| Objective:To explore the possible mechanism of thalidomide in treating patients with rheumatoid arthritis (RA) and study the lowest concentration of thalidomide effected in vitro, which provide experimental evidence for the clinical application of low-dose thalidomide. We observed the influence of thalidomide in fibroblast-like synoviocyte and peripheral blood mononuclear cells from patients withRA in vitro experiments. At the same time, we investigated the clinical effect and safety of low-dose thalidomide in treating patients with RA.Methods:1. The experimental study of thalidomide in treating patients with rheumatoid arthritis: FLS were separated and cultured in vitro. The MTT method was applied to study the growth inhibition of FLS treated with different concentrations of thalidomide (0μg/ml,10μg/ml,50μg/ml,100μg/ml,200μg/ml,500μg/ml). ELISA was used to determine the expression level of VEGF and TNF-αin cultured supematants of FLS added different concentrations of thalidomide (0μg/ml,50μg/ml,100μg/ml,200μg/ml). PBMCs were separated from patients with RA and cultured in vitro. The cultured cells were given different concentration of thalidomide (0μg/ml,50μg/ml,100μg/ml,200μg/ml). ELISA was used to determine the expression level of VEGF and TNF-αin the culture medium. 2. The clinical observation of low-dose thalidomide in treating patients with rheumatoid arthritis: 100 RA patients were randomly averagely divided into 4 groups, the controlled group, the treated group A, the treated group B and the treated group C. All patients were treated with MTX 10 mg per week and LEF 20 mg per day. The patients in treated group A were given thalidomide 50mg/d additionally. The patients in treated group B were given thalidomide 75mg/d additionally. The patients in treated group C were given thalidomide 100mg/d additionally. The laboratory index, clinical effect and safety were observed before treatment, 6 weeks, 12 weeks and 18weeks after treatment.Results:1. Different concentrations of thalidomide (50～500μg/ml) significantly inhibited the proliferation of RA FLS in a time-dependent and dose–dependent manner(P<0.05).2. Different concentration of thalidomide (50～200μg/ml) can significantly inhibit the expression level of VEGF and TNF-αin the culture medium from RA FLS (P<0.05). The effect was in a time-dependent and dose-dependent manner.3. Different concentration of thalidomide (50～200μg/ml) can significantly inhibit the expression level of VEGF and TNF-αin the culture medium from RA PBMCs (P<0.05). The effect was in a time-dependent and dose-dependent manner.4. After 18 weeks of treatment, the total number of patients finished the clinical trials were 77, 23 patients in the control group, 24 in the treated group A, 22 in the treated group B, 8 in the treated group C. The treatment effect was ecaluated in the patients of the control group, the treated group A and the treated group B who finished the trials. The treatment effect was not ecaluated in the treated group C, beacause most patients could not able to tolerate the adverse effects. But the side effects were ecaluated in the treated group C. 5. There was no significant different in the DAS-28 between the three groups after 6 weeks, 12 weeks and 18 weeks of treatment(P>0.05). After 12 weeks of treatment, the ESR and CRP levers in the treated group B were significantly reduced than the other two groups(P<0.05). The downtrend was more obvious after 18 weeks of treatment.6. After 18 weeks of treatment, the total effective rate of the control group was 78.3%, in the treated group A was 79.2% and in the treated group B was86.4%. The total effective rate of the treated group B was higher, but there was no significant different between the three groups(P>0.05) .7. 3 patients in the control group (13.0%), 4 patients in the treated group A (16.7%) and 6 patients in the treated group B (16.7%) experienced side effects during treatment. But there was no difference between the three groups(P>0.05). There were 19 patients (79.2%) experienced side effects in the treated group C, which was higher than the other three groups and the difference was significant (P <0.05).Conclusion:1. Thalidomide can treat RA patients by inhibiting the proliferation of RA FLS and inhibiting the secretion of VEGF and TNF-αof PBMCs and FLS of RA, that may be relation to the mechanism of thalidomide treating RA.. Thalidomide can produce a inhibitory effect at a low concentration, which indicates the clinical application of low-dose thalidomide may have some therapeutic effect in treating patients with RA.2. Low-dose thalidomide when added to the treatment of RA patients taking MTX and LEF can significantly reduce the laboratory indicators. It may help lessen inflammation and have a tendency to improve the therapeutic efficacy. 3. Low-dose thalidomide treating RA is safety, well tolerated and is worthy to be popularized applicated for the patients.4. Long-term efficacy and safety of low-dose thalidomide treating RA need to be confirmed throughout expanding the samples and extending the observation period in the further study.
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