Tumour necrosis factor alpha independent disease mechanisms in rheumatoid arthritis: a histopathological study on the effect of infliximab on rheumatoid nodules.
BACKGROUND
It has been suggested that the immunopathology of rheumatoid nodules parallels that of inflamed synovium in rheumatoid arthritis (RA).


OBJECTIVE
To analyse the effect of infliximab on the immunopathology of rheumatoid nodules in order to provide new insights into the relationship between synovial inflammation and rheumatoid nodules.


METHODS
Nodules were present at baseline in six patients with RA and after infliximab treatment in five patients, including paired nodules before and after treatment in three patients. In one patient, the nodule appeared during treatment. Paraffin sections were used for histological analysis. Frozen sections were stained by immunohistochemistry for cellular markers (CD3, CD4, CD8, CD16, CD20, CD68), blood vessels (CD146, vWF, alphavbeta3), and adhesion molecules (E-selectin, VCAM-1, ICAM-1).


RESULTS
No manifest immunopathological differences were found between the nodules before and after infliximab treatment. All nodules depicted the classical structure with a central necrotic zone, surrounding the palisade layer, and an outer connective tissue zone. Immunohistochemistry showed the presence of CD68+ and CD16+ macrophages in the palisade and the connective tissue zone, as well as a small number of CD3+, CD4+ T lymphocytes in the perivascular areas. Small vessels were seen in the connective tissue and were sometimes positive for the neovascularisation marker alphavbeta3. They expressed no VCAM-1, E-selectin weakly, but ICAM-1 strongly. ICAM-1 was also strongly expressed on palisade cells.


CONCLUSIONS
Despite an improvement of articular symptoms, infliximab treatment had no distinct effect on the histopathology of rheumatoid nodules, suggesting that different pathogenetic mechanisms mediate the two disease manifestations in RA.
Baeten
D
D
Department of Rheumatology, 0K12IB, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium. dominique.baeten@ugent.be
De Keyser
F
F
Veys
E M
EM
Theate
Y
Y
Houssiau
F A
FA
Durez
P
P
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012218:Rheumatoid Nodule / Q000188:drug therapy* / Q000473:pathology; D013585:Synovitis / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab