Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment.
OBJECTIVE
Assessment of the numbers and spatial distribution of cells producing interleukin 1alpha (IL1alpha), interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) in the synovial membranes of patients with rheumatoid arthritis (RA).


METHODS
Synovial tissue specimens from 40 patients with RA and eight patients with non-rheumatic disease were obtained by arthroscopy guided biopsy techniques or during joint surgery. A modified immunohistochemical method detecting cytokine producing rather than cytokine binding cells was applied to determine cytokine synthesis in fixed cryopreserved sections. Computerised image analysis methods provided comparative quantitative assessments.


RESULTS
A wide variation between subjects was recorded for both quantities and profiles of expressed cytokines, despite similar macroscopic and histopathological features of inflammation. IL1alpha and IL1beta were the most abundant monokines identified, though produced at different sites. IL1alpha was predominantly seen in vascular endothelial cells, whereas IL1beta staining was mainly shown in macrophages and fibroblasts. Concordant results for the detection of TNFalpha at protein and mRNA levels were obtained with an unexpectedly low number of TNFalpha producing cells compared with IL1 expressing cells in many patients with RA. Specimens acquired arthroscopically from areas with maximum signs of macroscopic inflammation showed an increased number of TNFalpha producing cells in pannus tissue compared with that occurring in synovial villi of a given joint. This clustered distribution was not found for cells expressing any of the other studied cytokines.


CONCLUSIONS
The recorded heterogeneous profile of proinflammatory cytokine synthesis in the synovial membrane among patients with RA may provide a clue for an understanding of the wide variation in responsiveness to different modes of antirheumatic treatment between patients.
Ulfgren
A K
AK
Department of Medicine Unit of Rheumatology, Karolinska Hospital, Stockholm, Sweden. Ann-Kristin.Ulfgren@cmm.ki.se
Gröndal
L
L
Lindblad
S
S
Khademi
M
M
Johnell
O
O
Klareskog
L
L
Andersson
U
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001182:Arthroscopy; D016022:Case-Control Studies; D002452:Cell Count; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000032:analysis / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D018709:Statistics, Nonparametric; D013583:Synovial Membrane / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha