Rheumatoid arthritis : pharmacological modulation of cytokines : aspects of clinical response and endocrine regulation
Rheumatoid arthritis (RA) is a systemic inflammatory disease primarily affecting the joints. In the pathogenesis several cells of the immune systeme and messengers of the immune systeme, cytokines, are important. In this thesis, the cytokine-modulating effects of two different treatments in RA, gold sodium thiomalate (GSTM) and the TNF-antagonist infliximab, are investigated. Further genetic factors potentially predicting clinical response to another TNF-antagonist, etanercept, are presented. Finally, the effect of TNF-antagonists on the hormone levels of the adrenal and gonadal axes is demonstrated.
The mechanism of action of GSTM is not fully understood. We studied 20 patients with RA during treatment with GSTM. The numbers of IL-6-, IL-10- and IFNgamma-producing cells measured with ELISPOT were significantly increased after four weeks treatment with GSTM, as was serum concentrations of IL-10. In addition a higher IL-10 production from peripheral blood mononuclear cells was recorded in patients without a subsequent skin rash. There was no correlation between clinical response and cytokine production. In conclusion, GSTM seems to have immunoregulatory properties that may be important for the therapeutic effect in RA.
The effect of TNF-antagonists on cytokine expression in the synovial membrane may be of relevance as additional therapeutic targets may be identified. We studied the effect of the TNF-antagonist infliximab on the synovial expression of TNF, IL-1alpha, IL-1beta, IFNgamma and IL-15 with immunohistochemistry. IL-15 is still present in the synovial tissue after treatment with infliximab as a remaining potential target. There was no correlation between synovial expression of IL-15 and response to therapy, but expression of TNF at baseline was exclusively seen in patients with good response to infliximab.
Genetic factors, such as HLADRB1/shared epitope or cytokine gene promoter polymorphisms, relevant to RA, were investigated concerning correlation with clinical response to the TNF-antagonist etanercept. The combination of the alleles 308TNFG/G and 1087IL-10G/G was correlated with a good response, compared with all other combinations. This combination may correlate with a presumed functional phenotype with a low immune response.
Both adrenal and gonadal axes are reported to be downregulated in RA with a decreased responsiveness to inflammatory stimuli. This down-regulation has been suggested to be the effect of proinflammatory cytokines. We studied ACTH, cortisol, DHEAS, LH, testosterone and estradiol during two years treatment with TNF-antagonists. An individual stability in hormone levels was recorded, with no effect of decreased disease activity on this stability. DHEAS increased in females without prednisolone treatment, with a correlation with improved physical function, possibly relevant to other effective treatments. A subset of women with low adrenal hormone levels had a disease onset at a young age. Presuming a stable individual hormonal homeostasis, these low adrenal hormone levels may even precede disease onset.
In conclusion, studies on cytokine-modulating treatment strategies in RA may provide information on mechanism of action and give further insight in potential pathogenetic mechanisms.
List of scientific papers
I. Ernestam S, Lampa J, Rogberg S, Ronnelid J, Klareskog L, Hafstrom I (2003). Evidence for immunostimulatory effects of intramuscular gold in patients with rheumatoid arthritis: correlation with skin reactions. J Rheumatol. 30(8): 1748-55.
https://pubmed.ncbi.nlm.nih.gov/12913930
II. Ernestam S, af Klint E, Catrina AI, Sundberg E, Engstrom M, Klareskog L, Ulfgren AK (2006). Synovial expression of IL-15 in rheumatoid arthritis is not influenced by blockade of tumour necrosis factor. Arthritis, Research and Therapy. [Accepted]
https://doi.org/10.1186/ar1871
III. Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J (2003). Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis. 62(6): 526-9.
https://doi.org/10.1136/ard.62.6.526
IV. Ernestam S, Hafstrom I, Carlstrom K, Werner S, Tengstrand B (2006). Serum markers of adrenal and gonadal activity in rheumatoid arthritis are stable during two years of treatment with TNF-antagonists, irrespective of clinical response. [Manuscript]
History
Defence date
2006-01-27Department
- Department of Medicine, Solna
Publication year
2006Thesis type
- Doctoral thesis
ISBN-10
91-7140-628-XNumber of supporting papers
4Language
- eng