Treatment of arthritis with tumour necrosis factor antagonists. Clinical, immunological and biochemical aspects

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

Abstract The treatment of arthritis has undergone a dramatic change since biological agents targeting specific mediators of the disease process have been introduced. Tumour necrosis factor (TNF) antagonists have been shown to reduce signs and symptoms of disease and to retard the development of tissue damage in the majority of patients.

This thesis focuses on clinical, immunological and biochemical aspects of treatment with TNF antagonists in patients with arthritis. In particular, the studies examine: (i) the feasibility of a structured protocol with central data handling for the prospective monitoring treatment efficacy and tolerability of new treatments in clinical practice, (ii) whether serum levels of cartilage oligomeric matrix protein (COMP) change during treatment with TNF antagonists in a way that corroborates a tissue protective effects of these agents in rheumatoid arthritis (RA), (iii) how different anti-rheumatic treatments modulate the immune response induced by polysaccharide or polypeptide vaccines in patients with RA and (iv) potential predictors of infusion reactions during treatment with infliximab. All the patients who participated in the studies were monitored according to a standardised clinical protocol of the South Swedish Arthritis Treatment Group (SSATG) developed at the Department of Rheumatology in Lund. We found that such a protocol could be used for monitoring newly introduced anti-rheumatic treatments both at a university department and at other rheumatology units. The performance of TNF antagonists regarding efficacy and safety complied with results of previously published clinical trials.

Serum levels of COMP were measured in RA patients treated with infliximab and etanercept during the initial 6 months of treatment. Serum COMP levels decreased in patients with and without a clinical response, suggesting a damage retarding effect of TNF antagonist treatment. Altogether, 149 patients with RA participated in studies of the immune response to pneumococcal or influenza vaccination. Patients treated with TNF antagonists and controls showed similar responses to pneumococcal vaccine, whereas methotrexate treated patients showed reduced response to this vaccine regardless of concomitant treatment with TNF antagonists. In contrast, RA patients treated with methotrexate without TNF antagonists had significantly better immune response to influenza vaccination than those receiving TNF antagonists alone or in combination with methotrexate and/or other disease modifying antirheumatic drugs. Possible predictors of infliximab related infusion reactions were studied in a cohort of 213 patients with RA and 76 patients with spondylarthropaties. Infliximab without methotrexate and positive baseline ANA (antinuclear antibodies) were independent risk factors for developing infusion reactions in RA but not in spondylarthropaties. In conclusion, a structured protocol with central data handling is feasible in clinical practice for documenting the efficacy of and adverse events associated with drugs used for the treatment of arthritis. Serum COMP has the potential to be a useful marker for evaluating tissue effects of novel treatment modalities in RA. Methotrexate treatment in RA reduces antibody response to pneumococcal vaccine, suggesting that RA patients should be vaccinated before the initiation of his treatment. The immune response to influenza vaccination is sufficiently good to warrant vaccination of all RA patients, regardless of treatment. Positive ANA at initiation of infliximab treatment and the use of infliximab as monotherapy is associated with increased risk of infusion reactions in RA.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Rheumatology
Supervisors/Advisors
  • Geborek, Pierre, Supervisor
  • Saxne, Tore, Supervisor
Award date2006 Dec 14
Publisher
ISBN (Print)91-85559-64-4
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-12-14
Time: 09:00
Place: Department of Rheumatology, Lund University Hospital, Kioskgatan 3, Lund, Sweden

External reviewer(s)

Name: Skogh, Thomas
Title: prof
Affiliation: Institution of moleculare and clinical medicine, Dept of Rheumatology, Linköping University Hospital

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<div class="article_info">Pierre Geborek, Meliha Crnkic, Ingemar F Petersson and Tore Saxne. <span class="article_issue_date">2002</span>. <a href="javascript:downloadFile(547644)" class="article_link">Etanercept, infliximab and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden.</a> <span class="journal_series_title">Ann Reum Dis</span>, <span class="journal_volume">vol 61</span> <span class="journal_pages">pp 793-798</span>. <span class="journal_distributor">BMJ</span></div>
<div class="article_info">Meliha Crnkic, Bengt Månsson, Lotta Larsson, Pierre Geborek, Dick Heinegård and Tore Saxne. <span class="article_issue_date">2003</span>. <a href="javascript:downloadFile(547645)" class="article_link">Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept.</a> <span class="journal_series_title">Arthritis Res Ther</span>, <span class="journal_volume">vol 5</span> <span class="journal_pages">pp 181-185</span>.</div>
<div class="article_info">Meliha Crnkic Kapetanovic, Tore Saxne, Anders Sjöholm, Lennart Truedsson, Göran Jönsson and Pierre Geborek. <span class="article_issue_date">2006</span>. <a href="javascript:downloadFile(547646)" class="article_link">Influence of methotrexate, TNF-blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis.</a> <span class="journal_series_title">Rheumatology</span>, <span class="journal_volume">vol 45</span> <span class="journal_pages">pp 106-111</span>. <span class="journal_distributor">Oxford University Press</span></div>
<div class="article_info">Meliha Crnkic Kapetanovic, Tore Saxne, Jan-Åke Nilsson and Pierre Geborek. <span class="article_issue_date">2006</span>. <span class="article_title">Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients.</span> <span class="journal_series_title">Rheumatology</span>, <span class="journal_volume">vol 2006</span> <span class="journal_distributor">Oxford University Press</span></div>
<div class="article_info">Meliha Crnkic Kapetanovic, Lotta Larsson, Lennart Truedsson, Gunnar Sturfelt, Tore Saxne and Pierre Geborek. <span class="article_issue_date">2006</span>. <a href="javascript:downloadFile(547647)" class="article_link">Predictors of infusion reactions during infliximab treatment in patients with arthritis.</a> <span class="journal_series_title">Arthritis Res Ther</span>, <span class="journal_volume">vol 8</span> <span class="journal_pages">pp 131</span>.</div>

Subject classification (UKÄ)

  • Rheumatology and Autoimmunity

Keywords

  • Skelett
  • muskelsystem
  • reumatologi
  • Skeleton
  • muscle system
  • rheumatology locomotion
  • ANA
  • infusion reaction
  • influenza vaccination
  • pneumococcal vaccination
  • COMP
  • TNF antagonists
  • spondylarthropathies
  • arthritis
  • rheumatoid arthritis

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