Fengshikang And Methotrexate In Combination For The Treatment Of Rheumatoid Arthritis (Damp-Heat Stagnation)

1.Objectives and significanceRamatiod arthritis(RA) is a chronic and progressive systematic disease commonly presenting as symmetric multiple arthrosynovitis and extra-articular lesions(rheumatoid nodules,vasculitis,peripheral neuritis,pleurisy,pneumonitis, pericarditis,etc.).Epidemiological investigation showes that the disease incidence is about 0.5-1%in the whole world,while in mainland China the incidence rate of RA is about 0.36-0.77%.RA is an intractable disease with a high disability rate,therefore,it is very important to perform an early treatment so as to control the disease development effectively.RA is a muti-factorial disease and the etiology is still not clear.Generally speaking,RA is a disease triggered on the base of genetic predisposition by external factors.Further more,there are many other factors are closely associated with RA,including sex,mental factors,climate,environment,ect..Recognition of T-cell lineage helps to make great advances in researches on pathomechanism of RA.At the current time,it is widely accepted that RA is resulted by the interactions between antigen presenting cell and CD4+T cell.Beside that,in inflammation responses mediated by T cell,TCRγδT cell also plays an important role.Th1/Th2 cell imbalance is also considered as one of the pathomechanism of RA,in which protective Th2 cytokines can be generated by natural killer T cells.In recent years it has been indicated that Cytokine network plays a key role in the damage of RA.Tumor necrosis factor-αand interleukin-1 are therefore highlighted as the most important two factors in the researches of RA,both of which are important inflammatory factors triggering the onset and development of synovitis and synovial antiogenesis.Beside that,other cytokines such as interleukin family, chemokine family and growth factor family can directly participate the tissue damage.The complexity of pathomechanisms results in multi-targets in the treatment of RA.However,the therapeutic effect varies a lot from different treatment methods. Currently methotrexate(MTX) is used as a primary drug in combination with nonsteroidal anti-inflammatory drugs(NSAIDs),disease-modifying antirheumatic drugs(DMARDs) and cortical hormone in the treatment of RA.Though these drugs can improve the disease condition to a large extent,even clinical cure can be attained, a long-term use may lead to various adverse reactions.For instance,NSAIDs causes gastrointestinal disorders and nephrotoxicity;DMARDs such as MTX and cyclophosphamide cause gastrointestinal disorders and hepatotoxicity;leflunomid (LEF) causes irregular menstruation,secondary pneumonia,scytitis,etc.;cortical hormone often amplifies inflammation if not correctly used,causing digestive ulcers and osteoporosis,etc..Recent years many biologic agents target to some key cytokines such as entananercept,infliximab and recombinant interleukin-1 have been applied in clinical treatment and certain therapic effect is attained.However,because of the high cost,secondary immunologic derangement and potential health risks, these agents can still not be widely used.MTX in combination with LEF is well accepted as a primary treatment protocol of active RA,but in the clinical application obvious side effects and poor compliance in RA patients are frequently observed. Further more,this combination treatment method is contraindicated for long-term use.Actually no record concerning "rheumatoid arthritis" in traditional Chinese medicine(TCM) files is found.According to TCM theory,RA can be classified as "impediment disease" category.It is also called "insensitive impediment","lame impediment" or "joint-running wind".TCM theory concerning impediment disease have undergone more than two thousand years,thus the cause,pathomechanism and pattern identification as the basis for determining treatment of impediment disease have been widely and deepgoingly discussed.In this way an intact theoretical system on the treatment of impediment disease is formed,and,the theoretical system, dominates the clinical treatment of impediment disease.In recent years,the traditional theory of wind-cold-damp stasis was greatly improved and extended, such as "kidney vacuity" theory,"vacuity-evil-stasis" theory,"damp-heat" theory, etc..Accordingly,TCM plays an more and more important role in the treatment of RA.As a result,the issues on how to use TCM,which is characterized with multiple treatment targets,to treat refractory diseases in combination with Western medicine (WM) is considered as one of the most important issues in TCM-WM research.Feng Shi Kang(FSK) is a preparation from a Chinese herbal formula formulated by Pro.WU Qi-fu which has been used in clinical treatment for more than twenty years,functioning as clearing heat,eliminating dampness,freeing the network vessels, quickening blood,rectifing Qi and relieving pains.The formula constitutes of cortex phellodendri amurensis,achyranthes bidentata blume,rhzoma atractylodis lanceae, rhizoma anemarrhenae,herba asari mandshurici,radix gentianae macrophyllae, rumulus ginnamomi and radix seu herba cynanchi,etc..In previous studies it has been indicated that FSK has anti-inflammatory and pain-relieving effects on both acute and chronic inflammation,such as inhibiting synovial hyperplasia,inflammatory cell infiltration and cartilage damage in AA animal models via adjusting T-Cell subsets and decreasing the amount of TNF-αand IL-1.This study is aimed to observe the clinical effect of FSK in combination with MTX on the treatment of RA,to compare and assess the clinical application value of this combination treatment method.2.Methods and projects2.1 Subjects2.1.1 Inclusion criteria(1) being aged from 18-65 years old;(2) fullfilling WM diagnostic criteria,i.e.,1987 ARA criteria for the classification of RA;(3) being in early or middle stage of disease progression and in active state of RA;(4) without use of anti-rheumatic TCM or WM drugs in 1 week following the onset of RA,or a short-term(3-5 days) use of anti-rheumatic TCM or WM drugs but with drug withdrawalled for more than 7 days;(5) fullfilling the criteria of TCM damp-heat impediment disease according to Guiding Principles for Clinical Study of New Chinese Medicines.2.1.1 Exclusion criteria(1) aged under 18 or above 65 years old;(2) pregnant and lactating women or patients of allergic physique;(3) patients with severe cardio-cerebral vascular diseases,hepatic,nephric,pulmonary diseases, hematopoietic diseases,or mental patients;(4) severe RA patients in advanced stage.2.2 Base-line data102 RA patients enrolled from the TCM Out-patient or In-patient Department of rheumatism of Nanfang Hospital were observed from Jan.2008 to Dec.2008.The patients were randomized into 2 groups,in which there were 53 and 49 cases respectively.No significant difference were observed in sex,disease course,disease stage,etc.2.3 Drug administrationThe treated group was orally administrated with FSK instant granules (constituting of compatible granules of cortex phellodendri amurensis,achyranthes bidentata blume,rhzoma atractylodis lanceae,rhizoma anemarrhenae,herba asari mandshurici,radix gentianae macrophyllae,rumulus ginnamomi and radix seu herba cynanchi).It was taken with warm boiled water a dose per day,thrice a day and 150 ml per time.MTX tablets were orally taken once a week,10 mg per time.The treatment course lasted for three months.The control group was administrated with LEF tablets,once a day,10 mg per time.The dose and administration method of MTX tablets in control group were same as that in treated group.The treatment course lasted for three months.2.4 Parameters observation2.4.1 Parameters of curative effect2.4.2 Clinical parameters:tender joint count,swollen joint count(according to 28-joint counting method),joint objective pain score(visual analogue scales),bath ankylosing spondylitis functional index(BASFI) and morning stiffness time were observed and recorded.2.4.3 Laboratory parameters:rheumatoid factor(RF),anti-cyclic citrulline peptide antibody(CCP),C-reactive protein(CRP) and blood sedimentation(BSR) were detected and recorded.2.4.4 Radiological observation:the radiological changes of bilateral hands were observed and the following criterion was applied to assess the disease severity:Stageâ… ,osteoporosis in periarticular tissues plus soft tissue swelling,without destruction of bone;stageâ…¡,osteoporosis in periarticular tissues,slight arthrostenosis and single destruction of subchondral bone;stageâ…¢,obvious destruction of articular cartilage and bone plus arthrentasis,dislocation or subluxation dislocation;stageâ…£,stageâ…¢plus fibrous ankylosis or bony ankylosis of joint.2.4.5 Evaluation criterion of therapic effects:According to American college of rheumatology 20,50,70,the therapic effects were evaluated.(An ACR 20 response is defined as a reduction of at least 20 percent in the number of tender joints and swollen joints plus an improvement of at least 20 percent in at least three of the following five criteria:patient's assessment of pain,patient's assessment of disease activity,physician's assessment of disease activity,patient's assessment of physical function,and serum C-reactive protein concentration.) Excellence:ACR₇₀ is attained (the observed parameters decreased≥70%);good:between ACR₅₀(the observed parameters decreased 50%≤and＜ACR₇₀;poor:under ACR₂₀(the observed parameters decreased＜20%).2.5 Safty evaluationThe changes of blood routine,hepatic function,renal function,gastrointestinal reactions and dermato-allergic reactions were closely monitored and detected.2.6 Statistical analysisThe software SPSS 13.0 was used to process all the data.All the measurement data was indicated in the format of mean±standard deviation.T-test was used to compare the measurement data between groups.Chi-square test was used to compare enumeration data.The significance level wasα=0.05. 3 Results3.1 Clinical parametersThe effect of two treatment methods on morning stiffness,tender joint count, swollen joint count and BASFI:after the treatment,the clinical parameters in the two groups were significantly improved(F=395.866,P=0.000;F=148.955,P=0.000; F=366.570,P=0.000;F=88.171,P=0.000;F=313.023,P=0.000;F=184.017,P=0.000; F=440.875,P=0.000;F=240.079,P=0.000;F=438.972,P=0.000;F=208.890, P=0.000) in comparison with the pro-treatment time.The clinical parameters such as joint tenderness index and joint pain index were better improved vs control(t=-3.915, P=0.000;t=-2.689,P=0.008) and significant difference was observed at 4 weeks following the treatment.However,no significant difference of morning stiffness time, swollen joint count and BASFI was observed in the two groups(t=-0.518,P=0.606; t=-1.018,P=0.311;t=-1.097,P=0.275).At 3 months following the treatment,tender joint count,swollen joint count,joint pain index and BASFI were all better improved vs control(t=-2.948,P=0.004;t=-2.680,P=0.009;t=-2.562,P=0.012;t=-2.962, P=0.004) except morning stiffness time(t=-1.581,P=0.117).3.2 Laboratory parametersThe effect on ESR,CRP,RF and CCP:in the two groups,the laboratory parameters were significantly improved(t=10.988,P=0.000;t=7.911,P=0.000; t=22.650,P=0.000;t=16.37,P=0.000;t=23.919,P=0.000;t=19.090,P=0.000; t=28.575,P=0.000;t=29.536,P=0.000) in comparison with those observed at pre-treatment time,and ESR was better improved vs control with significant difference observed(t=-4.502,P=0.000).Whereas no significant difference of CRP, RF and CCP was observed between the two groups(t=-1.742,P=0.085;t=-0.684, P=0.495;t=-0.391,P=0.697).3.3 General therapic effectAt 12 weeks following the treatment,satisfying therapic effect was attained in both groups.A general therapic effect rate of 81.1%and 59.2%was observed in treated group and control group respectively.The general therapic effect was significant better vs control(x²=6.288,P=0.043).3.4 Side effectsLower incidence of side effects including anorexia,nausea/vomiting,diarrhea, erythra,baldness,ALT and AST increase(＞60 U/L) and leucocyte decrease(＜3.5×10⁹/L) was observed in treated group in comparison with control group.The difference was significant(x²=8.758,,P=0.003).All the effects observed in the two groups are relatively slight and needed no extra treatment,which were spontaneously relieved or disappeared except for 7 anorexia,8 diarrhea,6 ALT increase and 5 nausea/vomiting cases in control group,needing symptomatic treatment(all of which were relieved in one week without affecting the clinical research procedures).4.ConclusionIn comparison with MTX plus LEF,the combination treatment method of FSK plus MTX in the treatment of active RA is more effective to improve the clinical symptoms and laboratory parameters of RA patients.The general therapic effect of FSK plus MTX is significantly better vs LEF plus MTX.When used in combination with MTX,FSK can improve the therapic effect of MTX in the treatment of RA as well as decrease the side effects of MTX.FSK in combination with MTX for the treatment of RA(Damp-Heat stagnation) is an acceptable treatment method with good therapic effect.