Study Of The Serum Of RANKL And OPG Combined With MRI In Diagnosis Of Early Rheumatoid Arthritis And Bone Joint Injury

BackgroundRheumatoid arthritis(RA) is an autoimmune disease characterized by chronic inflammatory of the synovial membrane, mainly involving the hands, feet and other joints. Local bone erosion and systemic bone loss especially osteoporosis(OP) is the major form of the bone and joint damage, eventually leading to joint destruction and loss of function. Local bone erosion and systemic OP, relating with osteoblast and osteoclast, are the main forms of bone and joint destruction in patients with RA. Bone metabolism is a dynamic equilibrium process including bone formation and bone resorption. If this balance is destroyed, it will result in the decrease of bone mineral density(BMD) and abnormality of bone structure, such as the bone destruction and OP. In recent years, the research hot spot for the early diagnosis of bone and joint injury in RA focuses primarily on imaging studies, especially magnetic resonance imaging. Although the MRI can make an early diagnosis for synovial inflammation, bone erosion and bone marrow edema, it can only find imaging positive patients with early RA. Receptor activator of nuclear factor KB ligand(RANKL) is found to be a factor of inducing osteoclast differentiation, development and function, osteoblast and activate T lymphocytes can also express RANKL. Receptor activator of nuclear factor KB(RANK) have been found to be key factors in the stimulation of osteoblast formation. It has been shown that the binding of RANKL to RANK on the surface of osteoclast precursors promotes the differentiation of these cells to mature osteoclasts. Osteoblasts and stromal cells also produce osteoprotegerin(OPG), a decoy receptor which binds RANKL, thus preventing its own binding to RANK. Thereby, OPG exerts a negativeregulation on osteoclastogenesis, promotes apoptosis of mature osteoclasts, and ultimately inhibits bone resorption. The damage mechanism of bone and joint in patients with RA is closely related to the broken bones and osteogenesis process, but the exact mechanism is unclear. RANKL/OPG/RANK system is found in recent years to play an important role in bone adjustion, and considered as key factor of bone regulating in RA, may associated with early bone and joint damage in RA patients.ObjectiveTo explore the value of co-examination of serum RANKL/OPG level and MRI of hands in the diagnosis of early RA and early detection of bone and joint damage in RA.MethodsTwo hundred and thirty-two cases of RA patients fulfilled the ACR diagnostic criteria in 1987 were recruited, including 111 cases of early RA(disease duration less than 1 year) and 121 cases of established RA(disease duration > 1 year), the control group contained 121 normal age-gender matched individuals. Their bone mineral density(BMD) in the femur(femoral neck, Wards triangle, greater trochanter, total hip) and lumbar spine(L2,3,4,L2-4) were measured with dual-energy X-ray absorptiometry(lunar Prodigy DF+310504, GE Health care, USA). Radiographs for two hands in all patients with RA were evaluated according to the Sharp’s method. MRI of hands were executed in early RA patients and RAMRIS were used to assess change of MRI. Serum levels of RANKL and OPG in 232 patients with RA and 121 healthy controls were detected by enzyme-linked immunosorbent assay(ELISA). We kept a record of all the clinical and laboratory indexes simultaneously.Results1. The difference of serum levels of RANKL and OPG among the control group was statistically significant(P<0.05), and among the three groups serum levels of RANKL showed a rising trend, while there was no obvious difference among the three groups with the ratio of RANKL/OPG(P> 0.05).2. There were significant differences about BMD at femur(femoral neck, Wards triangle, greater trochanter, total hip) and lumbar spine(L2,3,4,L2-4) among control group, early group and established group(P<0.0001), and the BMD showed a trend of decrease gradually. Furthermore, incidences of osteoporosis among the three groups were significant different, separately.(13.92%, 22/158 vs 23.39%,29/124 vs 35.69%, 101/283, χ2=42.137, P<0.0001)3. By X-ray examination of both hands, eighty-two cases with RA were classified as Ⅰstage and 29 cases as Ⅱstage, whose sharp score were all within 10 score. The manifestation of 37 patients with early RA patients on MRI scan for two hands demonstrated 33 cases of the bone erosion, 21 cases of bone marrow edema, 31 cases of synovitis, and 11 cases of tendinitis. Bi-variable correlation analysis among the various indexes showed that tendinitis was positively correlated with bone marrow edema(r=0.391,P<0.05)and synovitis(r=0.330,P<0.05), however there was no correlation among rest indexes.4. Each MRI index of patients with early RA had no any correlations with serum OPG, RANKL levels and the ratio of RANKL/OPG(P>0.05). Bone erosion score of MRI scan in patients with early RA correlated negatively with BMD in greater trochanter(r=-0.387,P<0.05), total hip(r =-0.358, P<0.05) and positively correlated with sharp score(r=0.721, P<0.05). Tendinitis score of MRI scan positively correlated with the swollen joint count(r = 0.371, P<0.05), tender joint count(r = 0.369, P<0.05), and CRP(r = 0.480, P<0.05). There were no correlation between bone marrow edema and synovitis scores of MRI scan with clinical and laboratory indexes. The serum level of OPG was positive in correlation with swollen joint count(r=0.193,P<0.05), tender joint count(r=0.209,P<0.05), VAS score(r=0.264,P<0.05), HAQ(r=0.337,P<0.05), DAS28(r=0.277, P<0.05), ESR(r=0.194, P<0.05), CRP(r=0.349, P<0.05), anti-CCP(r=0.212, P<0.05), bone erosion score(r=0.339, P<0.05), Sharp score(r=0.277, P<0.05), and was in no correlation with BMD of each detected region. The serum levelof RANKL was in no correlation with BMD of each detected region, clinical index and Sharp score(P>0.05).5. The serum levels of OPG, RANKL and RANKL/OPG ratio in established RA patients had no correlations with indexes of swollen joint count, tender joint count, VAS score, ESR, CRP, DAS28, RF, anti-CCP, HAQ, BMD and Sharp score(P >0.05).6. Positive rates of bone erosion, bone marrow edema, synovitis, tendinitis on MRI in early RA were 89.19%(33/37), 56.76%(21/37), 83.78%(31/37) and 29.73%(11/37) respectively. Positive rate of either indicator was 97.30%(36/37). Incidence of RF and anti-CCP in established RA were higher than that in early RA group [88.56%(325/367)vs 75.41%(138/183), χ2=28.348, P<0.0001; 86.08%(266/309)vs 72.78%(123/169), χ2=12.760, P<0.0001]. The positive rates of bone erosion, bone marrow edema, synovitis, tendinitis between RF, anti-CCP negative group and positive group didn’t differ with each other( P > 0.05).7. Difference of serum level of RANKL among control group, early RA group with negative RF(≤14 IU/ml) and established RA group with negative RF(≤14 IU/ml) were statistically significant(P<0.05), and the serum RANKL level showed a rising trend. There were no statistical difference about serum OPG level among the three groups(P>0.05). The serum level of OPG and RANKL were significant difference among the control group, early RA group and established RA group with positive RF of low titer degree(≤42 IU/ml)(P<0.05).8. Serum level of RANKL were significant different among control group, early RA group with negative anti-CCP(≤25 RU/ml) and established RA group with negative anti-CCP(≤25 RU/ml)(P<0.05), and the level of serum RANKL showed a trend of increasing gradually, whereas, no differences were found regard to serum OPG(P>0.05). Serum level of OPG and RANKL among control group, early RA group and established RA group with positive anti-CCP(≤75 RU/ml) of low titer degree RA group were significant different(P<0.05), and the level of serum RANKL showed atrend of increasing gradually, whereas, no differences were found regard to serum OPG(P>0.05).9. According to the analysis of the non-normal distribution data, we defined the serum level of OPG less than 178.80 pg/ml and the serum level of RANKL more than 109.56 pg/ml as abnormal. The number of patients with OPG reduction or bone erosion on MRI scan was 31, occupying 93.94%(31/33). The number of patients with OPG reduction or bone marrow edema was 24, occupying 72.73%(24/33). The number of patients with OPG reduction or synovitis was 29, occupying 87.88%(29/33). The number of patients with OPG reduction or tenosynovitis was 18, occupying 54.55%(18/33). The number of patients with OPG reduction or RAMRIS score above 0 was 33, occupying 100%(33/33). The number of patients with RANKL decrease or bone erosion, RANKL decrease or bone marrow edema, RANKL decrease or synovitis, RANKL decrease or tenosynovitis, RANKL decrease or RAMRIS score above 0, were 30, 24, 29, 19, 32, accounting for 90.91%(30/33), 72.73%(24/33), 87.88%(29/33), 57.57%(19/33) and 96.97%(32/33), separately.Conclusion1. The serum level of OPG in patients with early RA was lower than that in normal control and correlated with disease activity indexes and bone erosion, but serum OPG level increased continuously along with disease duration. The serum level of RANKL in RA patients had a persistently increased trend along with disease duration.2. Incidence of OP in RA patients increased gradually along with disease duration. BMD at every detected region of early RA decreased significantly.3. The positive rate of abnormality was higher on MRI scan than in X-ray examination. RAMRIS had good diagnostic value in diagnosis of early RA, especially the highest positive rate of bone erosion. Manifestations of MRI scan were correlated with BMD and sharp score. Tendinitis on MRI scan may have a certain value.4. Combination of MRI manifestation of two hands and abnormal change of serumlevel of OPG and RANKL could improve the diagnosis of early RA.