Original Research

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

More than 50 million US adults report experiencing chronic pain, with nearly 7% experiencing high-impact chronic pain.^1-3 Chronic pain negatively affects daily function, results in lost productivity, is a leading cause of disability, and is more prevalent among veterans compared with the general population.^1,2,4-6 Estimates from 2021 suggest the prevalence of chronic pain among veterans exceeds 30%; > 11% experienced high-impact chronic pain.¹

Primary care practitioners (PCPs) have a prominent role in chronic pain management. Pharmacologic options for treating pain, once a mainstay of therapy, present several challenges for patients and PCPs, including drug-drug interactions and adverse effects.⁷ The US opioid epidemic and shift to a biopsychosocial model of chronic pain care have increased emphasis on nonpharmacologic treatment options.^8,9 These include integrative modalities, which incorporate conventional approaches with an array of complementary health approaches.^10-12

Integrative therapy is a prominent feature in whole person care, which may be best exemplified by the US Department of Veterans Affairs (VA) Whole Health System of care.^13-14 Whole health empowers an individual to take charge of their health and well-being so they can “live their life to the fullest.”¹⁴ As implemented in the Veterans Health Administration (VHA), whole health includes the use of evidence-based complementary and integrative therapies, encompassing a multimodal pain management approach. Expanding the use of these therapies requires a better understanding of PCP and patient knowledge, interest, and use of integrative modalities for chronic pain.

METHODS

Using a cross-sectional survey design, PCPs and patients with chronic back pain affiliated with the VA Ann Arbor Healthcare System were invited to participate in separate but similar surveys to assess knowledge, interest, and use of nonpharmacologic integrative modalities for the treatment of chronic pain. In May, June, and July 2023, 78 PCPs received 3 email invitations to participate in an electronic (Qualtrics) survey. Patients were identified based on having an International Statistical Classification of Diseases, Tenth Revision code for low back pain (M54.5, M54.40, 41, 42, M54.89) on ≥ 2 outpatient encounters within 18 months (April 1, 2021, to March 31, 2023). A random sample of 200 patients was selected and sent a packet in September 2023 that included an introductory letter and a paper survey, along with a website link and QR code to complete the survey electronically if preferred. The introductory letter stated that participation is voluntary, had no impact on the health care currently received at the VA, and names are not attached to the survey, allowing them to remain anonymous. The packet also included a $10 gift card to encourage survey completion.

Both survey instruments are available upon request, were developed by the study team, and included a mix of yes/no questions, “select all that apply” items, Likert scale response items, and open-ended questions. For one question about which modalities they would like available, the respondent was instructed to select up to 5 modalities. The instruments were extensively pretested by members of the study team, which included 2 PCPs and a nonveteran with chronic back pain.

The list of integrative modalities included in the survey was derived from the tier 1 and tier 2 complementary and integrative health modalities identified in a VHA Directive on complementary and integrative health.^15,16 Tier 1 approaches are considered to have sufficient evidence and must be made available to veterans either within a VA medical facility or in the community. Tier 2 approaches are generally considered safe and may be made available but do not have sufficient evidence to mandate their provision. For participant ease, the integrative modalities were divided into 5 subgroups: manual therapies, energy/biofield therapies, mental health therapies, nutrition counseling, and movement therapies. The clinician survey assessed clinicians’ training and interest, clinical and personal use, and perceived barriers to providing integrative modalities for chronic pain. Professional and personal demographic data were also collected. Similarly, the patient survey assessed use of integrative therapies, perceptions of and interest in integrative modalities, and potential barriers to use. Demographic and health-related information was also collected.

Data analysis included descriptive statistics (eg, frequency counts, means, medians) and visual graphic displays. Separate analyses were conducted for clinicians and patients in addition to a comparative analysis of the use and potential interest in integrative modalities. Analysis were conducted using R software. This study was deemed nonresearch quality improvement by the VA Ann Arbor Healthcare System facility research oversight board and institutional review board approval was not solicited.

RESULTS

Twenty-eight clinicians completed the survey, yielding a participation rate of 36%. Participating clinicians had a median (IQR) age of 48 years (9.5), 15 self-identified as White (54%), 8 as Asian (29%), 15 as female (54%), 26 as non-Hispanic (93%), and 25 were medical doctors or doctors of osteopathy (89%). Nineteen (68%) worked at the main hospital outpatient clinic, and 9 practiced at community-based outpatient clinics (CBOCs). Thirteen respondents (46%) reported having no formal education or training in integrative approaches. Among those with prior training, 8 clinicians had nutrition counseling (29%) and 7 had psychologic therapy training (25%). Thirteen respondents (46%) also reported using integrative modalities for personal health needs: 8 used psychological therapies, 8 used movement therapies, 10 used integrative modalities for stress management or relaxation, and 8 used them for physical symptoms (Table 1).

Overall, 85 of 200 patients (43%) responded to the study survey. Two patients indicated they did not have chronic back pain and were excluded. Patients had a median (IQR) age of 66 (20) years, with 66 self-identifying as White (80%), 69 as male (83%), and 66 as non-Hispanic (80%). Forty-four patients (53%) received care at CBOCs. Forty-seven patients reported excellent, very good, or good overall health (57%), while 53 reported excellent, very good, or good mental health (64%). Fifty-nine patients reported back pain duration > 5 years (71%), and 67 (81%) indicated experiencing back pain flare-ups at least once per week over the previous 12 months. Sixty patients (72%) indicated they were somewhat or very interested in using integrative therapies as a back pain treatment; however, 40 patients (48%) indicated they had not received information about these therapies. Among those who indicated they had received information, the most frequently reported source was their PCP (41%). Most patients (72%) also reported feeling somewhat to very comfortable discussing integrative medicine therapies with their PCP.

Integrative Therapy Recommendations and Use

PCPs reported recommending multiple integrative modalities: 23 (82%) recommended cognitive-behavioral therapy, 22 (79%) recommended acupuncture, 21 (75%) recommended chiropractic, 19 (68%) recommended battlefield acupuncture, recommended massage 18 (64%), 17 (61%) recommended meditation or mindfulness, and 15 (54%) recommended movement therapies such as yoga or tai chi/qigong (Figure 1). The only therapies used by at least half of the patients were chiropractic used by 59 patients (71%) and acupuncture by 42 patients (51%). Thirty-eight patients (46%) reported massage use and 21 patients (25%) used cognitive-behavioral therapy (Table 2).

Integrative Therapies Desired

A majority of PCPs identified acupuncture (n = 20, 71%), chiropractic (n = 19, 68%), and massage (n = 19, 68%) as therapies they would most like to have available for patients with chronic pain (Figure 2). Similarly, patients identified massage (n = 42, 51%), chiropractic (n = 34, 41%), and acupuncture (n = 27, 33%) as most desired. Seventeen patients (21%) expressed interest in movement therapies.

Barriers to Integrative Therapies Use

When asked about barriers to use, 26 PCPs (93%) identified access to services as a somewhat or extremely likely barrier, and 22 identified time constraints (79%) (Table 3). However, 17 PCPs (61%) noted lack of familiarity, and 18 (64%) noted a lack of scientific evidence as barriers to recommending integrative modalities. Among patients, 33 (40%) indicated not knowing what services were available at their facility as a barrier, 32 (39%) were not familiar with specific therapies, and 21 (25%) indicated a lack of clarity about the benefits of a specific therapy. Only 14 patients (17%) indicated that there were no obstacles to use.

DISCUSSION

Use of integrative therapies, including complementary treatments, is an increasingly important part of chronic pain management. This survey study suggests VA PCPs are willing to recommend integrative therapies and patients with chronic back pain both desire and use several therapies. Moreover, both groups expressed interest in greater availability of similar therapies. The results also highlight key barriers, such as knowledge gaps, that should be addressed to increase the uptake of integrative modalities for managing chronic pain.

An increasing number of US adults are using complementary health approaches, an important component of integrative therapy.¹² This trend includes an increase in use for pain management, from 42.3% in 2002 to 49.2% in 2022; chiropractic care, acupuncture, and massage were most frequently used.¹² Similarly, chiropractic, acupuncture and massage were most often used by this sample of veterans with chronic back pain and were identified by the highest percentages of PCPs and patients as the therapies they would most like available.

There were areas where the opinions of patients and clinicians differed. As has been seen previously reported, clinicians largely recommended cognitive-behavioral therapy while patients showed less interest.¹⁷ Additionally, while patients expressed interest in the availability of movement therapies, such as yoga, PCPs expressed more interest in other strategies, such as trigger point injections. These differences may reflect true preference or a tendency for clinicians and patients to select therapies with which they are more familiar. Additional research is needed to better understand the acceptability and potential use of integrative health treatments across a broad array of therapeutic options.

Despite VHA policy requiring facilities to provide certain complementary and integrative health modalities, almost all PCPs identified access to services as a major obstacle.¹⁵ Based on evidence and a rigorous vetting process, services currently required on-site, via telehealth, or through community partners include acupuncture and battlefield acupuncture (battlefield auricular acupuncture), biofeedback, clinical hypnosis, guided imagery, medical massage therapy, medication, tai chi/qigong, and yoga. Optional approaches, which may be made available to veterans, include chiropractic and healing touch. Outside the VHA, some states have introduced or enacted legislation mandating insurance coverage of nonpharmacological pain treatments.¹⁸ However, these requirements and mandates do not help address challenges such as the availability of trained/qualified practitioners.^19,20 Ensuring access to complementary and integrative health treatments requires a more concerted effort to ensure that supply meets demand. It is also important to acknowledge the budgetary and physical space constraints that further limit access to services. Although expansion and integration of integrative medicine services remain a priority within the VA Whole Health program, implementation is contingent on available financial and infrastructure resources.

Time was also identified by PCPs as a barrier to recommending integrative therapies to patients. Developing and implementing time-efficient communication strategies for patient education such as concise talking points and informational handouts could help address this barrier. Furthermore, leveraging existing programs and engaging the entire health care team in patient education and referral could help increase integrative and complementary therapy uptake and use.

Although access and time were identified as major barriers, these findings also suggest that PCP and patient knowledge are another target area for enhancing the use of complementary and integrative therapies. Like prior research, most clinicians identified a lack of familiarity with certain services and a lack of scientific evidence as extremely or somewhat likely to affect their ability to offer integrative services to patients with chronic pain.²¹ Likewise, about 40% of patients identified being unfamiliar with a specific therapy as one of the major obstacles to receiving integrative therapies, with a similar number identifying PCPs as a source of information. The lack of familiarity may be due in part to the evolving nomenclature, with terms such as alternative, complementary, and integrative used to describe approaches outside what is often considered conventional medicine.¹⁰ On the other hand, there has also been considerable expansion in the number of therapies within this domain, along with an expanding evidence base. This suggests a need for targeted educational strategies for clinicians and patients, which can be rapidly deployed and continuously adapted as new therapies and evidence emerge.

Limitations

There are some inherent limitations with a survey-based approach, including sampling, non-response, and social desirability biases. In addition, this study only included PCPs and patients affiliated with a single VA medical center. Steps to mitigate these limitations included maintaining survey anonymity and reporting information about respondent characteristics to enhance transparency about the representativeness of the study findings.

CONCLUSIONS

Expanding the use of nonpharmacological pain treatments, including integrative modalities, is essential for safe and effective chronic pain management and reducing opioid use. Our findings show that VA PCPs and patients with chronic back pain are interested in and have some experience with certain integrative therapies. However, even within the context of a health care system that supports the use of integrative therapies for chronic pain as part of whole person care, increasing uptake will require addressing access and time-related constraints as well as ongoing clinician and patient education.

More than 50 million US adults report experiencing chronic pain, with nearly 7% experiencing high-impact chronic pain.^1-3 Chronic pain negatively affects daily function, results in lost productivity, is a leading cause of disability, and is more prevalent among veterans compared with the general population.^1,2,4-6 Estimates from 2021 suggest the prevalence of chronic pain among veterans exceeds 30%; > 11% experienced high-impact chronic pain.¹

Primary care practitioners (PCPs) have a prominent role in chronic pain management. Pharmacologic options for treating pain, once a mainstay of therapy, present several challenges for patients and PCPs, including drug-drug interactions and adverse effects.⁷ The US opioid epidemic and shift to a biopsychosocial model of chronic pain care have increased emphasis on nonpharmacologic treatment options.^8,9 These include integrative modalities, which incorporate conventional approaches with an array of complementary health approaches.^10-12

Integrative therapy is a prominent feature in whole person care, which may be best exemplified by the US Department of Veterans Affairs (VA) Whole Health System of care.^13-14 Whole health empowers an individual to take charge of their health and well-being so they can “live their life to the fullest.”¹⁴ As implemented in the Veterans Health Administration (VHA), whole health includes the use of evidence-based complementary and integrative therapies, encompassing a multimodal pain management approach. Expanding the use of these therapies requires a better understanding of PCP and patient knowledge, interest, and use of integrative modalities for chronic pain.

METHODS

Using a cross-sectional survey design, PCPs and patients with chronic back pain affiliated with the VA Ann Arbor Healthcare System were invited to participate in separate but similar surveys to assess knowledge, interest, and use of nonpharmacologic integrative modalities for the treatment of chronic pain. In May, June, and July 2023, 78 PCPs received 3 email invitations to participate in an electronic (Qualtrics) survey. Patients were identified based on having an International Statistical Classification of Diseases, Tenth Revision code for low back pain (M54.5, M54.40, 41, 42, M54.89) on ≥ 2 outpatient encounters within 18 months (April 1, 2021, to March 31, 2023). A random sample of 200 patients was selected and sent a packet in September 2023 that included an introductory letter and a paper survey, along with a website link and QR code to complete the survey electronically if preferred. The introductory letter stated that participation is voluntary, had no impact on the health care currently received at the VA, and names are not attached to the survey, allowing them to remain anonymous. The packet also included a $10 gift card to encourage survey completion.

Both survey instruments are available upon request, were developed by the study team, and included a mix of yes/no questions, “select all that apply” items, Likert scale response items, and open-ended questions. For one question about which modalities they would like available, the respondent was instructed to select up to 5 modalities. The instruments were extensively pretested by members of the study team, which included 2 PCPs and a nonveteran with chronic back pain.

The list of integrative modalities included in the survey was derived from the tier 1 and tier 2 complementary and integrative health modalities identified in a VHA Directive on complementary and integrative health.^15,16 Tier 1 approaches are considered to have sufficient evidence and must be made available to veterans either within a VA medical facility or in the community. Tier 2 approaches are generally considered safe and may be made available but do not have sufficient evidence to mandate their provision. For participant ease, the integrative modalities were divided into 5 subgroups: manual therapies, energy/biofield therapies, mental health therapies, nutrition counseling, and movement therapies. The clinician survey assessed clinicians’ training and interest, clinical and personal use, and perceived barriers to providing integrative modalities for chronic pain. Professional and personal demographic data were also collected. Similarly, the patient survey assessed use of integrative therapies, perceptions of and interest in integrative modalities, and potential barriers to use. Demographic and health-related information was also collected.

Data analysis included descriptive statistics (eg, frequency counts, means, medians) and visual graphic displays. Separate analyses were conducted for clinicians and patients in addition to a comparative analysis of the use and potential interest in integrative modalities. Analysis were conducted using R software. This study was deemed nonresearch quality improvement by the VA Ann Arbor Healthcare System facility research oversight board and institutional review board approval was not solicited.

RESULTS

Twenty-eight clinicians completed the survey, yielding a participation rate of 36%. Participating clinicians had a median (IQR) age of 48 years (9.5), 15 self-identified as White (54%), 8 as Asian (29%), 15 as female (54%), 26 as non-Hispanic (93%), and 25 were medical doctors or doctors of osteopathy (89%). Nineteen (68%) worked at the main hospital outpatient clinic, and 9 practiced at community-based outpatient clinics (CBOCs). Thirteen respondents (46%) reported having no formal education or training in integrative approaches. Among those with prior training, 8 clinicians had nutrition counseling (29%) and 7 had psychologic therapy training (25%). Thirteen respondents (46%) also reported using integrative modalities for personal health needs: 8 used psychological therapies, 8 used movement therapies, 10 used integrative modalities for stress management or relaxation, and 8 used them for physical symptoms (Table 1).

Overall, 85 of 200 patients (43%) responded to the study survey. Two patients indicated they did not have chronic back pain and were excluded. Patients had a median (IQR) age of 66 (20) years, with 66 self-identifying as White (80%), 69 as male (83%), and 66 as non-Hispanic (80%). Forty-four patients (53%) received care at CBOCs. Forty-seven patients reported excellent, very good, or good overall health (57%), while 53 reported excellent, very good, or good mental health (64%). Fifty-nine patients reported back pain duration > 5 years (71%), and 67 (81%) indicated experiencing back pain flare-ups at least once per week over the previous 12 months. Sixty patients (72%) indicated they were somewhat or very interested in using integrative therapies as a back pain treatment; however, 40 patients (48%) indicated they had not received information about these therapies. Among those who indicated they had received information, the most frequently reported source was their PCP (41%). Most patients (72%) also reported feeling somewhat to very comfortable discussing integrative medicine therapies with their PCP.

Integrative Therapy Recommendations and Use

PCPs reported recommending multiple integrative modalities: 23 (82%) recommended cognitive-behavioral therapy, 22 (79%) recommended acupuncture, 21 (75%) recommended chiropractic, 19 (68%) recommended battlefield acupuncture, recommended massage 18 (64%), 17 (61%) recommended meditation or mindfulness, and 15 (54%) recommended movement therapies such as yoga or tai chi/qigong (Figure 1). The only therapies used by at least half of the patients were chiropractic used by 59 patients (71%) and acupuncture by 42 patients (51%). Thirty-eight patients (46%) reported massage use and 21 patients (25%) used cognitive-behavioral therapy (Table 2).

Integrative Therapies Desired

A majority of PCPs identified acupuncture (n = 20, 71%), chiropractic (n = 19, 68%), and massage (n = 19, 68%) as therapies they would most like to have available for patients with chronic pain (Figure 2). Similarly, patients identified massage (n = 42, 51%), chiropractic (n = 34, 41%), and acupuncture (n = 27, 33%) as most desired. Seventeen patients (21%) expressed interest in movement therapies.

Barriers to Integrative Therapies Use

When asked about barriers to use, 26 PCPs (93%) identified access to services as a somewhat or extremely likely barrier, and 22 identified time constraints (79%) (Table 3). However, 17 PCPs (61%) noted lack of familiarity, and 18 (64%) noted a lack of scientific evidence as barriers to recommending integrative modalities. Among patients, 33 (40%) indicated not knowing what services were available at their facility as a barrier, 32 (39%) were not familiar with specific therapies, and 21 (25%) indicated a lack of clarity about the benefits of a specific therapy. Only 14 patients (17%) indicated that there were no obstacles to use.

DISCUSSION

Use of integrative therapies, including complementary treatments, is an increasingly important part of chronic pain management. This survey study suggests VA PCPs are willing to recommend integrative therapies and patients with chronic back pain both desire and use several therapies. Moreover, both groups expressed interest in greater availability of similar therapies. The results also highlight key barriers, such as knowledge gaps, that should be addressed to increase the uptake of integrative modalities for managing chronic pain.

An increasing number of US adults are using complementary health approaches, an important component of integrative therapy.¹² This trend includes an increase in use for pain management, from 42.3% in 2002 to 49.2% in 2022; chiropractic care, acupuncture, and massage were most frequently used.¹² Similarly, chiropractic, acupuncture and massage were most often used by this sample of veterans with chronic back pain and were identified by the highest percentages of PCPs and patients as the therapies they would most like available.

There were areas where the opinions of patients and clinicians differed. As has been seen previously reported, clinicians largely recommended cognitive-behavioral therapy while patients showed less interest.¹⁷ Additionally, while patients expressed interest in the availability of movement therapies, such as yoga, PCPs expressed more interest in other strategies, such as trigger point injections. These differences may reflect true preference or a tendency for clinicians and patients to select therapies with which they are more familiar. Additional research is needed to better understand the acceptability and potential use of integrative health treatments across a broad array of therapeutic options.

Despite VHA policy requiring facilities to provide certain complementary and integrative health modalities, almost all PCPs identified access to services as a major obstacle.¹⁵ Based on evidence and a rigorous vetting process, services currently required on-site, via telehealth, or through community partners include acupuncture and battlefield acupuncture (battlefield auricular acupuncture), biofeedback, clinical hypnosis, guided imagery, medical massage therapy, medication, tai chi/qigong, and yoga. Optional approaches, which may be made available to veterans, include chiropractic and healing touch. Outside the VHA, some states have introduced or enacted legislation mandating insurance coverage of nonpharmacological pain treatments.¹⁸ However, these requirements and mandates do not help address challenges such as the availability of trained/qualified practitioners.^19,20 Ensuring access to complementary and integrative health treatments requires a more concerted effort to ensure that supply meets demand. It is also important to acknowledge the budgetary and physical space constraints that further limit access to services. Although expansion and integration of integrative medicine services remain a priority within the VA Whole Health program, implementation is contingent on available financial and infrastructure resources.

Time was also identified by PCPs as a barrier to recommending integrative therapies to patients. Developing and implementing time-efficient communication strategies for patient education such as concise talking points and informational handouts could help address this barrier. Furthermore, leveraging existing programs and engaging the entire health care team in patient education and referral could help increase integrative and complementary therapy uptake and use.

Although access and time were identified as major barriers, these findings also suggest that PCP and patient knowledge are another target area for enhancing the use of complementary and integrative therapies. Like prior research, most clinicians identified a lack of familiarity with certain services and a lack of scientific evidence as extremely or somewhat likely to affect their ability to offer integrative services to patients with chronic pain.²¹ Likewise, about 40% of patients identified being unfamiliar with a specific therapy as one of the major obstacles to receiving integrative therapies, with a similar number identifying PCPs as a source of information. The lack of familiarity may be due in part to the evolving nomenclature, with terms such as alternative, complementary, and integrative used to describe approaches outside what is often considered conventional medicine.¹⁰ On the other hand, there has also been considerable expansion in the number of therapies within this domain, along with an expanding evidence base. This suggests a need for targeted educational strategies for clinicians and patients, which can be rapidly deployed and continuously adapted as new therapies and evidence emerge.

Limitations

There are some inherent limitations with a survey-based approach, including sampling, non-response, and social desirability biases. In addition, this study only included PCPs and patients affiliated with a single VA medical center. Steps to mitigate these limitations included maintaining survey anonymity and reporting information about respondent characteristics to enhance transparency about the representativeness of the study findings.

CONCLUSIONS

Expanding the use of nonpharmacological pain treatments, including integrative modalities, is essential for safe and effective chronic pain management and reducing opioid use. Our findings show that VA PCPs and patients with chronic back pain are interested in and have some experience with certain integrative therapies. However, even within the context of a health care system that supports the use of integrative therapies for chronic pain as part of whole person care, increasing uptake will require addressing access and time-related constraints as well as ongoing clinician and patient education.

More than 50 million US adults report experiencing chronic pain, with nearly 7% experiencing high-impact chronic pain.^1-3 Chronic pain negatively affects daily function, results in lost productivity, is a leading cause of disability, and is more prevalent among veterans compared with the general population.^1,2,4-6 Estimates from 2021 suggest the prevalence of chronic pain among veterans exceeds 30%; > 11% experienced high-impact chronic pain.¹

Primary care practitioners (PCPs) have a prominent role in chronic pain management. Pharmacologic options for treating pain, once a mainstay of therapy, present several challenges for patients and PCPs, including drug-drug interactions and adverse effects.⁷ The US opioid epidemic and shift to a biopsychosocial model of chronic pain care have increased emphasis on nonpharmacologic treatment options.^8,9 These include integrative modalities, which incorporate conventional approaches with an array of complementary health approaches.^10-12

Integrative therapy is a prominent feature in whole person care, which may be best exemplified by the US Department of Veterans Affairs (VA) Whole Health System of care.^13-14 Whole health empowers an individual to take charge of their health and well-being so they can “live their life to the fullest.”¹⁴ As implemented in the Veterans Health Administration (VHA), whole health includes the use of evidence-based complementary and integrative therapies, encompassing a multimodal pain management approach. Expanding the use of these therapies requires a better understanding of PCP and patient knowledge, interest, and use of integrative modalities for chronic pain.

METHODS

Using a cross-sectional survey design, PCPs and patients with chronic back pain affiliated with the VA Ann Arbor Healthcare System were invited to participate in separate but similar surveys to assess knowledge, interest, and use of nonpharmacologic integrative modalities for the treatment of chronic pain. In May, June, and July 2023, 78 PCPs received 3 email invitations to participate in an electronic (Qualtrics) survey. Patients were identified based on having an International Statistical Classification of Diseases, Tenth Revision code for low back pain (M54.5, M54.40, 41, 42, M54.89) on ≥ 2 outpatient encounters within 18 months (April 1, 2021, to March 31, 2023). A random sample of 200 patients was selected and sent a packet in September 2023 that included an introductory letter and a paper survey, along with a website link and QR code to complete the survey electronically if preferred. The introductory letter stated that participation is voluntary, had no impact on the health care currently received at the VA, and names are not attached to the survey, allowing them to remain anonymous. The packet also included a $10 gift card to encourage survey completion.

Both survey instruments are available upon request, were developed by the study team, and included a mix of yes/no questions, “select all that apply” items, Likert scale response items, and open-ended questions. For one question about which modalities they would like available, the respondent was instructed to select up to 5 modalities. The instruments were extensively pretested by members of the study team, which included 2 PCPs and a nonveteran with chronic back pain.

The list of integrative modalities included in the survey was derived from the tier 1 and tier 2 complementary and integrative health modalities identified in a VHA Directive on complementary and integrative health.^15,16 Tier 1 approaches are considered to have sufficient evidence and must be made available to veterans either within a VA medical facility or in the community. Tier 2 approaches are generally considered safe and may be made available but do not have sufficient evidence to mandate their provision. For participant ease, the integrative modalities were divided into 5 subgroups: manual therapies, energy/biofield therapies, mental health therapies, nutrition counseling, and movement therapies. The clinician survey assessed clinicians’ training and interest, clinical and personal use, and perceived barriers to providing integrative modalities for chronic pain. Professional and personal demographic data were also collected. Similarly, the patient survey assessed use of integrative therapies, perceptions of and interest in integrative modalities, and potential barriers to use. Demographic and health-related information was also collected.

Data analysis included descriptive statistics (eg, frequency counts, means, medians) and visual graphic displays. Separate analyses were conducted for clinicians and patients in addition to a comparative analysis of the use and potential interest in integrative modalities. Analysis were conducted using R software. This study was deemed nonresearch quality improvement by the VA Ann Arbor Healthcare System facility research oversight board and institutional review board approval was not solicited.

RESULTS

Twenty-eight clinicians completed the survey, yielding a participation rate of 36%. Participating clinicians had a median (IQR) age of 48 years (9.5), 15 self-identified as White (54%), 8 as Asian (29%), 15 as female (54%), 26 as non-Hispanic (93%), and 25 were medical doctors or doctors of osteopathy (89%). Nineteen (68%) worked at the main hospital outpatient clinic, and 9 practiced at community-based outpatient clinics (CBOCs). Thirteen respondents (46%) reported having no formal education or training in integrative approaches. Among those with prior training, 8 clinicians had nutrition counseling (29%) and 7 had psychologic therapy training (25%). Thirteen respondents (46%) also reported using integrative modalities for personal health needs: 8 used psychological therapies, 8 used movement therapies, 10 used integrative modalities for stress management or relaxation, and 8 used them for physical symptoms (Table 1).

Overall, 85 of 200 patients (43%) responded to the study survey. Two patients indicated they did not have chronic back pain and were excluded. Patients had a median (IQR) age of 66 (20) years, with 66 self-identifying as White (80%), 69 as male (83%), and 66 as non-Hispanic (80%). Forty-four patients (53%) received care at CBOCs. Forty-seven patients reported excellent, very good, or good overall health (57%), while 53 reported excellent, very good, or good mental health (64%). Fifty-nine patients reported back pain duration > 5 years (71%), and 67 (81%) indicated experiencing back pain flare-ups at least once per week over the previous 12 months. Sixty patients (72%) indicated they were somewhat or very interested in using integrative therapies as a back pain treatment; however, 40 patients (48%) indicated they had not received information about these therapies. Among those who indicated they had received information, the most frequently reported source was their PCP (41%). Most patients (72%) also reported feeling somewhat to very comfortable discussing integrative medicine therapies with their PCP.

Integrative Therapy Recommendations and Use

PCPs reported recommending multiple integrative modalities: 23 (82%) recommended cognitive-behavioral therapy, 22 (79%) recommended acupuncture, 21 (75%) recommended chiropractic, 19 (68%) recommended battlefield acupuncture, recommended massage 18 (64%), 17 (61%) recommended meditation or mindfulness, and 15 (54%) recommended movement therapies such as yoga or tai chi/qigong (Figure 1). The only therapies used by at least half of the patients were chiropractic used by 59 patients (71%) and acupuncture by 42 patients (51%). Thirty-eight patients (46%) reported massage use and 21 patients (25%) used cognitive-behavioral therapy (Table 2).

Integrative Therapies Desired

A majority of PCPs identified acupuncture (n = 20, 71%), chiropractic (n = 19, 68%), and massage (n = 19, 68%) as therapies they would most like to have available for patients with chronic pain (Figure 2). Similarly, patients identified massage (n = 42, 51%), chiropractic (n = 34, 41%), and acupuncture (n = 27, 33%) as most desired. Seventeen patients (21%) expressed interest in movement therapies.

Barriers to Integrative Therapies Use

When asked about barriers to use, 26 PCPs (93%) identified access to services as a somewhat or extremely likely barrier, and 22 identified time constraints (79%) (Table 3). However, 17 PCPs (61%) noted lack of familiarity, and 18 (64%) noted a lack of scientific evidence as barriers to recommending integrative modalities. Among patients, 33 (40%) indicated not knowing what services were available at their facility as a barrier, 32 (39%) were not familiar with specific therapies, and 21 (25%) indicated a lack of clarity about the benefits of a specific therapy. Only 14 patients (17%) indicated that there were no obstacles to use.

DISCUSSION

Use of integrative therapies, including complementary treatments, is an increasingly important part of chronic pain management. This survey study suggests VA PCPs are willing to recommend integrative therapies and patients with chronic back pain both desire and use several therapies. Moreover, both groups expressed interest in greater availability of similar therapies. The results also highlight key barriers, such as knowledge gaps, that should be addressed to increase the uptake of integrative modalities for managing chronic pain.

An increasing number of US adults are using complementary health approaches, an important component of integrative therapy.¹² This trend includes an increase in use for pain management, from 42.3% in 2002 to 49.2% in 2022; chiropractic care, acupuncture, and massage were most frequently used.¹² Similarly, chiropractic, acupuncture and massage were most often used by this sample of veterans with chronic back pain and were identified by the highest percentages of PCPs and patients as the therapies they would most like available.

There were areas where the opinions of patients and clinicians differed. As has been seen previously reported, clinicians largely recommended cognitive-behavioral therapy while patients showed less interest.¹⁷ Additionally, while patients expressed interest in the availability of movement therapies, such as yoga, PCPs expressed more interest in other strategies, such as trigger point injections. These differences may reflect true preference or a tendency for clinicians and patients to select therapies with which they are more familiar. Additional research is needed to better understand the acceptability and potential use of integrative health treatments across a broad array of therapeutic options.

Despite VHA policy requiring facilities to provide certain complementary and integrative health modalities, almost all PCPs identified access to services as a major obstacle.¹⁵ Based on evidence and a rigorous vetting process, services currently required on-site, via telehealth, or through community partners include acupuncture and battlefield acupuncture (battlefield auricular acupuncture), biofeedback, clinical hypnosis, guided imagery, medical massage therapy, medication, tai chi/qigong, and yoga. Optional approaches, which may be made available to veterans, include chiropractic and healing touch. Outside the VHA, some states have introduced or enacted legislation mandating insurance coverage of nonpharmacological pain treatments.¹⁸ However, these requirements and mandates do not help address challenges such as the availability of trained/qualified practitioners.^19,20 Ensuring access to complementary and integrative health treatments requires a more concerted effort to ensure that supply meets demand. It is also important to acknowledge the budgetary and physical space constraints that further limit access to services. Although expansion and integration of integrative medicine services remain a priority within the VA Whole Health program, implementation is contingent on available financial and infrastructure resources.

Time was also identified by PCPs as a barrier to recommending integrative therapies to patients. Developing and implementing time-efficient communication strategies for patient education such as concise talking points and informational handouts could help address this barrier. Furthermore, leveraging existing programs and engaging the entire health care team in patient education and referral could help increase integrative and complementary therapy uptake and use.

Although access and time were identified as major barriers, these findings also suggest that PCP and patient knowledge are another target area for enhancing the use of complementary and integrative therapies. Like prior research, most clinicians identified a lack of familiarity with certain services and a lack of scientific evidence as extremely or somewhat likely to affect their ability to offer integrative services to patients with chronic pain.²¹ Likewise, about 40% of patients identified being unfamiliar with a specific therapy as one of the major obstacles to receiving integrative therapies, with a similar number identifying PCPs as a source of information. The lack of familiarity may be due in part to the evolving nomenclature, with terms such as alternative, complementary, and integrative used to describe approaches outside what is often considered conventional medicine.¹⁰ On the other hand, there has also been considerable expansion in the number of therapies within this domain, along with an expanding evidence base. This suggests a need for targeted educational strategies for clinicians and patients, which can be rapidly deployed and continuously adapted as new therapies and evidence emerge.

Limitations

There are some inherent limitations with a survey-based approach, including sampling, non-response, and social desirability biases. In addition, this study only included PCPs and patients affiliated with a single VA medical center. Steps to mitigate these limitations included maintaining survey anonymity and reporting information about respondent characteristics to enhance transparency about the representativeness of the study findings.

CONCLUSIONS

Expanding the use of nonpharmacological pain treatments, including integrative modalities, is essential for safe and effective chronic pain management and reducing opioid use. Our findings show that VA PCPs and patients with chronic back pain are interested in and have some experience with certain integrative therapies. However, even within the context of a health care system that supports the use of integrative therapies for chronic pain as part of whole person care, increasing uptake will require addressing access and time-related constraints as well as ongoing clinician and patient education.

Background

Veterans may have a greater risk of experiencing human trafficking (HT) than the general population because of social aspects of health, including housing insecurity, justice involvement, food insecurity, and adverse childhood events.^1-4 Since 2023, the U.S. Department of Veterans Affairs (VA) has explored veterans’ experiences of HT through the Anti-Human Trafficking (AHT) Pilot Project.  This quality improvement project evaluated: 1) development of clinician AHT training materials to enhance identification and response to Veterans experiencing HT, and 2) educational resources aimed at raising awareness tailored to veterans and clinicians.

Methods

South Central Mental Illness Research, Education and Clinical Center (SCMIRECC) facilitated two focus group discussions with AHT coordinators implementing the pilot at six sites. Based on discussions and leadership input, SCMIRECC developed a training curriculum, with bi-weekly readings culminating in a two-hour workshop. Training evaluation followed Kirkpatrick’s model using questions adapted from the Provider Responses, Treatment, and Care for Trafficked People (PROTECT) Survey.^5,6 Veteran-facing materials, including a brochure and whiteboard video, were reviewed by two Veteran Consumer Advisory Boards (CAB). The brochures, whiteboard video, and awareness modules were developed and revised based on feedback from focus group discussions. VA Central Office cleared all materials.

Results

Coordinators were satisfied with the training (mean, 4.20). After the training, none of the coordinators (n = 6) felt unprepared to assist Veterans (pre-training mean, 2.25; post-training mean, 1.40), and confidence in documentation improved (pre-training mean, 3.00; post-training mean, 3.40). Veteran CAB members recommended simplified language and veteran-centered messaging. The coordinators found the brochures and training useful. Recommendations included adding more representation to brochure covers, advanced training, a list of commonly asked questions, and a simplified screening tool. Barriers included delays in material development due to language guidance under recent executive orders.

Conclusions

The AHT training improved coordinators’ preparedness and confidence in supporting Veterans with trafficking experiences. Feedback emphasized the value of concise, Veteran-centered materials and a practical HT screening tool. These findings support the continued implementation of AHT education across VA settings to enhance identification and response for Veterans at risk of HT.

Background

Veterans may have a greater risk of experiencing human trafficking (HT) than the general population because of social aspects of health, including housing insecurity, justice involvement, food insecurity, and adverse childhood events.^1-4 Since 2023, the U.S. Department of Veterans Affairs (VA) has explored veterans’ experiences of HT through the Anti-Human Trafficking (AHT) Pilot Project.  This quality improvement project evaluated: 1) development of clinician AHT training materials to enhance identification and response to Veterans experiencing HT, and 2) educational resources aimed at raising awareness tailored to veterans and clinicians.

Methods

South Central Mental Illness Research, Education and Clinical Center (SCMIRECC) facilitated two focus group discussions with AHT coordinators implementing the pilot at six sites. Based on discussions and leadership input, SCMIRECC developed a training curriculum, with bi-weekly readings culminating in a two-hour workshop. Training evaluation followed Kirkpatrick’s model using questions adapted from the Provider Responses, Treatment, and Care for Trafficked People (PROTECT) Survey.^5,6 Veteran-facing materials, including a brochure and whiteboard video, were reviewed by two Veteran Consumer Advisory Boards (CAB). The brochures, whiteboard video, and awareness modules were developed and revised based on feedback from focus group discussions. VA Central Office cleared all materials.

Results

Coordinators were satisfied with the training (mean, 4.20). After the training, none of the coordinators (n = 6) felt unprepared to assist Veterans (pre-training mean, 2.25; post-training mean, 1.40), and confidence in documentation improved (pre-training mean, 3.00; post-training mean, 3.40). Veteran CAB members recommended simplified language and veteran-centered messaging. The coordinators found the brochures and training useful. Recommendations included adding more representation to brochure covers, advanced training, a list of commonly asked questions, and a simplified screening tool. Barriers included delays in material development due to language guidance under recent executive orders.

Conclusions

The AHT training improved coordinators’ preparedness and confidence in supporting Veterans with trafficking experiences. Feedback emphasized the value of concise, Veteran-centered materials and a practical HT screening tool. These findings support the continued implementation of AHT education across VA settings to enhance identification and response for Veterans at risk of HT.

Background

Veterans may have a greater risk of experiencing human trafficking (HT) than the general population because of social aspects of health, including housing insecurity, justice involvement, food insecurity, and adverse childhood events.^1-4 Since 2023, the U.S. Department of Veterans Affairs (VA) has explored veterans’ experiences of HT through the Anti-Human Trafficking (AHT) Pilot Project.  This quality improvement project evaluated: 1) development of clinician AHT training materials to enhance identification and response to Veterans experiencing HT, and 2) educational resources aimed at raising awareness tailored to veterans and clinicians.

Methods

South Central Mental Illness Research, Education and Clinical Center (SCMIRECC) facilitated two focus group discussions with AHT coordinators implementing the pilot at six sites. Based on discussions and leadership input, SCMIRECC developed a training curriculum, with bi-weekly readings culminating in a two-hour workshop. Training evaluation followed Kirkpatrick’s model using questions adapted from the Provider Responses, Treatment, and Care for Trafficked People (PROTECT) Survey.^5,6 Veteran-facing materials, including a brochure and whiteboard video, were reviewed by two Veteran Consumer Advisory Boards (CAB). The brochures, whiteboard video, and awareness modules were developed and revised based on feedback from focus group discussions. VA Central Office cleared all materials.

Results

Coordinators were satisfied with the training (mean, 4.20). After the training, none of the coordinators (n = 6) felt unprepared to assist Veterans (pre-training mean, 2.25; post-training mean, 1.40), and confidence in documentation improved (pre-training mean, 3.00; post-training mean, 3.40). Veteran CAB members recommended simplified language and veteran-centered messaging. The coordinators found the brochures and training useful. Recommendations included adding more representation to brochure covers, advanced training, a list of commonly asked questions, and a simplified screening tool. Barriers included delays in material development due to language guidance under recent executive orders.

Conclusions

The AHT training improved coordinators’ preparedness and confidence in supporting Veterans with trafficking experiences. Feedback emphasized the value of concise, Veteran-centered materials and a practical HT screening tool. These findings support the continued implementation of AHT education across VA settings to enhance identification and response for Veterans at risk of HT.

Background

The Accreditation Council for Graduate Medical Education (ACGME) mandates an 80-hour weekly work limit for residents.¹ In contrast, decisions regarding undergraduate medical education (UME) are strongly influenced locally, with individual institutions setting academic policy for students. These differences in oversight reflect fundamental differences in residents’ and students’ roles in patient care, power, and responsibility. Considering rotation schedules, internal medicine (IM) clerkship directors have discussed the relative value of weekend vs weekday duty during inpatient rotations, a scheduling topic of interest to students as well, though these conversations are limited by a lack of knowledge regarding admission patterns. Addressing this information gap would inform policy decisions.

The Veterans Health Administration (VHA) is uniquely positioned to address questions about UME clinical experiences nationwide: annually, over 118,000 students representing 97% of US medical schools train at VHA facilities.^2,3 We aim to compare the number and variety of patient encounter opportunities presenting during inpatient VHA IM rotations on weekdays versus weekends to inform policy decisions for UME rotation schedules.

Innovation

The VHA Corporate Data Warehouse will be queried for all admissions, diagnoses, and length of stay on inpatient IM services at the 420 VHA hospitals affiliated with US medical schools from 2016-2026. We will aggregate case data for day of week, floor, hospital, and Veteran Integrated Service Network (VISN), and determine number of admissions by weekday (Monday-Friday) and weekend (Saturday-Sunday). Weekday vs. weekend admission data will be compared using generalized mixed effects models for clustered longitudinal data. Heterogeneity across hospitals and VISNs will be explored to examine unique regional trends.

Results

We have drafted strategies to query and curate relevant datasets, developed a preliminary analysis plan, and await data deployment from VHA data stewards.

Conclusions

We believe this will be the first VHA-wide evaluation of patient encounter trends on IM services to examine potential training experiences for medical students. This will increase understanding of the critical role VHA has in developing the nations’ healthcare workforce, and how patterns of opportunities for clinical education may be distributed over time, informing decisions about rotation schedules to maximize students’ abilities to interact with, learn from, and serve our nation’s veterans

Background

The Accreditation Council for Graduate Medical Education (ACGME) mandates an 80-hour weekly work limit for residents.¹ In contrast, decisions regarding undergraduate medical education (UME) are strongly influenced locally, with individual institutions setting academic policy for students. These differences in oversight reflect fundamental differences in residents’ and students’ roles in patient care, power, and responsibility. Considering rotation schedules, internal medicine (IM) clerkship directors have discussed the relative value of weekend vs weekday duty during inpatient rotations, a scheduling topic of interest to students as well, though these conversations are limited by a lack of knowledge regarding admission patterns. Addressing this information gap would inform policy decisions.

The Veterans Health Administration (VHA) is uniquely positioned to address questions about UME clinical experiences nationwide: annually, over 118,000 students representing 97% of US medical schools train at VHA facilities.^2,3 We aim to compare the number and variety of patient encounter opportunities presenting during inpatient VHA IM rotations on weekdays versus weekends to inform policy decisions for UME rotation schedules.

Innovation

The VHA Corporate Data Warehouse will be queried for all admissions, diagnoses, and length of stay on inpatient IM services at the 420 VHA hospitals affiliated with US medical schools from 2016-2026. We will aggregate case data for day of week, floor, hospital, and Veteran Integrated Service Network (VISN), and determine number of admissions by weekday (Monday-Friday) and weekend (Saturday-Sunday). Weekday vs. weekend admission data will be compared using generalized mixed effects models for clustered longitudinal data. Heterogeneity across hospitals and VISNs will be explored to examine unique regional trends.

Results

We have drafted strategies to query and curate relevant datasets, developed a preliminary analysis plan, and await data deployment from VHA data stewards.

Conclusions

We believe this will be the first VHA-wide evaluation of patient encounter trends on IM services to examine potential training experiences for medical students. This will increase understanding of the critical role VHA has in developing the nations’ healthcare workforce, and how patterns of opportunities for clinical education may be distributed over time, informing decisions about rotation schedules to maximize students’ abilities to interact with, learn from, and serve our nation’s veterans

Background

The Accreditation Council for Graduate Medical Education (ACGME) mandates an 80-hour weekly work limit for residents.¹ In contrast, decisions regarding undergraduate medical education (UME) are strongly influenced locally, with individual institutions setting academic policy for students. These differences in oversight reflect fundamental differences in residents’ and students’ roles in patient care, power, and responsibility. Considering rotation schedules, internal medicine (IM) clerkship directors have discussed the relative value of weekend vs weekday duty during inpatient rotations, a scheduling topic of interest to students as well, though these conversations are limited by a lack of knowledge regarding admission patterns. Addressing this information gap would inform policy decisions.

The Veterans Health Administration (VHA) is uniquely positioned to address questions about UME clinical experiences nationwide: annually, over 118,000 students representing 97% of US medical schools train at VHA facilities.^2,3 We aim to compare the number and variety of patient encounter opportunities presenting during inpatient VHA IM rotations on weekdays versus weekends to inform policy decisions for UME rotation schedules.

Innovation

The VHA Corporate Data Warehouse will be queried for all admissions, diagnoses, and length of stay on inpatient IM services at the 420 VHA hospitals affiliated with US medical schools from 2016-2026. We will aggregate case data for day of week, floor, hospital, and Veteran Integrated Service Network (VISN), and determine number of admissions by weekday (Monday-Friday) and weekend (Saturday-Sunday). Weekday vs. weekend admission data will be compared using generalized mixed effects models for clustered longitudinal data. Heterogeneity across hospitals and VISNs will be explored to examine unique regional trends.

Results

We have drafted strategies to query and curate relevant datasets, developed a preliminary analysis plan, and await data deployment from VHA data stewards.

Conclusions

We believe this will be the first VHA-wide evaluation of patient encounter trends on IM services to examine potential training experiences for medical students. This will increase understanding of the critical role VHA has in developing the nations’ healthcare workforce, and how patterns of opportunities for clinical education may be distributed over time, informing decisions about rotation schedules to maximize students’ abilities to interact with, learn from, and serve our nation’s veterans

Background

Integrative health (IH) combines conventional and complementary medicine in a coordinated, evidence-based approach to treat the whole person. Nearly 40% of American adults have used complementary health approaches,¹ yet IH exposure in medical training is limited. In 2022, the San Francisco VA Health Care Center launched a multidisciplinary clinical IH elective for University of California San Francisco (UCSF) internal medicine and SFVA nurse practitioner residents. Based on findings from a general and targeted needs assessment, including faculty and learner feedback, we found that the elective was well-received, but relied on one-on-one patient-based teaching. This structure created variable learning experiences and high faculty burden. Our project aims to formalize and evaluate the IH elective curriculum to better address the needs of both faculty and learners.

Methods

We used Kern’s six-step framework for curriculum development. To reduce variability, we sought to formalize the core curricular content by: 1) reviewing existing elective components, comparing them to similar curricula nationwide, and outlining foundational knowledge based on the exam domains of the American Board of Integrative Medicine (ABOIM);² 2) creating eleven learning objectives across three themes: patient-centered care, systems-based practice, and IH-specific knowledge; 3) developing IH subspecialty experience guides to standardize clinical teaching with suggested takeaways, guided reflection, and curated resources. To reduce faculty burden, we consolidated elective resources into a centralized e-learning hub. Trainees complete a pre/post self-assessment and evaluation at the end of the elective.

Results

We identified key learning opportunities in each IH shadowing experience to enhance learners’ knowledge. We developed an IH e-Learning Hub to provide easy access to elective materials and IH clinical tools. Evaluations from the first two learners who completed the elective indicate that the learning objectives were met and that learners gained increased knowledge of lifestyle medicine, mind-body medicine, manual medicine, and botanicals/dietary supplements. Learners valued increased IH subspecialty familiarity and reported high likelihood of future practice change.

Discussion

The project is ongoing. Next steps include collecting faculty evaluations about their experience, continuing to create and refine experience guides, promoting clinical tools for learner’s future practice, and developing strategies to recruit more learners to the elective.

Background

Integrative health (IH) combines conventional and complementary medicine in a coordinated, evidence-based approach to treat the whole person. Nearly 40% of American adults have used complementary health approaches,¹ yet IH exposure in medical training is limited. In 2022, the San Francisco VA Health Care Center launched a multidisciplinary clinical IH elective for University of California San Francisco (UCSF) internal medicine and SFVA nurse practitioner residents. Based on findings from a general and targeted needs assessment, including faculty and learner feedback, we found that the elective was well-received, but relied on one-on-one patient-based teaching. This structure created variable learning experiences and high faculty burden. Our project aims to formalize and evaluate the IH elective curriculum to better address the needs of both faculty and learners.

Methods

We used Kern’s six-step framework for curriculum development. To reduce variability, we sought to formalize the core curricular content by: 1) reviewing existing elective components, comparing them to similar curricula nationwide, and outlining foundational knowledge based on the exam domains of the American Board of Integrative Medicine (ABOIM);² 2) creating eleven learning objectives across three themes: patient-centered care, systems-based practice, and IH-specific knowledge; 3) developing IH subspecialty experience guides to standardize clinical teaching with suggested takeaways, guided reflection, and curated resources. To reduce faculty burden, we consolidated elective resources into a centralized e-learning hub. Trainees complete a pre/post self-assessment and evaluation at the end of the elective.

Results

We identified key learning opportunities in each IH shadowing experience to enhance learners’ knowledge. We developed an IH e-Learning Hub to provide easy access to elective materials and IH clinical tools. Evaluations from the first two learners who completed the elective indicate that the learning objectives were met and that learners gained increased knowledge of lifestyle medicine, mind-body medicine, manual medicine, and botanicals/dietary supplements. Learners valued increased IH subspecialty familiarity and reported high likelihood of future practice change.

Discussion

The project is ongoing. Next steps include collecting faculty evaluations about their experience, continuing to create and refine experience guides, promoting clinical tools for learner’s future practice, and developing strategies to recruit more learners to the elective.

Background

Integrative health (IH) combines conventional and complementary medicine in a coordinated, evidence-based approach to treat the whole person. Nearly 40% of American adults have used complementary health approaches,¹ yet IH exposure in medical training is limited. In 2022, the San Francisco VA Health Care Center launched a multidisciplinary clinical IH elective for University of California San Francisco (UCSF) internal medicine and SFVA nurse practitioner residents. Based on findings from a general and targeted needs assessment, including faculty and learner feedback, we found that the elective was well-received, but relied on one-on-one patient-based teaching. This structure created variable learning experiences and high faculty burden. Our project aims to formalize and evaluate the IH elective curriculum to better address the needs of both faculty and learners.

Methods

We used Kern’s six-step framework for curriculum development. To reduce variability, we sought to formalize the core curricular content by: 1) reviewing existing elective components, comparing them to similar curricula nationwide, and outlining foundational knowledge based on the exam domains of the American Board of Integrative Medicine (ABOIM);² 2) creating eleven learning objectives across three themes: patient-centered care, systems-based practice, and IH-specific knowledge; 3) developing IH subspecialty experience guides to standardize clinical teaching with suggested takeaways, guided reflection, and curated resources. To reduce faculty burden, we consolidated elective resources into a centralized e-learning hub. Trainees complete a pre/post self-assessment and evaluation at the end of the elective.

Results

We identified key learning opportunities in each IH shadowing experience to enhance learners’ knowledge. We developed an IH e-Learning Hub to provide easy access to elective materials and IH clinical tools. Evaluations from the first two learners who completed the elective indicate that the learning objectives were met and that learners gained increased knowledge of lifestyle medicine, mind-body medicine, manual medicine, and botanicals/dietary supplements. Learners valued increased IH subspecialty familiarity and reported high likelihood of future practice change.

Discussion

The project is ongoing. Next steps include collecting faculty evaluations about their experience, continuing to create and refine experience guides, promoting clinical tools for learner’s future practice, and developing strategies to recruit more learners to the elective.

Background

Among people who use drugs (PWUD), harm reduction (HR) is an evidence-based low barrier approach to mitigating ongoing substance use risks and is considered a key pillar of the Department of Health and Human Service’s Overdose Prevention Strategy.¹ Given the accessibility and continuity, primary care (PC) clinics are optimal sites for education about and provision of HR services.^2,3

Aim

1. Determining the impact of active and passive methods for HR supply.
2. Recognizing the importance of clinician addiction education in the provision of HR services.

Methods

In January 2024, physician and nurse practitioner trainees in the West Haven Veterans Affairs (VA) Center of Education (CoE) in Interprofessional Primary Care received addiction care and HR strategy education. Initially, all patients presenting to the CoE completed a single-item substance use screening. Patients screening positive were offered HR supplies, including fentanyl and xylazine test strips (FTS, XTS), during the encounter (active distribution). Starting October 2024, HR kiosks were implemented in the clinic lobby, offering patients self-serve access to HR supplies (passive distribution). Test strip uptake was tracked through clinical encounter documentation and weekly kiosk inventory.

Results

Between January 2024 and June 2024, 92 FTS and 84 XTS were actively distributed. Upon implementation of the harm reduction kiosk, 253 FTS and 164 XTS were distributed between October 2024 and February 2025. In the CoE, FTS and XTS distribution increased by 275% and 195%, respectively, through passive kiosk distribution relative to active distribution during clinical encounters.

Conclusions

HR kiosk implementation resulted in significantly increased test strip uptake in the CoE, proving passive distribution to be an effective low barrier method of increasing access to HR and substance use disorder (SUD) resources. Although this model may reduce stigma and logistical barriers when presenting for a healthcare encounter, it limits the ability to track and engage patients for more intensive services. While each approach has unique advantages and disadvantages, test strip demand via both methods highlights the significant need for HR resources in PC settings. Continuing education for PC clinicians on low barrier SUD care and HR is critical to optimizing care for this population.

Background

Among people who use drugs (PWUD), harm reduction (HR) is an evidence-based low barrier approach to mitigating ongoing substance use risks and is considered a key pillar of the Department of Health and Human Service’s Overdose Prevention Strategy.¹ Given the accessibility and continuity, primary care (PC) clinics are optimal sites for education about and provision of HR services.^2,3

Aim

1. Determining the impact of active and passive methods for HR supply.
2. Recognizing the importance of clinician addiction education in the provision of HR services.

Methods

In January 2024, physician and nurse practitioner trainees in the West Haven Veterans Affairs (VA) Center of Education (CoE) in Interprofessional Primary Care received addiction care and HR strategy education. Initially, all patients presenting to the CoE completed a single-item substance use screening. Patients screening positive were offered HR supplies, including fentanyl and xylazine test strips (FTS, XTS), during the encounter (active distribution). Starting October 2024, HR kiosks were implemented in the clinic lobby, offering patients self-serve access to HR supplies (passive distribution). Test strip uptake was tracked through clinical encounter documentation and weekly kiosk inventory.

Results

Between January 2024 and June 2024, 92 FTS and 84 XTS were actively distributed. Upon implementation of the harm reduction kiosk, 253 FTS and 164 XTS were distributed between October 2024 and February 2025. In the CoE, FTS and XTS distribution increased by 275% and 195%, respectively, through passive kiosk distribution relative to active distribution during clinical encounters.

Conclusions

HR kiosk implementation resulted in significantly increased test strip uptake in the CoE, proving passive distribution to be an effective low barrier method of increasing access to HR and substance use disorder (SUD) resources. Although this model may reduce stigma and logistical barriers when presenting for a healthcare encounter, it limits the ability to track and engage patients for more intensive services. While each approach has unique advantages and disadvantages, test strip demand via both methods highlights the significant need for HR resources in PC settings. Continuing education for PC clinicians on low barrier SUD care and HR is critical to optimizing care for this population.

Background

Among people who use drugs (PWUD), harm reduction (HR) is an evidence-based low barrier approach to mitigating ongoing substance use risks and is considered a key pillar of the Department of Health and Human Service’s Overdose Prevention Strategy.¹ Given the accessibility and continuity, primary care (PC) clinics are optimal sites for education about and provision of HR services.^2,3

Aim

1. Determining the impact of active and passive methods for HR supply.
2. Recognizing the importance of clinician addiction education in the provision of HR services.

Methods

In January 2024, physician and nurse practitioner trainees in the West Haven Veterans Affairs (VA) Center of Education (CoE) in Interprofessional Primary Care received addiction care and HR strategy education. Initially, all patients presenting to the CoE completed a single-item substance use screening. Patients screening positive were offered HR supplies, including fentanyl and xylazine test strips (FTS, XTS), during the encounter (active distribution). Starting October 2024, HR kiosks were implemented in the clinic lobby, offering patients self-serve access to HR supplies (passive distribution). Test strip uptake was tracked through clinical encounter documentation and weekly kiosk inventory.

Results

Between January 2024 and June 2024, 92 FTS and 84 XTS were actively distributed. Upon implementation of the harm reduction kiosk, 253 FTS and 164 XTS were distributed between October 2024 and February 2025. In the CoE, FTS and XTS distribution increased by 275% and 195%, respectively, through passive kiosk distribution relative to active distribution during clinical encounters.

Conclusions

HR kiosk implementation resulted in significantly increased test strip uptake in the CoE, proving passive distribution to be an effective low barrier method of increasing access to HR and substance use disorder (SUD) resources. Although this model may reduce stigma and logistical barriers when presenting for a healthcare encounter, it limits the ability to track and engage patients for more intensive services. While each approach has unique advantages and disadvantages, test strip demand via both methods highlights the significant need for HR resources in PC settings. Continuing education for PC clinicians on low barrier SUD care and HR is critical to optimizing care for this population.