Prevalence and Risk of Immunostimulatory Herbal Supplement Treatment Among Autoimmune Dermatology Patients

Abstract

Objective

We assess the prevalence and patterns of herbal supplement treatment among patients with autoimmune skin diseases, particularly dermatomyositis (DM) and cutaneous lupus erythematosus (CLE), and identify commonly taken supplements and their associated risks.

Methods

This study screened 673 adult patients with clinicopathologic evidence of DM or CLE at the University of Pennsylvania's rheumatologic‐dermatology clinic between January 2007 and February 2024. Demographic data, disease characteristics, and detailed information on herbal supplement treatment were collected. Predictors of supplement treatment were analyzed using chi‐square tests and reported as odds ratios.

Results

The prevalence of herbal supplement treatment was 32% among the cohort. The relative frequency of herbal supplement treatment was significantly higher in younger patients (44% of patients ages 18–29 years, reference; 29% ages 50–64 years, P = 0.02; 23% ages ≥65 years, P = 0.003) and in Hispanic/Latino patients (58% vs 31% White, P = 0.009). No significant difference in herbal supplement treatment was seen by sex (33% of female participants, 29% of male participants, P = 0.49), race (31% White, P = reference; 31% Black, P = 1.0; 38% Asian, P = 0.55), or disease (30% of patients with DM, 36% of patients with CLE; P = 0.12). Among patients with DM, 31% experienced a disease onset or exacerbation after supplement treatment compared with 10% of patients with CLE. Elderberry treatment was associated with the highest risk of exacerbation in both disease cohorts (62% DM, 50% CLE).

Conclusion

Herbal supplement treatment is prevalent among patients with autoimmune skin diseases, with immunostimulatory supplements posing a significant risk for immune dysregulation, particularly in DM. Providers should proactively screen and counsel patients regarding treatment with these supplements.

INTRODUCTION

In recent decades, complementary and alternative medicine (CAM) has seen a marked increase in popularity within the United States. Notably, the year 2020 marked a period of significant growth for the industry, with herbal supplement sales reaching an unprecedented $11.3 billion—a record 17% jump from the year prior. This spike has been largely attributed to the public's heightened health concerns amid the COVID‐19 pandemic, as herbal products marketed for immune support became especially sought after. ¹ , ²

SIGNIFICANCE & INNOVATIONS.

• More than one‐third of patients with dermatomyositis and cutaneous lupus erythematosus take immunostimulatory herbal supplements.

• Herbal supplement treatment was more common among younger age cohorts and Hispanic/Latino patients.

• Of the supplements taken by our patients, elderberry and spirulina carried the highest risk of disease onset or exacerbation.

• Immunostimulatory herbal supplements carry an inherent risk of immune dysregulation for patients with a personal or family history of autoimmune disease and should therefore be avoided in these patients.

The increase in prevalence of these supplements raises important questions about the evidence basis for their use. Historically, various forms of CAM, especially herbal supplements, have been widely used for centuries despite limited evidence in support of their safety and efficacy and a lack of Food and Drug Administration regulation. ² , ³ Moreover, there is growing evidence suggesting they may even be harmful for those with autoimmune conditions.

In recent years, several case reports have been published linking autoimmune disease onset or exacerbation to treatment with immunostimulatory herbal supplements, suggesting that they may act as a trigger for the disease process. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ The biologic plausibility of such effects has been supported by in vitro studies, namely, those demonstrating spirulina's potent stimulation of the toll‐like receptor 4 (TLR4) pathway—a critical mediator of inflammation—in the blood of patients with dermatomyositis (DM), more so than in healthy controls. ⁹

Despite the associated risk, prior data from our group suggest a paradoxically high prevalence of herbal supplement treatment among patients with DM compared with that of healthy controls. ⁴ These findings align with the results of a 2015 national consumer survey indicating heightened herbal supplement treatment among individuals with chronic medical conditions in contrast to the general population. ¹⁰ This high prevalence of treatment despite the known associated risks raises the question about specific motivations driving individuals to incorporate herbal supplements into their health regimens.

To explore patients’ rationale, a focus group was conducted in Germany, which identified common motivating factors such as dissatisfaction with conventional treatments, perceived benefits of herbal supplements, and cultural or family traditions. Notably, their findings highlighted that individuals with concern about their overall health status and a desire for self‐sufficiency were more inclined to take herbal supplements. ¹¹ This hints at the potential role of these supplements in the self‐management strategies of individuals with chronic diseases as a means to assert autonomy over their health. ¹⁰

The broader implications of these findings have yet to be fully understood. Given the continued surge in CAM treatment and the reported adverse outcomes associated with herbal supplement intake in the context of autoimmune diseases, there is a clear need to closely examine the relationship. Our study will contribute to a better understanding of the frequency and characteristics of herbal supplement treatment among adult patients with autoimmune skin diseases. Additionally, we aim to characterize the most used supplements and discern those that may present increased risks. By identifying the factors associated with herbal supplement treatment, we can begin to outline the risks and inform more effective screening and counseling strategies for this patient population.

PATIENTS AND METHODS

All patients with clinical or pathologic evidence of DM or cutaneous lupus erythematosus (CLE) seen in the principal investigator's clinic between January 2007 and February 2024 were invited to participate in the University of Pennsylvania's prospective longitudinal database studies for their respective diseases. Institutional review board (IRB) approval was obtained for the lupus and DM database studies (University of Pennsylvania IRB 805758 and 808230, respectively). Patients aged 18 or older were enrolled after signing IRB‐approved informed consent.

Clinical and demographic data collected included age, sex, race, ethnicity, disease onset date, disease flares, and herbal supplement treatment. Sex and race were self‐reported, and clinical information was collected by medical record chart review.

Patients were systematically surveyed about herbal supplement treatment in a stepwise manner to minimize recall bias. They were first asked about any herbal supplement treatment and were then given a handout listing common herbal supplements known to have immunostimulatory properties. Supplements specifically screened included spirulina, elderberry, ashwagandha, echinacea, chlorella, and alfalfa. Additional patient‐reported supplement treatment was categorized as “other.” Patient responses were recorded in their chart, including the type, frequency, and duration of herbal supplement treatment when available. Inclusion criteria were limited to patients systematically screened for herbal supplement treatment.

The impact of herbal supplement treatment was determined by retrospective chart review. A flare was defined by chart documentation of new or worsening skin lesions for both patients with CLE and those with DM and/or new or worsening muscle symptoms for patients with DM. Skin flares were determined by subjective patient report and objective exacerbation on physical examination. Muscle flares were determined by subjective patient report plus physical examination findings of increased weakness with or without laboratory findings indicative of muscle involvement. Temporal associations were drawn if there was chart documentation of patient‐reported flare and clinical or pathologic evidence of disease onset or flare after herbal supplement treatment, grouped as “exacerbation” for analysis. The association was considered unclear if other factors contributed to the disease exacerbation, such as medication discontinuation or excess sun exposure. No associations were drawn if the timing of herbal supplement treatment was unavailable. Supplements were considered to have no effect if patients’ disease remained stable after their treatment.

The primary objective was to characterize herbal supplement treatment among patients with DM and CLE, including identifying commonly used supplements and demographic features more prone to herbal supplement treatment. Our secondary objective was to identify herbal supplements that may pose a risk to those with autoimmune skin disease.

Demographics were analyzed with descriptive statistics. The frequency of supplement use was compared across demographics and disease types using chi‐square tests. Results were reported as odds ratios (ORs) with a significance level of 0.05.

RESULTS

Demographics

Six hundred seventy‐three patients were systematically screened for herbal supplement use and were included in the analysis. Of these patients, 379 (56%) had a diagnosis of DM and 294 (44%) of CLE. Our cohort had a mean ± SD age of 49 ± 15 years and was predominantly female (n = 576, 86%). A majority of patients were White (70%), followed by Black (21%), Asian (4%), Hispanic (4%), and unknown (1%) (Table 1).

Table 1.

Demographics and frequency of herbal supplement treatment^*

Demographics	Total, n (%)	Herbal supplement treatment, n (%)		P‐value
		Yes	No
Mean age ± SD, y	49 ± 15	46 ± 15	51 ± 15	0.0002
18–29	85 (13)	37 (44)	48 (56)	ref
30–49	240 (36)	87 (36)	153 (64)	0.29
50–64	234 (35)	68 (29)	166 (71)	0.02
65+	114 (17)	26 (23)	88 (77)	0.003
Sex
Female	576 (86)	190 (33)	386 (67)	0.49
Male	97 (14)	28 (29)	69 (71)
Race and ethnicity
White	471 (70)	145 (31)	326 (69)	ref
Black	142 (21)	44 (31)	98 (69)	1.0
Asian	26 (4)	10 (38)	16 (62)	0.55
Hispanic	24 (4)	14 (58)	10 (42)	0.009
Unknown	10 (1)	5 (50)	5 (50)	0.34
Disease
Dermatomyositis	379 (56)	113 (30)	266 (70)	0.12
CLE	294 (44)	105 (36)	189 (64)

^*Significant values, defined as P < 0.05, are listed in bold. CLE, cutaneous lupus erythematosus; ref, reference.

Prevalence of herbal supplement treatment

The overall prevalence of herbal supplement treatment within our cohort was 32%. Herbal supplement treatment differed significantly by age and ethnicity. Those who reported herbal supplement use were younger on average than those who did not (mean ± SD age 46 ± 15 years vs 51 ± 15 years, P = 0.0002). Specifically, the prevalence decreased with increasing age cohorts. The highest frequency of treatment was 42% among patients ages 18 to 29 years (P = reference), followed by 36% of patients ages 30 to 49 years (P = 0.29), 29% of patients ages 50 to 64 years (P = 0.02), and 23% of patients 65 years and older (P = 0.003). Compared with non‐Hispanic White patients, Hispanic patients reported a higher frequency of herbal supplement treatment (30% White vs 58% Hispanic, P = 0.007). Otherwise, no significant racial differences were noted, with 31% of Black patients, 38% of Asian patients, and 50% of other racial groups reporting herbal supplement treatment (all P > 0.05, Table 1).

Herbal supplement treatment did not significantly differ between patients with DM and those with CLE (30% vs 36%, P = 0.12; Table 1). However, among those taking herbal supplements, immunostimulatory supplement treatment was more frequently seen in patients with DM (Table 2). Particularly, patients with DM were 2.35 times more likely to report taking spirulina compared with patients with CLE (P = 0.02). Treatment with other immunostimulatory supplements such as elderberry (OR 2.11), ashwagandha (OR 2.13), and alfalfa (OR 2.74) were also more frequent among patients with DM, although not statistically significant (P > 0.05). Overall, the most frequently occurring immunostimulatory herbal supplements were spirulina (n = 47) and elderberry (n = 19). Less commonly used supplements included ashwagandha, echinacea, chlorella, and alfalfa.

Table 2.

Relative frequency and impact of supplement use by disease type^*

Supplement		DM (n = 113)	CLE (n = 105)	OR (P‐value) a , b
Total, n (%)
	Exacerbation	35 (31)	10 (10)	4.19 (0.0002)
Spirulina
	Treated	32 (28)	15 (14)	2.35 (0.02)
	Exacerbation	15 (47)	3 (20)	3.34 (0.15)
Elderberry
	Treated	13 (12)	6 (6)	2.11 (0.20)
	Exacerbation	8 (62)	3 (50)	NA
Ashwagandha
	Treated	9 (8)	4 (4)	2.13 (0.33)
	Exacerbation	2 (22)	1 (25)	NA
Echinacea
	Treated	7 (6)	6 (6)	1.12 (1.0)
	Exacerbation	1 (17)	1 (20)	NA
Chlorella
	Treated	6 (5)	5 (5)	1.09 (1.0)
	Exacerbation	2 (29)	1 (17)	NA
Alfalfa
	Treated	6 (5)	2 (2)	2.74 (0.33)
	Exacerbation	1 (17)	0 (0)	NA
Other
	Treated	78 (69)	92 (88)	0.32 (0.002)
	Exacerbation	20 (26)	7 (8)	4.10 (0.003)

^*Bold indicates significant values, defined by P < 0.05. CLE, cutaneous lupus erythematosus; DM, dermatomyositis; OR, odds ratio.

^a ORs of supplement treatment in patients with DM compared with patients with CLE (reference).

^b NA indicates no statistical comparison due to small sample size.

Impact of supplement treatment

In terms of the overall impact of supplement treatment, patients with DM were 4.19 times more likely to experience a disease exacerbation after supplement treatment compared with patients with CLE (OR 4.10, P = 0.0002, Table 2). Among those taking herbal supplements, 31% of patients with DM experienced either a disease flare (n = 14, 12%) or new‐onset disease (n = 21, 19%) after supplement treatment compared with 10% of patients with CLE (n = 8, 8% flare; n = 2, 2% new onset). Of the 23 patients with new‐onset disease after herbal supplement treatment, 14 (66%) had a personal or family history of autoimmune disease.

The supplement associated with the highest risk of disease exacerbation for both patients with DM and those with CLE was elderberry, which resulted in disease exacerbation in 62% and 50% of participants, respectively (Figure 1). Among patients with DM, a high frequency of disease exacerbation was observed after treatment with all other immunostimulatory herbal supplements, ranging from 17% to 47%, with particularly high risk from spirulina (47%). In contrast, patients with CLE experienced fewer adverse outcomes, ranging from 8% to 25%, with none reported after alfalfa treatment.

Figure 1.

Adverse outcomes of herbal supplement treatment by disease type.

In addition to the supplements that we screened for, other patient‐reported herbal supplements that resulted in adverse outcomes included herbal teas, moringa, Zyflamend, unspecified immune‐boosting supplements, green drinks, and protein powders. Turmeric was the most common patient‐reported herbal supplement taken (total n = 17; DM = 7, CLE = 10). Interestingly, no adverse outcomes were observed with its use, and one patient with DM noted an improvement in symptoms after use. However, the lack of systematic screening for these supplements precludes any associations from being drawn.

Patient perceptions on the impact of herbal supplement treatment varied. Many patients reported taking immunostimulatory herbal supplements because of the misconception that immune support might benefit their autoimmune condition. Others took these supplements because of concern for infections in the setting of taking immunosuppressant medication for their condition, and some were hoping to boost their overall health. Although few patients independently perceived their supplement intake as inducing their disease flare, all patients were receptive to education on the risks associated with immunostimulatory herbal supplements and discontinued their use.

DISCUSSION

The findings of our study underscore the significant integration of herbal supplements into the regimens of patients with autoimmune skin diseases, paralleling the national surge after the COVID‐19 pandemic. Our findings align with prior studies demonstrating high rates of CAM treatment in autoimmune populations despite the associated risks. ⁴ The appeal of these supplements, particularly among Hispanic/Latino and younger patient demographics, can be linked to cultural practices and the robust marketing strategies that target these populations. ¹¹ The higher treatment rates in these subgroups suggest a need for culturally sensitive educational initiatives that address the specific beliefs and practices related to CAM.

Immunostimulatory supplements, known for their purported immune‐boosting properties among the general population, pose a risk for patients with autoimmune diseases. The exacerbation rates among patients with DM after supplement treatment in our cohort are concerning, particularly with supplements such as elderberry and spirulina. Although weak evidence suggests that these supplements may be mildly beneficial in the context of viral illness, these immunostimulatory properties are also the likely mechanism by which they can exacerbate autoimmune disease. ¹²

The TLR4 pathway activation by spirulina in patients with DM could serve as a model for understanding how these supplements contribute to disease flares. In vitro studies revealed that spirulina‐treated peripheral blood mononuclear cells (PBMCs) from patients with DM resulted in much higher production of immunostimulatory cytokines than in healthy PBMCs treated the same way. ⁹ A similar differential response was observed in DM PBMCs after treatment with another popular herb‐based weight loss supplement, IsaLean. ⁷ In both, pathogenic cytokines were secreted in disproportionately higher levels in DM PBMCs compared with healthy control cells, and their secretion was suppressed after the addition of anti‐TLR4. TLR4 is a critical mediator of innate immune responses, and its overactivation can lead to a cascade of inflammatory cytokines that exacerbate autoimmune pathology. The disproportionate inflammatory response to spirulina and IsaLean seen in DM could reflect an inherent dysregulation of innate immune responses in this condition that is exacerbated by such supplements.

Elderberry is similarly known for its immunomodulating properties, mainly through its rich flavonoid content. Flavonoids can stimulate immune cells and promote cytokine production, which, in the context of autoimmune diseases, could potentially heighten immune dysregulation. In vitro studies have demonstrated that elderberry stimulates monocyte production of the inflammatory cytokines interleukin‐1b (IL‐1b), tumor necrosis factor alpha, IL‐6, and IL‐8 up to 45‐fold that of lipopolysaccharide. ¹³ Given elderberry's mechanistic link to spirulina and IsaLean, it is plausible to infer a similar pathway in the exacerbation of DM, although in vitro studies would be needed to confirm this.

Studies have shown that patients often turn to these alternatives because of dissatisfaction with conventional treatments, underscoring the need for providers to proactively inquire about CAM treatment, specifically screening for these immunostimulatory herbal supplements, as part of routine clinical assessments. It is crucial to provide patients with evidence‐based guidance on the potential risks of these supplements, balancing their autonomy and cultural preferences with medical safety.

Our study is not without limitations. The retrospective nature of disease exacerbation data and reliance on self‐reporting can introduce recall bias, and our cohort, being derived from a single center, may limit generalizability. Longitudinal case‐control studies with larger, diverse populations are needed to better understand the causal relationships and long‐term effects of herbal supplement treatment in autoimmune disease.

Future research should focus on elucidating the mechanisms by which these supplements influence disease activity. Moreover, as the interest in CAM continues to grow and expand, clinical trials assessing the safety and efficacy of commonly used supplements could inform guidance. In summary, given widespread treatment with herbal supplements and the inherent risk of immune dysregulation, it is imperative for the medical community to understand and manage their treatment in vulnerable populations.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Werth confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Helsinki Declaration requirements.

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