Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections

Objective: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks....

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Veröffentlicht in:Annals of the rheumatic diseases 2002-04, Vol.61 (4), p.358-361
Hauptverfasser: Ferraccioli, G, Mecchia, F, Di Poi, E, Fabris, M
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creator Ferraccioli, G
Mecchia, F
Di Poi, E
Fabris, M
description Objective: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. Results: In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Conclusions: Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor α is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.
doi_str_mv 10.1136/ard.61.4.358
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Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. Results: In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Conclusions: Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor α is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.</description><identifier>ISSN: 0003-4967</identifier><identifier>EISSN: 1468-2060</identifier><identifier>DOI: 10.1136/ard.61.4.358</identifier><identifier>PMID: 11874843</identifier><identifier>CODEN: ARDIAO</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><subject>ACA ; Adolescent ; Adult ; Aged ; ANA ; Antibiotics ; Antibodies, Anticardiolipin - analysis ; Antibodies, Antinuclear - analysis ; Anticardiolipin antibodies ; antinuclear antibodies ; Antirheumatic Agents - therapeutic use ; Arthritis, Rheumatoid - drug therapy ; Arthritis, Rheumatoid - immunology ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; C reactive protein ; Child ; Child, Preschool ; Chloroquine - therapeutic use ; Colonies &amp; territories ; Concise Report ; CRP ; CsA ; cyclosporin A ; Cyclosporine - therapeutic use ; Deoxyribonucleic acid ; disease modifying antirheumatic drugs ; DMARDs ; DNA ; Drug Combinations ; Drug therapy ; E coli ; Etanercept ; Fever ; Humans ; Immunoglobulin G - analysis ; Immunoglobulin G - therapeutic use ; Immunoglobulin M - analysis ; Immunoglobulins ; Immunology ; Infant ; Infant, Newborn ; Infections ; Laboratories ; Medical sciences ; methotrexate ; Methotrexate - therapeutic use ; Middle Aged ; MTX ; Pharmacology. Drug treatments ; Physiological aspects ; Receptors, Tumor Necrosis Factor - therapeutic use ; Rheumatoid arthritis ; Software ; Staphylococcal Infections - drug therapy ; Staphylococcal Infections - immunology ; staphylococcus ; Staphylococcus aureus ; TNFα ; tumour necrosis factor α</subject><ispartof>Annals of the rheumatic diseases, 2002-04, Vol.61 (4), p.358-361</ispartof><rights>Copyright 2002 by Annals of the Rheumatic Diseases</rights><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2002 BMJ Publishing Group Ltd.</rights><rights>Copyright: 2002 Copyright 2002 by Annals of the Rheumatic Diseases</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b610t-20c4fc27845bb4a1fbc203acc434ebced0b37227339f3772f9a991bce87be5523</citedby><cites>FETCH-LOGICAL-b610t-20c4fc27845bb4a1fbc203acc434ebced0b37227339f3772f9a991bce87be5523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1754062/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1754062/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=13564024$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11874843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferraccioli, G</creatorcontrib><creatorcontrib>Mecchia, F</creatorcontrib><creatorcontrib>Di Poi, E</creatorcontrib><creatorcontrib>Fabris, M</creatorcontrib><title>Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections</title><title>Annals of the rheumatic diseases</title><addtitle>Ann Rheum Dis</addtitle><description>Objective: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. Results: In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Conclusions: Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor α is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.</description><subject>ACA</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>ANA</subject><subject>Antibiotics</subject><subject>Antibodies, Anticardiolipin - analysis</subject><subject>Antibodies, Antinuclear - analysis</subject><subject>Anticardiolipin antibodies</subject><subject>antinuclear antibodies</subject><subject>Antirheumatic Agents - therapeutic use</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>C reactive protein</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chloroquine - therapeutic use</subject><subject>Colonies &amp; territories</subject><subject>Concise Report</subject><subject>CRP</subject><subject>CsA</subject><subject>cyclosporin A</subject><subject>Cyclosporine - therapeutic use</subject><subject>Deoxyribonucleic acid</subject><subject>disease modifying antirheumatic drugs</subject><subject>DMARDs</subject><subject>DNA</subject><subject>Drug Combinations</subject><subject>Drug therapy</subject><subject>E coli</subject><subject>Etanercept</subject><subject>Fever</subject><subject>Humans</subject><subject>Immunoglobulin G - analysis</subject><subject>Immunoglobulin G - therapeutic use</subject><subject>Immunoglobulin M - analysis</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Infections</subject><subject>Laboratories</subject><subject>Medical sciences</subject><subject>methotrexate</subject><subject>Methotrexate - therapeutic use</subject><subject>Middle Aged</subject><subject>MTX</subject><subject>Pharmacology. Drug treatments</subject><subject>Physiological aspects</subject><subject>Receptors, Tumor Necrosis Factor - therapeutic use</subject><subject>Rheumatoid arthritis</subject><subject>Software</subject><subject>Staphylococcal Infections - drug therapy</subject><subject>Staphylococcal Infections - immunology</subject><subject>staphylococcus</subject><subject>Staphylococcus aureus</subject><subject>TNFα</subject><subject>tumour necrosis factor α</subject><issn>0003-4967</issn><issn>1468-2060</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kk-P0zAQxSMEYkvhxhlZrIALLXHsxAkHpKr8FdVygT1wsRxn0rokcbDdwn4xPh8TGm0XVKEcouf56Y39ZqLoIY3nlLLshXLVPKNzPmdpfiuaUJ7lsyTO4tvRJI5jNuNFJs6ie95vUcY5ze9GZ5TmguecTaJfiy4YjR7GNqY3HVGoS1sZ8ASV28CuVcGaivQqGOiCJ8GBClCRHyZsCATVgdPQB2Id0bbbI2NspxoUbWk6NSgSNuBUf_WSVMaBDtilQvtRwN5U0GkgNVoo0lvvTdkAUd5bbQ4Gf5qZrkYepb8f3alV4-HB-J9GX96--bx8P1t9evdhuVjNyozGAXPQvNaJyHlallzRutRJzJTWnHEoNVRxyUSSCMaKmgmR1IUqCoqFXJSQpgmbRq8Ovv2ubKHS-DinGtk70yp3Ja0y8u9KZzZybfeSipTH2WDwdDRw9vsOfJCt8RqaBmOzOy8FxflwnNM0Ov8H3Nqdwxw9egl8ARc5Q-rxgVqrBiTmYbGrHizlIud5wZNisHp-AloDDko1toPa4PFNfHYCx6-C1uhT_GivHU7KQX0dB43lsJIS10lmVHKJK4n4o5sRHuFxBxF4MgLKa9XUTnXa-CPHUgwo4cd7Gh_g53VduW8yE0yk8uJyKb9e5KvXl_SjHPhnB75st_-_4m_2swp2</recordid><startdate>20020401</startdate><enddate>20020401</enddate><creator>Ferraccioli, G</creator><creator>Mecchia, F</creator><creator>Di Poi, E</creator><creator>Fabris, M</creator><general>BMJ Publishing Group Ltd and European League Against Rheumatism</general><general>BMJ</general><general>BMJ Publishing Group Ltd</general><general>Elsevier Limited</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20020401</creationdate><title>Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections</title><author>Ferraccioli, G ; Mecchia, F ; Di Poi, E ; Fabris, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b610t-20c4fc27845bb4a1fbc203acc434ebced0b37227339f3772f9a991bce87be5523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>ACA</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>ANA</topic><topic>Antibiotics</topic><topic>Antibodies, Anticardiolipin - analysis</topic><topic>Antibodies, Antinuclear - analysis</topic><topic>Anticardiolipin antibodies</topic><topic>antinuclear antibodies</topic><topic>Antirheumatic Agents - therapeutic use</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>C reactive protein</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chloroquine - therapeutic use</topic><topic>Colonies &amp; territories</topic><topic>Concise Report</topic><topic>CRP</topic><topic>CsA</topic><topic>cyclosporin A</topic><topic>Cyclosporine - therapeutic use</topic><topic>Deoxyribonucleic acid</topic><topic>disease modifying antirheumatic drugs</topic><topic>DMARDs</topic><topic>DNA</topic><topic>Drug Combinations</topic><topic>Drug therapy</topic><topic>E coli</topic><topic>Etanercept</topic><topic>Fever</topic><topic>Humans</topic><topic>Immunoglobulin G - analysis</topic><topic>Immunoglobulin G - therapeutic use</topic><topic>Immunoglobulin M - analysis</topic><topic>Immunoglobulins</topic><topic>Immunology</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Infections</topic><topic>Laboratories</topic><topic>Medical sciences</topic><topic>methotrexate</topic><topic>Methotrexate - therapeutic use</topic><topic>Middle Aged</topic><topic>MTX</topic><topic>Pharmacology. Drug treatments</topic><topic>Physiological aspects</topic><topic>Receptors, Tumor Necrosis Factor - therapeutic use</topic><topic>Rheumatoid arthritis</topic><topic>Software</topic><topic>Staphylococcal Infections - drug therapy</topic><topic>Staphylococcal Infections - immunology</topic><topic>staphylococcus</topic><topic>Staphylococcus aureus</topic><topic>TNFα</topic><topic>tumour necrosis factor α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferraccioli, G</creatorcontrib><creatorcontrib>Mecchia, F</creatorcontrib><creatorcontrib>Di Poi, E</creatorcontrib><creatorcontrib>Fabris, M</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annals of the rheumatic diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferraccioli, G</au><au>Mecchia, F</au><au>Di Poi, E</au><au>Fabris, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections</atitle><jtitle>Annals of the rheumatic diseases</jtitle><addtitle>Ann Rheum Dis</addtitle><date>2002-04-01</date><risdate>2002</risdate><volume>61</volume><issue>4</issue><spage>358</spage><epage>361</epage><pages>358-361</pages><issn>0003-4967</issn><eissn>1468-2060</eissn><coden>ARDIAO</coden><abstract>Objective: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Methods: Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. Results: In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Conclusions: Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor α is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and European League Against Rheumatism</pub><pmid>11874843</pmid><doi>10.1136/ard.61.4.358</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection
subjects ACA
Adolescent
Adult
Aged
ANA
Antibiotics
Antibodies, Anticardiolipin - analysis
Antibodies, Antinuclear - analysis
Anticardiolipin antibodies
antinuclear antibodies
Antirheumatic Agents - therapeutic use
Arthritis, Rheumatoid - drug therapy
Arthritis, Rheumatoid - immunology
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
C reactive protein
Child
Child, Preschool
Chloroquine - therapeutic use
Colonies & territories
Concise Report
CRP
CsA
cyclosporin A
Cyclosporine - therapeutic use
Deoxyribonucleic acid
disease modifying antirheumatic drugs
DMARDs
DNA
Drug Combinations
Drug therapy
E coli
Etanercept
Fever
Humans
Immunoglobulin G - analysis
Immunoglobulin G - therapeutic use
Immunoglobulin M - analysis
Immunoglobulins
Immunology
Infant
Infant, Newborn
Infections
Laboratories
Medical sciences
methotrexate
Methotrexate - therapeutic use
Middle Aged
MTX
Pharmacology. Drug treatments
Physiological aspects
Receptors, Tumor Necrosis Factor - therapeutic use
Rheumatoid arthritis
Software
Staphylococcal Infections - drug therapy
Staphylococcal Infections - immunology
staphylococcus
Staphylococcus aureus
TNFα
tumour necrosis factor α
title Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections
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