Long-term effects of combined laser acupuncture on depressive symptoms, disease activity and C-reactive protein in rheumatoid arthritis patients

Abstract

BACKGROUND

Rheumatoid arthritis (RA) is a prevalent chronic inflammatory disease in which persistent immune dysregulation targets the joints, causing progressive inflammation, pain, and impaired physical mobility. Although laser acupuncture treatment (LAT) has been increasingly integrated into conventional management of chronic diseases, its effects on depressive symptoms, disease activity, and inflammatory status in individuals with RA is unclear.

AIM

To evaluate the long-term effects of LAT on changes in these indicators.

METHODS

All participants with RA were recruited from one hospital between January and October 2024 and assigned to either a 3-month LAT program in addition to usual care or a reference group receiving usual care only. All participants were followed for 3 months after LAT completion. The primary outcomes were the Taiwanese Depression Questionnaire, Disease Activity Score in 28 joints, and C-reactive protein (CRP), assessed at baseline, 1 week and 3 months after LAT completion. The generalized estimating equations model was applied to estimate the effects of LAT, accounting for within-subject correlations over time.

RESULTS

This study enrolled 67 individuals with RA, including 32 in the LAT group and 35 in the usual care group. Generalized estimating equations analysis showed that adding LAT to usual care significantly reduced Taiwanese Depression Questionnaire scores, Disease Activity Score in 28 joints scores, and CRP levels. Notably, these improvements persisted for 3 months after LAT completion.

CONCLUSION

Addition of LAT to usual care significantly reduced depressive symptoms, disease activity, and CRP levels, suggesting that LAT may be incorporated into personalized care strategies to improve clinical outcomes for individuals living with RA.

Key Words: C-reactive protein; Depressive symptoms; Disease activity; Generalized estimating equations; Laser acupuncture treatment; Rheumatoid arthritis

Core Tip: This quasi-experimental study outlines the multi-dimensional benefits of the laser acupuncture treatment program for individuals with rheumatoid arthritis, including depressive symptoms, disease activity and inflammatory markers. Notably, monitoring participant follow-up used herein can robustly aid in interpretation of a trial’s results.

INTRODUCTION

Currently, accumulating evidence suggest that chronic inflammation plays a central role in several pathophysiological conditions[1]. Rheumatoid arthritis (RA), for example, is a common immune-mediated disease of the musculoskeletal system. Influenced by systemic inflammation, RA can manifest as a broad spectrum of symptoms, ranging from mild joint stiffness to severe functional disability. According to recent estimates, the global incidence of RA increased from approximately 7.9 million in 1990 to almost 18 million in 2021, an increase of about 125%[2,3], which poses a heavy economic burden on healthcare systems. In the United States, the total societal cost of treating RA is approximately 40 billion dollars each year, and the estimated medical expense per admission for an individual with RA is approximately USD 20919, which is thrice the expense incurred by individuals without the condition[4].

In addition to imposing a substantial economic burden, RA is also characterized by systemic inflammation that contributes to extra-articular manifestations and comorbidities like cardiovascular disease and depression, and is associated with a higher mortality rate[5]. In clinical practice, C-reactive protein (CRP) is typically assessed as a key indicator of inflammation to monitor disease activity in individuals with RA. Recent studies have shown that elevated serum CRP may be a risk factor of cardiovascular mortality in this group[6,7]. In addition, this marker is strongly associated with susceptibility to depression in individuals with RA, with each unit rise in CRP level contributing a 20% greater risk of experiencing depressive episodes[8]. Furthermore, patients with RA and comorbid depression would incur 7.2% higher medical expenses, and have a mortality risk that is more than double that of matched controls[9]. Therefore, implementing a complementary therapy alongside standard drug therapy is highly relevant in systemic inflammation management.

Given the non-invasive nature and minimal side effects, laser acupuncture treatment (LAT) has emerged as a focus of interest in the management of musculoskeletal disorders, particularly RA[10,11]. Several clinical studies reported that LAT combined with routine care may reduce the Disease Activity Score in 28 joints (DAS28), as well as serum CRP level among patients with RA[12,13]. In contrast, a recent meta-analysis including 793 individuals with RA found small, non-significant decreases in CRP and DAS28 after combining LAT manner[10]. This inconsistency in the findings of previous studies may reflect methodological limitations related to the intervention effects, particularly in failure to account for within-participant correlation and maturation effects over time, which may compromise related conclusions[14].

A review of the existing literature indicates that most studies have focused on survival[15], disease prevalence[16], and patterns of healthcare resource utilization[17]. However, evidence regarding the long-term effects of add-on LAT in individuals with RA remains limited. To address these gaps, we conducted a quasi-experimental study that followed-up participants with RA over a prolonged time, and we compared changes in depressive symptoms, disease activity, and inflammatory indicator before and after LAT sessions by fitting the generalized estimating equations (GEE) model. Findings of this study may provide valuable insights that can enable healthcare providers design individualized healthcare intervention strategies for individuals living with RA.

MATERIALS AND METHODS

Design and participants

Participants who visited the rheumatology and immunology clinic at a teaching hospital between January and October 2024 were enrolled. Eligible individuals met the following criteria: (1) Aged 20 years or older; (2) No cognitive impairment that could interfere with effective communication; and (3) Having been diagnosed with RA for longer than three months, based on the American College of Rheumatology and the European League Against Rheumatism 2010 classification criteria[18,19]. We estimated the required sample size considering an effect size of 0.40, based on previous research evaluating differences in CRP levels between treated and untreated cohorts of acupuncture[13]. In addition, considering other psychometric parameters, including an α of 0.05 and power of 0.8, a minimum sample of 64 participants was estimated using G-POWER 3.1 analytical software (Franz Faul, Universität Kiel, Germany). The 64 patients were divided into two, with each group comprising 32 patients.

Procedure

A flowchart of participant recruitment is shown in Figure 1. Before the commencement of the study, each participant was required to complete a questionnaire covering socioeconomic details, prescription medications, and self-health management practices. Three time points were designated for the assessment of outcome indicators: (1) Baseline (T0); (2) 7 days after LAT completion (T1); and (3) 3 months after LAT completion (T2). Throughout the study period, all measures were performed by a single interviewer who was blinded to study group assignments. In addition, all enrollees were contacted by telephone a few days before the scheduled assessment to minimize the dropout rate. The study protocol was approved by the Institutional Review Board and Ethics Committee of the teaching hospital (No. B11204006) and was registered on ClinicalTrials.gov (NCT06791980).

Figure 1 Participant recruitment flowchart. RA: Rheumatoid arthritis; LAT: Laser acupuncture treatment; CRP: C-reactive protein; DAS28: Disease Activity Score in 28 joints; TDQ: Taiwanese Depression Questionnaire.

Intervention

All participants were informed that they could choose to receive either standard care alone or standard care in conjunction with LAT program. Those receiving standard care alone were considered the control group and received one-on-one routine health education lasting approximately 20 minutes during each medical visit. The routine health education comprised consultations regarding disease symptoms, related treatments, or the clinician’s prescriptions. Patients were encouraged to express any concerns or raise questions about their condition throughout the study period.

Apart from the standard care, participants in the experimental group further received the LAT program over a period of 3 months. Before the first LAT session, the researcher guided participants through a process intended to help them understand and internalize information about respective disease and draw meaningful inferences. Subsequently, the participants took part in an in-person clinical evaluation administrated by a certified Chinese medicine practitioner. This evaluation included a review of their medical history, physical assessments, tongue and pulse diagnostics, and consultations focused on specific symptoms. This physician was also responsible for administering LAT using low-power laser light energy (Physiolaser Olympic Basic, RJ Laser, Germany). All the LAT sessions were performed in a private room to avoid any interruptions. During the treatment procedure, Binao (LI14), Liangqiu (ST34), Zusanli (ST36), and Quchi (LI11) were selected as the key acupoints. The selection of acupuncture points was based on the traditional Chinese medicine theory of ‘Bi’ syndrome, which uses local and distal points on channels that traverse the affected area, particularly in the treatment of metabolic dysregulations and musculoskeletal diseases[20,21]. Since LAT does not physically penetrate the skin, the bleeding, bruising, or infection was virtually nonexistent during this study. All enrollees were required to receive one package of laser acupuncture, comprising at least six treatment sessions, 15 minutes per session, and spread over 3 months. Weekly telephone contact of the participants by the research group was also carried out on a case-by-case basis when participants failed to maintain scheduled appointments or for special needs arising after discharge home.

Primary outcome measures

Several outcomes of interest were considered, including Taiwanese Depression Questionnaire (TDQ), CRP, and DAS28. Indicator of depressive symptoms was assessed using the TDQ. This instrument was selected because it was specifically developed for use in Asian cultural contexts. The scale comprises 18 items, each assessing relevant symptoms that occurred during the past week, on a scale from 0 (absence of symptoms) to 3 (presence of symptoms almost every day)[22]. The total score, therefore, ranges from 0 to 54. Using the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) as the benchmark, previous studies identified the optimal TDQ cutoff point as 19, at sensitivity and specificity of 0.94 and 0.86, respectively[23]. This scale has been widely applied and has demonstrated acceptable psychometric properties among Taiwanese individuals with chronic diseases[24,25]. The CRP levels and DAS28 scores were extracted from patients’ electronic medical records using the measurement recorded closest to each study assessment time.

Definition of covariates

The covariates included demographic and clinical characteristics. Demographic information included age, sex, educational level, family history, and daily behavioral habits, such as smoking and exercise patterns. All data were collected through standardized interview questionnaires. Those who answered “currently” or “yes/past” to smoking were classified as smokers. Those who exercised three or more times per week were considered to have a regular exercise habit. Clinical features included chronic diseases (psychiatric disorders, lung diseases, renal diseases, or malignancies), RA duration, self-reported fatigue measured by Visual Analog Scale, body mass index, and disease-modifying antirheumatic drug (DMARD) prescriptions. Those who had received biological DMARD for more than 3 months after RA were regarded as DMARD users. All the clinical data were extracted from patients’ medical records.

Statistical analysis

Descriptive statistics were used to summarize participant characteristics, with continuous variables presented as means and SD, and categorical variables as n (%). Baseline characteristics were compared between groups using the independent t test and χ² test, as appropriate. In addition, intergroup differences across the three time points were examined using the GEE model, a statistical procedure that extends generalized linear models to longitudinal or other clustered response data[26]. In the current investigation, baseline heterogeneity, referring to the initial differences between the treated and untreated groups, as well as maturation effects, defined as endogenous changes over time, were addressed using the GEE framework. If the interaction between group and time achieves statistical significance, it signifies that the extent of changes over time between the intervention and control groups is relevant. The first-order autoregressive correlation (AR-1) is chosen as the working framework since it captures the correlation structure in time-series data by assigning exponentially decreasing weights to observations as they become more temporally distant[14]. All analyses were conducted using SAS statistical software, Version 9.4. A threshold of P < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics of the participants

The demographic and clinical characteristics of the study sample are presented in Table 1. During the study period, a total of 67 participants with RA were recruited, including 32 in the LAT group and 35 in the non-LAT group. The mean age of enrollees was 59.0 years. The majority of participants were female (80.6%), unemployed (64.2%), living with others (85.1%), and had a high level of education (64.2%). Most participants reported engaging in regular exercise (61.2%). Nearly 80% were non-smokers (76.1%). The mean duration of RA was 9.2 years ± 6.3 years. More than half of the participants had ever received biological agents (68.7%) and had metabolic comorbidities (50.7%). The mean baseline TDQ score was 16.1. Average values for body mass index, DAS28, CRP, and fatigue were 23.7, 3.6, 1.1, and 4.1, respectively (Table 1).

Table 1 Demographic and clinical characteristics of study participants by group (n = 67), mean ± SD.

Variables	All participants (n = 67)		Laser acupuncture (n = 32)		Non-laser acupuncture (n = 35)		P value
	n	%	n	%	n	%
Demographic data
Sex							0.45
Male	13	19.4	5	15.6	8	22.9
Female	54	80.6	27	84.4	27	77.1
Job							0.07
Employed	24	35.8	8	25.0	16	45.7
Unemployed	43	64.2	24	75.0	19	54.3
Educational level							0.46
< 9th grade	24	35.8	10	31.3	14	40.0
≥ 9th grade	43	64.2	22	68.8	21	60.0
Household status							0.59
Alone	10	14.9	4	12.5	6	17.1
Cohabiting	57	85.1	28	87.5	29	82.9
Regular exercising							0.43
No	26	38.8	14	43.8	12	34.3
Yes	41	61.2	18	56.2	23	65.7
Smoking habit							0.84
No	51	76.1	24	75.0	27	77.1
Yes	16	23.9	8	25.0	8	22.9
Age (years)	59.0 ± 12.1		56.7 ± 11.7		61.1 ± 12.0
Clinical characteristics
Use of biological agents							0.13
No	21	31.3	10	31.3	11	31.4
Yes	46	68.7	22	68.7	24	68.6
Metabolic disorders							0.91
No	33	49.3	16	50.0	17	48.6
Yes	34	50.7	16	50.0	18	51.4
Disease duration	9.2 ± 6.3		9.5 ± 7.7		8.6 ± 5.4		0.65
DAS28	3.6 ± 1.5		4.1 ± 1.6		3.1 ± 1.3		0.07
CRP	1.1 ± 1.6		1.9 ± 2.3		0.3 ± 0.4		0.01
TDQ	16.1 ± 7.9		16.6 ± 8.2		15.7 ± 7.9		0.66
Fatigue	4.1 ± 2.5		5.0 ± 2.5		3.2 ± 2.8		0.01
BMI	23.7 ± 3.4		24.0 ± 0.6		23.5 ± 3.5		0.56

CRP: C-reactive protein; DAS28: Disease Activity Score in 28 joints; TDQ: Taiwanese Depression Questionnaire; BMI: Body mass index.

Comparisons of TDQ, DAS28, and CRP levels between the two groups

Table 2 presents the GEE analysis of the long-term efficacy of LAT. For depressive symptoms, no significant baseline difference in TDQ scores was observed between the two groups (P = 0.65). However, the GEE model showed a difference between them at T2, suggesting that a maturation effect may have occurred regardless of LAT use. After adjustment for the maturation effect over time, the combined LAT was significantly associated with reduced TDQ scores for the participants with RA during the study period, yielding differences of β = -1.24 (T1) and β = -9.34 (T2) (Figure 2A). Regarding the change of DAS28 score, the GEE framework showed comparable baseline DAS28 scores between the two groups (P = 0.06). However, the DAS28 score at T2 differed significantly from that at T0, indicating that a maturation effect may have influenced the association between LAT and DAS28. After adjustment for the maturation effect, the mean DAS28 scores in the treated group were significantly lower than those in the untreated group at both T1 and T2, with β = -0.73 and β = -1.05, respectively (Figure 2B).

Figure 2 Taiwanese Depression Questionnaire score, Disease Activity Score in 28 jointslevel, C-reactive protein level of patients in the treated and untreated groups. A: Taiwanese Depression Questionnaire score; B: Disease Activity Score in 28 jointslevel; C: C-reactive protein level. LAT: Laser acupuncture treatment; CRP: C-reactive protein; DAS28: Disease Activity Score in 28 joints; TDQ: Taiwanese Depression Questionnaire.

Table 2 Generalized estimating equations model of the effects of laser acupuncture treatment in individuals with rheumatoid arthritis (n = 67).

Variables	TDQ		DAS28		CRP
	Regression coefficient	P value	Regression coefficient	P value	Regression coefficient	P value
Intercept	15.67	< 0.001	3.142	< 0.001	0.37	< 0.001
Group 1 vs group 0	0.88	0.65	0.66	0.06	0.69	0.04
T1 vs T0	-0.91	0.08	-0.33	0.08	0.10	0.24
T2 vs T0	-4.21	0.03	-0.52	0.04	0.23	0.13
Interaction of T1 and group	-1.24	0.83	-0.73	0.006	-0.53	0.06
Interaction of T2 and group	-9.34	< 0.001	-1.05	0.001	-0.74	0.03

T0: Before laser acupuncture treatment (LAT) initiation; T1: 7 days after LAT initiation; T2: 3 months after LAT completion. The T1 × group interaction represents the difference between the treated and untreated groups from T0 to T1. The T2 × group interaction represents the difference between the treated and untreated groups from T0 to T2. CRP: C-reactive protein; DAS28: Disease Activity Score in 28 joints; TDQ: Taiwanese Depression Questionnaire.

For CRP concentration, the GEE analysis indicated a baseline difference between the two groups (P = 0.04). In addition, CRP levels at T1 and T2 were comparable to those measured at T0, suggesting that a maturation effect might have been absent. After accounting for the baseline difference, the decline in CRP levels was more pronounced in the LAT group than in the non-LAT group, particularly at T2 (β = -0.74, P = 0.03; Figure 2C).

DISCUSSION

Few studies, if any, have explored the long-term efficacy of combined LAT in individuals with RA. In this study, we found that adding LAT into routine care provided greater benefits for participants with RA, particularly in reducing depressive symptoms, disease activity, and inflammatory response. Importantly, the GEE statistical model was further adjusted for participants’ baseline characteristics and the temporal maturation effect, allowing for a rigorous evaluation of LAT’s impact.

Similar to prior evidence[27], the addition of LAT to routine care significantly reduced depressive symptoms at 3 months after the intervention, even though a maturation effect was apparent in the untreated group. Several explanations may account for this. It is well recognized that the overactive hypothalamus-pituitary-adrenal axis, a key element in responding to external stress, can be induced by the flare-up of peripheral inflammatory cytokines[28]. Both animal models and human experiments have shown that acupuncture can markedly inhibit the levels of inflammatory mediators through downregulation of the toll-like receptor 4/nuclear factor-kappa B pathway[29]. Aberrant activation of this signaling pathway would initiate the upregulation of downstream effector molecules, such as tumor necrosis factor-α, interleukin (IL)-1β and IL-6, all of which are deeply involved in the pathogenesis of depression[28,30]. Coincidentally, acupuncture has also been found to remodel neuronal structure and regulate neuronal and synaptic plasticity, stimulating the expression of brain-derived neurotrophic factor[29], a key protein related to neural repair and cognitive function[28]. Substantiated as a viable treatment for various neuroinflammation diseases, LAT remedy has also demonstrated a significant role in activating the brain-derived neurotrophic factor/TrkB signaling pathway, which in turn reduces neuronal apoptosis, and promotes neurogenesis to improve cognitive function, thereby lessening risk of depression[31].

In the group receiving the 3-month LAT intervention, the levels of CRP and DAS28 scores decreased markedly compared to measures in those who did not receive LAT. This finding is consistent with current research indicating that acupuncture therapy may serve as an effective complementary treatment for individuals with RA[12,13]. In rheumatology, CRP is incorporated into composite disease activity measures such as DAS28, which integrates tender and swollen joint counts (out of 28 specified joints), the patient’s global health assessment, and an acute-phase reactant (either erythrocyte sedimentation rate or CRP)[32]. In addition to alleviating localized inflammatory responses, adding acupuncture into usual care has been shown to improve joint range of motion by stimulating microcirculation and accelerating tissue repair, supported by evidence from randomized controlled trials[33]. Furthermore, after administering manual acupuncture at ST36 for 30 minutes per day over a 3-week period, it was observed that depressed rats experienced less inflammatory pain and foot swelling than untreated controls. This may have occurred through increased gene expression of tissue repair growth factors such as paternally expressed gene-3, growth/differentiation factor 5, and fibroblast growth factor 5, as well as increased expression of the anti-inflammatory cytokine IL-10[34]. These mechanisms may explain how LAT works in reducing CRP and DAS28 in patients with RA. However, this finding contrasts with those of some reports[10], which may reflect differences in study design, population characteristics, or disease severity. Of particular importance, the type of statistical analyses conducted may also explain the difference. Previous studies mainly relied on univariate analyses to determine pre-post acupuncture treatment variations rather than adopting more rigorous multivariate models to adjust for potential confounders, particularly maturation effect over time, thereby limiting accurate evaluation of intervention efficacy[14,26].

Despite promising findings, this study has some drawbacks that should be acknowledged. First, the present analysis relied on samples from a single hospital. Although many studies draw conclusions from nonrandom selection, the possibility of a non-representative sample may have potentially limited the generalizability of the findings. Accordingly, conducting similar studies in different demographic and geographic populations would be essential. Second, the application of a quasi-experimental study design instead of a randomized clinical trial may have compromised the study’s internal validity because of potential confounding variables, such as subjective symptoms or other clinical markers. Against this backdrop, we conducted GEE analysis to adjust for initial differences between the two groups and possible maturation effect, which may have minimized the potential of an inflated type I error[14]. Meanwhile, we carried out a sensitivity analysis using propensity score matching approach to reduce any imbalance between the two selected groups. For each RA patient who received LAT, one control patient without LAT was selected by 1:1 matching, based on a propensity score. The propensity score was calculated using logistic regression on the basis of patients’ demographics and baseline comorbidities at enrollment. Results of the re-analyses indicated that the protective effect of LAT was somewhat attenuated but remained statistically significant. For example, at T2, the reduction in depressive symptoms, DAS28 scores, and CRP levels were -6.28, -1.01, and -0.66, respectively. Nonetheless, further investigations involving larger groups of individuals with RA using randomized trials are still required to substantiate the finding of clinical benefits of LAT, particularly in terms of changes in clinical markers and pain level. Third, awareness of participation in the experimental group may have led some enrollees to alter their behavior, a phenomenon known as the Hawthorne effect, which may in turn have biased the internal validity of the results[35]. Consequently, implementing a paired random sampling strategy, employing a double-blind design, and extending the duration of follow-up would be beneficial to reduce the influence of the Hawthorne effect.

CONCLUSION

This study adds to the growing body of evidence on the benefits of integrating LAT into routine care for individuals with RA. Importantly, after fitting the GEE model, the present study confirmed that participants who received the adjunctive 3-month LAT program after RA onset showed improvements in distressing symptoms, disease activity, and inflammatory response. Long-term follow-up measurements of these outcomes further provided high-quality evidence for clinical decision-making pertaining to the practicability of LAT for the treatment of RA. Thus, this study ushered in a new era of taking a two-pronged approach to combating the elevated expression of inflammatory parameter and distressing symptoms caused by RA. In terms of clinical practice, we recommend that rheumatologist should pay closer attention on the potential dysregulated immune responses and psychological disturbance that accompanied the progression of RA. Importantly, the current study calls for urgent need to establish collaborative and tailored healthcare approaches for individuals with RA to more effectively manage extra-articular manifestations.

ACKNOWLEDGEMENTS

We thank the co-investigators in this project and the patients who responded to our survey.