Article

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.

Dermatosis papulosa nigra (DPN), a subvariant of seborrheic keratosis (SK), is characterized by benign pigmented epidermal neoplasms that typically manifest on the face, neck, and trunk in individuals with darker skin tones (Figure).^1,2 While DPN meets the diagnostic criteria for SK, certain characteristics can help distinguish these lesions from other SK types. Treatment of DPN in patients with skin of color requires caution, particularly regarding the use of abrasive methods as well as cryotherapy, which generally should be avoided. 

EPIDEMIOLOGY 

The incidence of SKs increases with age.3,4 Although it can occur in patients of all skin tones, SK is more common in lighter skin tones, while DPN predominantly is diagnosed in darker skin types.^1,4 The prevalence of DPN in Black patients ranges from 10% to 30%, and Black women are twice as likely to be diagnosed with DPN as men.² One study reported a first-degree relative with DPN in 84% (42/50) of patients.⁵ The number and size of DPN papules increase with age.¹ 

KEY CLINICAL FEATURES 

Dermatosis papulosa nigra and SK have distinctive morphologies: DPN typically manifests as raised, round or filiform, sessile, brown to black, 1- to 5-mm papules. 2 Seborrheic keratoses tend to be larger with a “stuck on” appearance and manifest as well-demarcated, pink to black papules or plaques that can range in size from millimeters to a few centimeters. ^3,4 In DPN, the lesions usually are asymptomatic but may be tender, pruritic, dry, or scaly and may become irritated.^1,2 They develop symmetrically in sun-exposed areas, and the most common sites are the malar face, temporal region, neck, and trunk.^1,2,6,7 Seborrheic keratoses can appear throughout the body, including in sun-exposed areas, but have varying textures (eg, greasy, waxy, verrucous).^3,4 

WORTH NOTING 

Dermatosis papulosa nigra and SK can resemble each other histologically: DPN demonstrates a fibrous stroma, papillomatosis, hyperkeratosis, and acanthosis at the intraepidermal layer, which are diagnostic criteria for SK.^2,4,8 However, other histologic features characteristic of SK that are not seen in DPN include pseudohorn cysts, spindle tumor cells, and basaloid cell nests.⁸ 

Dermoscopy can be useful in ruling out malignant skin cancers when evaluating pigmented lesions. The most common dermoscopic features of SK are cerebriform patterns such as fissures and ridges, comedolike openings, and pigmented fingerprintlike structures.^3,4 To a lesser degree, milialike cysts, sharp demarcation, and hairpin-shaped vascular structures also may be present.4 The dermoscopic findings of DPN have not been well evaluated, but one study revealed that DPN had similar dermoscopic features to SK with some predominant features.⁶ Ridges and fissures were seen in 59% of patients diagnosed with DPN followed by comedolike openings seen in 27% of patients. The coexistence of a cerebriform pattern with comedolike openings was infrequent, and milialike cysts were rare.⁶ 

While DPN and SK are benign, patients often seek treatment for cosmetic reasons. Factors to consider when choosing a treatment modality include location of the lesions, the patient’s skin tone, and postprocedural outcomes (eg, depigmentation, wound healing). In general, treatments for SK include cryotherapy, electrodesiccation and curettage, and topical therapeutics such as hydrogen peroxide 40%, topical vitamin D3, and nitric-zinc 30%-50% solutions. 4,8 Well-established treatment options for DPN include electrodesiccation, laser therapies, scissor excision, and cryotherapy, but topical options such as tazarotene also have been reported.^1,9 Of the treatments for DPN, electrodesiccation and laser therapy routinely are used.¹⁰ 

The efficacy of electrodessication and potassium titanyl phosphate (KTP) laser were assessed in a randomized, investigatorblinded split-face study.¹¹ Both modalities received high improvement ratings, with the results favoring the KTP laser. The patients (most of whom were Black) reported that KTP laser was more effective but more painful than electrodessication (P =.002).¹¹ In another randomized study, patients received 3 treatments—electrodessication, pulsed dye laser, and curettage—for select DPN papules.¹⁰ There was no difference in the degree of clearance, cosmetic outcome, or postinflammatory hyperpigmentation between the 3 modalities, but patients found the laser to be the most painful. 

It is important to exercise caution when using abrasive methods (eg, laser therapy, electrodesiccation, curettage) in patients with darker skin tones because of the increased risk for postinflammatory pigment alteration.^1,2,12 Adverse effects of treatment are a top concern in the management of DPN.^5,13 While cryotherapy is a preferred treatment of SK in lighter skin tones, it generally is avoided for DPN in darker skin types because melanocyte destruction can lead to cosmetically unsatisfactory and easily visible depigmentation.⁹ 

To mitigate postprocedural adverse effects, proper aftercare can promote wound healing and minimize postinflammatory pigment alteration. In one split-face study of Black patients, 2 DPN papules were removed from each side of the face using fine-curved surgical scissors.¹⁴ Next, a petrolatum-based ointment and an antibiotic ointment with polymyxin B sulfate/bacitracin zinc was applied twice daily for 21 days to opposite sides of the face. Patients did not develop infection, tolerated both treatments well, and demonstrated improved general wound appearance according to investigator- rated clinical assessment.¹⁴ Other reported postprocedural approaches include using topical agents with ingredients shown to improve hyperpigmentation (eg, niacinamide, azelaic acid) as well as photoprotection.¹² 

HEALTH DISPARITY HIGHLIGHT 

While DPN is benign, it can have adverse psychosocial effects on patients. A study in Senegal revealed that 60% (19/30) of patients with DPN experienced anxiety related to their condition, while others noted that DPN hindered their social relationships.¹³ In one US study of 50 Black patients with DPN, there was a moderate effect on quality of life, and 36% (18/50) of patients had the lesions removed. However, of the treated patients, 67% (12/18) reported few—if any—symptoms prior to removal.⁵ Although treatment of DPN is widely considered a cosmetic procedure, therapeutic management can address— and may improve—mental health in patients with skin of color.^1,5,13 Despite the high prevalence of DPN in patients with darker skin tones, data on treatment frequency and insurance coverage are not widely available, thus limiting our understanding of treatment accessibility and economic burden. 

Dermatosis papulosa nigra (DPN), a subvariant of seborrheic keratosis (SK), is characterized by benign pigmented epidermal neoplasms that typically manifest on the face, neck, and trunk in individuals with darker skin tones (Figure).^1,2 While DPN meets the diagnostic criteria for SK, certain characteristics can help distinguish these lesions from other SK types. Treatment of DPN in patients with skin of color requires caution, particularly regarding the use of abrasive methods as well as cryotherapy, which generally should be avoided. 

EPIDEMIOLOGY 

The incidence of SKs increases with age.3,4 Although it can occur in patients of all skin tones, SK is more common in lighter skin tones, while DPN predominantly is diagnosed in darker skin types.^1,4 The prevalence of DPN in Black patients ranges from 10% to 30%, and Black women are twice as likely to be diagnosed with DPN as men.² One study reported a first-degree relative with DPN in 84% (42/50) of patients.⁵ The number and size of DPN papules increase with age.¹ 

KEY CLINICAL FEATURES 

Dermatosis papulosa nigra and SK have distinctive morphologies: DPN typically manifests as raised, round or filiform, sessile, brown to black, 1- to 5-mm papules. 2 Seborrheic keratoses tend to be larger with a “stuck on” appearance and manifest as well-demarcated, pink to black papules or plaques that can range in size from millimeters to a few centimeters. ^3,4 In DPN, the lesions usually are asymptomatic but may be tender, pruritic, dry, or scaly and may become irritated.^1,2 They develop symmetrically in sun-exposed areas, and the most common sites are the malar face, temporal region, neck, and trunk.^1,2,6,7 Seborrheic keratoses can appear throughout the body, including in sun-exposed areas, but have varying textures (eg, greasy, waxy, verrucous).^3,4 

WORTH NOTING 

Dermatosis papulosa nigra and SK can resemble each other histologically: DPN demonstrates a fibrous stroma, papillomatosis, hyperkeratosis, and acanthosis at the intraepidermal layer, which are diagnostic criteria for SK.^2,4,8 However, other histologic features characteristic of SK that are not seen in DPN include pseudohorn cysts, spindle tumor cells, and basaloid cell nests.⁸ 

Dermoscopy can be useful in ruling out malignant skin cancers when evaluating pigmented lesions. The most common dermoscopic features of SK are cerebriform patterns such as fissures and ridges, comedolike openings, and pigmented fingerprintlike structures.^3,4 To a lesser degree, milialike cysts, sharp demarcation, and hairpin-shaped vascular structures also may be present.4 The dermoscopic findings of DPN have not been well evaluated, but one study revealed that DPN had similar dermoscopic features to SK with some predominant features.⁶ Ridges and fissures were seen in 59% of patients diagnosed with DPN followed by comedolike openings seen in 27% of patients. The coexistence of a cerebriform pattern with comedolike openings was infrequent, and milialike cysts were rare.⁶ 

While DPN and SK are benign, patients often seek treatment for cosmetic reasons. Factors to consider when choosing a treatment modality include location of the lesions, the patient’s skin tone, and postprocedural outcomes (eg, depigmentation, wound healing). In general, treatments for SK include cryotherapy, electrodesiccation and curettage, and topical therapeutics such as hydrogen peroxide 40%, topical vitamin D3, and nitric-zinc 30%-50% solutions. 4,8 Well-established treatment options for DPN include electrodesiccation, laser therapies, scissor excision, and cryotherapy, but topical options such as tazarotene also have been reported.^1,9 Of the treatments for DPN, electrodesiccation and laser therapy routinely are used.¹⁰ 

The efficacy of electrodessication and potassium titanyl phosphate (KTP) laser were assessed in a randomized, investigatorblinded split-face study.¹¹ Both modalities received high improvement ratings, with the results favoring the KTP laser. The patients (most of whom were Black) reported that KTP laser was more effective but more painful than electrodessication (P =.002).¹¹ In another randomized study, patients received 3 treatments—electrodessication, pulsed dye laser, and curettage—for select DPN papules.¹⁰ There was no difference in the degree of clearance, cosmetic outcome, or postinflammatory hyperpigmentation between the 3 modalities, but patients found the laser to be the most painful. 

It is important to exercise caution when using abrasive methods (eg, laser therapy, electrodesiccation, curettage) in patients with darker skin tones because of the increased risk for postinflammatory pigment alteration.^1,2,12 Adverse effects of treatment are a top concern in the management of DPN.^5,13 While cryotherapy is a preferred treatment of SK in lighter skin tones, it generally is avoided for DPN in darker skin types because melanocyte destruction can lead to cosmetically unsatisfactory and easily visible depigmentation.⁹ 

To mitigate postprocedural adverse effects, proper aftercare can promote wound healing and minimize postinflammatory pigment alteration. In one split-face study of Black patients, 2 DPN papules were removed from each side of the face using fine-curved surgical scissors.¹⁴ Next, a petrolatum-based ointment and an antibiotic ointment with polymyxin B sulfate/bacitracin zinc was applied twice daily for 21 days to opposite sides of the face. Patients did not develop infection, tolerated both treatments well, and demonstrated improved general wound appearance according to investigator- rated clinical assessment.¹⁴ Other reported postprocedural approaches include using topical agents with ingredients shown to improve hyperpigmentation (eg, niacinamide, azelaic acid) as well as photoprotection.¹² 

HEALTH DISPARITY HIGHLIGHT 

While DPN is benign, it can have adverse psychosocial effects on patients. A study in Senegal revealed that 60% (19/30) of patients with DPN experienced anxiety related to their condition, while others noted that DPN hindered their social relationships.¹³ In one US study of 50 Black patients with DPN, there was a moderate effect on quality of life, and 36% (18/50) of patients had the lesions removed. However, of the treated patients, 67% (12/18) reported few—if any—symptoms prior to removal.⁵ Although treatment of DPN is widely considered a cosmetic procedure, therapeutic management can address— and may improve—mental health in patients with skin of color.^1,5,13 Despite the high prevalence of DPN in patients with darker skin tones, data on treatment frequency and insurance coverage are not widely available, thus limiting our understanding of treatment accessibility and economic burden. 

Dermatosis papulosa nigra (DPN), a subvariant of seborrheic keratosis (SK), is characterized by benign pigmented epidermal neoplasms that typically manifest on the face, neck, and trunk in individuals with darker skin tones (Figure).^1,2 While DPN meets the diagnostic criteria for SK, certain characteristics can help distinguish these lesions from other SK types. Treatment of DPN in patients with skin of color requires caution, particularly regarding the use of abrasive methods as well as cryotherapy, which generally should be avoided. 

EPIDEMIOLOGY 

The incidence of SKs increases with age.3,4 Although it can occur in patients of all skin tones, SK is more common in lighter skin tones, while DPN predominantly is diagnosed in darker skin types.^1,4 The prevalence of DPN in Black patients ranges from 10% to 30%, and Black women are twice as likely to be diagnosed with DPN as men.² One study reported a first-degree relative with DPN in 84% (42/50) of patients.⁵ The number and size of DPN papules increase with age.¹ 

KEY CLINICAL FEATURES 

Dermatosis papulosa nigra and SK have distinctive morphologies: DPN typically manifests as raised, round or filiform, sessile, brown to black, 1- to 5-mm papules. 2 Seborrheic keratoses tend to be larger with a “stuck on” appearance and manifest as well-demarcated, pink to black papules or plaques that can range in size from millimeters to a few centimeters. ^3,4 In DPN, the lesions usually are asymptomatic but may be tender, pruritic, dry, or scaly and may become irritated.^1,2 They develop symmetrically in sun-exposed areas, and the most common sites are the malar face, temporal region, neck, and trunk.^1,2,6,7 Seborrheic keratoses can appear throughout the body, including in sun-exposed areas, but have varying textures (eg, greasy, waxy, verrucous).^3,4 

WORTH NOTING 

Dermatosis papulosa nigra and SK can resemble each other histologically: DPN demonstrates a fibrous stroma, papillomatosis, hyperkeratosis, and acanthosis at the intraepidermal layer, which are diagnostic criteria for SK.^2,4,8 However, other histologic features characteristic of SK that are not seen in DPN include pseudohorn cysts, spindle tumor cells, and basaloid cell nests.⁸ 

Dermoscopy can be useful in ruling out malignant skin cancers when evaluating pigmented lesions. The most common dermoscopic features of SK are cerebriform patterns such as fissures and ridges, comedolike openings, and pigmented fingerprintlike structures.^3,4 To a lesser degree, milialike cysts, sharp demarcation, and hairpin-shaped vascular structures also may be present.4 The dermoscopic findings of DPN have not been well evaluated, but one study revealed that DPN had similar dermoscopic features to SK with some predominant features.⁶ Ridges and fissures were seen in 59% of patients diagnosed with DPN followed by comedolike openings seen in 27% of patients. The coexistence of a cerebriform pattern with comedolike openings was infrequent, and milialike cysts were rare.⁶ 

While DPN and SK are benign, patients often seek treatment for cosmetic reasons. Factors to consider when choosing a treatment modality include location of the lesions, the patient’s skin tone, and postprocedural outcomes (eg, depigmentation, wound healing). In general, treatments for SK include cryotherapy, electrodesiccation and curettage, and topical therapeutics such as hydrogen peroxide 40%, topical vitamin D3, and nitric-zinc 30%-50% solutions. 4,8 Well-established treatment options for DPN include electrodesiccation, laser therapies, scissor excision, and cryotherapy, but topical options such as tazarotene also have been reported.^1,9 Of the treatments for DPN, electrodesiccation and laser therapy routinely are used.¹⁰ 

The efficacy of electrodessication and potassium titanyl phosphate (KTP) laser were assessed in a randomized, investigatorblinded split-face study.¹¹ Both modalities received high improvement ratings, with the results favoring the KTP laser. The patients (most of whom were Black) reported that KTP laser was more effective but more painful than electrodessication (P =.002).¹¹ In another randomized study, patients received 3 treatments—electrodessication, pulsed dye laser, and curettage—for select DPN papules.¹⁰ There was no difference in the degree of clearance, cosmetic outcome, or postinflammatory hyperpigmentation between the 3 modalities, but patients found the laser to be the most painful. 

It is important to exercise caution when using abrasive methods (eg, laser therapy, electrodesiccation, curettage) in patients with darker skin tones because of the increased risk for postinflammatory pigment alteration.^1,2,12 Adverse effects of treatment are a top concern in the management of DPN.^5,13 While cryotherapy is a preferred treatment of SK in lighter skin tones, it generally is avoided for DPN in darker skin types because melanocyte destruction can lead to cosmetically unsatisfactory and easily visible depigmentation.⁹ 

To mitigate postprocedural adverse effects, proper aftercare can promote wound healing and minimize postinflammatory pigment alteration. In one split-face study of Black patients, 2 DPN papules were removed from each side of the face using fine-curved surgical scissors.¹⁴ Next, a petrolatum-based ointment and an antibiotic ointment with polymyxin B sulfate/bacitracin zinc was applied twice daily for 21 days to opposite sides of the face. Patients did not develop infection, tolerated both treatments well, and demonstrated improved general wound appearance according to investigator- rated clinical assessment.¹⁴ Other reported postprocedural approaches include using topical agents with ingredients shown to improve hyperpigmentation (eg, niacinamide, azelaic acid) as well as photoprotection.¹² 

HEALTH DISPARITY HIGHLIGHT 

While DPN is benign, it can have adverse psychosocial effects on patients. A study in Senegal revealed that 60% (19/30) of patients with DPN experienced anxiety related to their condition, while others noted that DPN hindered their social relationships.¹³ In one US study of 50 Black patients with DPN, there was a moderate effect on quality of life, and 36% (18/50) of patients had the lesions removed. However, of the treated patients, 67% (12/18) reported few—if any—symptoms prior to removal.⁵ Although treatment of DPN is widely considered a cosmetic procedure, therapeutic management can address— and may improve—mental health in patients with skin of color.^1,5,13 Despite the high prevalence of DPN in patients with darker skin tones, data on treatment frequency and insurance coverage are not widely available, thus limiting our understanding of treatment accessibility and economic burden. 

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

About half of US adults aged ≥ 65 years report arthritis, and of those, 44% have an arthritis-attributable activity limitation.^1,2 Arthritis is a significant health issue for veterans, with veterans reporting higher rates of disability compared with the civilian population.³

Osteoarthritis (OA) is the most common type of arthritis.⁴ Among individuals aged ≥ 40 years, the incidence of OA is nearly twice as high among veterans compared with civilians and is a leading cause of separation from military service and disability.^5,6 OA pain and disability have been shown to be associated with increases in health care and medication use, including opioids, nonsteroidal anti-inflammatory medications, and muscle relaxants.^7,8 Because OA is chronic and has no cure, safe and effective management strategies—such as exercise— are critical to minimize pain and maintain physical function.⁹

Exercise can reduce pain and disability associated with OA and is a first-line recommendation in guidelines for the treatment of knee and hip OA.⁹ Given the limited exercise and high levels of physical inactivity among veterans with OA, there is a need to identify opportunities that support veterans with OA engaging in regular exercise.

Gerofit, an outpatient clinical exercise program available at 30 Veterans Health Administration (VHA) sites, may provide an opportunity for older veterans with arthritis to engage in exercise.¹⁰ Gerofit is specifically designed for veterans aged ≥ 65 years. It is not disease-specific and supports older veterans with multiple chronic conditions, including OA. Veterans aged ≥ 65 years with a referral from a VA clinician are eligible for Gerofit. Those who are unable to perform activities of daily living; unable to independently function without assistance; have a history of unstable angina, proliferative diabetic retinopathy, oxygen dependence, volatile behavioral issues, or are unable to work successfully in a group environment/setting; experience active substance abuse, homelessness, or uncontrolled incontinence; and have open wounds that cannot be appropriately dressed are excluded from Gerofit. Exercise sessions are held 3 times per week and last from 60 to 90 minutes. Sessions are supervised by Gerofit staff and include personalized exercise prescriptions based on functional assessments. Exercise prescriptions include aerobic, resistance, and balance/flexibility components and are modified by the Gerofit program staff as needed. Gerofit adopts a functional fitness approach and includes individual progression as appropriate according to evidence-based guidelines, using the Borg ratings of perceived exertion. ¹¹ Assessments are performed at baseline, 3 months, 6 months, and annually thereafter. Clinical staff conduct all assessments, including physical function testing, and record them in a database. Assessments are reviewed with the veteran to chart progress and identify future goals or needs. Veterans perform personalized self-paced exercises in the Gerofit group setting. Exercise prescriptions are continuously modified to meet individualized needs and goals. Veterans may participate continuously with no end date.

Participation in supervised exercise is associated with improved physical function and individuals with arthritis can improve function even though their baseline functional status is lower than individuals without arthritis. ¹² In this analysis, we examine the impact of exercise on the status and location of arthritis (upper body, lower body, or both). Lower body arthritis is more common than upper body arthritis and lower extremity function is associated with increased ability to perform activities of daily living, resulting in independence among older adults.^13,14 We also include upper body strength measures to capture important functional movements such as reaching and pulling.¹⁵ Among those who participate in Gerofit, the greatest gains in physical function occur during the initial 3 months, which tend to be sustained over 12 months.¹⁶ For this reason, this study focused on the initial 3 months of the program.

Older adults with arthritis may have pain and functional limitations that exceed those of the general older adult population. Exercise programs for older adults that do not specifically target arthritis but are able to improve physical function among those with arthritis could potentially increase access to exercise for older adults living with arthritis. Therefore, the purpose of this study was to determine whether change in physical function with participation in Gerofit for 3 months varies by arthritis status, including no arthritis, any arthritis, lower body arthritis, or both upper and lower body arthritis compared with no arthritis.

Methods

This is a secondary analysis of previously collected data from 10 VHA Gerofit sites (Ann Arbor, Baltimore, Greater Los Angeles, Canandaigua, Cincinnati, Miami, Honolulu, Denver, Durham, and Pittsburgh) from 2002 to 2019. Implementation data regarding the consistency of the program delivery at Gerofit expansion sites have been previously published.¹⁶ Although the delivery of Gerofit transitioned to telehealth due to COVID-19, data for this analysis were collected from in-person exercise sessions prior to the pandemic.¹⁷ Data were collected for clinical purposes. This project was part of the Gerofit quality improvement initiative and was reviewed and approved by the Durham Institutional Review Board as quality improvement.

Participants in Gerofit who completed baseline and 3-month assessments were included to analyze the effects of exercise on physical function. At each of the time points, physical functional assessments included: (1) usual gait speed (> 10 meters [m/s], or 10- meter walk test [10MWT]); (2) lower body strength (chair stands [number completed in 30 seconds]); (3) upper body strength (number of arm curls [5-lb for females/8-lb for males] completed in 30 seconds); and (4) 6-minute walk distance [6MWD] in meters to measure aerobic endurance). These measures have been validated in older adults.^18-21 Arm curls were added to the physical function assessments after the 10MWT, chair stands, and 6MWD; therefore, fewer participants had data for this measure. Participants self-reported at baseline on 45 common medical conditions, including arthritis or rheumatism (both upper body and lower body were offered as choices). Self-reporting has been shown to be an acceptable method of identifying arthritis in adults.²²

Descriptive statistics at baseline were calculated for all participants. One-way analysis of variance and X² tests were used to determine differences in baseline characteristics across arthritis status. The primary outcomes were changes in physical function measures from baseline to 3 months by arthritis status. Arthritis status was defined as: any arthritis, which includes individuals who reported upper body arthritis, lower body arthritis, or both; and arthritis status individuals reporting either upper body arthritis, lower body arthritis, or both. Categories of arthritis for arthritis status were mutually exclusive. Two separate linear models were constructed for each of the 4 physical function measures, with change from baseline to 3 months as the outcome (dependent variable) and arthritis status, age, and body mass index (BMI) as predictors (independent variables). The first model compared any arthritis with no arthritis and the second model compared arthritis status (both upper and lower body arthritis vs lower body arthritis) with no arthritis. These models were used to obtain mean changes and 95% CIs in physical function and to test for differences in the change in physical function measures by arthritis status. Statistical analyses were performed using R software, version 4.0.3.

Results

Baseline and 3-month data were available for 737 Gerofit participants and included in the analysis. The mean (SD) age was 73.5 (7.1) years. A total of 707 participants were male (95.9%) and 322 (43.6%) reported some arthritis, with arthritis in both the upper and lower body being reported by 168 participants (52.2%) (Table 1). There were no differences in age, sex, or race for those with any arthritis compared with those with no arthritis, but BMI was significantly higher in those reporting any arthritis compared with no arthritis. For the baseline functional measures, statistically significant differences were observed between those with no arthritis and those reporting any arthritis for the 10MWT (P = .001), chair stands (P = .046), and 6MWD (P = .001), but not for arm curls (P = .77), with those with no arthritis performing better.

All 4 arthritis status groups showed improvements in each of the physical function measures over 3 months. For the 10MWT the mean change (95% CI) in gait speed (m/s) was 0.06 (0.04-0.08) for patients with no arthritis, 0.07 (0.05- 0.08) for any arthritis, 0.07 (0.04-0.11) for lower body arthritis, and 0.07 (0.04- 0.09) for both lower and upper body arthritis. For the number of arm curls in 30 seconds the mean change (95% CI) was 2.3 (1.8-2.8) for patients with no arthritis, 2.1 (1.5-2.6) for any arthritis, 2.0 (1.1-3.0) for lower body arthritis, and 1.9 (1.1-2.7) for both lower and upper body arthritis. For the number of chair stands in 30 seconds the mean change (95% CI) was 2.1 (1.7-2.4) for patients with no arthritis, 2.2 (1.8-2.6) for any arthritis, 2.3 (1.6-2.9), for lower body arthritis, and 2.0 (1.5-2.5) for both lower and upper body arthritis. For the 6MWD distance in meters the mean change (95% CI) was 21.5 (15.5-27.4) for patients with no arthritis, 28.6 (21.9-35.3) for any arthritis, 30.4 (19.5-41.3) for lower body arthritis, and 28.6 (19.2-38.0) for both lower and upper body arthritis (Figure).

We used 2 models to measure the change from baseline to 3 months for each of the arthritis groups. Model 1 compared any arthritis vs no arthritis and model 2 compared lower body arthritis and both upper and lower body arthritis vs no arthritis for each physical function measure (Table 2). There were no statistically significant differences in 3-month change in physical function for any of the physical function measures between arthritis groups after adjusting for age and BMI.

Discussion

Participation in Gerofit was associated with functional gains among all participants over 3 months, regardless of arthritis status. Older veterans reporting any arthritis had significantly lower physical function scores upon enrollment into Gerofit compared with those veterans reporting no arthritis. However, compared with individuals who reported no arthritis, individuals who reported arthritis (any arthritis, lower body arthritis only, or both lower and upper body arthritis) experienced similar improvements (ie, no statistically significant differences in mean change from baseline to follow-up among those with and without arthritis). This study suggests that progressive, multicomponent exercise programs for older adults may be beneficial for those with arthritis.

Involvement of multiple sites of arthritis is associated with moderate to severe functional limitations as well as lower healthrelated quality of life.²³ While it has been found that individuals with arthritis can improve function with supervised exercise, even though their baseline functional status is lower than individuals without arthritis, it was not clear whether individuals with multiple joint involvement also would benefit.¹² The results of this study suggest that these individuals can improve across various domains of physical function despite variation in arthritis location and status. As incidence of arthritis increases with age, targeting older adults for exercise programs such as Gerofit may improve functional limitations and health-related quality of life associated with arthritis.²

We evaluated physical function using multiple measures to assess upper (arm curls) and lower (chair stands, 10MWT) extremity physical function and aerobic endurance (6MWD). Participants in this study reached clinically meaningful changes with 3 months of participation in Gerofit for most of the physical function measures. Gerofit participants had a mean gait speed improvement of 0.05 to 0.07 m/s compared with 0.10 to 0.30 m/s, which was reported previously. ^24,25 In this study, nearly all groups achieved the clinically important improvements in the chair stand in 30 seconds (2.0 to 2.6) and the 6MWD (21.8 to 59.1 m) that have been reported in the literature.^24-26

The Osteoarthritis Research Society International recommends the chair stand and 6MWD performance-based tests for individuals with hip and knee arthritis because they align with patient-reported outcomes and represent the types of activities relevant to this population.²⁷ The findings of this study suggest that improvement in these physical function measures with participation in exercise align with data from arthritis-specific exercise programs designed for wide implementation. Hughes and colleagues reported improvements in the 6MWD after the 8-week Fit and Strong exercise intervention, which included walking and lower body resistance training.²⁸ The Arthritis Foundation’s Walk With Ease program is a 6-week walking program that has shown improvements in chair stands and gait speed.²⁹ Another Arthritis Foundation program, People with Arthritis Can Exercise, is an 8-week course consisting of a variety of resistance, aerobic, and balance activities. This program has been associated with increases in chair stands but not gait speed or 6MWD.^30,31

This study found that participation in a VHA outpatient clinical supervised exercise program results in improvements in physical function that can be realized by older adults regardless of arthritis burden. Gerofit programs typically require 1.5 to 2.0 dedicated full-time equivalent employees to run the program effectively and additional administrative support, depending on size of the program.³² The cost savings generated by the program include reductions in hospitalization rates, emergency department visits, days in hospital, and medication use and provide a compelling argument for the program’s financial viability to health care systems through long-term savings and improved health outcomes for older adults.^33-36

While evidenced-based arthritis programs exist, this study illustrates that an exercise program without a focus on arthritis also improves physical function, potentially reducing the risk of disability related to arthritis. The clinical implication for these findings is that arthritis-specific exercise programs may not be needed to achieve functional improvements in individuals with arthritis. This is critical for under-resourced or exercise- limited health care systems or communities. Therefore, if exercise programming is limited, or arthritis-specific programs and interventions are not available, nonspecific exercise programs will also be beneficial to individuals with arthritis. Thus, individuals with arthritis should be encouraged to participate in any available exercise programming to achieve improvements in physical function. In addition, many older adults have multiple comorbidities, most of which improve with participation in exercise. ³⁷ Disease-specific exercise programs can offer tailored exercises and coaching related to common barriers in participation, such as joint pain for arthritis.³¹ It is unclear whether these additional programmatic components are associated with greater improvements in outcomes, such as physical function. More research is needed to explore the benefits of disease-specific tailored exercise programs compared with general exercise programs.

Strengths and Limitations

This study demonstrated the effect of participation in a clinical, supervised exercise program in a real-world setting. It suggests that even exercise programs not specifically targeted for arthritis populations can improve physical function among those with arthritis.

As a VHA clinical supervised exercise program, Gerofit may not be generalizable to all older adults or other exercise programs. In addition, this analysis only included a veteran population that was > 95% male and may not be generalizable to other populations. Arthritis status was defined by self-report and not verified in the health record. However, this approach has been shown to be acceptable in this setting and the most common type of arthritis in this population (OA) is a painful musculoskeletal condition associated with functional limitations.^4,22,38,39 Self-reported arthritis or rheumatism is associated with functional limitations.¹ Therefore, it is unlikely that the results would differ for physician-diagnosed or radiographically defined OA. Additionally, the study did not have data on the total number of joints with arthritis or arthritis severity but rather used upper body, lower body, and both upper and lower body arthritis as a proxy for arthritis status. While our models were adjusted for age and BMI, 2 known confounding factors for the association between arthritis and physical function, there are other potential confounding factors that were not included in the models. ^40,41 Finally, this study only included individuals with completed baseline and 3-month follow-up assessments, and the individuals who participated for longer or shorter periods may have had different physical function outcomes than individuals included in this study.

Conclusions

Participation in 3 months VHA Gerofit outpatient supervised exercise programs can improve physical function for all older adults, regardless of arthritis status. These programs may increase access to exercise programming that is beneficial for common conditions affecting older adults, such as arthritis.

About half of US adults aged ≥ 65 years report arthritis, and of those, 44% have an arthritis-attributable activity limitation.^1,2 Arthritis is a significant health issue for veterans, with veterans reporting higher rates of disability compared with the civilian population.³

Osteoarthritis (OA) is the most common type of arthritis.⁴ Among individuals aged ≥ 40 years, the incidence of OA is nearly twice as high among veterans compared with civilians and is a leading cause of separation from military service and disability.^5,6 OA pain and disability have been shown to be associated with increases in health care and medication use, including opioids, nonsteroidal anti-inflammatory medications, and muscle relaxants.^7,8 Because OA is chronic and has no cure, safe and effective management strategies—such as exercise— are critical to minimize pain and maintain physical function.⁹

Exercise can reduce pain and disability associated with OA and is a first-line recommendation in guidelines for the treatment of knee and hip OA.⁹ Given the limited exercise and high levels of physical inactivity among veterans with OA, there is a need to identify opportunities that support veterans with OA engaging in regular exercise.

Gerofit, an outpatient clinical exercise program available at 30 Veterans Health Administration (VHA) sites, may provide an opportunity for older veterans with arthritis to engage in exercise.¹⁰ Gerofit is specifically designed for veterans aged ≥ 65 years. It is not disease-specific and supports older veterans with multiple chronic conditions, including OA. Veterans aged ≥ 65 years with a referral from a VA clinician are eligible for Gerofit. Those who are unable to perform activities of daily living; unable to independently function without assistance; have a history of unstable angina, proliferative diabetic retinopathy, oxygen dependence, volatile behavioral issues, or are unable to work successfully in a group environment/setting; experience active substance abuse, homelessness, or uncontrolled incontinence; and have open wounds that cannot be appropriately dressed are excluded from Gerofit. Exercise sessions are held 3 times per week and last from 60 to 90 minutes. Sessions are supervised by Gerofit staff and include personalized exercise prescriptions based on functional assessments. Exercise prescriptions include aerobic, resistance, and balance/flexibility components and are modified by the Gerofit program staff as needed. Gerofit adopts a functional fitness approach and includes individual progression as appropriate according to evidence-based guidelines, using the Borg ratings of perceived exertion. ¹¹ Assessments are performed at baseline, 3 months, 6 months, and annually thereafter. Clinical staff conduct all assessments, including physical function testing, and record them in a database. Assessments are reviewed with the veteran to chart progress and identify future goals or needs. Veterans perform personalized self-paced exercises in the Gerofit group setting. Exercise prescriptions are continuously modified to meet individualized needs and goals. Veterans may participate continuously with no end date.

Participation in supervised exercise is associated with improved physical function and individuals with arthritis can improve function even though their baseline functional status is lower than individuals without arthritis. ¹² In this analysis, we examine the impact of exercise on the status and location of arthritis (upper body, lower body, or both). Lower body arthritis is more common than upper body arthritis and lower extremity function is associated with increased ability to perform activities of daily living, resulting in independence among older adults.^13,14 We also include upper body strength measures to capture important functional movements such as reaching and pulling.¹⁵ Among those who participate in Gerofit, the greatest gains in physical function occur during the initial 3 months, which tend to be sustained over 12 months.¹⁶ For this reason, this study focused on the initial 3 months of the program.

Older adults with arthritis may have pain and functional limitations that exceed those of the general older adult population. Exercise programs for older adults that do not specifically target arthritis but are able to improve physical function among those with arthritis could potentially increase access to exercise for older adults living with arthritis. Therefore, the purpose of this study was to determine whether change in physical function with participation in Gerofit for 3 months varies by arthritis status, including no arthritis, any arthritis, lower body arthritis, or both upper and lower body arthritis compared with no arthritis.

Methods

This is a secondary analysis of previously collected data from 10 VHA Gerofit sites (Ann Arbor, Baltimore, Greater Los Angeles, Canandaigua, Cincinnati, Miami, Honolulu, Denver, Durham, and Pittsburgh) from 2002 to 2019. Implementation data regarding the consistency of the program delivery at Gerofit expansion sites have been previously published.¹⁶ Although the delivery of Gerofit transitioned to telehealth due to COVID-19, data for this analysis were collected from in-person exercise sessions prior to the pandemic.¹⁷ Data were collected for clinical purposes. This project was part of the Gerofit quality improvement initiative and was reviewed and approved by the Durham Institutional Review Board as quality improvement.

Participants in Gerofit who completed baseline and 3-month assessments were included to analyze the effects of exercise on physical function. At each of the time points, physical functional assessments included: (1) usual gait speed (> 10 meters [m/s], or 10- meter walk test [10MWT]); (2) lower body strength (chair stands [number completed in 30 seconds]); (3) upper body strength (number of arm curls [5-lb for females/8-lb for males] completed in 30 seconds); and (4) 6-minute walk distance [6MWD] in meters to measure aerobic endurance). These measures have been validated in older adults.^18-21 Arm curls were added to the physical function assessments after the 10MWT, chair stands, and 6MWD; therefore, fewer participants had data for this measure. Participants self-reported at baseline on 45 common medical conditions, including arthritis or rheumatism (both upper body and lower body were offered as choices). Self-reporting has been shown to be an acceptable method of identifying arthritis in adults.²²

Descriptive statistics at baseline were calculated for all participants. One-way analysis of variance and X² tests were used to determine differences in baseline characteristics across arthritis status. The primary outcomes were changes in physical function measures from baseline to 3 months by arthritis status. Arthritis status was defined as: any arthritis, which includes individuals who reported upper body arthritis, lower body arthritis, or both; and arthritis status individuals reporting either upper body arthritis, lower body arthritis, or both. Categories of arthritis for arthritis status were mutually exclusive. Two separate linear models were constructed for each of the 4 physical function measures, with change from baseline to 3 months as the outcome (dependent variable) and arthritis status, age, and body mass index (BMI) as predictors (independent variables). The first model compared any arthritis with no arthritis and the second model compared arthritis status (both upper and lower body arthritis vs lower body arthritis) with no arthritis. These models were used to obtain mean changes and 95% CIs in physical function and to test for differences in the change in physical function measures by arthritis status. Statistical analyses were performed using R software, version 4.0.3.

Results

Baseline and 3-month data were available for 737 Gerofit participants and included in the analysis. The mean (SD) age was 73.5 (7.1) years. A total of 707 participants were male (95.9%) and 322 (43.6%) reported some arthritis, with arthritis in both the upper and lower body being reported by 168 participants (52.2%) (Table 1). There were no differences in age, sex, or race for those with any arthritis compared with those with no arthritis, but BMI was significantly higher in those reporting any arthritis compared with no arthritis. For the baseline functional measures, statistically significant differences were observed between those with no arthritis and those reporting any arthritis for the 10MWT (P = .001), chair stands (P = .046), and 6MWD (P = .001), but not for arm curls (P = .77), with those with no arthritis performing better.

All 4 arthritis status groups showed improvements in each of the physical function measures over 3 months. For the 10MWT the mean change (95% CI) in gait speed (m/s) was 0.06 (0.04-0.08) for patients with no arthritis, 0.07 (0.05- 0.08) for any arthritis, 0.07 (0.04-0.11) for lower body arthritis, and 0.07 (0.04- 0.09) for both lower and upper body arthritis. For the number of arm curls in 30 seconds the mean change (95% CI) was 2.3 (1.8-2.8) for patients with no arthritis, 2.1 (1.5-2.6) for any arthritis, 2.0 (1.1-3.0) for lower body arthritis, and 1.9 (1.1-2.7) for both lower and upper body arthritis. For the number of chair stands in 30 seconds the mean change (95% CI) was 2.1 (1.7-2.4) for patients with no arthritis, 2.2 (1.8-2.6) for any arthritis, 2.3 (1.6-2.9), for lower body arthritis, and 2.0 (1.5-2.5) for both lower and upper body arthritis. For the 6MWD distance in meters the mean change (95% CI) was 21.5 (15.5-27.4) for patients with no arthritis, 28.6 (21.9-35.3) for any arthritis, 30.4 (19.5-41.3) for lower body arthritis, and 28.6 (19.2-38.0) for both lower and upper body arthritis (Figure).

We used 2 models to measure the change from baseline to 3 months for each of the arthritis groups. Model 1 compared any arthritis vs no arthritis and model 2 compared lower body arthritis and both upper and lower body arthritis vs no arthritis for each physical function measure (Table 2). There were no statistically significant differences in 3-month change in physical function for any of the physical function measures between arthritis groups after adjusting for age and BMI.

Discussion

Participation in Gerofit was associated with functional gains among all participants over 3 months, regardless of arthritis status. Older veterans reporting any arthritis had significantly lower physical function scores upon enrollment into Gerofit compared with those veterans reporting no arthritis. However, compared with individuals who reported no arthritis, individuals who reported arthritis (any arthritis, lower body arthritis only, or both lower and upper body arthritis) experienced similar improvements (ie, no statistically significant differences in mean change from baseline to follow-up among those with and without arthritis). This study suggests that progressive, multicomponent exercise programs for older adults may be beneficial for those with arthritis.

Involvement of multiple sites of arthritis is associated with moderate to severe functional limitations as well as lower healthrelated quality of life.²³ While it has been found that individuals with arthritis can improve function with supervised exercise, even though their baseline functional status is lower than individuals without arthritis, it was not clear whether individuals with multiple joint involvement also would benefit.¹² The results of this study suggest that these individuals can improve across various domains of physical function despite variation in arthritis location and status. As incidence of arthritis increases with age, targeting older adults for exercise programs such as Gerofit may improve functional limitations and health-related quality of life associated with arthritis.²

We evaluated physical function using multiple measures to assess upper (arm curls) and lower (chair stands, 10MWT) extremity physical function and aerobic endurance (6MWD). Participants in this study reached clinically meaningful changes with 3 months of participation in Gerofit for most of the physical function measures. Gerofit participants had a mean gait speed improvement of 0.05 to 0.07 m/s compared with 0.10 to 0.30 m/s, which was reported previously. ^24,25 In this study, nearly all groups achieved the clinically important improvements in the chair stand in 30 seconds (2.0 to 2.6) and the 6MWD (21.8 to 59.1 m) that have been reported in the literature.^24-26

The Osteoarthritis Research Society International recommends the chair stand and 6MWD performance-based tests for individuals with hip and knee arthritis because they align with patient-reported outcomes and represent the types of activities relevant to this population.²⁷ The findings of this study suggest that improvement in these physical function measures with participation in exercise align with data from arthritis-specific exercise programs designed for wide implementation. Hughes and colleagues reported improvements in the 6MWD after the 8-week Fit and Strong exercise intervention, which included walking and lower body resistance training.²⁸ The Arthritis Foundation’s Walk With Ease program is a 6-week walking program that has shown improvements in chair stands and gait speed.²⁹ Another Arthritis Foundation program, People with Arthritis Can Exercise, is an 8-week course consisting of a variety of resistance, aerobic, and balance activities. This program has been associated with increases in chair stands but not gait speed or 6MWD.^30,31

This study found that participation in a VHA outpatient clinical supervised exercise program results in improvements in physical function that can be realized by older adults regardless of arthritis burden. Gerofit programs typically require 1.5 to 2.0 dedicated full-time equivalent employees to run the program effectively and additional administrative support, depending on size of the program.³² The cost savings generated by the program include reductions in hospitalization rates, emergency department visits, days in hospital, and medication use and provide a compelling argument for the program’s financial viability to health care systems through long-term savings and improved health outcomes for older adults.^33-36

While evidenced-based arthritis programs exist, this study illustrates that an exercise program without a focus on arthritis also improves physical function, potentially reducing the risk of disability related to arthritis. The clinical implication for these findings is that arthritis-specific exercise programs may not be needed to achieve functional improvements in individuals with arthritis. This is critical for under-resourced or exercise- limited health care systems or communities. Therefore, if exercise programming is limited, or arthritis-specific programs and interventions are not available, nonspecific exercise programs will also be beneficial to individuals with arthritis. Thus, individuals with arthritis should be encouraged to participate in any available exercise programming to achieve improvements in physical function. In addition, many older adults have multiple comorbidities, most of which improve with participation in exercise. ³⁷ Disease-specific exercise programs can offer tailored exercises and coaching related to common barriers in participation, such as joint pain for arthritis.³¹ It is unclear whether these additional programmatic components are associated with greater improvements in outcomes, such as physical function. More research is needed to explore the benefits of disease-specific tailored exercise programs compared with general exercise programs.

Strengths and Limitations

This study demonstrated the effect of participation in a clinical, supervised exercise program in a real-world setting. It suggests that even exercise programs not specifically targeted for arthritis populations can improve physical function among those with arthritis.

As a VHA clinical supervised exercise program, Gerofit may not be generalizable to all older adults or other exercise programs. In addition, this analysis only included a veteran population that was > 95% male and may not be generalizable to other populations. Arthritis status was defined by self-report and not verified in the health record. However, this approach has been shown to be acceptable in this setting and the most common type of arthritis in this population (OA) is a painful musculoskeletal condition associated with functional limitations.^4,22,38,39 Self-reported arthritis or rheumatism is associated with functional limitations.¹ Therefore, it is unlikely that the results would differ for physician-diagnosed or radiographically defined OA. Additionally, the study did not have data on the total number of joints with arthritis or arthritis severity but rather used upper body, lower body, and both upper and lower body arthritis as a proxy for arthritis status. While our models were adjusted for age and BMI, 2 known confounding factors for the association between arthritis and physical function, there are other potential confounding factors that were not included in the models. ^40,41 Finally, this study only included individuals with completed baseline and 3-month follow-up assessments, and the individuals who participated for longer or shorter periods may have had different physical function outcomes than individuals included in this study.

Conclusions

Participation in 3 months VHA Gerofit outpatient supervised exercise programs can improve physical function for all older adults, regardless of arthritis status. These programs may increase access to exercise programming that is beneficial for common conditions affecting older adults, such as arthritis.

About half of US adults aged ≥ 65 years report arthritis, and of those, 44% have an arthritis-attributable activity limitation.^1,2 Arthritis is a significant health issue for veterans, with veterans reporting higher rates of disability compared with the civilian population.³

Osteoarthritis (OA) is the most common type of arthritis.⁴ Among individuals aged ≥ 40 years, the incidence of OA is nearly twice as high among veterans compared with civilians and is a leading cause of separation from military service and disability.^5,6 OA pain and disability have been shown to be associated with increases in health care and medication use, including opioids, nonsteroidal anti-inflammatory medications, and muscle relaxants.^7,8 Because OA is chronic and has no cure, safe and effective management strategies—such as exercise— are critical to minimize pain and maintain physical function.⁹

Exercise can reduce pain and disability associated with OA and is a first-line recommendation in guidelines for the treatment of knee and hip OA.⁹ Given the limited exercise and high levels of physical inactivity among veterans with OA, there is a need to identify opportunities that support veterans with OA engaging in regular exercise.

Gerofit, an outpatient clinical exercise program available at 30 Veterans Health Administration (VHA) sites, may provide an opportunity for older veterans with arthritis to engage in exercise.¹⁰ Gerofit is specifically designed for veterans aged ≥ 65 years. It is not disease-specific and supports older veterans with multiple chronic conditions, including OA. Veterans aged ≥ 65 years with a referral from a VA clinician are eligible for Gerofit. Those who are unable to perform activities of daily living; unable to independently function without assistance; have a history of unstable angina, proliferative diabetic retinopathy, oxygen dependence, volatile behavioral issues, or are unable to work successfully in a group environment/setting; experience active substance abuse, homelessness, or uncontrolled incontinence; and have open wounds that cannot be appropriately dressed are excluded from Gerofit. Exercise sessions are held 3 times per week and last from 60 to 90 minutes. Sessions are supervised by Gerofit staff and include personalized exercise prescriptions based on functional assessments. Exercise prescriptions include aerobic, resistance, and balance/flexibility components and are modified by the Gerofit program staff as needed. Gerofit adopts a functional fitness approach and includes individual progression as appropriate according to evidence-based guidelines, using the Borg ratings of perceived exertion. ¹¹ Assessments are performed at baseline, 3 months, 6 months, and annually thereafter. Clinical staff conduct all assessments, including physical function testing, and record them in a database. Assessments are reviewed with the veteran to chart progress and identify future goals or needs. Veterans perform personalized self-paced exercises in the Gerofit group setting. Exercise prescriptions are continuously modified to meet individualized needs and goals. Veterans may participate continuously with no end date.

Participation in supervised exercise is associated with improved physical function and individuals with arthritis can improve function even though their baseline functional status is lower than individuals without arthritis. ¹² In this analysis, we examine the impact of exercise on the status and location of arthritis (upper body, lower body, or both). Lower body arthritis is more common than upper body arthritis and lower extremity function is associated with increased ability to perform activities of daily living, resulting in independence among older adults.^13,14 We also include upper body strength measures to capture important functional movements such as reaching and pulling.¹⁵ Among those who participate in Gerofit, the greatest gains in physical function occur during the initial 3 months, which tend to be sustained over 12 months.¹⁶ For this reason, this study focused on the initial 3 months of the program.

Older adults with arthritis may have pain and functional limitations that exceed those of the general older adult population. Exercise programs for older adults that do not specifically target arthritis but are able to improve physical function among those with arthritis could potentially increase access to exercise for older adults living with arthritis. Therefore, the purpose of this study was to determine whether change in physical function with participation in Gerofit for 3 months varies by arthritis status, including no arthritis, any arthritis, lower body arthritis, or both upper and lower body arthritis compared with no arthritis.

Methods

This is a secondary analysis of previously collected data from 10 VHA Gerofit sites (Ann Arbor, Baltimore, Greater Los Angeles, Canandaigua, Cincinnati, Miami, Honolulu, Denver, Durham, and Pittsburgh) from 2002 to 2019. Implementation data regarding the consistency of the program delivery at Gerofit expansion sites have been previously published.¹⁶ Although the delivery of Gerofit transitioned to telehealth due to COVID-19, data for this analysis were collected from in-person exercise sessions prior to the pandemic.¹⁷ Data were collected for clinical purposes. This project was part of the Gerofit quality improvement initiative and was reviewed and approved by the Durham Institutional Review Board as quality improvement.

Participants in Gerofit who completed baseline and 3-month assessments were included to analyze the effects of exercise on physical function. At each of the time points, physical functional assessments included: (1) usual gait speed (> 10 meters [m/s], or 10- meter walk test [10MWT]); (2) lower body strength (chair stands [number completed in 30 seconds]); (3) upper body strength (number of arm curls [5-lb for females/8-lb for males] completed in 30 seconds); and (4) 6-minute walk distance [6MWD] in meters to measure aerobic endurance). These measures have been validated in older adults.^18-21 Arm curls were added to the physical function assessments after the 10MWT, chair stands, and 6MWD; therefore, fewer participants had data for this measure. Participants self-reported at baseline on 45 common medical conditions, including arthritis or rheumatism (both upper body and lower body were offered as choices). Self-reporting has been shown to be an acceptable method of identifying arthritis in adults.²²

Descriptive statistics at baseline were calculated for all participants. One-way analysis of variance and X² tests were used to determine differences in baseline characteristics across arthritis status. The primary outcomes were changes in physical function measures from baseline to 3 months by arthritis status. Arthritis status was defined as: any arthritis, which includes individuals who reported upper body arthritis, lower body arthritis, or both; and arthritis status individuals reporting either upper body arthritis, lower body arthritis, or both. Categories of arthritis for arthritis status were mutually exclusive. Two separate linear models were constructed for each of the 4 physical function measures, with change from baseline to 3 months as the outcome (dependent variable) and arthritis status, age, and body mass index (BMI) as predictors (independent variables). The first model compared any arthritis with no arthritis and the second model compared arthritis status (both upper and lower body arthritis vs lower body arthritis) with no arthritis. These models were used to obtain mean changes and 95% CIs in physical function and to test for differences in the change in physical function measures by arthritis status. Statistical analyses were performed using R software, version 4.0.3.

Results

Baseline and 3-month data were available for 737 Gerofit participants and included in the analysis. The mean (SD) age was 73.5 (7.1) years. A total of 707 participants were male (95.9%) and 322 (43.6%) reported some arthritis, with arthritis in both the upper and lower body being reported by 168 participants (52.2%) (Table 1). There were no differences in age, sex, or race for those with any arthritis compared with those with no arthritis, but BMI was significantly higher in those reporting any arthritis compared with no arthritis. For the baseline functional measures, statistically significant differences were observed between those with no arthritis and those reporting any arthritis for the 10MWT (P = .001), chair stands (P = .046), and 6MWD (P = .001), but not for arm curls (P = .77), with those with no arthritis performing better.

All 4 arthritis status groups showed improvements in each of the physical function measures over 3 months. For the 10MWT the mean change (95% CI) in gait speed (m/s) was 0.06 (0.04-0.08) for patients with no arthritis, 0.07 (0.05- 0.08) for any arthritis, 0.07 (0.04-0.11) for lower body arthritis, and 0.07 (0.04- 0.09) for both lower and upper body arthritis. For the number of arm curls in 30 seconds the mean change (95% CI) was 2.3 (1.8-2.8) for patients with no arthritis, 2.1 (1.5-2.6) for any arthritis, 2.0 (1.1-3.0) for lower body arthritis, and 1.9 (1.1-2.7) for both lower and upper body arthritis. For the number of chair stands in 30 seconds the mean change (95% CI) was 2.1 (1.7-2.4) for patients with no arthritis, 2.2 (1.8-2.6) for any arthritis, 2.3 (1.6-2.9), for lower body arthritis, and 2.0 (1.5-2.5) for both lower and upper body arthritis. For the 6MWD distance in meters the mean change (95% CI) was 21.5 (15.5-27.4) for patients with no arthritis, 28.6 (21.9-35.3) for any arthritis, 30.4 (19.5-41.3) for lower body arthritis, and 28.6 (19.2-38.0) for both lower and upper body arthritis (Figure).

We used 2 models to measure the change from baseline to 3 months for each of the arthritis groups. Model 1 compared any arthritis vs no arthritis and model 2 compared lower body arthritis and both upper and lower body arthritis vs no arthritis for each physical function measure (Table 2). There were no statistically significant differences in 3-month change in physical function for any of the physical function measures between arthritis groups after adjusting for age and BMI.

Discussion

Participation in Gerofit was associated with functional gains among all participants over 3 months, regardless of arthritis status. Older veterans reporting any arthritis had significantly lower physical function scores upon enrollment into Gerofit compared with those veterans reporting no arthritis. However, compared with individuals who reported no arthritis, individuals who reported arthritis (any arthritis, lower body arthritis only, or both lower and upper body arthritis) experienced similar improvements (ie, no statistically significant differences in mean change from baseline to follow-up among those with and without arthritis). This study suggests that progressive, multicomponent exercise programs for older adults may be beneficial for those with arthritis.

Involvement of multiple sites of arthritis is associated with moderate to severe functional limitations as well as lower healthrelated quality of life.²³ While it has been found that individuals with arthritis can improve function with supervised exercise, even though their baseline functional status is lower than individuals without arthritis, it was not clear whether individuals with multiple joint involvement also would benefit.¹² The results of this study suggest that these individuals can improve across various domains of physical function despite variation in arthritis location and status. As incidence of arthritis increases with age, targeting older adults for exercise programs such as Gerofit may improve functional limitations and health-related quality of life associated with arthritis.²

We evaluated physical function using multiple measures to assess upper (arm curls) and lower (chair stands, 10MWT) extremity physical function and aerobic endurance (6MWD). Participants in this study reached clinically meaningful changes with 3 months of participation in Gerofit for most of the physical function measures. Gerofit participants had a mean gait speed improvement of 0.05 to 0.07 m/s compared with 0.10 to 0.30 m/s, which was reported previously. ^24,25 In this study, nearly all groups achieved the clinically important improvements in the chair stand in 30 seconds (2.0 to 2.6) and the 6MWD (21.8 to 59.1 m) that have been reported in the literature.^24-26

The Osteoarthritis Research Society International recommends the chair stand and 6MWD performance-based tests for individuals with hip and knee arthritis because they align with patient-reported outcomes and represent the types of activities relevant to this population.²⁷ The findings of this study suggest that improvement in these physical function measures with participation in exercise align with data from arthritis-specific exercise programs designed for wide implementation. Hughes and colleagues reported improvements in the 6MWD after the 8-week Fit and Strong exercise intervention, which included walking and lower body resistance training.²⁸ The Arthritis Foundation’s Walk With Ease program is a 6-week walking program that has shown improvements in chair stands and gait speed.²⁹ Another Arthritis Foundation program, People with Arthritis Can Exercise, is an 8-week course consisting of a variety of resistance, aerobic, and balance activities. This program has been associated with increases in chair stands but not gait speed or 6MWD.^30,31

This study found that participation in a VHA outpatient clinical supervised exercise program results in improvements in physical function that can be realized by older adults regardless of arthritis burden. Gerofit programs typically require 1.5 to 2.0 dedicated full-time equivalent employees to run the program effectively and additional administrative support, depending on size of the program.³² The cost savings generated by the program include reductions in hospitalization rates, emergency department visits, days in hospital, and medication use and provide a compelling argument for the program’s financial viability to health care systems through long-term savings and improved health outcomes for older adults.^33-36

While evidenced-based arthritis programs exist, this study illustrates that an exercise program without a focus on arthritis also improves physical function, potentially reducing the risk of disability related to arthritis. The clinical implication for these findings is that arthritis-specific exercise programs may not be needed to achieve functional improvements in individuals with arthritis. This is critical for under-resourced or exercise- limited health care systems or communities. Therefore, if exercise programming is limited, or arthritis-specific programs and interventions are not available, nonspecific exercise programs will also be beneficial to individuals with arthritis. Thus, individuals with arthritis should be encouraged to participate in any available exercise programming to achieve improvements in physical function. In addition, many older adults have multiple comorbidities, most of which improve with participation in exercise. ³⁷ Disease-specific exercise programs can offer tailored exercises and coaching related to common barriers in participation, such as joint pain for arthritis.³¹ It is unclear whether these additional programmatic components are associated with greater improvements in outcomes, such as physical function. More research is needed to explore the benefits of disease-specific tailored exercise programs compared with general exercise programs.

Strengths and Limitations

This study demonstrated the effect of participation in a clinical, supervised exercise program in a real-world setting. It suggests that even exercise programs not specifically targeted for arthritis populations can improve physical function among those with arthritis.

As a VHA clinical supervised exercise program, Gerofit may not be generalizable to all older adults or other exercise programs. In addition, this analysis only included a veteran population that was > 95% male and may not be generalizable to other populations. Arthritis status was defined by self-report and not verified in the health record. However, this approach has been shown to be acceptable in this setting and the most common type of arthritis in this population (OA) is a painful musculoskeletal condition associated with functional limitations.^4,22,38,39 Self-reported arthritis or rheumatism is associated with functional limitations.¹ Therefore, it is unlikely that the results would differ for physician-diagnosed or radiographically defined OA. Additionally, the study did not have data on the total number of joints with arthritis or arthritis severity but rather used upper body, lower body, and both upper and lower body arthritis as a proxy for arthritis status. While our models were adjusted for age and BMI, 2 known confounding factors for the association between arthritis and physical function, there are other potential confounding factors that were not included in the models. ^40,41 Finally, this study only included individuals with completed baseline and 3-month follow-up assessments, and the individuals who participated for longer or shorter periods may have had different physical function outcomes than individuals included in this study.

Conclusions

Participation in 3 months VHA Gerofit outpatient supervised exercise programs can improve physical function for all older adults, regardless of arthritis status. These programs may increase access to exercise programming that is beneficial for common conditions affecting older adults, such as arthritis.

Osteoporotic fragility fractures constitute a significant public health concern, with 1 in 2 women and 1 in 5 men aged > 50 years sustaining an osteoporotic fracture.¹ Osteoporotic fractures are costly and associated with reduced quality of life and impaired survival.^2-6 Many interventions including fall mitigation, calcium, vitamin D supplementation, and osteoporosis—specific medications reduce fracture risk.⁷ New medications for treating osteoporosis, including anabolic therapies, are costly and require clinical oversight to ensure safe delivery. This includes laboratory monitoring, timing of in-clinic dosing and provision of sequence therapy.^8,9 COVID-19 introduced numerous barriers to osteoporosis care, raising concerns for medication interruption and patients lost to follow-up, which made monitoring these high risk and costly medications even more important.

The US Department of Veterans Affairs (VA) was an early adopter of using the electronic health record to analyze and implement system-wide processes for population management and quality improvement.¹⁰ This enabled the creation of clinical dashboards to display key performance indicator data that support quality improvement and patient care initiatives.^11-15 The VA Puget Sound Health Care System (VAPSHCS) has a dedicated osteoporosis clinic focused on preventing and treating veterans at high risk for fracture. Considering the growing utilization of osteoporosis medications, particularly those requiring timed sequential therapy to prevent bone mineral density loss and rebound osteoporotic fractures, close monitoring and follow-up is required. The COVID-19 pandemic made clear the need for proactive osteoporosis management. This article describes the creation and use of an automated clinic dashboard to identify and contact veterans with osteoporosis-related care needs, such as prescription refills, laboratory tests, and clinical visits.

Methods

An automated dashboard was created in partnership with VA pharmacy clinical informatics to display the osteoporosis medication prescription (including last refill), monitoring laboratory test values and most recent osteoporosis clinic visit for each clinic patient. Data from the VA Corporate Data Warehouse were extracted. The resulting tables were used to create a patient cohort with ≥ 1 active medication for alendronate, zoledronic acid, the parathyroid hormone analogues (PTH) teriparatide or abaloparatide, denosumab, or romosozumab. Notably, alendronate was the only oral bisphosphonate prescribed in the clinic. These data were formatted and displayed using Microsoft SQL Server Reporting Services. The secure and encrypted dashboard alerts the clinic staff when prescriptions, appointments, or laboratory tests, such as estimated glomerular filtration rate, 25-hydroxy vitamin D, calcium, and PTH are overdue or out of reference range. The dashboard tracked the most recent clinic visit or dual-energy X-ray absorptiometry (DXA) scan if performed within the VA. Overdue laboratory test alerts for bisphosphonates were flagged if delayed 12 months and 6 months for all other medications.

On March 20, 2021, the VAPSHCS osteoporosis clinic was staffed by 1 endocrinologist, 1 geriatrician, 1 rheumatologist, and 1 registered nurse (RN) coordinator. Overdue or out-of-range alerts were reviewed weekly by the RN coordinator, who addressed alerts. For any overdue laboratory work or prescription refills, the RN coordinator alerted the primary osteoporosis physician via the electronic health record for updated orders. Patients were contacted by phone to schedule a clinic visit, complete ordered laboratory work, or discuss osteoporosis medication refills based on the need identified by the dashboard. A letter was mailed to the patient requesting they contact the osteoporosis clinic for patients who could not be reached by phone after 2 attempts. If 3 attempts (2 phone calls and a letter) were unsuccessful, the osteoporosis physician was alerted so they could either call the patient, alert the primary referring clinician, or discontinue the osteoporosis medication.

Results

As of March 20, 2021, 139 patients were included on the dashboard. Ninety-two patients (66%) had unmet care needs and 29% were female. Ages ranged from 40 to 100 years (Table). The dashboard alerted the team to 3 patients lost to follow-up, all of whom had transferred to care outside the clinic. Twenty-three patients (17%) had overdue medications, including 2 (9%) who had not refilled oral bisphosphonate and 18 (78%) who were overdue for intravenous bisphosphonate treatment. One veteran flagged as overdue for their denosumab injection was unable to receive it due to a significant change in health status. Two veterans were overdue for a PTH analogue refill, 1 of whom had completed their course and transitioned to bisphosphonate.

The most common alert was 40 patients (29%) with overdue laboratory tests, 37 of which were receiving bisphosphonates. One patient included on the dashboard was taking romosozumab and all their monitoring parameters were up to date, thus their data were not included in the Table to prevent possible identification.

Discussion

A dashboard alerted the osteoporosis clinic team to veterans who were overdue for visits, laboratory work, and prescription renewals. Overall, 92 patients (66%) had unmet care needs identified by the dashboard, all of which were addressed with phone calls and/or letters. Most of the overdue medication refills and laboratory tests were for patients taking bisphosphonates avoiding VAPSHCS during the COVID-19 pandemic. The dashboard enabled the RN coordinator to promptly contact the patient, facilitate coordination of care requirements, and guarantee the safe and efficient delivery of osteoporosis care.

The VA has historically been a leader in the creation of clinical dashboards to support health campaigns.^11,12 These dashboards have successfully improved quality metrics towards the treatment of hepatitis C virus, heart failure, and highrisk opioid prescribing.^13-15 Data have shown that successful clinical dashboard implementation must be done in conjunction with protected time or staff to support care improvements.¹⁶ Additionally, the time required for clinical dashboards can limit their sustainability and feasibility.¹⁷ A study aimed at improving osteoporosis care for patients with Parkinson disease found that weekly multidisciplinary review of at-risk patients resulted in all new patients and 91% of follow-up patients receiving evidence- based osteoporosis treatments.¹⁷ However, despite the benefits, the intervention required significant time and resources. In contrast, the osteoporosis dashboard implemented at VAPSHCS was not time or resource intensive, requiring about 1 hour per week for the RN coordinator to review the dashboard and coordinate patient care needs.

Limitations

This study setting is unique from other health care organizations or VA health care systems. Implementation of a similar dashboard in other clinical settings where patients receive medical care in multiple health care systems may differ. The VA dedicates resources to support veteran population health management, which may not be available in other health care systems.^11,12 These issues may pose a barrier to implementing a similar osteoporosis dashboard in non-VA facilities. In addition, it is significant that while the dashboard can be reconfigured and adapted to track veterans across different VA facilities, certain complexities arise if essential data, such as laboratory tests and DXA imaging, are conducted outside of VA facilities. In such cases, manual entry of this information into the dashboard would be necessary. Because the dashboard was quickly developed during the COVID-19 pandemic, this study lacked preimplementation data on laboratory testing, medication refills, and DXA imaging, which would have enabled a comparison of adherence before and after dashboard implementation. Finally, we acknowledge the delay in publishing these findings; however, we believe sharing innovative approaches to providing care for high-risk populations is essential, as demonstrated during the COVID-19 pandemic.

Conclusions

An osteoporosis clinic dashboard served as a valuable clinical support tool to ensure safe and effective osteoporosis medication delivery at VAPSHCS. Considering the growing utilization of osteoporosis medications, this dashboard plays a vital role in facilitating care coordination for patients receiving these high-risk treatments.¹⁸ Use of the dashboard supported the effective use of high-cost osteoporosis medications and is likely to improve clinical osteoporosis outcomes.

Despite the known fracture risk reduction, osteoporosis medication adherence is low.^19,20 Maintaining consistent pharmacotherapy for osteoporosis is essential not only for fracture prevention but also reducing health care costs related to osteoporosis and preserving patient independence and functionality.^21-24 While initially developed in response to the COVID-19 pandemic, the dashboard remains useful. The VAPSHCS osteoporosis clinic is now staffed by 2 physicians (endocrine and rheumatology) and the dashboard is still in use. The RN coordinator spends about 15 minutes per week using the dashboard and managing the 67 veterans on osteoporosis therapy. This dashboard represents a sustainable clinical tool with the capacity to minimize osteoporosis care gaps and improve outcomes.

Osteoporotic fragility fractures constitute a significant public health concern, with 1 in 2 women and 1 in 5 men aged > 50 years sustaining an osteoporotic fracture.¹ Osteoporotic fractures are costly and associated with reduced quality of life and impaired survival.^2-6 Many interventions including fall mitigation, calcium, vitamin D supplementation, and osteoporosis—specific medications reduce fracture risk.⁷ New medications for treating osteoporosis, including anabolic therapies, are costly and require clinical oversight to ensure safe delivery. This includes laboratory monitoring, timing of in-clinic dosing and provision of sequence therapy.^8,9 COVID-19 introduced numerous barriers to osteoporosis care, raising concerns for medication interruption and patients lost to follow-up, which made monitoring these high risk and costly medications even more important.

The US Department of Veterans Affairs (VA) was an early adopter of using the electronic health record to analyze and implement system-wide processes for population management and quality improvement.¹⁰ This enabled the creation of clinical dashboards to display key performance indicator data that support quality improvement and patient care initiatives.^11-15 The VA Puget Sound Health Care System (VAPSHCS) has a dedicated osteoporosis clinic focused on preventing and treating veterans at high risk for fracture. Considering the growing utilization of osteoporosis medications, particularly those requiring timed sequential therapy to prevent bone mineral density loss and rebound osteoporotic fractures, close monitoring and follow-up is required. The COVID-19 pandemic made clear the need for proactive osteoporosis management. This article describes the creation and use of an automated clinic dashboard to identify and contact veterans with osteoporosis-related care needs, such as prescription refills, laboratory tests, and clinical visits.

Methods

An automated dashboard was created in partnership with VA pharmacy clinical informatics to display the osteoporosis medication prescription (including last refill), monitoring laboratory test values and most recent osteoporosis clinic visit for each clinic patient. Data from the VA Corporate Data Warehouse were extracted. The resulting tables were used to create a patient cohort with ≥ 1 active medication for alendronate, zoledronic acid, the parathyroid hormone analogues (PTH) teriparatide or abaloparatide, denosumab, or romosozumab. Notably, alendronate was the only oral bisphosphonate prescribed in the clinic. These data were formatted and displayed using Microsoft SQL Server Reporting Services. The secure and encrypted dashboard alerts the clinic staff when prescriptions, appointments, or laboratory tests, such as estimated glomerular filtration rate, 25-hydroxy vitamin D, calcium, and PTH are overdue or out of reference range. The dashboard tracked the most recent clinic visit or dual-energy X-ray absorptiometry (DXA) scan if performed within the VA. Overdue laboratory test alerts for bisphosphonates were flagged if delayed 12 months and 6 months for all other medications.

On March 20, 2021, the VAPSHCS osteoporosis clinic was staffed by 1 endocrinologist, 1 geriatrician, 1 rheumatologist, and 1 registered nurse (RN) coordinator. Overdue or out-of-range alerts were reviewed weekly by the RN coordinator, who addressed alerts. For any overdue laboratory work or prescription refills, the RN coordinator alerted the primary osteoporosis physician via the electronic health record for updated orders. Patients were contacted by phone to schedule a clinic visit, complete ordered laboratory work, or discuss osteoporosis medication refills based on the need identified by the dashboard. A letter was mailed to the patient requesting they contact the osteoporosis clinic for patients who could not be reached by phone after 2 attempts. If 3 attempts (2 phone calls and a letter) were unsuccessful, the osteoporosis physician was alerted so they could either call the patient, alert the primary referring clinician, or discontinue the osteoporosis medication.

Results

As of March 20, 2021, 139 patients were included on the dashboard. Ninety-two patients (66%) had unmet care needs and 29% were female. Ages ranged from 40 to 100 years (Table). The dashboard alerted the team to 3 patients lost to follow-up, all of whom had transferred to care outside the clinic. Twenty-three patients (17%) had overdue medications, including 2 (9%) who had not refilled oral bisphosphonate and 18 (78%) who were overdue for intravenous bisphosphonate treatment. One veteran flagged as overdue for their denosumab injection was unable to receive it due to a significant change in health status. Two veterans were overdue for a PTH analogue refill, 1 of whom had completed their course and transitioned to bisphosphonate.

The most common alert was 40 patients (29%) with overdue laboratory tests, 37 of which were receiving bisphosphonates. One patient included on the dashboard was taking romosozumab and all their monitoring parameters were up to date, thus their data were not included in the Table to prevent possible identification.

Discussion

A dashboard alerted the osteoporosis clinic team to veterans who were overdue for visits, laboratory work, and prescription renewals. Overall, 92 patients (66%) had unmet care needs identified by the dashboard, all of which were addressed with phone calls and/or letters. Most of the overdue medication refills and laboratory tests were for patients taking bisphosphonates avoiding VAPSHCS during the COVID-19 pandemic. The dashboard enabled the RN coordinator to promptly contact the patient, facilitate coordination of care requirements, and guarantee the safe and efficient delivery of osteoporosis care.

The VA has historically been a leader in the creation of clinical dashboards to support health campaigns.^11,12 These dashboards have successfully improved quality metrics towards the treatment of hepatitis C virus, heart failure, and highrisk opioid prescribing.^13-15 Data have shown that successful clinical dashboard implementation must be done in conjunction with protected time or staff to support care improvements.¹⁶ Additionally, the time required for clinical dashboards can limit their sustainability and feasibility.¹⁷ A study aimed at improving osteoporosis care for patients with Parkinson disease found that weekly multidisciplinary review of at-risk patients resulted in all new patients and 91% of follow-up patients receiving evidence- based osteoporosis treatments.¹⁷ However, despite the benefits, the intervention required significant time and resources. In contrast, the osteoporosis dashboard implemented at VAPSHCS was not time or resource intensive, requiring about 1 hour per week for the RN coordinator to review the dashboard and coordinate patient care needs.

Limitations

This study setting is unique from other health care organizations or VA health care systems. Implementation of a similar dashboard in other clinical settings where patients receive medical care in multiple health care systems may differ. The VA dedicates resources to support veteran population health management, which may not be available in other health care systems.^11,12 These issues may pose a barrier to implementing a similar osteoporosis dashboard in non-VA facilities. In addition, it is significant that while the dashboard can be reconfigured and adapted to track veterans across different VA facilities, certain complexities arise if essential data, such as laboratory tests and DXA imaging, are conducted outside of VA facilities. In such cases, manual entry of this information into the dashboard would be necessary. Because the dashboard was quickly developed during the COVID-19 pandemic, this study lacked preimplementation data on laboratory testing, medication refills, and DXA imaging, which would have enabled a comparison of adherence before and after dashboard implementation. Finally, we acknowledge the delay in publishing these findings; however, we believe sharing innovative approaches to providing care for high-risk populations is essential, as demonstrated during the COVID-19 pandemic.

Conclusions

An osteoporosis clinic dashboard served as a valuable clinical support tool to ensure safe and effective osteoporosis medication delivery at VAPSHCS. Considering the growing utilization of osteoporosis medications, this dashboard plays a vital role in facilitating care coordination for patients receiving these high-risk treatments.¹⁸ Use of the dashboard supported the effective use of high-cost osteoporosis medications and is likely to improve clinical osteoporosis outcomes.

Despite the known fracture risk reduction, osteoporosis medication adherence is low.^19,20 Maintaining consistent pharmacotherapy for osteoporosis is essential not only for fracture prevention but also reducing health care costs related to osteoporosis and preserving patient independence and functionality.^21-24 While initially developed in response to the COVID-19 pandemic, the dashboard remains useful. The VAPSHCS osteoporosis clinic is now staffed by 2 physicians (endocrine and rheumatology) and the dashboard is still in use. The RN coordinator spends about 15 minutes per week using the dashboard and managing the 67 veterans on osteoporosis therapy. This dashboard represents a sustainable clinical tool with the capacity to minimize osteoporosis care gaps and improve outcomes.

Osteoporotic fragility fractures constitute a significant public health concern, with 1 in 2 women and 1 in 5 men aged > 50 years sustaining an osteoporotic fracture.¹ Osteoporotic fractures are costly and associated with reduced quality of life and impaired survival.^2-6 Many interventions including fall mitigation, calcium, vitamin D supplementation, and osteoporosis—specific medications reduce fracture risk.⁷ New medications for treating osteoporosis, including anabolic therapies, are costly and require clinical oversight to ensure safe delivery. This includes laboratory monitoring, timing of in-clinic dosing and provision of sequence therapy.^8,9 COVID-19 introduced numerous barriers to osteoporosis care, raising concerns for medication interruption and patients lost to follow-up, which made monitoring these high risk and costly medications even more important.

The US Department of Veterans Affairs (VA) was an early adopter of using the electronic health record to analyze and implement system-wide processes for population management and quality improvement.¹⁰ This enabled the creation of clinical dashboards to display key performance indicator data that support quality improvement and patient care initiatives.^11-15 The VA Puget Sound Health Care System (VAPSHCS) has a dedicated osteoporosis clinic focused on preventing and treating veterans at high risk for fracture. Considering the growing utilization of osteoporosis medications, particularly those requiring timed sequential therapy to prevent bone mineral density loss and rebound osteoporotic fractures, close monitoring and follow-up is required. The COVID-19 pandemic made clear the need for proactive osteoporosis management. This article describes the creation and use of an automated clinic dashboard to identify and contact veterans with osteoporosis-related care needs, such as prescription refills, laboratory tests, and clinical visits.

Methods

An automated dashboard was created in partnership with VA pharmacy clinical informatics to display the osteoporosis medication prescription (including last refill), monitoring laboratory test values and most recent osteoporosis clinic visit for each clinic patient. Data from the VA Corporate Data Warehouse were extracted. The resulting tables were used to create a patient cohort with ≥ 1 active medication for alendronate, zoledronic acid, the parathyroid hormone analogues (PTH) teriparatide or abaloparatide, denosumab, or romosozumab. Notably, alendronate was the only oral bisphosphonate prescribed in the clinic. These data were formatted and displayed using Microsoft SQL Server Reporting Services. The secure and encrypted dashboard alerts the clinic staff when prescriptions, appointments, or laboratory tests, such as estimated glomerular filtration rate, 25-hydroxy vitamin D, calcium, and PTH are overdue or out of reference range. The dashboard tracked the most recent clinic visit or dual-energy X-ray absorptiometry (DXA) scan if performed within the VA. Overdue laboratory test alerts for bisphosphonates were flagged if delayed 12 months and 6 months for all other medications.

On March 20, 2021, the VAPSHCS osteoporosis clinic was staffed by 1 endocrinologist, 1 geriatrician, 1 rheumatologist, and 1 registered nurse (RN) coordinator. Overdue or out-of-range alerts were reviewed weekly by the RN coordinator, who addressed alerts. For any overdue laboratory work or prescription refills, the RN coordinator alerted the primary osteoporosis physician via the electronic health record for updated orders. Patients were contacted by phone to schedule a clinic visit, complete ordered laboratory work, or discuss osteoporosis medication refills based on the need identified by the dashboard. A letter was mailed to the patient requesting they contact the osteoporosis clinic for patients who could not be reached by phone after 2 attempts. If 3 attempts (2 phone calls and a letter) were unsuccessful, the osteoporosis physician was alerted so they could either call the patient, alert the primary referring clinician, or discontinue the osteoporosis medication.

Results

As of March 20, 2021, 139 patients were included on the dashboard. Ninety-two patients (66%) had unmet care needs and 29% were female. Ages ranged from 40 to 100 years (Table). The dashboard alerted the team to 3 patients lost to follow-up, all of whom had transferred to care outside the clinic. Twenty-three patients (17%) had overdue medications, including 2 (9%) who had not refilled oral bisphosphonate and 18 (78%) who were overdue for intravenous bisphosphonate treatment. One veteran flagged as overdue for their denosumab injection was unable to receive it due to a significant change in health status. Two veterans were overdue for a PTH analogue refill, 1 of whom had completed their course and transitioned to bisphosphonate.

The most common alert was 40 patients (29%) with overdue laboratory tests, 37 of which were receiving bisphosphonates. One patient included on the dashboard was taking romosozumab and all their monitoring parameters were up to date, thus their data were not included in the Table to prevent possible identification.

Discussion

A dashboard alerted the osteoporosis clinic team to veterans who were overdue for visits, laboratory work, and prescription renewals. Overall, 92 patients (66%) had unmet care needs identified by the dashboard, all of which were addressed with phone calls and/or letters. Most of the overdue medication refills and laboratory tests were for patients taking bisphosphonates avoiding VAPSHCS during the COVID-19 pandemic. The dashboard enabled the RN coordinator to promptly contact the patient, facilitate coordination of care requirements, and guarantee the safe and efficient delivery of osteoporosis care.

The VA has historically been a leader in the creation of clinical dashboards to support health campaigns.^11,12 These dashboards have successfully improved quality metrics towards the treatment of hepatitis C virus, heart failure, and highrisk opioid prescribing.^13-15 Data have shown that successful clinical dashboard implementation must be done in conjunction with protected time or staff to support care improvements.¹⁶ Additionally, the time required for clinical dashboards can limit their sustainability and feasibility.¹⁷ A study aimed at improving osteoporosis care for patients with Parkinson disease found that weekly multidisciplinary review of at-risk patients resulted in all new patients and 91% of follow-up patients receiving evidence- based osteoporosis treatments.¹⁷ However, despite the benefits, the intervention required significant time and resources. In contrast, the osteoporosis dashboard implemented at VAPSHCS was not time or resource intensive, requiring about 1 hour per week for the RN coordinator to review the dashboard and coordinate patient care needs.

Limitations

This study setting is unique from other health care organizations or VA health care systems. Implementation of a similar dashboard in other clinical settings where patients receive medical care in multiple health care systems may differ. The VA dedicates resources to support veteran population health management, which may not be available in other health care systems.^11,12 These issues may pose a barrier to implementing a similar osteoporosis dashboard in non-VA facilities. In addition, it is significant that while the dashboard can be reconfigured and adapted to track veterans across different VA facilities, certain complexities arise if essential data, such as laboratory tests and DXA imaging, are conducted outside of VA facilities. In such cases, manual entry of this information into the dashboard would be necessary. Because the dashboard was quickly developed during the COVID-19 pandemic, this study lacked preimplementation data on laboratory testing, medication refills, and DXA imaging, which would have enabled a comparison of adherence before and after dashboard implementation. Finally, we acknowledge the delay in publishing these findings; however, we believe sharing innovative approaches to providing care for high-risk populations is essential, as demonstrated during the COVID-19 pandemic.

Conclusions

An osteoporosis clinic dashboard served as a valuable clinical support tool to ensure safe and effective osteoporosis medication delivery at VAPSHCS. Considering the growing utilization of osteoporosis medications, this dashboard plays a vital role in facilitating care coordination for patients receiving these high-risk treatments.¹⁸ Use of the dashboard supported the effective use of high-cost osteoporosis medications and is likely to improve clinical osteoporosis outcomes.

Despite the known fracture risk reduction, osteoporosis medication adherence is low.^19,20 Maintaining consistent pharmacotherapy for osteoporosis is essential not only for fracture prevention but also reducing health care costs related to osteoporosis and preserving patient independence and functionality.^21-24 While initially developed in response to the COVID-19 pandemic, the dashboard remains useful. The VAPSHCS osteoporosis clinic is now staffed by 2 physicians (endocrine and rheumatology) and the dashboard is still in use. The RN coordinator spends about 15 minutes per week using the dashboard and managing the 67 veterans on osteoporosis therapy. This dashboard represents a sustainable clinical tool with the capacity to minimize osteoporosis care gaps and improve outcomes.