Clinical Efficacy of Gandakang Tablets plus Methylprednisolone in Patients with Systemic Lupus Erythematosus.

Objective: To evaluate the clinical efficacy of Gandakang tablets plus methylprednisolone in patients with systemic lupus erythematosus (SLE).
Methods: From February 2015 to February 2019, 60 eligible patients with SLE were recruited and assigned via the random number table method at a ratio of 1 : 1 to receive either methylprednisolone (control group) or Gandakang tablets plus methylprednisolone (observation group). The primary endpoint was clinical efficacy, and the secondary endpoints included Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, immunoglobulin (Ig), inflammatory factor levels, and adverse events.
Results: Gandakang tablets plus methylprednisolone were associated with a significantly higher treatment efficacy versus methylprednisolone alone (P < 0.05). Gandakang tablets plus methylprednisolone resulted in significantly lower SLEDAI scores and lower levels of IgG, IgM, IgA, tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and interleukin-6 (IL-6) versus single medication of methylprednisolone (P < 0.05). The two groups showed a similar incidence of adverse events (P > 0.05). Patients given Gandakang tablets plus methylprednisolone had higher mental health, emotional role, physical role, social functioning, and bodily pain scores versus those receiving the monotherapy of methylprednisolone (P < 0.05).
Conclusion: Gandakang tablets plus methylprednisolone is effective in the treatment of SLE by enhancing the patients' immunity, mitigating the inflammatory response, eliminating negative emotions, and improving their quality of life.

1. Introduction

Systemic lupus erythematosus (SLE) is a connective tissue disease secondary to autoimmune system disorders [1] and is associated with the presence of pathogenic antibodies in the serum that binds to self-antigens to form immune complexes, leading to the involvement and damage of multiple organ systems [2]. Its pathogenesis is still poorly understood. In recent years, with the development of medical technology, considerable progress has been realized in the treatment of SLE in China, with significant enrichment in the 10-year survival [3]. It has been noted that cumulative organ damage caused by the disease will seriously compromise the prognosis [4]. Therefore, the mitigation of the toxic side effects of low-dose drugs while ensuring the therapeutic benefits is the current priority of clinical research [5]. Methylprednisolone tablets are commonly used for SLE to hinder the growth of connective tissue and alleviate the inflammatory response. However, the long-term use of methylprednisolone is predisposed to consequences such as gastrointestinal bleeding, which results in poor long-term efficacy [6]. Gandakang tablet is a herbal preparation made from Radix Bupleuri, Radix Rubiae, Rhizoma Imperatae, Fructus Amomi, Radix Angelicae Sinensis, Xiang Qu, Poria, Pheretima, Rhizoma Atractylodis Macrocephalae, Pericarpium Citri Reticulate Viride, Carapax Trionycis, Fructus Aurantii Immaturus, Radix Paeoniae Alba, Radix Codonopsis, and Radix Glycyrrhizae, which dredges the liver and strengthens the spleen, resolves blood stasis, and unblocks the collaterals. Accordingly, this study aims to investigate the clinical efficacy of Gandakang tablets plus methylprednisolone in the treatment of SLE.

2. Materials and Methods

2.1. General Information

From February 2015 to February 2019, 60 eligible patients with SLE were recruited and assigned via the random number table method at a ratio of 1 : 1 to a control group or an observation group. The two groups showed similar baseline features (P > 0.05), as shown in Table 1. This study was approved by the hospital ethics committee (No. 7929HMU201).

Table 1

Comparison of baseline data between the two groups of patients.

Groups	n	Gender [n]		Age (years)	Course (months)
		Male	Female
Observation group	30	4	26	28.29 ± 2.51	22.73 ± 2.15
Control group	30	5	25	28.23 ± 2.65	22.65 ± 1.82
X 2		6.876		9.867	7.253
P value		0.652		0.672	0.867

Inclusion criteria [7]: ① patients who met the H1 classification criteria for SLE; ② patients without a history of hormone or immunosuppressive therapy in the last 3 months before treatment; ③ patients who were informed of the purpose and process of the study and signed the informed consent form. Exclusion criteria: ① patients with severe mental illness; ② patients with allergies to the drugs used in this study; ③ patients during lactation or pregnancy; ④ patients with other types of rheumatic diseases; ⑤ patients with dysfunction of vital organs such as the kidney and liver.

2.2. Methods

Patients in the control group were given methylprednisolone powder injection (Pfizer Manufacturing Belgium NV) intravenously at 15–30 mg/kg and repeated every 4–6 h. The treatment spanned 48 hours. Patients in the observation group were given methylprednisolone powder (the medication was identical to that for the control group) plus Gandakang tablets orally, 3 g/d, 3 times/d. The efficacy was determined after 12 weeks of treatment in all groups.

2.3. Observational Indicators

Clinical Efficacy. Markedly effective: facial pigmentation completely disappears. Effective: facial pigmentation is significantly alleviated. Ineffective: no improvement or even aggravation of facial pigmentation is found. The total clinical efficacy = (the number of markedly effective cases + the number of effective cases)/total number of cases ∗ 100%.

Immunoglobulins (Ig). Five ml of morning fasting venous blood was collected from the patients of both groups and centrifuged to determine the levels of IgG, IgM, and IgA in both groups using the immunoturbidimetric method.

Inflammatory Factor Level. Three milliliters of morning venous blood was collected from the patients of both groups and serum was obtained by centrifugation. The levels of tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and interleukin-6 (IL-6) were determined using an enzyme-linked immunosorbent assay.

Adverse Events. Adverse events such as headaches were recorded in both groups.

The degree of disease was assessed before and after treatment using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), which includes 24 items such as epilepsy, psychiatric symptoms, visual impairment, organic brain syndrome, arthritis, vasculitis, and myositis. The higher the score, the more severe the condition.

The MOS 36-item short-form health survey (SF-36) was used to assess the quality of life of the patients. The evaluation indexes of the scale included mental health, emotional role, physical role, social functioning, and bodily pain, with a full score of 100 points.

2.4. Statistical Methods

SPSS25.0 statistical software was adopted for processing data in this study. The measurement data were expressed as (mean ± standard error) using the independent paired t-test, and the count data were expressed as [n(%)] using the chi-square test. Differences are considered statistically significant at P < 0.05.

3. Results

3.1. Clinical Efficacy

Gandakang tablets plus methylprednisolone were associated with a significantly higher treatment efficacy versus methylprednisolone alone (P < 0.05) (Table 2).

Table 2

Comparison of clinical efficacy between the two groups of patients.

Groups	n	Markedly effective	Effective	Ineffective	Total efficacy
Observation group	30	17	12	1	29 (96.67)
Control group	30	10	12	8	22 (73.33)
χ 2					4.706
P value					0.030

3.2. Disease Condition

Gandakang tablets plus methylprednisolone resulted in significantly lower SLEDAI scores versus methylprednisolone alone (P < 0.05) (Table 3).

Table 3

Comparison of SLEDAI scores between the two groups of patients.

Groups	n	SLEDAI scores
		Before treatment	After treatment
Observation group	30	8.85 ± 0.59	4.25 ± 0.71
Control group	30	8.81 ± 0.67	5.93 ± 0.82
t		15.653	12.980
P value		0.087	0.021

3.3. Immunoglobulins

Before treatment, there was no statistically significant difference in the levels of IgG, IgM, and IgA between the two groups (P > 0.05). Gandakang tablets plus methylprednisolone resulted in significantly lower SLEDAI scores and lower levels of IgG, IgM, and IgA versus the single medication of methylprednisolone (P < 0.05) (Table 4).

Table 4

Comparison of immunoglobulins between the two groups of patients.

Groups	n	IgG (g/L)		IgA (g/L)		IgM (g/L)
		Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Observation group	30	7.13 ± 0.35	6.32 ± 0.31	1.35 ± 0.23	1.01 ± 0.05	1.33 ± 0.26	1.08 ± 0.07
Control group	30	7.26 ± 0.43	5.13 ± 0.28	1.33 ± 0.24	1.19 ± 0.08	1.32 ± 0.13	1.19 ± 0.05
t		27.982	20.023	11.235	18.767	17.865	20.223
P value		0.541	0.012	0.623	0.032	0.232	0.003

3.4. Inflammatory Factor Levels

Before treatment, there was no statistically significant difference between the levels of TNF-α, IL-4, and IL-6 in the two groups (P > 0.05). The patients receiving combined treatment had lower levels of TNF-α, IL-4, and IL-6 versus monotherapy of methylprednisolone (P < 0.05) (Table 5).

Table 5

Comparison of inflammatory factors between the two groups of patients.

Groups	n	IL-4 (pg/mL)		IL-6 (pg/mL)		TNF-α (ng/L)
		Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Observation group	30	7.65 ± 0.72	3.93 ± 0.68	16.66 ± 0.59	9.42 ± 0.75	139.94 ± 4.23	106.26 ± 2.89
Control group	30	7.72 ± 0.79	5.08 ± 0.75	16.57 ± 0.78	11.52 ± 0.84	139.98 ± 4.64	152.45 ± 4.52
t		23.231	19.076	22.563	17.023	15.043	19.765
P value		0.672	0.034	0.770	0.022	0.332	0.015

3.5. Adverse Events

In the control group, there were 3 cases of headache and 4 cases of vomiting, and the incidence of adverse reactions was 23.33% (7/30). In the observation group, there were 2 cases of headache and 2 cases of vomiting, and the incidence of adverse reactions was 13.33% (4/30). No significant differences were observed in the incidence of adverse events between the two groups (P > 0.05) (Table 6).

Table 6

Comparison of adverse reactions between the two groups.

Groups	n	Headache	Vomiting	Total incidence
Control group	30	3	4	7 (23.33%)
Observation group	30	3	2	4 (13.33%)
χ 2				1.002
P value				0.317

3.6. Symptom Remission

Gandakang tablets plus methylprednisolone were associated with a better remission rate versus methylprednisolone (P < 0.05) (Table 7).

Table 7

Comparison of symptom remission between the two groups.

Groups	n	Facial erythema	Joint pain	High fever
Observation group	30	9	10	13
Control group	30	21	27	28
χ 2		9.600	20.376	17.329
P value		0.002	≤0.001	≤0.001

3.7. Quality of Life

Before treatment, there was no statistically significant difference between the mental health, emotional role, physical role, and social functioning scores of the two groups (P > 0.05). Patients given Gandakang tablets plus methylprednisolone had higher mental health, emotional role, physical role, social functioning, and bodily pain scores versus those receiving the monotherapy of methylprednisolone (P < 0.05) (Table 8).

Table 8

Comparison of the quality of life of patients in the two groups before and after treatment.

Groups	n	Mental health		Emotional role		Physical role		Social functioning
		Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Observation group	30	77.23 ± 5.61	92.15 ± 6.63	71.76 ± 7.13	91.58 ± 7.15	61.33 ± 5.46	86.18 ± 7.22	73.46 ± 6.16	90.58 ± 6.15
Control group	30	77.29 ± 5.33	82.24 ± 5.97	71.69 ± 6.94	82.83 ± 6.78	61.42 ± 5.53	72.45 ± 7.17	73.79 ± 5.95	82.42 ± 7.78
t		13.324	16.324	17.014	16.210	15.023	20.332	18.543	21.067
P value		0.456	0.021	0.650	0.013	0.322	0.012	0.765	0.028

4. Discussion

Systemic lupus erythematosus is a common disease in rheumatology [4] and an inflammatory connective tissue disease triggered by autoimmune abnormalities, with pathological changes such as connective tissue fibrosis mucus edema, inflammatory response, and vascular abnormalities [8]. Its clinical manifestations include fever, skin and mucous membrane damage, joint pain, and organ damage, and delayed treatment may trigger irreversible damage to various systems such as nerves and blood [9]. Currently, pharmacological treatment is the mainstay in clinical practice, in which glucocorticoids can effectively offset the disorders of the autoimmune system [10]. However, long-term administration of glucocorticoids in large doses may give rise to a cascade of adverse reactions that may seriously compromise the patient's quality of life. Systemic lupus erythematosus is an autoimmune and inflammatory connective tissue disease that involves multiple organs [11]. Stimulation by estrogen, genetic, environmental, infectious, and endocrine factors leads to a decrease in T lymphocytes and a proliferation of B cells, which is consequently associated with the direct binding of autoantibodies to the tissue cells and subsequent local tissue damage and inflammatory reactions [12]. Currently, glucocorticoids are the main drug for the treatment of the disease [13]. However, long-term administration of high-dose glucocorticoids increases the risk of adverse drug reactions and drug dependency, while reduction of the drug dose is presumably associated with relapse [14, 15].

The results of this study showed that Gandakang tablets plus methylprednisolone were associated with higher efficacy and lower levels of IgG, IgM, IgA, TNF-α, IL-4, and IL-6 versus methylprednisolone, indicating that the combined treatment can effectively reduce the level of inflammatory factors in SLE patients, regulate their immune function, and facilitate rapid recovery. Methylprednisolone is a mild glucocorticoid with strong anti-inflammatory effects and is widely used in the treatment of rheumatic diseases and endocrine disorders [16]. As mentioned before, long-term high doses of methylprednisolone may lead to adverse effects such as Cushing's syndrome and femoral head necrosis. Moreover, methylprednisolone tablets also reduce capillary permeability and effectively prevent the entry of toxic substances and vascular endothelial dysfunction [17]. Nonetheless, monotherapy of methylprednisolone fails to achieve satisfactory efficacy, which underlines the significance of the combined use of other drugs. Many SLE patients have autoimmune disorders with significantly higher immunoglobulin levels than those of healthy individuals [18, 19]. The decreased levels of IgG, IgM, and IgA after treatment are ascribed to the fact that Gandakang tablets effectively inhibit the abnormal proliferation of B lymphocytes in patients and nonspecifically remove antigen-sensitive small lymphocytes, thereby downregulating IgG, IgM, and IgA levels and facilitating the restoration of patients' immune function. In addition, the drug is degraded by the liver and only a small amount of active metabolites passes the blood-brain barrier, which efficiently reduces adverse reactions and synergizes with methylprednisolone tablets to promote patients' recovery to the maximum extent.

The results of this study showed better quality of life for patients given Gandakang tablets plus methylprednisolone versus those receiving methylprednisolone alone. Furthermore, patients' negative emotions can be mitigated after treatment, which contributes to the recovery of mental health, and the improvement of quality of life.

In conclusion, Gandakang tablets plus methylprednisolone are effective in the treatment of SLE, which improves the immunity of patients, mitigates inflammatory responses, eliminates their negative emotions, and enhances their quality of life. The proposed use of Gandakang tablets is simultaneous and additional to methylprednisolone therapy.