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  • 1.
    Ge, Changrong
    et al.
    Karolinska Inst, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Liang, Bibo
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Lonnblom, Erik
    Karolinska Inst, Sweden.
    Lundstrom, Susanna L.
    Karolinska Inst, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Ayoglu, Burcu
    KTH Royal Inst Technol, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Malmstrom, Vivianne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Klareskog, Lars
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Toes, Rene E. M.
    Leiden Univ, Netherlands.
    Rispens, Theo
    Univ Amsterdam, Netherlands.
    Dobritzsch, Doreen
    Uppsala Univ, Sweden.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies2019Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, nr 2, s. 210-221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

  • 2.
    Liu, Ke
    et al.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kurien, Biji T.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    Zimmerman, Sarah L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Taft, Diana H.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Lazaro, Sara
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Weaver, Carrie A.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adler, Adam J.
    Oklahoma City VA Medical Centre, OK USA; Oklahoma Medical Research Fdn, OK 73104 USA.
    Chodosh, James
    Massachusetts Eye and Ear Infirm, MA 02114 USA; Harvard University, MA USA.
    Radfar, Lida
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Stone, Donald U.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Lewis, David M.
    University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Li, Shibo
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Koelsch, Kristi A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Igoe, Ann
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Talsania, Mitali
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Kumar, Jay
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Maier-Moore, Jacen S.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA; University of Texas El Paso, TX 79968 USA.
    Harris, Valerie M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN USA.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Lessard, James A.
    Valley Bone and Joint Clin, ND USA.
    Lu, Xianglan
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    -Eric Gottenberg, Jacques
    Strasbourg University, France.
    -Manuel Anaya, Juan
    University of Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England.
    Huang, Andrew J. W.
    University of Minnesota, MN USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Hughes, Pamela
    University of Minnesota, MN USA.
    Mei, Gabor G.
    MedImmune, MD USA; National Institute Dent and Craniofacial Research, MD USA.
    Miceli-Richard, Corinne
    University of Paris 11, France; INSERM, France.
    Keystone, Edward C.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Bykerk, Vivian P.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Hirschfield, Gideon
    University of Birmingham, England.
    Xie, Gang
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Ng, Wan-Fai
    NIHR Newcastle Biomed Research Centre, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten. Newcastle University, England.
    Omda, Roald
    Stavanger University Hospital, Norway.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Rohrer, Michael
    University of Minnesota, MN USA.
    Sega, Barbara M.
    University of Minnesota, MN 55455 USA; Hennepin County Medical Centre, MN 55415 USA.
    Vvse, Timothy J.
    Kings Coll London, England.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Pons-Este, Bernardo
    Sanatorio Parque, Argentina.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; Centre Pfizer University of Granada Junta de Andalucia Genom, Spain.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Thompson, Susan D.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Edberg, Jeffrey C.
    University of Alabama Birmingham, AL USA.
    Kimberly, Robert P.
    University of Alabama Birmingham, AL USA.
    Alarcon, Gracicla S.
    University of Alabama Birmingham, AL USA.
    Langefeld, Carl L.
    Wake Forest University, NC 27109 USA.
    Gilkeson, Gary S.
    Medical University of S Carolina, SC USA.
    Kamen, Diane L.
    Medical University of S Carolina, SC USA.
    Tsao, Betty P.
    University of Calif Los Angeles, CA 90095 USA.
    Joseph McCune, W.
    University of Michigan, MI 48109 USA.
    Salmon, Jane E.
    Hospital Special Surg, NY 10021 USA; Weill Cornell Med, NY USA.
    Merrill, Joan T.
    University of Oklahoma, OK USA; University of Oklahoma, OK 73190 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA; University of Calif Los Angeles, CA 90095 USA.
    Utset, Tammy
    University of Chicago, IL 60637 USA.
    Bottinger, Erwin P.
    Mt Sinai Hospital, NY 10029 USA.
    Amos, Christopher I.
    Dartmouth Coll, NH 03755 USA.
    Siminovitch, Katherine A.
    Mt Sinai Hospital, Canada; University of Toronto, Canada; Toronto Gen Hospital, Canada.
    Mariette, Xavier
    University of Paris 11, France; INSERM, France.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Harley, John B.
    University of Cincinnati, OH USA; Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; Cincinnati VA Medical Centre, OH USA.
    Hal Scofield, R.
    University of Oklahoma, OK 73190 USA; Oklahoma City VA Medical Centre, OK USA.
    X Chromosome Dose and Sex Bias in Autoimmune Diseases2016Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, nr 5, s. 1290-1300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

  • 3.
    Maritati, Federica
    et al.
    Parma University Hospital, Italy.
    Fenoglio, Roberta
    G Bosco Hospital, Italy; University of Turin, Italy.
    Pillebout, Evangeline
    St Louis Hospital, France.
    Emmi, Giacomo
    University of Florence, Italy.
    Urban, Maria L.
    Parma University Hospital, Italy.
    Rocco, Rossana
    Parma University Hospital, Italy.
    Nicastro, Maria
    Parma University Hospital, Italy.
    Incerti, Monia
    Parma University Hospital, Italy.
    Goldoni, Matteo
    University of Parma, Italy.
    Trivioli, Giorgio
    Parma University Hospital, Italy.
    Silvestri, Elena
    University of Florence, Italy.
    Mohammad, Aladdin J.
    Lund University, Sweden; University of Cambridge, England.
    Jayne, David
    University of Cambridge, England.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Segelmark, Mårten
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Novikov, Pavel
    Sechenov First Moscow State Medical University, Russia.
    Harris, Helen
    Whytemans Brae Hospital, Scotland.
    Roccatello, Dario
    G Bosco Hospital, Italy; University of Turin, Italy.
    Vaglio, Augusto
    Parma University Hospital, Italy.
    Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schonlein)2018Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, nr 1, s. 109-114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ObjectiveAdult-onset IgA vasculitis (Henoch-Schonlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. MethodsIn this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. ResultsTwenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P amp;lt; 0.0001), CRP level (P = 0.0005), BVAS (P amp;lt; 0.0001), and prednisone dose (P amp;lt; 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. ConclusionOur data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.

  • 4.
    Pope, Janet E
    et al.
    University of Western Ontario, London, Ontario, Canada.
    Weisman, Michael H
    Cedars-Sinai Medical Center, Los Angeles, California, USA.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    The effect of ethnicity on cardiovascular outcomes in systemic lupus erythematosus is perhaps not a paradox.2017Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, nr 9, s. 1707-1709Artikel i tidskrift (Refereegranskat)
  • 5.
    Sharma, Rohan
    et al.
    University of Oklahoma, OK USA; Department Vet Affairs Medical Centre, OK USA.
    Harris, Valerie M.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Cavett, Joshua
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Kurien, Biji T.
    University of Oklahoma, OK USA; Department Vet Affairs Medical Centre, OK USA.
    Liu, Ke
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH USA.
    Koelsch, Kristi A.
    University of Oklahoma, OK USA; Department Vet Affairs Medical Centre, OK USA.
    Fayaaz, Anum
    Department Vet Affairs Medical Centre, OK USA.
    Chaudhari, Kaustubh S.
    Department Vet Affairs Medical Centre, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Lewis, David
    University of Oklahoma, OK USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA; King Khalid Eye Specialist Hospital, Saudi Arabia.
    Erick Kaufman, C.
    University of Oklahoma, OK USA.
    Li, Shibo
    University of Oklahoma, OK USA.
    Segal, Barbara
    University of Minnesota, MN 55455 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Pons-Estel, Bernardo
    Sanatorio Parque, Argentina.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Lu, Xianglan
    University of Oklahoma, OK USA.
    Gottenberg, Jacques-Eric
    Strasbourg University, France.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Cunninghame-Graham, Deborah S.
    Kings Coll London, England.
    Huang, Andrew J. W.
    University of Minnesota, MN USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Hughes, Pamela
    University of Minnesota, MN USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Keystone, Edward C.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Bykerk, Vivian P.
    Hospital Special Surg, NY 10021 USA.
    Hirschfield, Gideon
    University of Birmingham, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Magnusson Bucher, Sara
    Örebro University Hospital, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Rhodus, Nelson L.
    University of Minnesota, MN USA.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Rohrer, Michael
    University of Minnesota, MN USA.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Alarcon-Riquelme, Marta
    Karolinska Institute, Sweden; University of Granada, Spain.
    Mariette, Xavier
    University of Paris Sud, France.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Harley, John B.
    University of Cincinnati, OH USA; Ohio Department Vet Affairs Medical Centre, OH USA.
    Ng, Wan-Fai
    Newcastle University, England.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Hal Scofield, R.
    University of Oklahoma, OK USA; Department Vet Affairs Medical Centre, OK USA.
    Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjogrens Syndrome2017Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, nr 11, s. 2187-2192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. Sjogrens syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of similar to 10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. Methods. We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. Results. Among similar to 2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among similar to 2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in similar to 1 in 25,000-50,000 live female births, while partial triplications are even rarer. Conclusion. Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.

  • 6.
    Svärd, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ilar, Anna
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Klareskog, Lars
    Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, Solna, Stockholm, Sweden.
    Bengtsson, Camilla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis2015Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr 8, s. 2032-2037Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Smoking and HLA-DRB1/shared epitope (SE) are well-known interacting risk factors for developing rheumatoid arthritis (RA) with IgG anticitrullinated protein/peptide antibodies (ACPA). It remains unknown to what extent SE-genes and smoking associate with mucosal immune responses.

    Objectives This study was done to explore relations between cigarette smoking habits and SE versus circulating IgA and IgG anti-cyclic citrullinated peptide antibodies (anti-CCP) among early RA patients.

    Methods Patients from two early-RA cohorts were analysed, EIRA-1 (n=1663) and TIRA-2 (n=199). The patients were grouped into four subsets based on anti-CCP: IgG-/IgA-, IgG-/IgA+, IgG+/IgA- and IgG+/IgA+. Interaction between smoking and SE was calculated by the attributable proportion due to deviation from additivity. Analyzed controls (n=1100) were randomly selected from the EIRA-1 study base.

    Results Anti-CCP occurrence was similar in the two cohorts. Only in EIRA was IgA anti-CCP detected alone in a minority of cases (3%). Smoking was significantly overrepresented among IgA anti-CCP+ patients with or without IgG-class anti-CCP, but not with IgG anti-CCP alone. Presence of SE genes was overrepresented among IgG anti-CCP+ patients with or without IgA-class anti-CCP, but not with IgA anti-CCP alone. Smoking and SE interacted regarding the risk of IgG+/IgA+ RA (AP=0.5, 95 % CI=0.4-0.6), whereas no significant interaction was observed regarding IgG-/IgA+ or IgG+/IgA- RA.

    Conclusions Association between cigarette smoking and anti-CCP is limited to cases with IgA-class antibodies in addition to IgG anti-CCP. This suggests a causal relation between chronic mucosal irritation/inflammation, induction of a systemic IgA anti-CCP response and subsequent development of RA.

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