浙江中醫(yī)藥大學(xué)中醫(yī)臨床基礎(chǔ)研究所 杭州 310053

The autoimmune systemic lupus erythematosus(SLE),characterized by excessive production of autoantibodies leading to ultimate injure upon multiple vital organs such as brain,kidney and heart,is severe one of connective tissue diseases with a defected capacity of eliminating depositing immune complex.Although the pathogenesis remains unclear,the onset of SLE is widely believed to be correlated to genetic,endocrine and environmental factors[1].

In Chinese medicine(CM),the main pathogenesis of SLE is thought to be heat-toxicity,Yin-deficiency and blood stasis,therefore,the combined use of detoxifying,removing stasis and nourishing Yin is well recognized as the primary strategy to treat it[2].Meanwhile,CM,in the combination of steroids and immunosuppressors show remarkable effect and safety in clinical practice.Allour work based on the heat-toxicity,blood stasis and Yin-deficiency syndrome of SLE and the CM research using detoxifying,removing stasis and nourishing Yin method is summarized in this paper to discuss how to correctly use CM,in combination with western medicine or not,to treat SLE.

1 Distinct syndrome and differentiation of SLE

SLE has manifestations of the excess syndrome but an origin of deficiency syndrome,which indicates the cause,Yin-deficiency of the liver and kidney,and the diverse expressions of heat-toxicity and blood stasis.The Yin-deficiency of liver and kidney makes patients susceptible to SLE and heat-toxicity,together with blood stasis,invading the human body,i.e.the skin,meridian,even bones,and internal organs.Therefore,clinical symptoms may vary,and false symptoms are prevalent in clinical practices and make it difficult to understand the pathogenesis of SLE.In principle,CM treatment for SLE should be based on the pathogenesis of mixed damage of heat-toxicity and blood stasis with innate Yin-deficiency,while applying flexible compatibility for temporary accompanied symptoms[3].

1.1 Heat-toxicity In the acute onset of aggressive SLE,overproduced autoantibodies and immune globulins,which will transform to immune complex further,are gigantically consuming serous complements and considered as the main components which have the similar properties as heat-toxicity.The immune complex,or heat-toxicity,is the leading cause of acute SLE.It manifests severe symptoms like high fever,oral ulcer,global erythema,even insane and delirium,with yellow dry coating on the red tongue and wiry-rapid pulse,due to its capability of mediating systematic inflammation and tissue damage.

1.2 Blood stasis Blood stasis,also known as static blood,is the prominent pathogenesis throughout the progression of SLE[4].It is noteworthy that blood stasis can be caused by multifarious pathogeny,At the onset of emerging heat-toxicity may speed up the blood flow,while permeabilized blood vessels caused by generalized vascular injury make it easier for blood to flow out and form stasis.Common symptoms are multiple ecchymoses,ulcerating skin and hair loss,with a dark reddish tongue and wiry pulse.

At the late phase,over-consumed Qi failed to promote blood circulation around the body and Qi movement is also influenced by the prolonged activity of SLE.Therefore,blood stasis results from such disruption of the circulation of Qi and blood among internal organs.And patients of this phase are usually featured as abnormal menstruation,even amenorrhea,and symptoms of deficiency like atrophoderma,fatigue,and interstitial lung disease,with a dark tongue and feeble pulse.Besides,patients with SLE usually need lifelong medication,however,steroids or non-steroid immunosuppressors both work by indiscriminately suppressing the immune responses,which makes it worse for the self-build-up against SLE and would meanwhile contribute to the generation of blood stasis.

Featured small vasculitis of allergic reactions result from the deposition of the excessive immune complex will continuously invade the vascular walls and give rise to the ultimate ischemia and dysfunc-tion of local tissues.The pathologic changes like microangiopathy and microthrombus observed under the microscope are also consistent with blood stasis.

1.3 Yin-deficiency SLE has manifestations of the excess syndrome but an origin of deficiency syndrome.The insufficient Yin of the kidney,which functions as storing the congenital foundation,would lead to holistic failure in controlling the heat and blood movement.Meanwhile,the uncontrolled heat would make heat-toxicity,and abnormal blood movement is the cause of blood stasis.As a consequence,heat-toxicity and blood-stasis together result to excessive consumption of Yin and make vicious cycle in the human body.That’s the reason why SLE is lingering and hard to cure.Deficiency symptoms like night sweat,flushing cheek,dry throat,tinnitus,sore lumbus,and much hair loss can be seen,with a thready pulse.It is noteworthy that in the late phase of SLE,with the retreating heat-toxicity and the loss of Qi and blood,Yin-deficiency syndrome would be more transparent and endogenous heat would be relatively prosperous,although complements of most patients might rise to a healthy level.

Besides,the kidney is believed to possess the original essence of human so that the deficiency of the kidney also indicates the genetic abnormity which has been long-time investigated.Emerging evidence of genome-wide association study(GWAS)has uncovered more than 80 SNPs,which are correlated with incidence of SLE,and massive research has demonstrated how micromutation could lead to a vast difference in phenotype from multiple levels in SLE[5].

2 The therapeutic effect of Chinese medicine in treating SLE

2.1 The therapeutic effect of Jiedu Quyu Ziyin prescription It’s recorded in the classic Jingui Yaolue(The Synopsis of Prescriptions of the Golden Chamber) that Shengma Biejia decoction can treat Yinyangdu(Yin-Yang toxin),which shares hallmark clinical manifestation of lupus with SLE,and abundant effort has been made to decipher the potential mechanisms behind its long-run efficiency on SLE treatment[6].Also,with the everlasting accumulation of the understanding upon SLE,a prescription,named Jiedu Quyu Ziyin prescription(JP),based on Shengma Biejia decoction,of more accurate therapy was formed and showed the tremendous preventive and curative ability for SLE,especially for the nephritis and neuropsychiatric damage related to SLE.

The JP is made up with rational compatibility of the monarch,minister,assistant and guide.The monarch drug is rehmanniae radix,which functions as cooling the blood and tonifying Yin,and minister drugs are cimicifugae rhizome and oldenlandia diffusa for clearing and detoxifying the heat-toxicity.In addition,various herbs,moutan cortex,centellae herba and radix paeoniae rubra are assistant for eliminating the blood-stasis and promoting the blood flow.And guide drugs are artemisiae annuae herba,fructus citri sarcodactylis and glycyrrhizae radix et rhizome for helping to manage the movement of Qi and reconcile all these herbs.

Based on the clinical trial of 147 SLE patients,JP,combined with glucocorticoid(GCs),it showed the remarkable therapeutic effect on the symptoms associated with active SLE,such as skin lesion,fever,oral ulcers,hair loss and abnormal menstruation.JP could also increase the reduced blood platelet,hemoglobin and serum level of complement C3 and decrease the erythrocyte sedimentation rate(ESR),compared with the single use of GCs.JP had higher overall efficiency and potential power in helping the withdraw of GCs and reducing the complications and adverse reactions[7].

2.2 Cooperative effect of integrated medicine SLE patients share the same problem of abnormal function of hypothalamic-pituitary-thyroid(HPT)and hypothalamic-pituitary-adrenal(HPA)axis,which mainly leads to the disordered circadian rhythm of endogenous cortisol and breakdown of immune homeostasis.Therefore,at present,glucocorticoids,including pred-nisone,prednisolone,and methylprednisolone,remain the cornerstone to the treatment of SLE;however,such set of medications often leads to hormone metabolism disorders,which would trigger gluoocortic syndrome manifested as moon face,acne,buffalo hump and abdominal striae.Immunodeficiency disorders like Cushing's syndrome,anovulation,gluconeogenesis-related hyperglycemia are involved as well.Also,glucocorticoids-treated SLE patients have a higher chance to come up with complications like hypertension and arteriosclerosis with increased risk of infection.And pulse therapy of high-dose methylprednisolone is the leading cause of steroid-induced osteoporosis of axial skeleton.All those above limits the treatment on SLE and calls for better treatment.

Various CMs have been reported to balance the immune system and suppress inflammatory responses while having a little side effect on the human body and offer new ideas for SLE treatment with integrative medicine.The integrative use of JP and GCs could rapidly prevent the activity of SLE and eliminate the potential damage to organs,with mutual assistance of each other.For refractory SLE patients,who are not sensitive to routine GCs treatment and have a complex medical history,such cooperative effect usually offers excellent outcomes.And integrative use of CM and western medicine(WM)is widespread in CM clinic for most patients who seek for the help of CM and have a complicated medication history of glucocorticoids or non-steroid antiinflammatory drugs,and the cooperative effect is the novel hotspot in China.The cooperative effect of integrated medicine of CM and WM is the way in which CM reaches its full potentials and WM could surmount its side effects.

Such cooperative effect has various advantages.First,clinical trials have demonstrated that combined use of JP and GCs show a higher rate of relapsefree cases and overall lower dosage of GCs administration.It is noteworthy that compared with the single use of GCs,combined use of JP and GCs could dramatically improve the decreased serum adrenocorticotropin(ATCH)and cortisol which indicates that HPA is one of the targets of JP,or CM,in treating SLE[8].CM,with the core of holistic views,works on multiple targets and systems.Beside JP’s direct effect on the secretion of endogenous ATCH and cortisol by improving the self-regulation of HPA,JP could significantly inhibit the secretion of various cytokines,like interferon γ,tumor necrosis factor(TNF)and interleukin-6,which could substantially contribute the undesirable invasion on HPA axis.

Next,the preventive effect of JP for SLE-associated complications,in combination with GCs,is outstanding based on various clinicaltrials.JP showed remarkable efficacy in relieving the thrombopenia by potentially preventing the overconsumption and destruction ofplatelets.Furthermore,JP can help to increase the serum level of vitamin D and prevent bone restoration by inhibiting the excretion of urinary calcium and parathyroid hormone[9].Besides,JP could correct thyroid dysfunction by inhibiting the production of anti-thyroid autoantibodies and promoting thyrotropin production[10].

3 The mechanisms how JP treat SLE

Given the remarkable efficacy of JP on SLE,Underlying mechanisms related the metabolism,microbiome and molecular factors are summarized to discuss how CM treats SLE.

3.1 Molecular factors SLE involves a complicated breakdown of both innate and acquired immunity,in which Toll-like receptors(TLR),estrogen receptor(ER)and DNA methylation play essential roles in the development of SLE.And lymphocytes like T cells and B cells,as the phenotype,are the crucial regulator and indicator of SLE activity.In the MRL/lpr model,JP can rebuild the balance between TH 17 and regulatory T cells via CaMK4 signal pathway and limit the progression of SLE towards nephritis[11].Expression of TLR9 is also regulated by downregulating the expression of TGF-β-MAPK pathway.In addition,JP has a modest effect on suppressing the over-activated lymphocyte,by adjusting the interaction of T cells and B cells,and promoting DNA methylation besides improving the SLE outcome[12-13].

In vitro researches also indicate that JP can rebalance ERα/β,downregulate the expression of the extracellular signal-regulated kinase(ERK)and phosphorylated ERK.Moreover,TLR9 is also involved in the regulation ofJP,as wellas the downstream molecules like myeloid differential protein-88(MYD88),nuclear factor kappa-B(NF-κB)and interferon-γ(IFN-γ).The JP treating rat serum was proved to suppress the over-expression of B-cell activating factor(BAFF)and its receptor(BAFF-R)in YAC-1 and WEHI-231 cell line[14].

3.2 Metabolism The deep dysfunction of unsaturated fatty acids and various amino acids is the hallmark of the disorder in SLE,of which the loss of balance among eicosapentaenoic acid(EPA),docosahexaenoic acid(DHA)and arachidonic acid significantly contribute to the formation of perihistologic inflammation[15].In the pristine-induced model,JP could dramatically upregulate the content of EPA,and amino acids biomarkers,glycine,phenylalanine,and tryptophan were also upregulated to the normal level.Notably,JP showed better effect than prednisone for prednisone which could solely regulate phenylalanine,while JP had multiple-target regulation.

Dyslipidemia related to the elevated triglycerides(TG),total cholesterol(TC),low-density lipoprotein(LDL)and decreased high-density lipoprotein can be observed in most SLE patients.And it’s even worse that GCs treatment does no good for such disorder which is one of the significant risk factors promoting the progression of SLE,especially for SLE-associated atherosclerosis.Moreover,statins treatment on patients with complex medication history showed low efficiency for preventing comorbidity.However,in lupus-prone MRL/lpr model,JP showed the prior capacity of regulating the acylcarnitine and triglyceride,which may be a potential new treatment for patients with SLE-associated atherosclerosis.

3.3 Microbiome The intestine is the most extensive immune system in the human body.Emerging evidence upon intestinal microbes is revealing its sig nificant role in SLE development[16].Studies have found that SLE patients have long been undergoing autoimmune disorders,and most cases are accompanied by dysfunction of the gastrointestinal function.The prevalence of gastrointestinal symptoms is positively correlated with the activity of SLE.The production of antibodies has been confirmed to influence the colonization of the intestinal microbes,and the species and abundance of beneficial bacteria.Intestinal microbes are increasingly becoming a research hotspot and potential therapy.

JP can reduce the abundance of pathogenic bacteria such as Parabacteroides and increase the abundance of beneficial bacteria like Odoribacter and Ruminococcus by treating the gastrointestinal disorder in lupus-prone mice model[17].Interestingly,prednisone shows no influence on the distribution of microbiome species compared with JP treatment.JP can also significantly reduce the expression of TLR7,TLR9 and IL-6 in the intestine,indicating CM could treat SLE with multiple targets.

4 Discussion

Heterogeneous SLE results in autoimmune responses of multiple organs.Routine GCs has more than prominent efficiency but potential impairment to the human immune system by suppressing immune responses.Consequent enhanced risk of infection and dysfunction of microbiome and metabolism may give rise to severe adverse reactions in clinic.Novel biologics have been on clinical trials while most of those failed in clinical trials for SLE are highly heterogeneous and influenced by mixed etiologies.

CM has been used in China for over 2000 years to cure SLE,and precise prescription has been formed as the result of continuous perseverance CM doctors.JP is already proven to have notable treatment on SLE by inhibiting the progression and activity.Multiple influences on widely associated gene and proteins and the distinct regulation upon metabolism and microbiome,as well as the adjuvant role for GCs treatment and withdrawal,make JP a more and more significant role in clinic.Anyway,the dual effect of multifarious polysaccharides in complicated prescription remains the limitation to full acceptance of most clinicians who know little about CM.False symptoms could also lead to misunderstanding of the actual disease condition,which prompt clinicians to pay more attention to grasping the accurate differentiation.