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Manivel, Vivek AnandORCID iD iconorcid.org/0000-0002-6746-7372
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Mannes, M., Pechtl, V., Hafner, S., Dopler, A., Eriksson, O., Manivel, V. A., . . . Schmidt, C. Q. (2023). Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals. Blood Advances, 7(20), 6367-6380
Öppna denna publikation i ny flik eller fönster >>Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals
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2023 (Engelska)Ingår i: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 7, nr 20, s. 6367-6380Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5 '-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.

Ort, förlag, år, upplaga, sidor
American Society of Hematology, 2023
Nationell ämneskategori
Hematologi Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:uu:diva-516655 (URN)10.1182/bloodadvances.2023010817 (DOI)001093385100001 ()37428869 (PubMedID)
Forskningsfinansiär
Deutsche Forschungsgemeinschaft (DFG), SCHM 3018/4-1Deutsche Forschungsgemeinschaft (DFG), CRC1149 A01
Tillgänglig från: 2023-11-27 Skapad: 2023-11-27 Senast uppdaterad: 2023-11-27Bibliografiskt granskad
Lopes, V., Birgersson, U., Manivel, V. A., Hulsart Billström, G., Gallinetti, S., Aparicio, C. & Hong, J. (2023). Human Whole Blood Interactions with Craniomaxillofacial Reconstruction Materials: Exploring In Vitro the Role of Blood Cascades and Leukocytes in Early Healing Events. Journal of Functional Biomaterials, 14(7), Article ID 361.
Öppna denna publikation i ny flik eller fönster >>Human Whole Blood Interactions with Craniomaxillofacial Reconstruction Materials: Exploring In Vitro the Role of Blood Cascades and Leukocytes in Early Healing Events
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2023 (Engelska)Ingår i: Journal of Functional Biomaterials, ISSN 2079-4983, E-ISSN 2079-4983, Vol. 14, nr 7, artikel-id 361Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The present study investigated early interactions between three alloplastic materials (calcium phosphate (CaP), titanium alloy (Ti), and polyetheretherketone (PEEK) with human whole blood using an established in vitro slide chamber model. After 60 min of contact with blood, coagulation (thrombin-antithrombin complexes, TAT) was initiated on all test materials (Ti > PEEK > CaP), with a significant increase only for Ti. All materials showed increased contact activation, with the KK-AT complex significantly increasing for CaP (p < 0.001), Ti (p < 0.01), and PEEK (p < 0.01) while only CaP demonstrated a notable rise in KK-C1INH production (p < 0.01). The complement system had significant activation across all materials, with CaP (p < 0.0001, p < 0.0001) generating the most pronounced levels of C3a and sC5b-9, followed by Ti (p < 0.001, p < 0.001) and lastly, PEEK (p < 0.001, p < 0.01). This activation correlated with leukocyte stimulation, particularly myeloperoxidase release. Consequently, the complement system may assume a more significant role in the early stages post implantation in response to CaP materials than previously recognized. Activation of the complement system and the inevitable activation of leukocytes might provide a more favorable environment for tissue remodeling and repair than has been traditionally acknowledged. While these findings are limited to the early blood response, complement and leukocyte activation suggest improved healing outcomes, which may impact long-term clinical outcomes.

Ort, förlag, år, upplaga, sidor
MDPI AG, 2023
Nyckelord
biomaterials, human whole blood, coagulation, complement, calcium phosphate
Nationell ämneskategori
Biomaterialvetenskap Odontologi
Identifikatorer
urn:nbn:se:uu:diva-508838 (URN)10.3390/jfb14070361 (DOI)001036180100001 ()37504856 (PubMedID)
Tillgänglig från: 2023-08-16 Skapad: 2023-08-16 Senast uppdaterad: 2023-08-16Bibliografiskt granskad
Adler, A., Manivel, V. A., Fromell, K., Teramura, Y., Nilsson Ekdahl, K. & Nilsson, B. (2022). A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein. Frontiers in Immunology, 13, Article ID 891994.
Öppna denna publikation i ny flik eller fönster >>A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein
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2022 (Engelska)Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, artikel-id 891994Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Complement components have a reputation to be very labile. One of the reasons for this is the spontaneous hydrolysis of the internal thioester that is found in both C3 and C4 (but not in C5). Despite the fact that approximate to 20,000 papers have been published on human C3 there is still no reliable method to store the protein without generating C3(H2O), a fact that may have affected studies of the conformation and function of C3, including recent studies on intracellular C3(H2O). The aim of this work was to define the conditions for storage of native C3 and to introduce a robust method that makes C3 almost resistant to the generation of C3(H2O). Here, we precipitated native C3 at the isoelectric point in low ionic strength buffer before freezing the protein at -80 degrees C. The formation of C3(H2O) was determined using cation exchange chromatography and the hemolytic activity of the different C3 preparations was determined using a hemolytic assay for the classical pathway. We show that freezing native C3 in the precipitated form is the best method to avoid loss of function and generation of C3(H2O). By contrast, the most efficient way to consistently generate C3(H2O) was to incubate native C3 in a buffer at pH 11.0. We conclude that we have defined the optimal storage conditions for storing and maintaining the function of native C3 without generating C3(H2O) and also the conditions for consistently generating C3(H2O).

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A.FRONTIERS MEDIA SA, 2022
Nyckelord
C3, C3(H2O), thioester, storage, freezing
Nationell ämneskategori
Immunologi inom det medicinska området Immunologi
Identifikatorer
urn:nbn:se:uu:diva-476176 (URN)10.3389/fimmu.2022.891994 (DOI)000797921100001 ()35592325 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2016-01060Vetenskapsrådet, 2016-04519Vetenskapsrådet, 2020-05762Vetenskapsrådet, 2021-02252
Tillgänglig från: 2022-06-09 Skapad: 2022-06-09 Senast uppdaterad: 2024-01-17Bibliografiskt granskad
Skendros, P., Germanidis, G., Mastellos, D. C., Antoniadou, C., Gavriilidis, E., Kalopitas, G., . . . Lambris, J. D. (2022). Complement C3 inhibition in severe COVID-19 using compstatin AMY-101. Science Advances, 8(33), Article ID eabo2341.
Öppna denna publikation i ny flik eller fönster >>Complement C3 inhibition in severe COVID-19 using compstatin AMY-101
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2022 (Engelska)Ingår i: Science Advances, E-ISSN 2375-2548, Vol. 8, nr 33, artikel-id eabo2341Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 <= 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Ort, förlag, år, upplaga, sidor
American Association for the Advancement of Science (AAAS)American Association for the Advancement of Science (AAAS), 2022
Nationell ämneskategori
Kardiologi
Identifikatorer
urn:nbn:se:uu:diva-483879 (URN)10.1126/sciadv.abo2341 (DOI)000842064500018 ()35977025 (PubMedID)
Tillgänglig från: 2022-09-08 Skapad: 2022-09-08 Senast uppdaterad: 2024-01-15Bibliografiskt granskad
Suzuki, H., Adler, A., Huang, T., Kuramochi, A., Ohba, Y., Sato, Y., . . . Teramura, Y. (2022). Impact of spontaneous liposome modification with phospholipid polymer-lipid conjugates on protein interactions. Science and Technology of Advanced Materials, 23(1), 845-857
Öppna denna publikation i ny flik eller fönster >>Impact of spontaneous liposome modification with phospholipid polymer-lipid conjugates on protein interactions
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2022 (Engelska)Ingår i: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 23, nr 1, s. 845-857Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Liposome surface coating has been studied to avoid the immunological responses caused by the complement system, and alternative materials to poly(ethylene glycol) (PEG) have been explored recently since the production of anti-PEG IgM antibodies has been found in humans. We previously reported a liposome coating with poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC))-conjugated lipids (PMPC-lipids) and demonstrated its protective effect on blood protein interactions. Here, we attempted to modify the liposome surface by exogenously adding PMPC-lipids, which were spontaneously incorporated into the outer membrane via hydrophobic interactions. The polymerization degree of the PMPC segment was regulated from 10 to 100. The incorporated ratio of PMPC-lipid increased with a decrease in the degree of PMPC polymerization. Due to surface modification with PMPC-lipids, increase in the length of the PMPC-chain increased the size of the liposomes. The modified liposomes were kept stable for 14 d in terms of their size, polydispersity, and surface properties, where approximately 70% of PMPC-lipids were incorporated into the liposome surface. We demonstrated that liposome surface modification with PMPC-lipids can inhibit protein adsorption when exposed to serum, regardless of the degree of polymerization of PMPC. In addition, the PMPC-lipid modified surface was not recognized by the anti-PEG IgM antibody, whereas PEG-lipid was recognized by the antibody. Thus, we successfully fabricated an inert liposome surface via spontaneous modification with PMPC-lipids, where only the outer bilayer surface was modified. This technique can be available for full loading of water-soluble active pharmaceutical ingredient inside the modified liposome.

Ort, förlag, år, upplaga, sidor
Taylor & Francis Group, 2022
Nyckelord
2-Methacryloyloxyethyl phosphorylcholine (MPC) polymer, liposomes, surface modification, anti-PEG antibody
Nationell ämneskategori
Biokemi och molekylärbiologi Fysikalisk kemi
Identifikatorer
urn:nbn:se:uu:diva-492237 (URN)10.1080/14686996.2022.2146466 (DOI)000894246300001 ()36518982 (PubMedID)
Tillgänglig från: 2023-01-03 Skapad: 2023-01-03 Senast uppdaterad: 2023-01-03Bibliografiskt granskad
Elbagir, S., Grosso, G., Mohammed, N. A., ElShafie, A. I., Elagib, E. M., Zickert, A., . . . Svenungsson, E. (2021). Associations with thrombosis are stronger for antiphosphatidylserine/prothrombin antibodies than for the Sydney criteria antiphospholipid antibody tests in SLE. Lupus, 30(8), 1289-1299
Öppna denna publikation i ny flik eller fönster >>Associations with thrombosis are stronger for antiphosphatidylserine/prothrombin antibodies than for the Sydney criteria antiphospholipid antibody tests in SLE
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2021 (Engelska)Ingår i: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 30, nr 8, s. 1289-1299Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: Antiphosphatidylserine/prothrombin complex antibodies (aPS/PT) are risk factors for thrombosis, yet further validation of their clinical relevance in different ethnic groups is required. We investigated the performance of aPS/PT of IgA/G/M isotypes among Sudanese and Swedish systemic lupus erythematosus (SLE) patients.

Methods: Consecutive SLE patients/matched controls from Sudan (n = 91/102) and Sweden (n = 332/163) were included. All patients fulfilled the 1982 ACR SLE classification criteria. IgA/G/M of aPS/PT, anti-cardiolipin and anti-beta(2)glycoprotein I (anti-beta(2)GPI) were tested in both cohorts, and lupus anticoagulant (LA) also in the Swedish cohort. Clinical antiphospholipid syndrome-related events and atherosclerosis, measured as carotid plaques were assessed for associations. Univariate and multivariate analyses adjusting for cardiovascular risk factors were performed.

Results: Sudanese SLE patients had higher levels of IgM aPS/PT, but using national cut-offs, the frequency of positivity was similar to Swedish patients for all isotypes. Among Swedish patients, all isotypes of aPS/PT associated with venous thromboembolism (VTE), while only IgA aPS/PT associated with arterial thrombosis (AT). aPS/PT antibodies associated strongly with LA and they were, independently, the best predictor for VTE. Double positivity for aPS/PT and anti-beta(2)GPI associated with higher VTE risk than the conventional triple positivity. Carotid plaques did not associate with any antiphospholipid antibody.

Conclusions: IgA aPS/PT associated with AT, and the association of IgG/M aPS/PT with VTE outperforms LA and criteria antiphospholipid antibodies in Swedish SLE patients. Furthermore, double positivity for aPS/PT and anti-beta(2)GPI performed better than conventional triple positivity. Future studies need to address if aPS/PT can replace LA, as this would simplify clinical procedures.

Ort, förlag, år, upplaga, sidor
Sage PublicationsSAGE PUBLICATIONS LTD, 2021
Nyckelord
Antiphosphatidylserine, prothrombin, carotid plaques, lupus anticoagulant, systemic lupus erythematosus, thrombosis
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:uu:diva-454290 (URN)10.1177/09612033211014570 (DOI)000651159600001 ()33957795 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2019-01632Vetenskapsrådet, 2018-02535Hjärt-Lungfonden, 20170257Hjärt-Lungfonden, 20190510Reumatikerförbundet, R-932093Reumatikerförbundet, R-840401Stiftelsen Konung Gustaf V:s 80-årsfond, FAI-2019-0577Stiftelsen Konung Gustaf V:s 80-årsfond, FAI-20190628Svenska läkaresällskapet, SLS-713911Stockholms läns landsting
Tillgänglig från: 2021-09-28 Skapad: 2021-09-28 Senast uppdaterad: 2024-01-15Bibliografiskt granskad
Mallavarpu Ambrose, J., Priya Veeraraghavan, V., Kullappan, M., Chellapandiyan, P., Krishna Mohan, S. & Manivel, V. A. (2021). Comparison of Immunological Profiles of SARS-CoV-2 Variants in the COVID-19 Pandemic Trends: An Immunoinformatics Approach. Antibiotics, 10(5), Article ID 535.
Öppna denna publikation i ny flik eller fönster >>Comparison of Immunological Profiles of SARS-CoV-2 Variants in the COVID-19 Pandemic Trends: An Immunoinformatics Approach
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2021 (Engelska)Ingår i: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 10, nr 5, artikel-id 535Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The current dynamics of the COVID-19 pandemic have become a serious concern with the emergence of a series of mutant variants of the SARS-CoV-2 virus. Unlike the previous strain, it is reported that the descendants are associated with increased risk of transmission yet causing less impact in terms of hospital admission, the severity of illness, or mortality. Moreover, the vaccine efficacy is also not believed to vary among the population depending on the variants of the virus and ethnicity. It has been determined that the mutations recorded in the spike gene and protein of the newly evolved viruses are specificallyresponsible for this transformation in the behavior of the virus and its disease condition. Hence, this study aimed to compare the immunogenic profiles of the spike protein from the latest variants of the SARS-CoV-2 virus concerning the probability of COVID-19 severity. Genome sequences of the latest SARS-CoV-2 variants were obtained from GISAID and NCBI repositories. The translated protein sequences were run against T-cell and B-cell epitope prediction tools. Subsequently, antigenicity, immunogenicity, allergenicity, toxicity, and conservancy of the identified epitopes were ascertained using various prediction servers. Only the non-allergic and non-toxic potential epitopes were matched for population relevance by using the Human Leucocyte Antigen population registry in IEDB. Finally, the selected epitopes were validated by docking and simulation studies. The evaluated immunological parameters would concurrently reveal the severity of COVID-19, determining the infection rate of the pathogen. Our immunoinformatics approach disclosed that spike protein of the five variants was capable of forming potential T and B-cell epitopes with varying immune responses. Although the Wuhan strain showed a high number of epitope/HLA combinations, relatively less antigenicity and higher immunogenicity results in poor neutralizing capacity, which could be associated with increased disease severity. Our data demonstrate that increased viral antigenicity with moderate to high immunogenicity, and several potential epitope/HLA combinations in England strain, the USA, India, and South Africa variants, could possess a high neutralizing ability. Therefore, our findings reinforce that the newly circulating variants of SARS-CoV-2 might be associated with more infectiousness and less severe disease condition despite their greater viremia, as reported in the recent COVID-19 cases, whichconsequently determine their increased epidemiological fitness.

Ort, förlag, år, upplaga, sidor
MDPI, 2021
Nyckelord
SARS-CoV-2 variants, SARS-CoV-2 antigenicity, SARS-CoV-2 immunogenicity, SARS-CoV-2 epitope prediction, immunoinformatics approach, COVID-19 severity, infection rate, epidemiological fitness, vaccine modification
Nationell ämneskategori
Infektionsmedicin Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:uu:diva-445037 (URN)10.3390/antibiotics10050535 (DOI)000653453100001 ()34066389 (PubMedID)
Tillgänglig från: 2021-06-14 Skapad: 2021-06-14 Senast uppdaterad: 2024-01-15Bibliografiskt granskad
Svensson, F. G., Manivel, V. A., Seisenbaeva, G. A., Kessler, V. G., Nilsson, B., Nilsson Ekdahl, K. & Fromell, K. (2021). Hemocompatibility of Nanotitania-Nanocellulose Hybrid Materials. Nanomaterials, 11(5), Article ID 1100.
Öppna denna publikation i ny flik eller fönster >>Hemocompatibility of Nanotitania-Nanocellulose Hybrid Materials
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2021 (Engelska)Ingår i: Nanomaterials, E-ISSN 2079-4991, Vol. 11, nr 5, artikel-id 1100Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In order to develop a new type of improved wound dressing, we combined the wound healing properties of nanotitania with the advantageous dressing properties of nanocellulose to create three different hybrid materials. The hemocompatibility of the synthesized hybrid materials was evaluated in an in vitro human whole blood model. To our knowledge, this is the first study of the molecular interaction between hybrid nanotitania and blood proteins. Two of the hybrid materials prepared with 3 nm colloidal titania and 10 nm hydrothermally synthesized titania induced strong coagulation and platelet activation but negligible complement activation. Hence, they have great potential as a new dressing for promoting wound healing. Unlike the other two, the third hybrid material using molecular ammonium oxo-lactato titanate as a titania source inhibited platelet consumption, TAT generation, and complement activation, apparently via lowered pH at the surface interface. It is therefore suitable for applications where a passivating surface is desired, such as drug delivery systems and extracorporeal circuits. This opens the possibility for a tailored blood response through the surface functionalization of titania.

Ort, förlag, år, upplaga, sidor
MDPIMDPI, 2021
Nyckelord
nanocellulose, titania, coagulation, platelets, complement system, contact system
Nationell ämneskategori
Materialkemi Medicinska material och protesteknik
Identifikatorer
urn:nbn:se:uu:diva-445594 (URN)10.3390/nano11051100 (DOI)000657022100001 ()33923181 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2014-3938Vetenskapsrådet, 2018-03811Vetenskapsrådet, 2016-2075Vetenskapsrådet, 2016-04519
Tillgänglig från: 2021-07-15 Skapad: 2021-07-15 Senast uppdaterad: 2024-01-15Bibliografiskt granskad
Rönnelid, J., Knight, A., Lysholm, J., Manivel, V. A., Sohrabian, A., Larsson, A. & Weitoft, T. (2021). High levels of interleukin-6 in rheumatoid arthritis joint fluids can stimulate local production of C-reactive protein resulting in elevated circulating levels [Letter to the editor]. Joint Bone Spine, 88(3), Article ID 105159.
Öppna denna publikation i ny flik eller fönster >>High levels of interleukin-6 in rheumatoid arthritis joint fluids can stimulate local production of C-reactive protein resulting in elevated circulating levels
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2021 (Engelska)Ingår i: Joint Bone Spine, ISSN 1297-319X, E-ISSN 1778-7254, Vol. 88, nr 3, artikel-id 105159Artikel i tidskrift, Letter (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
ElsevierElsevier BV, 2021
Nyckelord
C-reactive protein, Interleukin-6, Rheumatoid arthritis, Synovial fluid
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:uu:diva-439142 (URN)10.1016/j.jbspin.2021.105159 (DOI)000678538100005 ()33561534 (PubMedID)
Anmärkning

Shared last authorship: Anders Larsson and Tomas Weitoft

Tillgänglig från: 2021-03-30 Skapad: 2021-03-30 Senast uppdaterad: 2024-01-15Bibliografiskt granskad
Pertsinidou, E., Manivel, V. A., Westerlind, H., Klareskog, L., Alfredsson, L., Mathsson Alm, L., . . . Rönnelid, J. (2021). Rheumatoid arthritis autoantibodies and their association with age and sex. Clinical and Experimental Rheumatology, 39(4), 879-882
Öppna denna publikation i ny flik eller fönster >>Rheumatoid arthritis autoantibodies and their association with age and sex
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2021 (Engelska)Ingår i: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 39, nr 4, s. 879-882Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective. To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset. Methods. Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based on RA-free controls, close to the 98.4% anti-CCP2 specificity. Results. Anti-CCP2 was found in 1020 patients (64%), IgA RF in 692 (43%), IgG RF in 529 (33%) and IgM RF in 916 (57%) of the patients. When assessed one by one, anti-CCP2 and IgM RF were both associated with lower age at RA diagnosis. When assessed in one joint model, the association to IgM RF weakened and a strong association between IgA RF and higher age at RA diagnosis appeared. IgA RF and IgG RF associated with male sex, and IgM RF with female sex, with no difference for anti-CCP2. When the model was adjusted for sex, the association between IgM RF and age disappeared, whereas the strong associations between IgA RF and high age and between anti-CCP2 and low age at diagnosis remained. Further adjustments for smoking, shared epitope and inclusion year did not change the outcome. Univariate analyses stratified on anti-CCP2 and IgA RF status confirmed the findings. Conclusion. Anti-CCP associate with low, and IgA RF with high age at RA onset. RFs and anti-CCP2 display opposing association with sex. These results underscore that studies on RA phenotypes in relation to autoantibodies should accommodate age and sex.

Ort, förlag, år, upplaga, sidor
CLINICAL & EXPER RHEUMATOLOGY, 2021
Nyckelord
rheumatoid arthritis, age of onset, rheumatoid factor, anti-citrullinated protein antibodies
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:uu:diva-456205 (URN)000691869100023 ()33822709 (PubMedID)
Forskningsfinansiär
NordForsk, 90825
Tillgänglig från: 2021-10-28 Skapad: 2021-10-28 Senast uppdaterad: 2021-10-28Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-6746-7372

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