hosp, OH USA; Loyola Univ, IL 60611 USA.
    Lundström, Emeli
    Karolinska Univ Hosp, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden.
    Baecklund, Eva
    Uppsala Univ, Sweden.
    Jonsson, Roland
    Univ Bergen, Norway.
    Hammenfors, Daniel
    Haukeland Hosp, Norway.
    Forsblad-d’Elia, Helena
    Univ Gothenburg, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Mandl, Thomas
    Lund Univ, Sweden; Novartis, Sweden.
    Bucher, Sara
    Orebro Univ, Sweden.
    Norheim, Katrine B.
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Johnsen, Svein Joar Auglaend
    Stavanger Univ Hosp, Norway.
    Omdal, Roald
    Univ Bergen, Norway; Stavanger Univ Hosp, Norway.
    Kvarnström, Marika
    Karolinska Univ Hosp, Sweden; Stockholm Hlth Serv, Sweden.
    Wahren-Herlenius, Marie
    Karolinska Univ Hosp, Sweden; Univ Bergen, Norway.
    Truedsson, Lennart
    Lund Univ Hosp, Sweden.
    Nilsson, Bo
    Uppsala Univ, Sweden.
    Kozyrev, Sergey V
    Uppsala Univ, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT & Harvard, MA 02142 USA.
    Yu, Chack-Yung
    Nationwide Childrens Hosp, OH USA.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren’s Syndrome2022Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 74, nr 11, s. 1842-1850Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogrens syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.

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  • 42.
    Skoog, Johan
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Svensson, Christina
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Zachrisson, Helene
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärtcentrum, Fysiologiska kliniken US.
    The Diagnostic Performance of an Extended Ultrasound Protocol in Patients With Clinically Suspected Giant Cell Arteritis2022Ingår i: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 8, artikel-id 807996Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectiveTo evaluate the diagnostic performance of an extended ultrasound protocol in patients referred under the suspicion of giant cell arteritis (GCA). MethodsConsecutive patients with suspected GCA were examined with an extended color duplex ultrasound (CDU) protocol during a period of 2 years. The extended CDU protocol included temporal, axillary, subclavian, brachiocephalic, and carotid arteries. The reference was clinically diagnosed GCA, confirmed after >= 6-month follow-up. Hypo- or medium-echogenic, circumferential, homogenous wall thickening, and/or a positive compression sign in temporal arteries, were regarded as typical signs of arteritis. ResultsOf the eligible 201 patients, 83 (41%) received a clinical GCA diagnosis at follow-up >= 6 months post CDU examination. Among these cases, 48 (58%) demonstrated inflammation solely in temporal arteries, 8 (10%) showed abnormalities restricted to extra-cranial vessels, and 23 (28%) patients displayed inflammatory changes in both temporal and extra-cranial arteries. Color duplex ultrasound of temporal arteries yielded a diagnostic sensitivity and specificity [95% confidence intervals (CI)] of 86% (76-92%) and 99% (95-99%), respectively. By adding axillary artery examination, the sensitivity increased to 92% (83-97%) while the specificity remained unchanged. Further, inclusion of subclavian artery marginally increased the sensitivity by 1%. Finally, by also including brachiocephalic and common carotid arteries resulted in a sensitivity of 95% (88-99%) and a specificity of 98% (94-99%). ConclusionsColor duplex ultrasound examination demonstrated a high accuracy in diagnosing patients both with cranial and extra-cranial GCA. Further examination of brachiocephalic and common carotid arteries can increase the sensitivity without affecting the specificity when temporal and axillary findings are indecisive. Finally, the extended CDU protocol allows measurement of the general burden of inflammation, which could be relevant for future monitoring purposes.

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  • 43.
    Saleh, Muna Atallah
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Compagno, Michele
    Lund Univ, Sweden.
    Pihl, Sofia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken US.
    Strevens, Helena
    Lund Univ, Sweden.
    Persson, Barbro
    Uppsala Univ, Sweden.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Nilsson, Bo
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Variation of Complement Protein Levels in Maternal Plasma and Umbilical Cord Blood during Normal Pregnancy: An Observational Study2022Ingår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, nr 13, artikel-id 3611Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The complement system constitutes a crucial part of the innate immunity, mediating opsonization, lysis, inflammation, and elimination of potential pathogens. In general, there is an increased activity of the complement system during pregnancy, which is essential for maintaining the hosts defense and fetal survival. Unbalanced or excessive activation of the complement system in the placenta is associated with pregnancy complications, such as miscarriage, preeclampsia, and premature birth. Nonetheless, the actual clinical value of monitoring the activation of the complement system during pregnancy remains to be investigated. Unfortunately, normal reference values specifically for pregnant women are missing, and for umbilical cord blood (UCB), data on complement protein levels are scarce. Herein, complement protein analyses (C1q, C3, C4, C3d levels, and C3d/C3 ratio) were performed in plasma samples from 100 healthy, non-medicated and non-smoking pregnant women, collected during different trimesters and at the time of delivery. In addition, UCB was collected at all deliveries. Maternal plasma C1q and C3d/C3 ratio showed the highest mean values during the first trimester, whereas C3, C4, and C3d had rising values until delivery. We observed low levels of C1q and C4 as well as increased C3d and C3d/C3 ratio, particularly during the first trimester, as a sign of complement activation in some women. However, the reference limits of complement analyses applied for the general population appeared appropriate for the majority of the samples. As expected, the mean complement concentrations in UCB were much lower than in maternal plasma, due to the immature complement system in neonates.

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  • 44.
    Stockfelt, Marit
    et al.
    Univ Gothenburg, Sweden.
    Larsson, Gunilla
    Univ Gothenburg, Sweden.
    Engstrom, Hanna
    Univ Gothenburg, Sweden.
    Puttonen, Henri
    Sahlgrens Univ Hosp, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Inst UCL, England; UCL Inst Neurol, England.
    Blennow, Kaj
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Strevens, Helena
    Skane Univ Hosp, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Sennstrom, Maria Majczuk
    Karolinska Univ Hosp, Sweden.
    Zickert, Agneta
    Karolinska Univ Hosp, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden.
    Trysberg, Estelle
    Univ Gothenburg, Sweden.
    Jacobsson, Bo
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Inst Publ Hlth, Norway.
    Ekwall, Anna-Karin Hultgard
    Univ Gothenburg, Sweden.
    Christenson, Karin
    Univ Gothenburg, Sweden.
    Bylund, Johan
    Univ Gothenburg, Sweden.
    Svensson, Mattias N. D.
    Univ Gothenburg, Sweden.
    Lundell, Anna-Carin
    Univ Gothenburg, Sweden.
    Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies2021Ingår i: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 8, nr 1, artikel-id e000463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy. Methods At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies. The proportion of low-density granulocytes (LDGs) and the activation status of LDG and normal-density granulocytes were examined with flow cytometry. The chemokines CXCL8 and CXCL1 were quantified with a cytometric bead-based assay and interferon alpha (IFN alpha) protein levels with a Simoa method. IFN alpha-stimulated maternal-derived decidual stromal cells were examined for CXCL8 gene expression with qPCR. A pathologist, blinded to the patient background, examined all placentas. Results Women with SLE had significantly higher proportions of LDG in peripheral blood compared with controls (p=0.02), and LDG in both peripheral and intervillous blood were more activated in SLE relative to healthy pregnancies (peripheral blood: p=0.002 and intervillous blood: p=0.05). There were higher levels of CXCL8 and CXCL1 in intervillous compared with peripheral blood in women with SLE (p=0.004 and p=<0.0001, respectively) but not in controls. In SLE pregnancy, IFN alpha was detectable in 6 out of 10 intervillous blood samples but only in one control. Stimulation with IFN alpha upregulated CXCL8 gene expression in decidual stromal cells from both SLE and healthy pregnancy. Histological chorioamnionitis was present in 6 out of 12 placentas from women with SLE and in 1 out of 10 controls. Conclusions In women with SLE, locally produced chemokines in the placenta are increased and may attract and activate neutrophils. This in turn could contribute to placental inflammation and dysfunction and increased risk of placenta-related pregnancy complications.

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  • 45.
    Ahmad, Awais
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Heijke, R.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Wirestam, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes2021Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 203, nr 1, s. 22-31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjogrens syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2 center dot 9%) and three pSS (2 center dot 6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9 center dot 6%) had PBC-associated autoantibodies, 15 (5 center dot 5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7 center dot 4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7 center dot 4%). The prevalence of SMA (4 center dot 4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8 center dot 1%) had PBC-associated, 12 (10 center dot 8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

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  • 46.
    Sjöwall, Johanna
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Infektionskliniken i Östergötland.
    Xirotagaros, Georgios
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Hudkliniken i Östergötland.
    Anderson, Chris
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Hudkliniken i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab2021Ingår i: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 12, artikel-id 645298Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.

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  • 47.
    Walhelm, Tomas
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Gunnarsson, Iva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Heijke, Rebecca
    Dept Internal Med, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Trysberg, Estelle
    Univ Gothenburg, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland. Dept Internal Med, Jönköping, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Reumatologiska kliniken i Östergötland.
    Clinical Experience of Proteasome Inhibitor Bortezomib Regarding Efficacy and Safety in Severe Systemic Lupus Erythematosus: A Nationwide Study2021Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, artikel-id 756941Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As treatment options in advanced systematic lupus erythematosus (SLE) are limited, t