Asymptomatic synovitis precedes clinically manifest arthritis

Kraan, Maarten C.; Versendaal, Hans; Jonker, Margreet; Bresnihan, Barry; Post, Wendy J.; Hart, Bert A. ’t; Breedveld, Ferdinand C.; Tak, Paul P.

doi:10.1002/1529-0131(199808)41:8<1481::aid-art19>3.0.co;2-o

Cited by 226 publications

(155 citation statements)

References 27 publications

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“…This is consistent with previous studies showing a strong correlation between macrophages and arthritis activity (35,45,51,52). It appears unlikely that alefacept had a direct effect on ST macrophages in light of its specificity.…”

Section: Discussionsupporting

confidence: 93%

“…To reduce sampling error, a minimum of 6 tissue specimens were processed for immunohistochemistry and for formalin fixation, each as described previously (33)(34)(35). Immunohistochemical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Endogenous peroxidase activity was inhibited using 0.1% sodium azide and 0.3% H 2 O 2 in phosphate buffered saline (PBS). Staining for cell markers and cytokines was performed as described previously (35). Following a primary step of incubation with mAb, bound antibody was detected according to a 3-step immunoperoxidase method.…”

Section: Methodsmentioning

confidence: 99%

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Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Kraan

Kuijk

Dinant

et al. 2002

Arthritis & Rheumatism

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135

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Objective. To investigate whether alefacept (a fully human lymphocyte function-associated antigen 3 [LFA-3]/IgG1 fusion protein that blocks the LFA-3/CD2 interaction) is able to reduce the signs and symptoms of joint inflammation in patients with active psoriatic arthritis (PsA).Methods. Eleven patients with active PsA were treated with alefacept for 12 weeks in an open-label and explorative study. Clinical joint assessment and laboratory assessments were performed at baseline and after 4, 9, 12, and 16 weeks of treatment. Serial synovial tissue (ST) biopsy specimens from an inflamed index joint (knee, ankle, wrist, or metacarpophalangeal joint) were obtained by arthroscopy at baseline and after 4 and 12 weeks of treatment.Results. At the completion of treatment, 6 of 11 patients (55%) fulfilled the Disease Activity Score (DAS) response criteria. Nine patients (82%) fulfilled the DAS response criteria at any point during the study. There was a statistically significant reduction in CD4؉ lymphocytes (P < 0.05), CD8؉ lymphocytes (P ‫؍‬ 0.05), and CD68؉ macrophages (P < 0.02) in the ST after 12 weeks of treatment compared with baseline. The ST and peripheral blood of those patients fulfilling the DAS response criteria contained more CD45RO؉ cells at baseline and displayed a significant reduction in these cells compared with nonresponding patients.Conclusion. The changes in ST, together with the improvement in clinical joint scores, after treatment with alefacept support the hypothesis that T cell activation plays an important role in this chronic inflammatory disease. Furthermore, since alefacept, a T cellspecific agent, led to decreased macrophage infiltration, the data indicate that T cells are highly involved in synovial inflammation in PsA.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Kraan

Kuijk

Dinant

et al. 2002

Arthritis & Rheumatism

Self Cite

135

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“…A ctivated neutrophils and their products, including reactive oxygen species and myeloperoxidase, are present in increased concentrations in the synovial fluid of patients with active rheumatoid arthritis (RA), 3 as well as in the pannuscartilage junction, and have been implicated in disease pathogenesis and joint destruction (1). Although angiogenesis, synovial hyperplasia and lymphocytic infiltrates are present in the preclinical stages of arthritis in humans (2,3) and rodents (4,5), neutrophils are either absent or present in low numbers at this stage.…”

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confidence: 99%

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

Laragione

Yarlett

Mello

et al. 2007

The Journal of Immunology

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Neutrophils are required for the development of arthritis, and their migration into the synovial tissue coincides with the onset of clinical disease. Synovial neutrophil numbers also correlate with rheumatoid arthritis disease activity and severity. We hypothesized that certain arthritis severity genes regulate disease via the regulation of neutrophil migration into the joint. This hypothesis was tested in the synovial-like air pouch model injected with carrageenan using arthritis-susceptible DA and arthritis-resistant F344 rats. DA had nearly 3-fold higher numbers of exudate neutrophils compared with F344 (p < 0.001). Five DA.F344(QTL) strains congenic for severity loci and protected from autoimmune arthritis were studied. Only DA.F344(Cia4) (chromosome 7) and DA.F344(Cia6) (chromosome 8) congenics had significantly lower exudate neutrophil counts compared with DA. TNF-α levels were 2.5-fold higher in DA exudates as compared with F344 exudates, and that difference was accounted for by the Cia4 locus. Exudate levels of NO, a known inhibitor of neutrophil chemotaxis, were higher in F344, compared with DA, and that difference was accounted for by Cia6. This is the first time that non-MHC autoimmune arthritis loci are found to regulate three central components of the innate immune response implicated in disease pathogenesis, namely neutrophil migration into an inflammatory site, as well as exudate levels of TNF-α and NO. These observations underscore the importance of identifying the Cia4 and Cia6 genes, and suggest that they should generate useful novel targets for development of new therapies.

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“…Therefore, those functions could be studied in congenics and compared with the parental strains, providing early clues to arthritis gene function. For example, while synovial hyperplasia, angiogenesis and lymphocytic infiltration are detected in preclinical stages of arthritis in rodents 63,64 and humans, 65,66 the presence of neutrophils in the joints appears to correlate with disease onset. Therefore, better understanding the processes regulating neutrophil migration into the joint cavity could identify potentially novel ways of treating disease.…”

Section: Using Congenic Strains To Identify Genes and Their Functionsmentioning

confidence: 99%

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

Gulko

2007

Genes Immun

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Rheumatoid arthritis (RA) is a chronic and potentially debilitating autoimmune disease. While novel therapies have emerged in recent years, disease remission is rarely achieved. RA is a complex trait, and the identifying of its susceptibility and severity genes has been anticipated to generate new targets for therapeutic intervention. However, finding those genes and understanding their function has been a challenging task. Studies in rodent intercrosses and congenics generated from inbred strains have been an important complementary strategy to identify arthritis genes, and understand how they operate to regulate disease. Furthermore, these new rodent arthritis genes will be new targets for therapeutic interventions, and will identify new candidate genes or candidate pathways for association studies in RA. In this review-opinion article I discuss RA genetics, difficulties involved in gene identification, and how rodent models can facilitate (1) the discovery of both arthritis susceptibility and severity genes, (2) studies of gene-environment interactions, (3) studies of gene-gender interactions, (4) epistasis, (5) functional characterization of the specific genes, (6) development of novel therapies and (7) how the information generated from rodent studies will be useful to understanding and potentially treating RA.

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Asymptomatic synovitis precedes clinically manifest arthritis

Abstract: The findings support the view that asymptomatic synovitis precedes clinically manifest arthritis in both early and established RA. This implies that the debut of RA already represents a chronic phase of the disease.

Cited by 226 publications

References 27 publications

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

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