Disease Activity And Drug Therapy Response Detected By In Vivo USPIO-Enhanced MRI In A Model Of Antigen-Induced Arthritis

Backgrounds and Objectives Rheumatoid arthritis (RA) is well known to be a chronic autoimmune/inflammatory disease.The hallmark feature of the illness is persistent and recurrent attacks. In view of the pathological feature of RA ,it is characterized by chronic proliferative synovitis at the early phase of the disease. In recent years, numerous study demonstrated that macrophages are abundantly present in the inflamed synovial lining and sublining layers,The proliferaion and activation of macrophages in the inflamed synovial membrane plays an important role in both chronic inflammation and joint destruction in rheumatoid arthritis,principally by producing many proinflammatory cytokines . Moreover,the treatment strategy about RA has changed markedly during the past decade, with emphasis on completely suppressing joint inflammation and preventing structural joint damage and functional disability as early as possible during the course of the disease.Owing to this early and extensive treatment approach, there is a growing need for sensitive and specific tools to give early diagnosis and monitor disease activity and evaluate treatment efficacy.as well as prevent irreversible joint damage.Assessment of disease activity and therapy response in patients with rheumatoid arthritis is currently based on physical examination and laboratory parameters, as well as findings on radiology. The main drawbacks of these methods are their subjective character, lackness of stability, difficulty in standardization, and the fact that they are not the direct methods to monitor inflammation within the synovial tissue. Synovial biopsy could be an alternative, however, it is certainly too invasive to be used in serial studies. Thus, a noninvasive imaging modality to monitor cellular infiltration in synovitis would be highly desirable.Imaging methods used in the diagnosis and monitoring of rheumatoid arthritis are almost exclusively limitted to the anatomical level. The majority of current imaging methods used in clinical medicine are not able to reflect and predict damage of joint, and can not provide any information about cellular and molecular mechanisms. Most of the commonly used contrast agents in clinical are unspecific and have not interaction with specific molecular targets. With the advances in the cellular and molecular basis of the disease and the development of ultrasmall superparamagnetic iron oxide (USPIO, a target-specific imaging agents ),it is possible to evaluate cellular and molecular events in RA non-invasively.The objectives of this study are:(1)To probe the feasibility of USPIO-enhanced MRI in detection of disease activity and follow-up treatment efficacy in a model of antigen-induced arthritis with the help of dexamethasone and gadolinium(III) chloride intervention.(2)To investigate the potential inhibition effects of gadolinium(III) chloride on macrophages.Materials and Methods Monoarthritis was induced in the right knee of thirty-five rabbits. These arthritic rabbits were randomly subdivided into 3 groups: (1) Placebo-treated group(n=15).Fifteen rabbits received 5 ml /kg of normal saline solution daily;(2)Dexamethasone-treated group(n=15).Fifteen rabbits treated.with 0.3 mg/kg of dexamethasone daily p.o;(3)Gadolinium(III) chloride-treated group (n=5):Five rabbits treated with 10 mg/kg of GdCl3 daily i.v.. All knees in 35 rabbits were examined by MR imaging before and 2 and 24 hours after USPIO injection at d3,d7,d10 after placebo treatment or dexamethasone treatment respectively,. MR imaging was performed only on day 3 after gadolinium(III) chloride treatment. The MR protocol included spin-echo T1-weighted imaging, fast spin-echo T2-weighted imaging and gradient echo T2*-weighted imaging. All imaging data were analyzed quantitatively and qualitatively according to the signal characteristics and enhacing pattern. MR and histopathologic findings were compared. Paired t-test was carried out to analyze the signal change of inflammatory synovial membrane before and after injection of USPIO at each time point after treatment. The thickness andΔSNR of synovium in right knees between placebo-treated group and dexamethasone-treated group or gadolinium(III) chloride-treated group were further compared by independent samples t-test respectively.Results All knees with intraarticular injection of antigen suspension developed unilateral arthritis.The pathology of arthritic knee joints demonstrated hyperplastic synovium.The hyperplastic synovium in right knee appeared as slightly long or isointense T1 and long T2 or T2* signal. 1)In placebo-treated group,no significant difference was found between the thickness of synovium in right knee before and after treatment at different time points.There is great significant difference between the signal of synovium in right arthritis prior to and after USPIO injection at three time points in 3 MR sequences (SE T1WI, FSE T2WI and GRE T2*WI),Pathological examination exhibited thickening of synovium and formation of pannus, infiltration of numerous macrophages into synovium and absorption of iron particles into macrophages; 2) In dexamethasone-treated group, no significant difference existed between the thickness of synovium in right knee before and after treatment at d3 and d7 , however, significant difference was found between the thickness of synovium in right knees before and after treatment at d10.The synovium in dexamethasone-treated group is thiner than that in placebo-treated group with statistical significance only at d10,but significant difference still existd between the signal of synovium in right arthritis prior to and after USPIO injection at d3 in 3 MR sequences (SE T1WI, FSE T2WI and GRE T2*WI). Pathological examination exhibited thickening of synovium and formation of pannus, infiltration of numerous macrophages into synovium and absorption of iron particles into macrophages.Significant difference between the signal of right arthritis synovium before and after USPIO administration can be found only in T1WI sequence at d7 and pathological examination demonstrated that a little macrophages infiltrated into thickening synovium and iron particles were embedded into macrophages. No significant difference was found between the SNR calculated from signal intensity measurements in the synovial tissue before and after USPIO-enhanced images in FSE T2WI and GRE T2*WI at d10, and only few macrophages and iron particles were demonstrated in slightly thickening synovium on pathological examination.,No significant difference was found between theΔSNR in placebo-treated group and dexamethasone-treated group on SE T1WI,however,the difference can be found on FSE T2WI and GRE T2*WI at d7 and d10 but d3. 3) In gadolinium(III) chloride-treated group,no significant difference existed between the thickness of synovium in right knees before and after treatment. Significant difference can be found between the signal of synovium before and after USPIO administration only on T1WI sequence, and a little iron-loaded macrophages were found in slightly thickening synovium by pathological examination. Great significant difference was found between theΔSNR of synovium in placebo-treated group and gadolinium(III) chloride-treated group on FSE T2WI and GRE T2*WI.Conclusions 1) Delayed USPIO-enhanced T2- and T2*-weighted MRI is capable of monitoring disease activity and drug therapy response earlier than morphological change. Early USPIO-enhanced T1-weighted MRI is likely to have a contribution to assess the perfusion characteristics of synovial tissue. 2)It is futher proved that USPIO enhanced MRI is feasibe to be used to visualize macrophage activity in vivo in RA and USPIO can be used as a specific marker to label macrophages in the arthritis synovium; The pathological basis of signal change on MRI is that iron oxide was phagocytized into macrophages. 3) Gadolinium chloride might has inhibitory effect on macrophages within the arthritis and this effects can be early detected by USPIO-enhanced MRI.