Clinical And Experimental Studies Of Treatment With Inflammatory Arthritis

Objective:1. To evaluate the efficacy of methotrexate (MTX), leflunomide (LEF) and therapeutic alliance (MTX+LEF) with lesser dosage MTX and LEF in the joint disease of psoriatic arthritis (PsA).2. To evaluate the efficacy of MTX, LEF and MTX+LEF in the skin disease of PsA.3. To evaluate the safety of MTX, LEF and MTX+LEF in the treatment of PsA.4. To investigate the parameters predicting the clinical response to three treatment programs.Methods:1. This was a two-center, open-lable, controlled clinical trial lasting 24 weeks. 46 patients of PsA received a kind of treatment programs of MTX, LEF and MTX+LEF. The primary end point was proportion of psoriatic arthritis response criteria (PsARC ) responder, the secondary end point was proportion of modified 20% improvement of American College of Rheumatology ( ACR20 ) responder. The efficacy of joint disease was assessed and change of every assessed parameter were analysed.2. The efficacy of psoriatic rash wase evaluated by 50% and 70% improvement of psoriasis area and severity index scores ( PASI50 and PASI75) , and changes of PASI and dermatology life quality index (DLQI) were analysed.3. The safety of fifty-one patients of PsA (including forty-six patients finishing assessment of clinical efficacy and five patients withdrawing from treatment due to adverse effects) were evaluated in the study end point.4. The parameters predicting the clinical response were analysed with Logisticregression liklihood ratio tests in the study end point by PsARC as responder. Results:1. At week 4, 28.6%-50% and 12.5%-38.5% of patients in three groups reached the primary end point of PsARC and secondary end point of modified ACR20. The proportion of patients in three groups reaching PsARC and ACR20 showed quick improvement from week 8 to week 24. The percent of patients achieving PsARC and ACR20 were >68.8% and >50% at week 24. There was no statistical difference in achieving PsARC and ACR20 among three groups at week 24 (P >0.05 ) .2. At week 24, various measures except ESR were improved compared with base-line values (P<0.05). Compared with improvement in the MTX group at end point, Tender joint counts, swollen joint counts, HAQ, PGA were significant low in the LEF group; swollen joint counts, HAQ, ESR were significant low in the MTX+LEF group( P<0.05). All measures were lower in the LEF group than that of MTX+LEF group, but there were no statistical significance.3. At week 4, 12.5%-50% of patients in three groups reached improvement of PASI50. The proportion of patients in three groups reached PASI50 showed continuing improvement from week 8 to week 24. The percent of patients achieving PASI50 and PASI75 were >50% and >30% at week 24. At the end point, the percent of patients achieving PASI75 and PASI50 in the LEF group were significantly lower than that of MTX and MTX+LEF group (P<0.05) .4. At week 24, improvement of DLQI scores over base-line were significant greater in the MTX and MTX+LEF groups (P<0.05-0.01) , whereas no difference was observed in the LEF group. The improvement in the LEF group was significant lower than that in the MTX and MTX+LEF group at week 24 (P<0.05 ).5. There were no serious adverse reactions. In the MTX, LEF and MTX+LEF group the incidence of treatment related adverse events was 38.5%, 38.9% and 35%, respectively. There was no difference in three groups. The most frequently treatment related adverse events in the MTX and MTX+LEF groupwere gastrointerstinal complaint and in the LEF group was slightly elevated liver enzyme levels. Except a MTX-treated patient with ALT elevations >5 times over the upper limit of normal, the intensity of other adverse events was rated as mild or moderate during the whole study. There was no significant difference in all adverse reactions in three groups.6. Logistic regression analysis showed higher ESR levels was related to a higher likelihood to response, axial arthropathy of PsA, elder, more swollen joint counts, higher score of PGA and DLQI were related to a lower likelihood to response. Conclusion:1. Therapeutic alliance with lesser dosage MTX and LEF (MTX+LEF) resulted in rapid, significant improvement in joint and skin disease of patients with PsA, the efficacy of joint and skin involvement were equal to that of MTX. Compared with LEF, treatment with MTX+LEF significantly ameliorated the sympotoms of psoriatic rash. MTX+LEF was safe and well tolerated. Therapeutic alliance of MTX+LEF was not associated with an increase the rate of adverse events, compared with MTX and LEF.Objective:1. To assess the clinical efficacy and safety of anti-CD20 antibody (Rituximab) in active rheumatoid arthritis (RA) with positive rheumatoid factor (RF) and to investigate the parameters predicting the clinical response.2. To assess the influence of rituximab on peripheral blood cell and immunoglobulin.3. To investigate the influence of rituximab on T cell function. Methods:1. This was a 24-week, open-lable, clinical trial. 12 patients of active RA with positive RF were treated with 500 mg or 1000 mg intravenous infusions of rituximab on days 1 and 15. The primary end point was proportion of ACR20 responders. The secondary end point was proportion of ACR50, ACR70 responders. The disease activity was assessed by European League Against Rheumatism (EULAR) criteria. The efficacy and safety were assessed. And the parameters predicting the clinical response of rituximab were analysed with Logistic regression liklihood ratio tests.2. Peripheral blood cells and immunoglobulin were detected at after and before rituximab influsion, week 4, 8, 16, 24 and the changes of peripheral blood cells and immunoglobulin were analysed.3. Peripheral blood mononuclear cells (PBMC) were collected from 12 patients and 12 healthy controls at baseline, week 2, 8. The number of T cells that secret interferon-γ (IFN-γ) and interleukin 2 (IL-2) after anti-CD3/anti-CD28 stimulation was detected by ELISPOT. The number of cells that spontaneously secret TNF-α and IL-6 was assayed by ELISPOT. The influence of rituximab on T cell function was analysed.Rusults:1. At week 24, 75% of patients of rituximab treatment reached the primary end point of ACR20. The percent of patients achieving the secondary end points of ACR50, ACR70 were 16.67% and 8.3%. The percent of patients achieving ACR20 and ACR50 were 25% and 8.3% at week 4. The peak percent of patients achieving ACR20 and ACR50 were observed at week 8, 83.3% and 50% respectively. The trend maintained to week 16, and a proportion of patients achieved ACR70 response. The rate of reaching ACR20 was significant higher at week 8, 16, 24 than week 4 (P<0.05). There were no differences in the percent of patients reaching ACR50 and ACR70 at different observed point.2. At week 24, the percent of patients achieving the EULAR moderate, good, low disease activity and remission response were 58.3%, 8.3%, 8.3% and 8.3% respectively. The peak percentages of patients achieving the EULAR moderate response showed at week 16, DAS28 score were significant reduction at week 8, 16, 24 compared with base-line (P<0.01) .3. Improvements over base-line values for four measures including patient's assessment of pain, physician's global assessment, PGA, HAQ were significantly decreased at week 4 (P<0.05-0.01) . Improvements over base-line values for all measures including patient's assessment of pain, physician's global assessment, PGA, HAQ, tender joint score, swollen joint score, ESR/CRP, were significantly decreased at week 8,16,24 (P<0.05-0.01) . FACIT-F score was significant reduction at week 24 compared with base-line.4. Lymphocyte and monocyte counts were decreased significantly between after and before rituximab infusion (P<0.01), and recovered to normal levels at week 4. Monocyte counts improved significantly over base-line from week 8 to week 24 but within upper limit of normal. Leucocyte and neutrophil in 25% patients were seen transient decrease and resolved at week 24.5. Immunoglubulin (IgM, IgG, IgA) levels decreased significantly at week 8 compared with that of base-line, and returned to base-line levels at week 16, 24. Immunoglubulin (IgM, IgG, IgA) levels were normal during the study.6. There were no serious adverse reactions. The incidence of rituximab related adverse event was 41.7%. The intensity of all adverse events was rated as mild or moderate and transient during the whole study. The most frequently treatment related adverse events was the upper respiratory infection.7. Logistic regression analysis showed swollen joint counts and titre of RF predicted ACR20 response.8. After rituximab treatment, the number of T cells that secret IL-2 and IFN-γ was significantly decreased (P<0.01), the number of TNF-α secreting monocytes was decreased (P<0.05) but IL-6 secreting cells did not change significantly.Conclusion:1. Treatment with rituximab resulted in rapid and significant improvement in patients with active RA with positive RF. The clinical efficacy obtained to best during week 8 and 16, and maintained to week 24.2. Rituximab was safe and well tolerated, it was not associated with an increase the risk of infection. The incidence of rituximab infusion related adverse event was seldom.3. Transient decrease of lymphocyte, monocyte and immunoglobulin were seen within 24 hours after rituximab infusion.4. Lower swollen joint counts and titre of RF was related to higher likelihood to response.5. Rituximab treatment reduced the cytokine secretion from T cells and monocytes in RA patients of dramatically depleted B cells.