Analysis Of Influencing Factors And Mechanism Of Rheumatoid Arthritis Complicated With Depression

Rheumatoid arthritis（RA）is the most common systemic autoimmune disease in rheumatoid immunology that can affect multiple surrounding joints.Its pathogenesis is complex and the morbidity rate is high,and it is more common in women and middle-aged people.During the development of the disease,patients may develop symptoms such as morning stiffness,swelling,and even joint deformity and disability.The disease can also involve multiple tissues and organs such as the cardiovascular and lungs,which seriously affects the quality of life of patients.RA has a long course of disease,and patients need to suffer from the decline of joint function for a long time and continue to pay medical expenses.Most studies have shown that RA patients are more prone to depression than the normal population,and depression is one of the most common comorbidities associated with RA.RA complicated with depression is affected by many factors,and the pathogenesis of comorbidity is complex and unclear.The patient’s gender,occupation,education,economic status and marital status may all lead to depression.In recent years,studies have shown that the pathogenesis of RA complicated with depression may be related to inflammatory cytokines and tryptophan（TRP）metabolic pathways.TRP is mainly（95%）degraded by the kynurenine（KYN）pathway.The first rate-limiting enzyme of the kynurenine pathway（KP）is indoleamine2,3-dioxygenase（IDO）.In the acute or chronic period of RA,the inflammatory response represented by interferon gamma（IFN-γ）Cytokine levels are elevated,and IDO is activated in vivo,resulting in increased production of KYN and other metabolites.When the level of neurotoxic quinolinic acid（QUIN）,a further product of metabolic pathway,is higher than that of neuroprotective canine urinary quinolinic acid（KYNA）,the increased QUIN can activate the N-methyl-D-aspartate receptor（NMDAR）,resulting in depression,which may be the mechanism of their comorbidity.This study is divided into two parts,combining clinical cases with animal experiments to study the prevalence and influencing factors of RA associated depression,and to explore the mechanism of their comorbidity.Part 1 Prevalence and influencing factors of rheumatoid arthritis complicated by depression ObjectiveThrough in-depth communication and investigation of clinical patients with RA,the incidence of depression in RA patients was studied,and the influencing factors of depression in RA were analyzed.MethodClinically,60 inpatients who met the inclusion criteria of RA were selected as the experimental group,and 60 physical examination subjects were selected as the control group.Two experienced clinical pharmacists conducted face-to-face communication with the patients,using visual analogue scale（VAS）,Assessment tools such as Health Assessment Questionnaire（HAQ）and Hamilton Depression Scale（HAMD）were used to comprehensively assess the physical function and mental state of patients.The basic information of the patients was recorded in detail.To compare the difference in the incidence of depression between RA patients and the general population,and to analyze the influencing factors of RA complicated with depression.ResultIn clinical cases,the incidence of depression in the RA group and the control group was 36.67% and 8.33%,respectively,and the difference was statistically significant（P<0.01）,indicating that RA patients had obvious depression tendency compared with the normal population.Statistical analysis showed that the occupation,family monthly income,number of tender joints,VAS score and HAQ score of RA patients were significantly different between the depression group and the non-depression group.ConclusionThe depressive tendency of RA patients is significantly higher than that of the general population.RA associated depression may be affected by the patient’s occupation,family income,the number of tendered joints,the degree of pain,joint activity and other factors,among which the HAQ score representing joint activity is the most critical risk factor for RA associated depression.Part II Study on the mechanism of action of rheumatoid arthritis complicated by depression ObjectiveCombining clinical cases with animal experiments to verify the correlation between the inflammatory cytokine IFN-γ and the contents of IDO,KYN and QUIN in KP metabolism,and to explore the mechanism of RA complicated with depression Clinical patients provide new treatment strategies.Method30 blood samples were randomly selected from 60 RA clinical cases and physical examiners,The levels of IFN-γ and KP metabolites in the experimental group and the control group were determined by ELISA kit,and the contents of IFN-γ,IDO,KYN and other substances in RA patients and the general population were compared.For in-depth research,this project uses K/Bx N mice as an animal experimental model of rheumatoid arthritis.To verify the effect of IFN-γ on inducing depression in RA,we randomly divided K/Bx N mice into RA group（n=9）and RA+IFN-γ group（n=9）.C57BL/6J mice（n=9）served as control group（group C）.Group C and RA were not given additional treatment,and mice in RA+IFN-γ group were injected with 50 ug of anti-IFN-γneutralizing antibody by tail vein,once every two days,for a total of two injections.Behavioral tests were performed on all mice before and after injection.All mice were sacrificed after the behavioral test,and the brain and serum of the mice were simultaneously collected at the first time.The contents of IFN-γ,IDO,KYN,5-HT and other substances in mouse serum were determined by ELISA kit.Furthermore,the levels of KYN,5-HT,TRP and neurotoxic metabolite QUIN,which is associated with depression,were further determined in the bilateral hippocampus of mice.Since QUIN can activate NMDAR,the protein expression of NMDAR subunit NR2 B was determined to verify whether NMDAR was changed.ResultThe serum IFN-γ,IDO and KYN contents of RA patients were higher than those of the control group,and the TRP contents were lower than those of the control group by ELISA.In animal experiments,RA mice exhibited depression-like behaviors（reduced sugar water preference,increased immobility time for forced swimming and tail suspension）compared with controls.When mice were injected with IFN-γ neutralizing antibodies into their tail veins,the mice’s depression-like behaviors were reversed.The contents of IFN-γ,IDO and KYN in the serum of RA mice were higher than those of the control group,and the content of TRP was lower than that of the control group.The contents of 5-HT and TRP in the hippocampus of RA mice were lower than those of the control group,while the contents of QUIN and NR2 B were higher than those of the control group.After adding IFN-γ neutralizing antibody to mouse serum and brain,the measurement results of each index were reversed.ConclusionThe mechanism of RA combined with depression may be as follows: after the inflammatory cytokine IFN-γ in RA patients induces the transformation of TRP into KYN,the increased KYN enters the brain through the blood-brain barrier and leads to the increase of neurotoxic QUIN,which activates NMDAR and leads to the occurrence of depression.SummaryRA patients have obvious tendency to depression,and patients’ joint mobility is the most critical risk factor for depression.The mechanism of RA complicated with depression may be that IFN-γ activates IDO to initiate KP metabolism and finally activate NMDAR.