Cytokines in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic disease characterised by inflammation in several joints. Cytokines appear to be important as both disease promoting and disease- suppressing mediators in the disease. The use of arthroscopic biopsy for examination of rheumatoid arthritis synovial tissue has opened up a field for understanding pathogenesis and evaluating therapy in patients. The studies performed during this thesis have been concerned mainly with development of methodologies for analysing cytokine expression in inflamed joints and with the use of these methodologies to understand pathogenetic features of RA and effects of TNF-blockade on cytokine patterns. A new immunohistochemical method for detection of intracellular cytokines was devised for sections from the RA synovium. This method allowed the discrimination of cytokine-producing cells from cytokine-binding cells in the tissue sections. Using this method a limited production of T cell derived cytokines was recorded in the synovial membrane. Furthermore, we also determined a limited amount of constantly expressed TNF[alpha].

The T cells in RA synovium and synovial fluid were demonstrated to have a diminished CD3[zeta] expression, something that hampers the intracellular signalling after stimulation of the T cells. An image digitilised analysis technique was developed and evaluated for measuring expression of cell surface molecules in synovial tissue. By using immunohistochemical and digital image analysis an intraarticular and interindividual variation of monokine expression was demonstrated in synovial membranes from both early and late RA patients. In the joints from RA patients treated with anti-TNF[alpha] neutralising monoclonal antibodies synovial biopsies were investigated for cytokine production before and after treatment with monoclonal anti-TNF-antibodies. This treatment led to a diminshed but not totally abrogated TN17-production in all the treated patients and a diminshed IL-1 production in some of the patients. The patients that responded best to this therapy were the ones with the highest expression of TNF[alpha] before starting treatment. In summary, these studies have demonstrated that immunohistochemical detection of cytokine production in RA joints can be performed reproducibly and quantitatively and may be used to evaluate effects and modes of action of new therapies in individual patients.

List of scientific papers

I. Ulfgren AK, Lindblad S, Klareskog L, Andersson J, Andersson U (1995). Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann Rheum Dis. 54(8):654-661.
https://pubmed.ncbi.nlm.nih.gov/7677442

II. Matsuda M, Ulfgren AK, Lenkei R, Petersson M, Ochoa AC, Lindblad S, Andersson P, Klareskog L, Kiessling R. (1998). Decreased expression of signal-transducing CD3 zeta chains in T cells from the joints and peripheral blood of rheumatoid arthritis patients. Scand J Immunol. 47(3):254-262.
https://pubmed.ncbi.nlm.nih.gov/9519864

III. Cunnane G, Björk L, Ulfgren AK, Lindblad S, FitzGerald O, Bresnihan B, Andersson U. (1999). Quantitative analysis of synovial membrane inflammation: a comparison between automated and conventional microscopic measurements. Ann Rheum Dis. 58(8):493-499.
https://pubmed.ncbi.nlm.nih.gov/10419868

IV. Ulfgren AK, Gröndal L, Lindblad S, Khademi M, Johnell O, Klareskog L, Andersson U (2000). Interindividual and intraarticular variation of proinflammatory cytokines in rheumatoid arthritis: potetial implication for RA therapy. Ann Rheum Dis. [Accepted]

V. Ulfgren AK, Andersson U, Engström M, Klarskog L, Maini R, Taylor P (1999). Systemic anti-TNFalpha therapy in rheumatoid arthritis down-regulates synovial TNFalpha formation. Arthritis Rheum. [Accepted]