Johan Rönnelid

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (109)636.1 Total impact

  • Arthritis Research & Therapy 12/2015; 17(1). · 4.12 Impact Factor
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    ABSTRACT: Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjögren syndrome (n = 54) served as controls. CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher's exact test revealed striking differences between methods regarding associations with certain disease phenotypes. CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.
    The Journal of rheumatology. 02/2015;
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    ABSTRACT: Introduction Rheumatoid arthritis (RA) patients with autoantibodies against collagen type II (CII) are characterized by acute RA onset with elevated inflammatory measures and early joint erosions as well as increased production of tumor necrosis factor-¿ (¿¿F-¿) by peripheral blood mononuclear cells (PBMC) stimulated by anti-CII immune complexes (IC) in vitro. Polymorphonuclear granulocytes (PMN) are abundant in RA synovial fluids, where they might interact directly with anti-CII IC in the articular cartilage, but no studies have investigated PMN responses towards anti-CII IC. The aim was to investigate whether PMN react towards anti-CII IC, and to what extent such reactivity might relate to the clinical acute onset RA phenotype associated with elevated levels of anti-CII. Methods PMN and PBMC isolated from healthy donors were stimulated with IC made with a set of 72 baseline patient sera (24 anti-CII positive, 48 anti-CII negative) chosen from a clinically well-characterized RA cohort with two-year radiological follow-up with Larsen scoring. PMN expression of cluster of differentiation (CD)11b, CD66b, CD16 and CD32 was measured by flow cytometry, whereas PMN production of myeloperoxidase (MPO) and interleukin (IL)-17, and PBMC production of ¿¿F-¿ was measured with enzyme linked immunosorbent assay. Results PMN expression of CD11b, CD66b and MPO, and PBMC production of ¿¿F-¿ were upregulated whereas PMN expression of CD16 and CD32 were downregulated by anti-CII IC. CD16, CD66b, and MPO production correlated to serum anti-CII levels (Spearman¿s ¿¿=¿0.315, 0.675 and 0.253, respectively). CD16 was associated with early joint erosions (P¿=¿0.024, 0.034, 0.046 at baseline, one and two years) and CD66b was associated with changes in joint erosions (P¿=¿0.017 and 0.016, at one and two years compared to baseline, respectively). CD66b was associated with baseline C-reactive protein and PBMC production of ¿¿F-¿ was associated with baseline erythrocyte sedimentation rate, in accordance with our earlier findings. No clinical associations were observed for MPO or IL-17. Conclusion PMN responses against anti-CII IC are more closely associated with early joint erosions than are PBMC cytokine responses. PMN reactivity against anti-CII IC may contribute to joint destruction in newly diagnosed RA patients with high levels of anti-CII.
    Arthritis Research & Therapy 01/2015; · 4.12 Impact Factor
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    ABSTRACT: African patients with Leishmania donovani infections have signs of strong systemic inflammation and high levels of circulating immune complexes (IC) and rheumatoid factor (RF), all serologic markers of rheumatic disease. As inflammation in general is associated with citrullination, we sought to investigate ACPA responses in Sudanese Leishmania patients. Serum samples were collected from Sudanese visceral leishmaniasis (VL) and post-kala azar dermal leishmaniasis (PKDL) patients as well as from ACPA-positive Sudanese rheumatoid arthritis patients, and compared to healthy Sudanese controls. Levels of circulating C1q-binding IC and anti-cyclic citrullinated peptide (CCP)2 were investigated using ELISA and RF was measured with nephelometry. C1q adsorbtion was carried out to investigate anti-CCP2 content in IC. Citrulline specificity was evaluated with control plates with cyclic arginine-containing control peptides. Leishmania-infected patients had elevated levels of RF and circulating IC but also a significant increase in anti-CCP2 (12%) as compared to healthy controls. Anti-CCP2 positive Leishmania patients displayed lower anti-CCP2 levels than Sudanese RA patients, and anti-CCP2 levels in Leishmania patients showed a continuum not resembling the dichotomous pattern seen in RA patients. Whereas the anti CCP reactivity of Sudanese RA sera was strictly citrulline dependent, anti-CCP2 positive Leishmania sera reacted equally well with ELISA plates containing arginine control peptides. There was a strong correlation between anti-CCP2 and circulating IC among the Leishmania patients, but IC depletion only marginally diminished anti-CCP2 levels.Our findings stress the importance to interpret a positive CCP test carefully when evaluated in non-rheumatic conditions associated with macrophage activation.This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 01/2015; · 1.88 Impact Factor
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    ABSTRACT: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD.
    Journal of Clinical Immunology 11/2014; · 2.65 Impact Factor
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    ABSTRACT: To analyse if predictors of radiographic progression differ between patients treated with or without prednisolone in early rheumatoid arthritis (RA). Radiographs of hands and feet were assessed using the modified Sharp/van der Heijde score and radiographic progression was defined as an increase in the total Sharp score above 5.8 (the smallest detectable change).
    BMJ Open 07/2014; 4(7):e005246. · 2.06 Impact Factor
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    ABSTRACT: Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA).
    Arthritis Research & Therapy 06/2014; 16(3):R129. · 4.12 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: BackgroundEarly appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA).MethodsThe Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage.ResultsElevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up.ConclusionsAnti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied.
    Pediatric Rheumatology 06/2014; 12:22. · 1.62 Impact Factor
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    ABSTRACT: Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA. Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA. Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA. Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
    Annals of the rheumatic diseases 05/2014; · 9.27 Impact Factor
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    ABSTRACT: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.
    PLoS ONE 04/2014; 9(4):e93180. · 3.53 Impact Factor
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    ABSTRACT: Smoking can induce autoantibodies in persons who are genetically predisposed to rheumatoid arthritis. We investigated the association between smoking and antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE), a question not previously addressed. Further, we explored the relationship between smoking, aPL and vascular events (arterial and venous, VE). In this cross-sectional study, clinical evaluation and questionnaire data were collected from 367 prevalent SLE patients. At the same time, we measured aPL (anticardiolipin (aCL), anti-β2 glycoprotein-1 (aβ2GP1) antibodies IgG/IgM/IgA, and lupus anticoagulant (LA)), and a large set of other SLE-associated autoantibodies for comparison. Association analyses using logistic regression models with smoking, (ever, former and current with never as reference) and antibody status as outcome variable were performed. As a secondary outcome, we investigated the associations between aPL, smoking and VE. In multivariable-adjusted models ever, and in particular former, cigarette smoking was associated with the most pathogenic aPL; LA, aCL IgG and aβ2GP1 IgG. Other SLE-associated autoantibodies were not associated with smoking. The combination of smoking and aPL was strongly associated with VE. We noted a positive interaction between smoking-LA and smoking-'triple aPL' positivity for previous VE. We investigated a large set of commonly occurring autoantibodies in SLE, but only aPL were positively associated with a history of smoking. This association was especially apparent in former smokers. Among ever regular smokers who were aPL positive, we observed a strikingly high frequency of former VE. The underlying mechanisms and temporality between smoking, aPL and VE need further investigations.
    Annals of the rheumatic diseases 04/2014; · 9.27 Impact Factor
  • Annals of the rheumatic diseases 03/2014; · 9.27 Impact Factor
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    Annals of the Rheumatic Diseases 03/2014; 16(2):405. · 9.27 Impact Factor
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    ABSTRACT: RA patients with anti-collagen antibodies (anti-CII) are characterised by acute RA onset (Mullazehi et al, ARD 2007) and early joint erosions (Mullazehi et al ART 2012), as well as increased production of TNF by peripheral blood mononuclear cells from anti-CII immune complexes (IC) in vitro (Mullazehi et al A&R 2006). We have previously (abstract EWRR 2012) shown that polymorphonuclear neutrophil granulocytes (PMN) react towards anti-CII IC. The aim was to investigate whether functional PMN responses are associated with the clinical acute onset RA phenotype. A set of 72 baseline patient sera (24 anti-CII positive, 24 anti-CII negative/RF positive and 24 anti-CII negative/RF negative) was chosen from a clinically well-characterised RA cohort with 2-year radiological follow-up (Larsen score). PMN and PBMC isolated from healthy donors were stimulated with anti-CII IC prepared with sera from the patients. PMN expression of CD16 and CD66b were measured by flow cytometry, and PMN production of myeloperoxidase (MPO) and IL-17, and PBMC production of TNF was measured with ELISA. CD66b, MPO, and TNF were significantly up-regulated and CD16 was significantly down-regulated by IC made with anti-CII positive sera. Even anti-CII low positive sera were able to impact the expression of CD16, CD66b and TNF. There was linear correlation to CD16, CD66b, MPO and TNF production in relation to anti-CII levels (r = -0.3152, 0.6755, 0.2532 and 0.5846, respectively). CD16 correlated with early joint erosion (p = 0.024, 0.034, 0.046 at baseline, one and two years) and CD66b was associated with changes in joint erosion (p = 0.017 and 0.016, at one and two years compared to baseline, respectively). CD66b was associated with baseline CRP and PBMC production of TNF was associated with baseline ESR, in accordance to our earlier findings. No correlations were observed with IL-17. We have earlier shown that PBMC anti-CII IC-induced production of TNF was associated with CRP and ESR in newly diagnosed RA patients. Here we show that PMN reactivity against anti-CII IC is uniquely associated with joint destruction. PMN reactivity towards anti-CII IC in cartilage of patients can contribute to joint destruction in newly diagnosed RA patients.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A5. · 9.27 Impact Factor
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    ABSTRACT: To investigate if changes in the lungs are present in rheumatoid arthritis (RA) patients early in the disease process and to address the contribution of these changes to the initiation of the disease. 24 RA patients with patient-reported symptom duration less than one year and naive to DMARD treatment and 15 healthy individuals were subjected to bronchoscopy and mucosal bronchial biopsies were retrieved. Histological analysis for identification of inducible bronchia associated lymphoid tissues (iBALT) and lymphocyte infiltration, as well as immunohistochemistry (IHC) for PAD enzymes, CD3, HLA-DQ and HLA-DR were performed. Presence of citrullinated targets were detected by IHC using biotinylated ACPA isolated from synovial fluid of RA patients. Mass spectrometry was used for identification of citrullinated epitopes in 6 lung and 8 synovial biopsies from RA patients. An in-house ELISA was setup to measure reactivity against new identified citrullinated targets in the serum of RA patients in two distinct early RA cohorts (n = 393) and a cohort of non-RA patients (n = 236) as disease controls. Bronchial lymphocyte infiltration and iBALT formation was observed in 55% of the ACPA+ RA patients but only 17% of ACPA- patients and 7% of healthy volunteers. Higher expression of CD3, HLA-DQ, HLA-DR and citrullinated targets was observed in bronchial biopsies of ACPA+ as compare to ACPA- RA patients. BAL fluids were enriched in both IgG and IgA ACPA as compared to paired serum samples. Mass spectrometry identified 5 proteins in the synovium (in total 8 sites) and 4 in the lungs (in total 6 sites) containing citrullinated residues. Two vimentin derived citrullinated peptides were present in a majority of both synovial and lung biopsies with slightly higher citrullinated/unmodified peptides ratios in the smokers as compared to non-smokers.14.5% of the RA patients tested by ELISA showed antibody reactivity against the new identified citrullinated target compared to 3.4% in the disease controls. Signs of inflammation and local ACPA enrichment are present early in bronchial tissues of ACPA+ RA patients. Shared citrullinated targets in the lung and joints as well as systemic reactivity against these targets are present in RA patients. Our findings support the notion that early inflammatory events in the lungs may represent a critical initiating factor in the development of ACPA+ RA.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A4-5. · 9.27 Impact Factor
  • Open Journal of Rheumatology and Autoimmune Diseases 01/2014;
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    ABSTRACT: Objective The pathophysiology of the postpolio syndrome is not fully understood. Increased cytokine levels in cerebrospinal fluid and peripheral blood indicate a systemic inflammatory process. Decreased cytokine levels and the clinical effect of intravenous immunoglobulin treatment further indicate an inflammatory/immunological pathogenesis. The aim of the present study was to evaluate whether an autoimmune process follows the initial infection, by means of analyzing immune complexes. Patients and methods Circulating immune complexes were analyzed from blood samples of 20 postpolio patients and 95 healthy controls. To compensate for differences in age between patients and controls, a sub-analysis was performed using only the 30 oldest controls. Tumor necrosis factor-inducing properties of polyethylene glycol-precipitated immune complexes were compared between the postpolio patients and ten healthy controls. Results When comparing levels in postpolio patients to the whole control group, including the 30 oldest investigated, there were no statistically significant differences. No difference was found in tumor necrosis factor levels induced by immune complexes when comparing patients and controls. Conclusions There was no increase in circulating immune complex or in tumor necrosis factor-inducing effects of circulating immune complex between postpolio patients and healthy controls, indicating that the postpolio syndrome is not due to an autoimmune reaction.
    Results in Immunology. 01/2014;
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    ABSTRACT: To investigate biomarker patterns in rheumatoid arthritis (RA) with extraarticular manifestations. Cartilage oligomeric matrix protein (COMP), COMP-C3b, and soluble terminal complement complexes (sTCC) were measured by ELISA. COMP-C3b levels were higher in patients with RA than in healthy controls and lower in extraarticular RA (ExRA) than in RA controls. In patients with ExRA, sTCC levels were higher than in RA controls, and correlated inversely with serum COMP-C3b levels in the ExRA group. Patients with ExRA had lower levels of COMP-C3b. This may be a consequence of complement consumption or a lower potential for COMP from these patients to activate complement.
    The Journal of Rheumatology 11/2013; 40(12). · 3.17 Impact Factor
  • Annals of the rheumatic diseases 06/2013; · 9.27 Impact Factor

Publication Stats

3k Citations
636.10 Total Impact Points

Institutions

  • 2003–2015
    • Uppsala University
      • • Department of Immunology, Genetics and Pathology
      • • The Rudbeck Laboratory
      • • Department of Medical Sciences
      Uppsala, Uppsala, Sweden
  • 2013
    • Lund University
      • Department of Clinical Sciences
      Lund, Skane, Sweden
  • 2012
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Umeå University
      • Department of Public Health and Clinical Medicine
      Umeå, Västerbotten, Sweden
  • 2006–2011
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1992–2010
    • Uppsala University Hospital
      • Department of Clinical Immunology and Transfusion Medicine
      Uppsala, Uppsala, Sweden
  • 2009
    • University of Birmingham
      Birmingham, England, United Kingdom
    • Swedish University of Agricultural Sciences
      • Institutionen för kliniska vetenskaper
      Uppsala, Uppsala, Sweden
  • 1994–2009
    • Karolinska University Hospital
      • Department of Rheumatology
      Tukholma, Stockholm, Sweden
  • 1995–2008
    • Karolinska Institutet
      • • Institutionen för medicin, Huddinge
      • • Department of Rheumatology
      Solna, Stockholm, Sweden
  • 2007
    • Malmö University
      Malmö, Skåne, Sweden
    • Linköping University
      Linköping, Östergötland, Sweden