Efficacy Of Infliximab In Refractory Psoriatic Arthritis:22-week Clinical Study,52-week Follow-up And Analysis Of TCM Syndrome

BackgroudsPsoriatic arthritis (PsA) is a inflammatory arthritis that occurs in association with skin psoriasis, and leads to joint together with soft tissue pain, swollen, tender, stiff, movement disorders.It has prolonged course and relapses easily.At the late course of disease,the joints would rigid and result in disability. In addition, some patients have the performance of dactylitis, enthesitis, systemic damage and so on,which seriously affect the quality of life. Studies have shown that the prevalence of PsA in China is about0.1%.Non-steroidal anti-inflammatory drugs(NSAIDs) and non-biological disease modifying anti-rheumatic drugs(DMARDs) are the main therapeutics of PsA, which strive to achieve the relief of pain and slow joint damage, improve joint symptoms and skin lesions of psoriasis.But part of the patients with PsA accepted normative NSAIDs and non-biological DMARDs therapy fail to improve the condition. We call them patients with refractory psoriatic arthritis.PsA pathogenesis is not yet clear, but a number of studies in recent years found that the levels of tumor necrosis factor-a(TNF-a) were significantly increased in the synovium, synovial fluid, skin lesions, serum of patients with PsA. TNF-a plays an important role in the pathogenesis of PsA. A large number of results of clinical trials have shown that TNF-a antagonists can improve the joint symptoms and skin lesions of patients with PsA, even refractory PsA. Evidence-based medicine also has relevant evidence.Infliximab (INF) is a human-mouse monoclonal anti-TNF-a antibody that specifically targets blocking TNF-a and receptor-binding.Foreign literature reported that treatment of PsA with infliximab improve the clinical symptoms rapidly and safely, long-term treatment is well tolerated and sustained remission of disease.Refractory patients with PsA has a good effect,too.At present, it is deficiency of domestic clinical studies.In addition, having a long course of disease as well as relapses easily,PsA needs long-term treatment, however, infliximab is expensive.After controling refractory PsA disease, most patients are hard to accept infliximab treatment sustainedly. How to maintain the efficacy effectively, economically and sustainedly is the focus of clinical research.Traditional medicine do not have clear records of PsA, but their joint symptoms identified the disease as "arthralgia syndrome", skin symptoms identified the disease as "white mange". Recorded in the ancient literature of PsA-related syndromes, but its traditional Chinese medicine(TCM) syndrome is no unified understanding, more than by the physicians on the basis of their clinical experience summary form.With the development of molecular biology, molecular immunology and drug experiments science research,the research from the levels of cytokines concerning the mechanism of the medical treatment of diseases is a hot spot issue, the study found a single herb or compound Chinese medicine treat psoriasis through reducing the level of TNF-a, which arouses us to research TCM related syndrome of refractory PsA and the efficacy of infliximab in refractory PsA with different syndromes. Objective1To evaluate22-week efficacy and safety of infliximab in refractory psoriatic arthritis.2. To evaluate the efficacy and safety of different treatment regimens in refractory psoriatic arthritis through52-week follow-up in the purpose of finding treatment options of sustained clinical improvement and offering guidline of clinical treatment.3. To explore the distribution of TCM syndrome in refractory psoriatic arthritis and the22-week efficacy of infliximab in different TCM syndromes provides a reference with integrated traditional Chinese and western medicine syndrome differentiation and treatment.Methods1.22-week clinical study of infliximab therapy for refractory psoriatic arthritis and analysis of TCM syndrome1.1Patients18cases of patients with psoriatic arthritis from Nanfang Hospital TCM rheumatology department in February2009to August2010were diagnosed according to the PsA2006CASPAR classification criteria and aged24to52years old, with active disease:>3swollen and>3tender joints, PASI scores>10, erythrocyte sedimentation rate (ESR)≥28mm/hour and (or) C-reactive protein (CRP)>10mg/L after therapy for standard treatment by NSAIDs and non-biological DMARDs at least six months. All patients had no active infection, congestive heart failure, important organ failure, malignancies, demyelinating diseases, other rheumatic diseases, without serious infection history nearly six months, not allergy to the composition of the mouse protein.All understand and consent their treatment program. 1.2DrugsAll patients received infusions of Infliximab3mg/kg at week0,2,6and14in combination with one NSAIDs,stable doses of non-biological DMARDs nearly six months.The doses did not increase during the observation.1.3TCM syndromes and clinical evaluationBased on"diagnostic efficacy criteria of TCM disease and syndrome" promulgated in1994by the State Administration of TCM concerning "arthralgia syndrome"and "white mange",two TCM rheumatologists entitled associate professor executed syndrome differentiation together among18patients with refractory PsA.Efficacy of each TCM syndrome type were compared before (baseline) and after (22weeks) treatment. The22-week efficacy of different syndrome types were compared.1.4Outcome measuresThe primary outcome measures were the percentages of patients achieved the psoriatic arthritis response criteria (PsARC) and the psoriasis area and severity index50%response(PASI50) at week2,14,22.Meanwhile,Subordinate indexes including the percentages of patients achieved PASI75and PASI90, swollen and tender joint counts, the patient and evaluator global assessments,the score of PASI and HAQ, the level of CRP and ESR were evaluated.1.5Safety evaluationBlood routine examination,autoantibody,liver function,renal function,tuberculosis antibody.chest X-ray and other tests were made before the treatment and during observations,at the same time,the adverse events were recorded.2. Study of52-week follow-up2.1Follow-up patients and methods17patients with PsA who achived the PsARC and (or) PASI50improvement (15 patients achived the PsARC and PASI50improvement,1patients achived the PsARC improvement,1patients achived PASI50improvement)at week22were followed up for a period of52weeks by outpatient clinic or telephone(outpatient follow-up at week52),1time per4-12weeks.If disease deteriorated, shortened follow-up time. Record the reasons for the lost.2.2Follow-up contentsTreatment programs, the time of each treatment program failed to maintain PsARC and (or) PASI50,swollen and tender joint counts, the patient and evaluator global assessments,the score of PASI and HAQ, the level of CRP and ESR were evaluated,Safety evaluation(blood routine examination, autoantibody, liver function, renal function, tuberculosis antibody, chest X-ray and other tests were regularly reviewed and the adverse events were recorded).3Statistical analysisAll data used SPSS13.0statistical analysis software.Measurement data are expressed as mean±standard deviation or median (interquartile range).The two sets of measurement data were compared using independent samples t test or Wilcoxon rank sum test, the difference before and after treatment with paired t-test or Wilcoxon signed rank sum test. The individual efficacy indicators in various time points (baseline, week2,week14, week14) were compared by repeated measures analysis of variance.Count data using y2test. The ratios of different treatment groups maintaining PsARC and PASI50were drawn by Kaplan-Meier curve,and the two groups were compared using the log-rank test. P<0.05was considered statistically significant.Results1.22-week clinical study of infliximab therapy for refractory psoriatic arthritis and analysis of TCM syndrome 1.1The overall efficacyThe percentages of patients achieved the PsARC and PASI50both were55.6%(10cases) at week2,72.2%(13cases) and83.3%(15cases) at week14separately and88.9%(16cases) at week22.33.3%(6cases) of patiens got PASI75at week2,50.0%(9cases) at week14and72.2%(13cases) at week22, the same point in time, the percentages of the patients who obtained PASI90were22.2%(4cases),38.9%(7cases) and61.1%(11cases). Improvements of other measures were significantly compared with baseline(P<0.05).1.2TCM syndromes and clinical evaluationThere are8cases(44.4%) of liver and kidney deficiency type,7cases(38.9%) of damp-heat accumulation type,2cases(11.l%) of blood-hot air dryness syndrome, and1case(5.6%) of wind-cold syndrome according to syndrome differentiation.The type of liver and kidney deficiency and the type of damp-heat accumulation are in the majority.Each outcome measures in blood-hot air dryness syndrome or wind-cold syndrome after treatment was better than base line.Owing to the fewer number of two types,we mainly compared with the outcome measures between the liver and kidney deficiency syndrome group and the group of damp-heat accumulation type.Improvements of each outcome measures in two groups was significantly compared with baseline(P<0.05). Statistical analysis of the two groups at baseline data were comparable (P>0.05).The proportion of patients who obtained PsARCand PASI50improvement between the two groups at week22and the individual outcome measures considered as no statistically significant (P>0.05),which showed that Infliximab treatment of two sets of type had good effect and the effects were considerable.1.3Safety evaluation A period of22weeks of observation showed that there were3cases (16.7%) adverse reactions, among them,2cases (11.1%) of upper respiratory tract infections,1case (5.6%) of lung infection,but the symptoms were mild and were recovered after symptomatic treatment.There are no serious tinfusion reactions, liver and kidney function impairment, lupus-like syndrome and tumorigenesis.2. Study of52-week follow-up2.1Follow-up situationAll17cases of patients with refractory PsA included in the follow-up study have completed52weeks of follow-up.2.2Treatment programs and improvement of PsARC and PASI50Summarized17cases of patients with refractory PsA treatment programs, there are four kinds, according to this subgroup of patients.Group A:2cases (12%) patients (only reached PsARC or PASI50at follow-up baseline) accepted IFN3mg/kg at the follow-up baseline, combined NSAIDs and non-biological DMARDs in22weeks of clinical study.At eighth week.they reached the PsARC and PASI50improve.Continuing IFN3mg/kg (1/8week) up to52weeks, PsARC and PASI50improvement were maintained.Group B:7cases (41%) patients discontinued IFN, continuing to use the NSAIDs and non-biological DMARDs in22weeks of clinical observation.2cases (28.6%) patients continued to maintain PsARC and PASI50improved to52weeks of follow-up,however,5cases (71.4%) patients did not to maintain PsARC and (or) PASI50improve, the time of emergence at8th week (2cases),10th week (1case),14th weeks (1case),20th week (1case),2cases (40%) plus IFN3mg/kg×1treatment and reached PsARC and PASI50improvement2weeks later, following the use of NSAIDs and non-biological DMARDs to52weeks of follow-up, sustained PsARC and PASI50,3cases (60%) patients increased the non-biological DMARDs doses and achieved PsARC and PASI50after8to10weeks,maintaining the condition to52weeks of follow-up.Group C:7cases (41%) continued to IFN (3mg/kg at baseline of follow-up, IFN3mg/kg8weeks laterâ†'1/10weeks x2â†'1/12weeks x2), in combination with NSAIDs and non-biological DMARDs.6cases (85.7%) patients to sustained PsARC and PASI50to week52, only1cases (14.3%) did not maintain PsARC standard at week27, plused IFN3mg/kg one time, he reached PsARC improve2weeks later. IFN treatment changed to1/8weeks at the following52weeks,the disease was controled.Group D:1cases (6%) patients discontinued all the treatment. Rash emerged at28weeks, PASI score was1.8points.The patient did not acccept therapy at the following follow-up, sometimes one to two joint swelling or pain, PASI scores changed from1.2to4.2points,but PsARC and PASI50improvement maintained.2.3The PsARC and PASI50improve between Group B Group CThe follow-up baseline data of Groups B and C are comparable statistically (P>0.05). Following up to52weeks,the percentage of maintain PsARC and PASI50improvement in Group B was28.6%(2cases), the median time of PsARC and PASI50unimprove is week14; The percentages of Group C was85.7%(6cases), the time of the patients did not maintain PsARC and PASI50improvement was week27. The two groups maintain ing PsARC and PASI50improvement rate had a significant difference (χ2=5.517, P=0.019), which suggested that treatment options of Group C are better than Group B.2.4Single endpoint included in the overall at different time pointsSingle endpoint included in the overall at follow-up52-week were exceler than the baseline(17patients enrolled the follow-up) of22weeks clinical study (P <0.05), and were compatible with the baseline of follow-up (P>0.05). 2.5Safety EvaluationThere were three cases (17.6%)of adverse reactions in52weeks follow-up.1patients (50.0%)in Group A got severe lung infection at week47and recovered after2weeks anti-infective therapy; there was no adverse reactions occur in Group B;2cases (28.6%) in group were tested ANA positive without lupus-like syndrome, we did not stop infliximab treatment,1patients had ANA negative at week52. Comparison of the incidence of adverse reactions among the three groups, the statistical test shows no significant difference (P>0.05). Research in general does not appear to infusion reactions and no kidney function damage, lupus-like syndrome and tumorigenesis happen.Conclusion1.For the patients with refractory PsA who had previous failure of NSAIDs and standard non-biological DMARDs treatment,infliximab therapy can improve joint symptoms and skin lesions quickly, effectively and safety.2.There are liver and kidney deficiency type,damp-heat accumulation type,blood-heat syndrome and wind-cold syndrome in the distribution of18patients with refractory PsA,the type of liver and kidney deficiency and the type of damp-heat accumulation are in the majority. For the above-mentioned syndrome type,infliximab therapy is in effect. Infliximab22-week efficacy of liver and kidney deficiency type and damp-heat accumulation type was no significant difference.3.Most of refractory PsA patients who achieved clinical improvement by infliximab treatment will discontinue infliximab,but continue to receive NSAIDs and non-biological DMARDs, only a small number of patients can continue to maintain clinical improvement,when the clinical improvement can not maintain,re-use of infliximab or strengthen of non-biological DMARDs treatment can control the disease; Continued to regulate the use of infliximab(1/8weeks) can continue to control the disease; Stretching infliximab use of time gradually is a good method of maintaining the clinical improvement,and it is worthy to learn;Monitoring of adverse reactions can not be ignored in the long-term treatment. Owing to small sample size, the conclusion requires a large sample, multi-center randomized controlled study to further verify.