| Background:Rheumatoid Arthritis(RA)is a chronic,progressive,and invasive autoimmune disease.Pain is one of its most important symptoms.Due to the high incidence,prevalence,multidimensionality and complexity of RA pain,pain management has always been an urgent problem to be solved in clinical practice.The Nursing Science Precision Health(NSPH)model is a suitable model for symptom management proposed by the National Institutes of Health(NIH)in recent years.The model implements scientific symptom management by four gradually deepening parts.Specifically,A:accurate measurement of symptoms;B:characterization of symptom related phenotype including lifestyle and environmental factors;C:characterization of symptom related genotype and other biomarkers;D:discovery,design,and clinical application of intervention target.These four parts not only reflect the characteristics of nursing,but also are interdisciplinary collaboration based on scientific information and data.The present study explored pain management of RA based on the NSPH model,which also investigated the patients’ needs,cognition and experience in the development of RA pain through qualitative studies,and analyzed the complex manifestation mechanism of pain through cross-sectional studies of RA pain.The study analyzed the clinical phenotypic characteristics of RA pain,explored the mechanism and biomarkers of pain occurrence and development,and identified new targets and optimal timing for intervention.The study proposed accurate and effective intervention strategies,thus reaching an intervention solution to RA pain,and provided whole-process,dynamic and accurate pain management for RA patients.Objectives:1.To analyze the clinical phenotypic characteristics of RA pain based on accurate measurement.2.To explore the biological mechanism of RA pain based on the exploration of the relevant biological markers.3.To develop a precision intervention program based on the integration of key precision intervention elements for RA pain,thus implementing and testing the effectiveness of the program.Methods:Following the framework of Nursing Science Precision Health(NSPH),the study developed a systematic approach with three pillars:1.Study on the clinical phenotypic characteristics of RA pain based on accurate measurement(1)Investigation on the status of the Global Pain Scale and the clinical phenotypic characteristics of RA patients:The Chinese version of the Global Pain Scale(GPS)was introduced to measure the multiple dimension of RA pain;the reliability and validity of the GPS(Chinese version)was evaluated.(2)Qualitative study on pain experience of RA patients:Qualitative interviews were conducted with the theme of "Pain experience among RA patients",focusing on the needs,cognition and experience in the pain development,and establishing relevant variables associated with the clinical phenotypic characteristics of RA pain.(3)Study on pain status of RA patients and path analysis of their quality of life:A cross-sectional investigation was conducted among RA patients from rheumatology departments of 5 hospitals in Nantong,Shanghai,Suzhou,Changzhou and Zhengzhou of China.The associated phenotypic characteristics of pain were analyzed using the Body Image Disorder Questionnaire(BIDQ),Disease Activity Score in 28 joints(DAS28),Hospital Anxiety and Depression Scale(HADS),Fatigue Severity Scale(FSS),Pittsburgh Sleep Quality Index(PSQI)Short Form Health Survey(SF-36),Global Pain Scale(GPS),Visual Analogue Scale(VAS),and Social Support Revalued Scale(SSRS).2.Research on the biological mechanism of RA pain based on the exploration of relevant biological markers(1)Network meta-analysis of RA pain intervention:A systematic literature review was performed to conduct network meta-analysis of RA pain intervention,and effective intervention elements were extracted for the application in basic and clinical studies.(2)Exploration on the mechanism of RA pain occurrence and development:Through the combination of pain phenotype analysis and biological research,the exploration on the mechanism of RA pain occurrence and development was carried out,and search for pain-related biological markers as one of the important intervention targets for pain treatment.3.Based on the integration of precise intervention elements,the precise intervention plan for RA pain was constructed(1)Preliminary construction of precise intervention program for RA patients’pain based on MRC complex intervention framework:Based on above mentioned studies,we identified the key intervention elements:intervention target,intervention technology,intervention timing,intervention content and evaluation criteria,and constructed precise intervention strategies for RA patients’ pain.(2)Expert demonstration of constructing precise intervention strategy for RA patients’ pain based on MRC complex intervention framework:The scientific merits,security and feasibility of the program was evaluated through expert group meetings before the final intervention program was formed.Results:1.The clinical phenotypic characteristics of RA pain were accurately measured and evaluated(1)Reasearch on the reliability and validity of Chinese version of GPS in RA patientsCorrelation analysis results showed that Pearson correlation coefficients between 20 items and the total score ranged from 0.829 to 0.910,and the correlation coefficients of all items were greater than 0.800,and the item score was positively correlated with the total score.Pearson correlation coefficients of all items were statistically significant(P<0.001).The Chinese version of GPS KMO=0.980,Bartlett’s spherical test approximate Chi-square distribution is 15967.408,degree of freedom is 190,P<0.001,reached a significant level,which is suitable for factor analysis.The factor loads of measurement items were all over 0.870,and the sum of squares of extracted loads were all over 80%,indicating that the extraction of four factors was reasonable and the scale had good structural validity.The Cronbach’s α coefficient of GPS in Chinese version is 0.984.The reliability coefficients of pain dimension,emotional feeling dimension of pain,clinical manifestation dimension of pain,pain and daily behavior ability were 0.949,0.957,0.951 and 0.961,respectively.Cronbach’s α of each item was greater than 0.900,indicating that the scale had good reliability.Correlation coefficient r=0.57(P<0.001),GPS scores were highly positively correlated with VAS scores,suggesting that GPS had good standard validity.(2)Qualitative study on pain experience of RA patientsFifteen patients with RA were interviewed about their pain experience.Six themes were extracted:complexity and irregularity of pain,ineffective pain relief strategies,strong negative emotions caused by pain,pain induced daily activities limitations,changes in social support systems,and increased medical costs.The clinical phenotypic characteristics of pain were analyzed,which provided a basis for the inclusion of assessment tools in cross-sectional studies.(3)Study on pain status of RA patients and path analysis of their quality of lifeIn a cross-sectional study,603 RA patients were screened,of whom 580(96.18%)were enrolled.The structural equation model fits well with the data.Chi-square fit statistics/degree of freedom(χ2/DF)=3.960,root mean square error of approximation(RMSEA)=0.072,goodness-of-fit index(GFI)=0.968,adjusted goodness of fit index(AGFI)=0.928,normed fit index(NFI)=0.955,relative fit index(RFI)=0.916,incremental fit index(IFI)=0.966,Tucker-Lewis Index(TLI)=0.936,comparative fit index(CFI)=0.966.The standardized factor load of pain is 0.99,which is the most important factor affecting the quality of life.Pain in RA patients was significantly associated with disease activity,fatigue,sleep and body image disorders.Age and comorbidities(diabetes,hypertension,etc.)can directly affect the patients’quality of life,while pain and body image disorders,disease activity,fatigue,sleep quality and depressive symptom clusters can further affect the patients’ quality of life through the intermediary variable of body function.In the subgroup analysis of quality of life,age,place of residence,education,income,course of disease,comorbidity and other clinical phenotypic characteristics were different between groups.2.Research on the biological mechanism of RA pain based on the exploration of relevant biological markers(1)Network meta-analysis of RA pain intervention to screen the literature basis of pain management strategies for RA patients17,083 articles were screened,including 10,232 in Chinese and 6,851 in English.EndNote X8 software was used to remove duplicated literatures,after which,7898 articles were left.After reading titles and abstracts,a preliminary screening was conducted and 3628 literatures that might meet the inclusion criteria were obtained.After further reading the paper,2702 Chinese literatures were selected according to the criteria of sorting.Finally,135 literatures were selected for this study,including 61 Chinese literatures and 74 English literatures.The role of six outcome indicators,namely,effects of pain score,number of painful joints,disease activity,C-reactive protein(CRP),erythrocyte sedimentation rate(ESR)and rheumatoid factor(RF)(biological indicators related to RA)in RA patients were investigated by eight basic drugs plus non-drug therapy.In terms of improving the pain score,CRP and RF of RA patients,basic drug therapy plus moxibustion intervention has the best effect.Therefore,moxibustion is listed as an intervention strategy of basic research on RA pain and has been transformed into clinical application.(2)Explored the mechanism of RA pain occurrence and development and found that P2X7R(biological marker)mediated the occurrence and development of RA pain,and moxibustion intervention can effectively relieve pain through this intervention target1)In the CIA group(bovine type II collagen-induced rat arthritis),pain behavior tests showed a decreased pain threshold and increased tenderness.Intrathecal injection of A438079(inhibitor of P2X7R)significantly reversed pain behavior with short-term efficacy of 4 hours and long-term efficacy of 48 hours.Western Blot analysis showed that P2X7R expression was increased at L4-L6-associated Dorsal Root Ganglion(DRG)and Spinal Cord(SC)at weeks 2 and 5 after modeling.Immunofluorescence results showed that P2X7R in DRG was mainly expressed in satellite glia.In SC,it was expressed in astrocytes.Electrophysiological results showed that neural excitability of DRG neurons and synaptic transmission in SC were enhanced in CIA Rats.After moxibustion at multiple acupuncture points(Shenshu,Zusanli and Ashi)for 2 weeks(20 min/time/day),the pain,synovial inflammation,bone destruction and cell excitability of electrophysiological examination were alleviated in CIA rats.The concentration of P2X7R in serum of CIA rats increased by Elisa,but decreased after moxibustion intervention.2)Elisa results of serum of RA patients and healthy persons showed that the concentration of P2X7R in RA patients increased,and the results were statistically significant.3.Based on the integration of precise intervention elements,a precise intervention program for RA pain was constructed(1)Preliminary construction of precise intervention scheme for RA patients’ pain based on MRC complex intervention frameworkBased on the above research results,the intervention technology,intervention timing and intervention target were extracted,which will be further validated by clinical practice.P2X7R mediated early RA pain,which may be a non-inflammatory pain biological indicator.Objective indicators of RA pain evaluation were included to form the first draft of the intervention plan.(2)Expert demonstration of constructing precise intervention strategy for RA patients’ pain based on MRC complex intervention frameworkExpert evaluation was conducted upon the first draft of the intervention plan.A total of 11 experts were invited,and the indicator familiarity(Ca)and expert judgment basis(Cs)of the participating experts were 0.94 and 0.90.The expert authority coefficient(Cr)was 0.92,indicating that the expert authority was high and the results were reliable.Finally,a precise intervention plan for RA pain management was formed:Early RA as the best intervention timing;the combination of consistent basic drugs plus moxibustion at multiple acupoints(Shenshu,Zusanli and Ashi);20 minutes per time as the best intervention dose;2 weeks of continuous intervention.Conclusions:1.The Chinese version of GPS has high reliability and validity in RA patients.Compared with other pain assessment tools,the Chinese version of GPS can accurately assess the characteristics of pain symptoms in RA patients from multiple dimensions(Nociception,emotional feelings,clinical manifestations and daily activities).Through exploring the experience and cognition of the pain occurrence and development among RA patients,it has been shown that he clinical phenotypic characteristics of RA pain were correlated with emotion(perception),behavioral restriction(behavior),social support system(environment)and economic burden(environment).The obtained pain-related multidimensional assessment was used for clinical investigation and analysis:pain has the greatest impact on the quality of life,and interacts with other symptoms(fatigue,depression,body image disorder,etc.)to form a cluster of symptoms,which plays a decisive role in the influence of physical function of RA patients.2.It was found that P2X7R is a biological marker of RA pain(measurable index in serum).Through experimental studies,the treatment of P2X7R inhibitor can reverse the pain behavior,which is expected to be a new target of precise intervention and an objective evaluation index.According to the results of network meta-analysis,moxibustion is an effective intervention technology for clinical pain intervention and adjuvant treatment.In this study,experimental research has confirmed that moxibustion can effectively relieve RA pain through this intervention target,and relevant intervention elements can be applied into clinical intervention strategies for RA pain.3.Based on evidence analysis and basic empirical evidence,a precise intervention plan for RA pain was drafted(intervention elements,intervention targets,intervention techniques,intervention timing,intervention contents and evaluation indicators),and improved through expert group meetings.Phenotypic characteristics and biomarkers were explored based on NSPH model,so as to formulate effective intervention methods for patients to prevent and control the occurrence and development of symptoms,laying a theoretical and empirical foundation for clinical application of RA management. |
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