ABSTRACT
INTRODUCTION: Structural damage progression is a major outcome in rheumatoid arthritis (RA). Its evaluation and follow-up in trials should involve radiographic scoring by 1 or 2 readers (reference assessment), which is challenging in large longitudinal cohorts with multiple assessments. OBJECTIVES: To compare the reproducibility of multireader and reference assessment to improve the feasibility of detecting radiographic progression in a large cohort of patients with early arthritis (ESPOIR). METHODS: We used 3 sessions to train 12 rheumatologists in radiographic scoring by the van der Heijde-modified Sharp score (SHS). Multireader scoring was based on 10 trained-reader assessments, each reader scoring a random sample of 1/5 of all available radiographs (for double scoring for each X-ray set) for patients included in the ESPOIR cohort with complete radiographic data at M0 and M60. Reference scoring was performed by 2 experienced readers. Scoring was performed blindly to clinical data, with radiographs in chronological order. We compared multireader and reference assessments by intraclass correlation coefficients (ICCs) for SHS and significant radiographic progression (SRP). RESULTS: The intrareader and inter-reader reproducibility for trained assessors increased during the training sessions (ICC 0.79 to 0.94 and 0.76 to 0.92), respectively. For the 524 patients included, agreement between multireader and reference assessment of SHS progression between M0 and M60 and SRP assessment were almost perfect, ICC (0.88 (95% CI 0.82 to 0.93)) and (0.99 (95% CI 0.99 to 0.99)), respectively. CONCLUSIONS: Multireader assessment of radiographic structural damage progression is comparable to reference assessment and could be used to improve the feasibility of radiographic scoring in large longitudinal cohort with numerous X-ray evaluations.
ABSTRACT
The protein kinase C (PKC) family is involved in the regulation of many intracellular signalling pathways. Here, we report that the PKCδ isoform regulates IL-12p40/p70 production in macrophages and DC and that PKCδ deficiency in mice transforms the 129/Sv healer to a non-healer strain during cutaneous leishmaniasis. Leishmania major-infected PKCδ(-/-) 129/Sv mice developed a rapid increase in footpad swelling and parasite burden with disease progression, leading to necrosis and ulceration similar to non-healer BALB/c mice. Moreover, PKCδ(-/-) mice failed to develop delayed-type hypersensitivity responses against Leishmania antigen. PKCδ(-/-) macrophages were fully functional with normal MHC class II surface expression and GM-CSF production, recruitment to the draining lymph node and killing effector functions by NO production. In contrast, macrophages and DC produced significantly reduced IL-12p40 and IL-12p70 compared to the WT cells. Decreased IL-12 production resulted in diminished Th1 differentiation, as determined by a striking reduction in IFN-γ by antigen-specific stimulated CD4(+) T cells isolated from popliteal lymph nodes of L. major-infected PKCδ(-/-) mice, explaining the "non-healer" phenotype. We conclude from these data that PKCδ is a regulator of IL-12p40/p70 production by DC and macrophages, driving the healer phenotype during cutaneous leishmaniasis.
