Article

Key clinical point: Temporarily discontinuing endocrine therapy (ET) to attempt pregnancy did not increase the recurrence risk for breast cancer (BC) in young women with early hormone receptor-positive (HR+) BC.

Major finding: After a median follow-up of 41 months, 44 patients had BC and the incidence of BC events was not higher among patients who interrupted ET vs control individuals with BC from an external cohort who received treatment with different adjuvant endocrine strategies (hazard ratio 0.81; 95% CI 0.57-1.15). Pregnancy was reported by 368 patients and 317 patients had ≥1 live birth.

Study details: Findings are from a single-group trial including 516 premenopausal women aged ≤42 years with stage I, II, or III HR+ BC treated with ET for 18-30 months who discontinued ET to attempt pregnancy.

Disclosures: This study was supported by the ETOP IBCSG Partners Foundation and other sources. Some authors declared serving as consultants; receiving grants, contracts, or travel support; or having other ties with several sources.

Source: Partridge AH et al for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388(18):1645-1656 (May 4). Doi: 10.1056/NEJMoa2212856

Key clinical point: Temporarily discontinuing endocrine therapy (ET) to attempt pregnancy did not increase the recurrence risk for breast cancer (BC) in young women with early hormone receptor-positive (HR+) BC.

Major finding: After a median follow-up of 41 months, 44 patients had BC and the incidence of BC events was not higher among patients who interrupted ET vs control individuals with BC from an external cohort who received treatment with different adjuvant endocrine strategies (hazard ratio 0.81; 95% CI 0.57-1.15). Pregnancy was reported by 368 patients and 317 patients had ≥1 live birth.

Study details: Findings are from a single-group trial including 516 premenopausal women aged ≤42 years with stage I, II, or III HR+ BC treated with ET for 18-30 months who discontinued ET to attempt pregnancy.

Disclosures: This study was supported by the ETOP IBCSG Partners Foundation and other sources. Some authors declared serving as consultants; receiving grants, contracts, or travel support; or having other ties with several sources.

Source: Partridge AH et al for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388(18):1645-1656 (May 4). Doi: 10.1056/NEJMoa2212856

Key clinical point: Temporarily discontinuing endocrine therapy (ET) to attempt pregnancy did not increase the recurrence risk for breast cancer (BC) in young women with early hormone receptor-positive (HR+) BC.

Major finding: After a median follow-up of 41 months, 44 patients had BC and the incidence of BC events was not higher among patients who interrupted ET vs control individuals with BC from an external cohort who received treatment with different adjuvant endocrine strategies (hazard ratio 0.81; 95% CI 0.57-1.15). Pregnancy was reported by 368 patients and 317 patients had ≥1 live birth.

Study details: Findings are from a single-group trial including 516 premenopausal women aged ≤42 years with stage I, II, or III HR+ BC treated with ET for 18-30 months who discontinued ET to attempt pregnancy.

Disclosures: This study was supported by the ETOP IBCSG Partners Foundation and other sources. Some authors declared serving as consultants; receiving grants, contracts, or travel support; or having other ties with several sources.

Source: Partridge AH et al for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388(18):1645-1656 (May 4). Doi: 10.1056/NEJMoa2212856

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

Inpatient dermatology consultation services are becoming increasingly prevalent in hospital institutions.^1-3 Although often underutilized as a consulting service, dermatology-related admissions cost hundreds of millions of dollars for the health care system.^1,2 Misdiagnosis, prolonged hospital stays, and incorrect treatment are common results of lack of involvement by a skin expert.^1-3 The importance of consultative inpatient dermatology cannot be understated. Accreditation Council for Graduate Medical Education requirements for proficiency in dermatology residency include exposure to inpatient dermatology, and it is our duty as residents to aid our colleagues in the management and treatment of cutaneous disease.

Although exposure to inpatient dermatology varies across residency programs, nearly every dermatology resident is bound to perform a consultation and be involved in the care of a hospitalized patient. At our program at the University of Utah (Salt Lake City), we have robust inpatient exposure, and after numerous hours spent on the forefront of inpatient dermatology, I have accrued a list of specific tips and techniques that have aided me as a resident clinician.

Pre-Rounding More Thoroughly

When I started as a postgraduate year 2 (PGY-2) on the inpatient dermatology rotation, I found myself perplexed. I had learned how to round in internal medicine but was unaccustomed to the nuances of specialty rounds. My list included calciphylaxis, small vessel vasculitis, cellulitis, stasis dermatitis, toxic epidermal necrolysis, and atypical mycobacterial infection. The first few days of service were undeniably difficult due to the daily consultations, complexity of admitted patients, and need for efficiency. I sometimes overlooked important laboratory test results, medication changes, and interdisciplinary discussions that prolonged rounding. As dermatologists, we are responsible for the largest organ of the body, and it is important to approach patients in a comprehensive manner. Pre-rounding should include reviewing interdisciplinary notes, laboratory values/results, and medications, and performing a focused skin examination with a review of systems during the encounter. Importantly, most electronic medical record systems offer an automated rounding sheet. In Epic (Epic Systems Corporation), I would use the bone marrow transplant rounding sheet, which includes laboratory test results, vitals, and medications. After printing out the rounding sheet, I would note important updates for each patient. Although pre-rounding and chart review requires time and effort, it aided me in providing elevated patient care and becoming more efficient during rounds. Over time I have come to strongly appreciate the term dermatology hospitalist. Cutaneous manifestations of systemic disease require thoughtful consideration and workup.

New Patient Consultations: Must-Ask Questions

Holding the university inpatient pager can be stressful. At the University of Utah, we often carry 5 to 10 patients on our list and receive 3 to 4 new consultations a day, sometimes right before 5 pm. When receiving new consultations, it is important to obtain the whole story from the requesting provider. Some of the questions may seem obvious, but I am frequently reminded of the inefficiencies I encountered as a first-year dermatology resident. Remember to always be kind to your consulting colleagues. Dermatology is a difficult discipline, and describing rashes is no easy task. Here is my systematic approach to questions that should be asked of the requesting provider during each new patient consultation:

• What is the patient’s name, room number, and medical record number?
• Is this patient getting admitted or admitted currently?
• Is the rash the reason for admission? (This can greatly help with triaging the urgency of evaluation.)
• Is the rash painful?
• Is this patient ill?
• How would you describe the rash?

When evaluating new patients, it is crucial to remember the morphology camps. Formulating a differential diagnosis on a complex patient can be difficult; however, remembering the morphology camps of acneiform, dermal, eczematous, erythematous, subcutaneous, vasculitic, vasculopathic, and vesiculobullous lesions can be extremely helpful. Additionally, it is crucial to perform a thorough and complete skin examination on every patient. When emphasizing the importance of this, I often am reminded of a humbling moment early in my training. Our team was consulted on a patient with cellulitis and stasis dermatitis. It was a busy day, and my examination was quick and focused on the lower and upper extremities, chest, and back. The patient improved from a cutaneous standpoint and was discharged. At follow-up the next week, one of my attending providers biopsied an atypical macule on the retroauricular region, which was found to be consistent with a stage 1A melanoma. Even on the longest and most tiring hospital days, it is important to perform a full-body skin examination on each patient. You may end up saving a life.

An Organized Toolbox: What to Carry

Similar to our ophthalmology colleagues who are seen carrying around a suitcase in the hospital, I highly recommend some form of a toolbox or bag for performing inpatient biopsies (Table). Carrying around an organized bag, albeit bulky and unfashionable, has saved me numerous trips back to clinic for unexpected complications including fixing leaky vessels, closing stubborn ulcers, and coordinating sedated biopsies in the operating room.

Final Thoughts

As I near the completion of my residency journey, I hope these tips will aid budding and current dermatology residents at excelling as dermatology hospitalists during inpatient rotations. Dermatologists can make a profound impact on a variety of patients, especially when treating hospitalized patients on the clinical forefront. Our role extends beyond the skin, as cutaneous manifestations of internal disease are not uncommon.

Inpatient dermatology consultation services are becoming increasingly prevalent in hospital institutions.^1-3 Although often underutilized as a consulting service, dermatology-related admissions cost hundreds of millions of dollars for the health care system.^1,2 Misdiagnosis, prolonged hospital stays, and incorrect treatment are common results of lack of involvement by a skin expert.^1-3 The importance of consultative inpatient dermatology cannot be understated. Accreditation Council for Graduate Medical Education requirements for proficiency in dermatology residency include exposure to inpatient dermatology, and it is our duty as residents to aid our colleagues in the management and treatment of cutaneous disease.

Although exposure to inpatient dermatology varies across residency programs, nearly every dermatology resident is bound to perform a consultation and be involved in the care of a hospitalized patient. At our program at the University of Utah (Salt Lake City), we have robust inpatient exposure, and after numerous hours spent on the forefront of inpatient dermatology, I have accrued a list of specific tips and techniques that have aided me as a resident clinician.

Pre-Rounding More Thoroughly

When I started as a postgraduate year 2 (PGY-2) on the inpatient dermatology rotation, I found myself perplexed. I had learned how to round in internal medicine but was unaccustomed to the nuances of specialty rounds. My list included calciphylaxis, small vessel vasculitis, cellulitis, stasis dermatitis, toxic epidermal necrolysis, and atypical mycobacterial infection. The first few days of service were undeniably difficult due to the daily consultations, complexity of admitted patients, and need for efficiency. I sometimes overlooked important laboratory test results, medication changes, and interdisciplinary discussions that prolonged rounding. As dermatologists, we are responsible for the largest organ of the body, and it is important to approach patients in a comprehensive manner. Pre-rounding should include reviewing interdisciplinary notes, laboratory values/results, and medications, and performing a focused skin examination with a review of systems during the encounter. Importantly, most electronic medical record systems offer an automated rounding sheet. In Epic (Epic Systems Corporation), I would use the bone marrow transplant rounding sheet, which includes laboratory test results, vitals, and medications. After printing out the rounding sheet, I would note important updates for each patient. Although pre-rounding and chart review requires time and effort, it aided me in providing elevated patient care and becoming more efficient during rounds. Over time I have come to strongly appreciate the term dermatology hospitalist. Cutaneous manifestations of systemic disease require thoughtful consideration and workup.

New Patient Consultations: Must-Ask Questions

Holding the university inpatient pager can be stressful. At the University of Utah, we often carry 5 to 10 patients on our list and receive 3 to 4 new consultations a day, sometimes right before 5 pm. When receiving new consultations, it is important to obtain the whole story from the requesting provider. Some of the questions may seem obvious, but I am frequently reminded of the inefficiencies I encountered as a first-year dermatology resident. Remember to always be kind to your consulting colleagues. Dermatology is a difficult discipline, and describing rashes is no easy task. Here is my systematic approach to questions that should be asked of the requesting provider during each new patient consultation:

• What is the patient’s name, room number, and medical record number?
• Is this patient getting admitted or admitted currently?
• Is the rash the reason for admission? (This can greatly help with triaging the urgency of evaluation.)
• Is the rash painful?
• Is this patient ill?
• How would you describe the rash?

When evaluating new patients, it is crucial to remember the morphology camps. Formulating a differential diagnosis on a complex patient can be difficult; however, remembering the morphology camps of acneiform, dermal, eczematous, erythematous, subcutaneous, vasculitic, vasculopathic, and vesiculobullous lesions can be extremely helpful. Additionally, it is crucial to perform a thorough and complete skin examination on every patient. When emphasizing the importance of this, I often am reminded of a humbling moment early in my training. Our team was consulted on a patient with cellulitis and stasis dermatitis. It was a busy day, and my examination was quick and focused on the lower and upper extremities, chest, and back. The patient improved from a cutaneous standpoint and was discharged. At follow-up the next week, one of my attending providers biopsied an atypical macule on the retroauricular region, which was found to be consistent with a stage 1A melanoma. Even on the longest and most tiring hospital days, it is important to perform a full-body skin examination on each patient. You may end up saving a life.

An Organized Toolbox: What to Carry

Similar to our ophthalmology colleagues who are seen carrying around a suitcase in the hospital, I highly recommend some form of a toolbox or bag for performing inpatient biopsies (Table). Carrying around an organized bag, albeit bulky and unfashionable, has saved me numerous trips back to clinic for unexpected complications including fixing leaky vessels, closing stubborn ulcers, and coordinating sedated biopsies in the operating room.

Final Thoughts

As I near the completion of my residency journey, I hope these tips will aid budding and current dermatology residents at excelling as dermatology hospitalists during inpatient rotations. Dermatologists can make a profound impact on a variety of patients, especially when treating hospitalized patients on the clinical forefront. Our role extends beyond the skin, as cutaneous manifestations of internal disease are not uncommon.

Inpatient dermatology consultation services are becoming increasingly prevalent in hospital institutions.^1-3 Although often underutilized as a consulting service, dermatology-related admissions cost hundreds of millions of dollars for the health care system.^1,2 Misdiagnosis, prolonged hospital stays, and incorrect treatment are common results of lack of involvement by a skin expert.^1-3 The importance of consultative inpatient dermatology cannot be understated. Accreditation Council for Graduate Medical Education requirements for proficiency in dermatology residency include exposure to inpatient dermatology, and it is our duty as residents to aid our colleagues in the management and treatment of cutaneous disease.

Although exposure to inpatient dermatology varies across residency programs, nearly every dermatology resident is bound to perform a consultation and be involved in the care of a hospitalized patient. At our program at the University of Utah (Salt Lake City), we have robust inpatient exposure, and after numerous hours spent on the forefront of inpatient dermatology, I have accrued a list of specific tips and techniques that have aided me as a resident clinician.

Pre-Rounding More Thoroughly

When I started as a postgraduate year 2 (PGY-2) on the inpatient dermatology rotation, I found myself perplexed. I had learned how to round in internal medicine but was unaccustomed to the nuances of specialty rounds. My list included calciphylaxis, small vessel vasculitis, cellulitis, stasis dermatitis, toxic epidermal necrolysis, and atypical mycobacterial infection. The first few days of service were undeniably difficult due to the daily consultations, complexity of admitted patients, and need for efficiency. I sometimes overlooked important laboratory test results, medication changes, and interdisciplinary discussions that prolonged rounding. As dermatologists, we are responsible for the largest organ of the body, and it is important to approach patients in a comprehensive manner. Pre-rounding should include reviewing interdisciplinary notes, laboratory values/results, and medications, and performing a focused skin examination with a review of systems during the encounter. Importantly, most electronic medical record systems offer an automated rounding sheet. In Epic (Epic Systems Corporation), I would use the bone marrow transplant rounding sheet, which includes laboratory test results, vitals, and medications. After printing out the rounding sheet, I would note important updates for each patient. Although pre-rounding and chart review requires time and effort, it aided me in providing elevated patient care and becoming more efficient during rounds. Over time I have come to strongly appreciate the term dermatology hospitalist. Cutaneous manifestations of systemic disease require thoughtful consideration and workup.

New Patient Consultations: Must-Ask Questions

Holding the university inpatient pager can be stressful. At the University of Utah, we often carry 5 to 10 patients on our list and receive 3 to 4 new consultations a day, sometimes right before 5 pm. When receiving new consultations, it is important to obtain the whole story from the requesting provider. Some of the questions may seem obvious, but I am frequently reminded of the inefficiencies I encountered as a first-year dermatology resident. Remember to always be kind to your consulting colleagues. Dermatology is a difficult discipline, and describing rashes is no easy task. Here is my systematic approach to questions that should be asked of the requesting provider during each new patient consultation:

• What is the patient’s name, room number, and medical record number?
• Is this patient getting admitted or admitted currently?
• Is the rash the reason for admission? (This can greatly help with triaging the urgency of evaluation.)
• Is the rash painful?
• Is this patient ill?
• How would you describe the rash?

When evaluating new patients, it is crucial to remember the morphology camps. Formulating a differential diagnosis on a complex patient can be difficult; however, remembering the morphology camps of acneiform, dermal, eczematous, erythematous, subcutaneous, vasculitic, vasculopathic, and vesiculobullous lesions can be extremely helpful. Additionally, it is crucial to perform a thorough and complete skin examination on every patient. When emphasizing the importance of this, I often am reminded of a humbling moment early in my training. Our team was consulted on a patient with cellulitis and stasis dermatitis. It was a busy day, and my examination was quick and focused on the lower and upper extremities, chest, and back. The patient improved from a cutaneous standpoint and was discharged. At follow-up the next week, one of my attending providers biopsied an atypical macule on the retroauricular region, which was found to be consistent with a stage 1A melanoma. Even on the longest and most tiring hospital days, it is important to perform a full-body skin examination on each patient. You may end up saving a life.

An Organized Toolbox: What to Carry

Similar to our ophthalmology colleagues who are seen carrying around a suitcase in the hospital, I highly recommend some form of a toolbox or bag for performing inpatient biopsies (Table). Carrying around an organized bag, albeit bulky and unfashionable, has saved me numerous trips back to clinic for unexpected complications including fixing leaky vessels, closing stubborn ulcers, and coordinating sedated biopsies in the operating room.

Final Thoughts

As I near the completion of my residency journey, I hope these tips will aid budding and current dermatology residents at excelling as dermatology hospitalists during inpatient rotations. Dermatologists can make a profound impact on a variety of patients, especially when treating hospitalized patients on the clinical forefront. Our role extends beyond the skin, as cutaneous manifestations of internal disease are not uncommon.

The history and findings in this case are suggestive of chronic kidney disease (CKD).

CKD affects between 8% and 16% of the population worldwide. Risk factors for CKD are numerous and include T2D, hypertension, and prediabetes. Diabetes is the leading cause of CKD. Up to 40% of patients with diabetes develop diabetic kidney disease, which can progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation. In fact, diabetic kidney disease is the top cause of ESRD in the United States.

Diagnostic criteria for CKD include elevated urinary albumin excretion (albuminuria) and/or eGFR < 60 mL/1.73 m² that persists for more than 3 months. The normal presentation of diabetic kidney disease includes long-standing diabetes, retinopathy, albuminuria without gross hematuria, and gradually progressive decline of eGFR. However, signs of diabetic kidney disease may be present in patients at diagnosis or without retinopathy in T2D. Reduced eGFR without albuminuria has been frequently reported in both type 1 diabetes (T1D) and T2D and is becoming increasingly common as the prevalence of diabetes rises in the United States.

Chronic kidney disease is usually identified through routine screening with serum chemistry profile and urine studies or as an incidental finding. Less often, patients may present with symptoms, such as gross hematuria, "foamy urine" (a sign of albuminuria), nocturia, flank pain, or decreased urine output. In advanced cases, patients may report fatigue, poor appetite, nausea, vomiting, a metallic taste, unintentional weight loss, pruritus, changes in mental status, dyspnea, and/or peripheral edema.

The American Diabetes Association (ADA) 2023 Standards of Care in Diabetes describes five stages of CKD. Stages 1-2 are defined by evidence of high albuminuria with eGFR ≥ 60 mL/min/1.73 m², while stages 3-5 are defined by progressively lower ranges of eGFR. Of note, at any eGFR, the degree of albuminuria is associated with risk for cardiovascular disease, CKD progression, and mortality. Thus, as noted by the ADA Standards, both eGFR and albuminuria should be used to guide treatment decisions; additionally, eGFR levels are essential for modifying drug dosages or restrictions of use, and the degree of albuminuria should influence selection of antihypertensive agents and glucose-lowering medications.

According to the ADA 2023 Standards of Care in Diabetes, for people with non–dialysis-dependent CKD, dietary protein intake should be ∼0.8 g/kg body weight per day (the recommended daily allowance), as this level has been shown to slow GFR decline compared with higher levels of dietary protein intake, with evidence of a greater effect over time. Conversely, higher levels of dietary protein intake (> 20% of daily calories from protein or > 1.3 g/kg/d) have been associated with increased albuminuria, more rapid kidney function loss, and cardiovascular disease mortality. For patients on dialysis, higher levels of dietary protein intake should be considered, because malnutrition is a significant problem in some of these patients.

Urinary excretion of sodium and potassium may be impaired in patients with reduced eGFR. Thus, restriction of dietary sodium to < 2300 mg/d may help to control blood pressure and reduce cardiovascular risk, and restriction of dietary potassium may be necessary to control serum potassium concentration. 

Intensive glycemic control with the goal of achieving near-normoglycemia has been shown to delay the onset and progression of albuminuria and reduced eGFR in patients with diabetes. Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of T1D while a variety of agents were used in clinical trials of T2D, supporting the conclusion that glycemic control itself helps prevent CKD and its progression. However, the presence of CKD affects the risks and benefits of intensive glycemic control and several glucose-lowering medications. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of T2D, increased adverse effects of intensive glycemic control (hypoglycemia and mortality) were seen among patients with kidney disease at baseline. Moreover, it may take at least 2 years to see improved eGFR outcomes as an effect of intensive glycemic control. Therefore, in some patients with prevalent CKD and substantial comorbidity, target A1c levels may be less intensive.

According to guidance from the US Food and Drug Administration, eGFR should be monitored while taking metformin and metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m². Clinicians should assess the benefits and risks of continuing treatment when eGFR falls to < 45 mL/min/1.73 m². 

The ADA recommends that sodium–glucose cotransporter 2 inhibitors be given to all patients with stage 3 CKD or higher and T2D, regardless of glycemic control, as they have been shown to delay CKD progression and reduce heart failure risk independent of glycemic control. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) also have direct effects on the kidney and have been reported to improve renal outcomes compared with placebo. In patients for whom cardiovascular risk is a predominant problem, the ADA suggests using GLP-1 RAs for cardiovascular risk reduction.

Comprehensive guidance on the management of CKD in patients with T2D is available in the ADA 2023 Standards of Care in Diabetes.

Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia

Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.

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

The history and findings in this case are suggestive of chronic kidney disease (CKD).

CKD affects between 8% and 16% of the population worldwide. Risk factors for CKD are numerous and include T2D, hypertension, and prediabetes. Diabetes is the leading cause of CKD. Up to 40% of patients with diabetes develop diabetic kidney disease, which can progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation. In fact, diabetic kidney disease is the top cause of ESRD in the United States.

Diagnostic criteria for CKD include elevated urinary albumin excretion (albuminuria) and/or eGFR < 60 mL/1.73 m² that persists for more than 3 months. The normal presentation of diabetic kidney disease includes long-standing diabetes, retinopathy, albuminuria without gross hematuria, and gradually progressive decline of eGFR. However, signs of diabetic kidney disease may be present in patients at diagnosis or without retinopathy in T2D. Reduced eGFR without albuminuria has been frequently reported in both type 1 diabetes (T1D) and T2D and is becoming increasingly common as the prevalence of diabetes rises in the United States.

Chronic kidney disease is usually identified through routine screening with serum chemistry profile and urine studies or as an incidental finding. Less often, patients may present with symptoms, such as gross hematuria, "foamy urine" (a sign of albuminuria), nocturia, flank pain, or decreased urine output. In advanced cases, patients may report fatigue, poor appetite, nausea, vomiting, a metallic taste, unintentional weight loss, pruritus, changes in mental status, dyspnea, and/or peripheral edema.

The American Diabetes Association (ADA) 2023 Standards of Care in Diabetes describes five stages of CKD. Stages 1-2 are defined by evidence of high albuminuria with eGFR ≥ 60 mL/min/1.73 m², while stages 3-5 are defined by progressively lower ranges of eGFR. Of note, at any eGFR, the degree of albuminuria is associated with risk for cardiovascular disease, CKD progression, and mortality. Thus, as noted by the ADA Standards, both eGFR and albuminuria should be used to guide treatment decisions; additionally, eGFR levels are essential for modifying drug dosages or restrictions of use, and the degree of albuminuria should influence selection of antihypertensive agents and glucose-lowering medications.

According to the ADA 2023 Standards of Care in Diabetes, for people with non–dialysis-dependent CKD, dietary protein intake should be ∼0.8 g/kg body weight per day (the recommended daily allowance), as this level has been shown to slow GFR decline compared with higher levels of dietary protein intake, with evidence of a greater effect over time. Conversely, higher levels of dietary protein intake (> 20% of daily calories from protein or > 1.3 g/kg/d) have been associated with increased albuminuria, more rapid kidney function loss, and cardiovascular disease mortality. For patients on dialysis, higher levels of dietary protein intake should be considered, because malnutrition is a significant problem in some of these patients.

Urinary excretion of sodium and potassium may be impaired in patients with reduced eGFR. Thus, restriction of dietary sodium to < 2300 mg/d may help to control blood pressure and reduce cardiovascular risk, and restriction of dietary potassium may be necessary to control serum potassium concentration. 

Intensive glycemic control with the goal of achieving near-normoglycemia has been shown to delay the onset and progression of albuminuria and reduced eGFR in patients with diabetes. Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of T1D while a variety of agents were used in clinical trials of T2D, supporting the conclusion that glycemic control itself helps prevent CKD and its progression. However, the presence of CKD affects the risks and benefits of intensive glycemic control and several glucose-lowering medications. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of T2D, increased adverse effects of intensive glycemic control (hypoglycemia and mortality) were seen among patients with kidney disease at baseline. Moreover, it may take at least 2 years to see improved eGFR outcomes as an effect of intensive glycemic control. Therefore, in some patients with prevalent CKD and substantial comorbidity, target A1c levels may be less intensive.

According to guidance from the US Food and Drug Administration, eGFR should be monitored while taking metformin and metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m². Clinicians should assess the benefits and risks of continuing treatment when eGFR falls to < 45 mL/min/1.73 m². 

The ADA recommends that sodium–glucose cotransporter 2 inhibitors be given to all patients with stage 3 CKD or higher and T2D, regardless of glycemic control, as they have been shown to delay CKD progression and reduce heart failure risk independent of glycemic control. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) also have direct effects on the kidney and have been reported to improve renal outcomes compared with placebo. In patients for whom cardiovascular risk is a predominant problem, the ADA suggests using GLP-1 RAs for cardiovascular risk reduction.

Comprehensive guidance on the management of CKD in patients with T2D is available in the ADA 2023 Standards of Care in Diabetes.

Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia

Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.

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

The history and findings in this case are suggestive of chronic kidney disease (CKD).

CKD affects between 8% and 16% of the population worldwide. Risk factors for CKD are numerous and include T2D, hypertension, and prediabetes. Diabetes is the leading cause of CKD. Up to 40% of patients with diabetes develop diabetic kidney disease, which can progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation. In fact, diabetic kidney disease is the top cause of ESRD in the United States.

Diagnostic criteria for CKD include elevated urinary albumin excretion (albuminuria) and/or eGFR < 60 mL/1.73 m² that persists for more than 3 months. The normal presentation of diabetic kidney disease includes long-standing diabetes, retinopathy, albuminuria without gross hematuria, and gradually progressive decline of eGFR. However, signs of diabetic kidney disease may be present in patients at diagnosis or without retinopathy in T2D. Reduced eGFR without albuminuria has been frequently reported in both type 1 diabetes (T1D) and T2D and is becoming increasingly common as the prevalence of diabetes rises in the United States.

Chronic kidney disease is usually identified through routine screening with serum chemistry profile and urine studies or as an incidental finding. Less often, patients may present with symptoms, such as gross hematuria, "foamy urine" (a sign of albuminuria), nocturia, flank pain, or decreased urine output. In advanced cases, patients may report fatigue, poor appetite, nausea, vomiting, a metallic taste, unintentional weight loss, pruritus, changes in mental status, dyspnea, and/or peripheral edema.

The American Diabetes Association (ADA) 2023 Standards of Care in Diabetes describes five stages of CKD. Stages 1-2 are defined by evidence of high albuminuria with eGFR ≥ 60 mL/min/1.73 m², while stages 3-5 are defined by progressively lower ranges of eGFR. Of note, at any eGFR, the degree of albuminuria is associated with risk for cardiovascular disease, CKD progression, and mortality. Thus, as noted by the ADA Standards, both eGFR and albuminuria should be used to guide treatment decisions; additionally, eGFR levels are essential for modifying drug dosages or restrictions of use, and the degree of albuminuria should influence selection of antihypertensive agents and glucose-lowering medications.

According to the ADA 2023 Standards of Care in Diabetes, for people with non–dialysis-dependent CKD, dietary protein intake should be ∼0.8 g/kg body weight per day (the recommended daily allowance), as this level has been shown to slow GFR decline compared with higher levels of dietary protein intake, with evidence of a greater effect over time. Conversely, higher levels of dietary protein intake (> 20% of daily calories from protein or > 1.3 g/kg/d) have been associated with increased albuminuria, more rapid kidney function loss, and cardiovascular disease mortality. For patients on dialysis, higher levels of dietary protein intake should be considered, because malnutrition is a significant problem in some of these patients.

Urinary excretion of sodium and potassium may be impaired in patients with reduced eGFR. Thus, restriction of dietary sodium to < 2300 mg/d may help to control blood pressure and reduce cardiovascular risk, and restriction of dietary potassium may be necessary to control serum potassium concentration. 

Intensive glycemic control with the goal of achieving near-normoglycemia has been shown to delay the onset and progression of albuminuria and reduced eGFR in patients with diabetes. Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of T1D while a variety of agents were used in clinical trials of T2D, supporting the conclusion that glycemic control itself helps prevent CKD and its progression. However, the presence of CKD affects the risks and benefits of intensive glycemic control and several glucose-lowering medications. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of T2D, increased adverse effects of intensive glycemic control (hypoglycemia and mortality) were seen among patients with kidney disease at baseline. Moreover, it may take at least 2 years to see improved eGFR outcomes as an effect of intensive glycemic control. Therefore, in some patients with prevalent CKD and substantial comorbidity, target A1c levels may be less intensive.

According to guidance from the US Food and Drug Administration, eGFR should be monitored while taking metformin and metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m². Clinicians should assess the benefits and risks of continuing treatment when eGFR falls to < 45 mL/min/1.73 m². 

The ADA recommends that sodium–glucose cotransporter 2 inhibitors be given to all patients with stage 3 CKD or higher and T2D, regardless of glycemic control, as they have been shown to delay CKD progression and reduce heart failure risk independent of glycemic control. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) also have direct effects on the kidney and have been reported to improve renal outcomes compared with placebo. In patients for whom cardiovascular risk is a predominant problem, the ADA suggests using GLP-1 RAs for cardiovascular risk reduction.

Comprehensive guidance on the management of CKD in patients with T2D is available in the ADA 2023 Standards of Care in Diabetes.

Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia

Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.

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

A broad shave biopsy was performed at the base of the lesion and the results were consistent with a thick nodular melanoma with a Breslow depth of 5.5 mm.

Melanoma is the deadliest skin cancer in the United States with mortality risk corresponding with the depth of the tumor.¹ Nodular melanomas grow faster than all other types of melanoma. For this reason, a concerning raised lesion with a risk of melanoma should not be observed for change over time; it should be biopsied promptly. In this case, a depth of 5.5 mm was cause for quick action. Patients with tumors > 1 mm in depth (and some tumors > 0.8 mm) should be offered sentinel lymph node biopsy (SLNB) along with wide local excision to evaluate for lymphatic spread. Patients with thinner tumors may undergo wide local excision without SLNB.

In this case, National Comprehensive Cancer Network guidelines would dictate a 2-cm margin for a wide local incision; the patient underwent a modified version of this with Surgical Oncology to accommodate maintenance of hand function. This patient’s SLNB was negative, so the melanoma was classified as Stage IIC.

In the recent past, there were no additional treatments for patients with late Stage II disease (thick tumors without evidence of metastasis). However, in December 2021, the US Food and Drug Administration approved the use of immunotherapy with pembrolizumab in patients with node-negative late Stage II melanoma after demonstration of improved recurrence-free survival in the KEYNOTE trial.² Evidence of improved long-term survival is mixed with adjuvant therapy, and studies evaluating the best role of adjuvant therapy are ongoing.

This patient was started on a regimen of pembrolizumab 200 mg IV every 3 weeks, which he will continue for as long as 1 year. He has tolerated this regimen without difficulty and has no evidence of disease.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A broad shave biopsy was performed at the base of the lesion and the results were consistent with a thick nodular melanoma with a Breslow depth of 5.5 mm.

Melanoma is the deadliest skin cancer in the United States with mortality risk corresponding with the depth of the tumor.¹ Nodular melanomas grow faster than all other types of melanoma. For this reason, a concerning raised lesion with a risk of melanoma should not be observed for change over time; it should be biopsied promptly. In this case, a depth of 5.5 mm was cause for quick action. Patients with tumors > 1 mm in depth (and some tumors > 0.8 mm) should be offered sentinel lymph node biopsy (SLNB) along with wide local excision to evaluate for lymphatic spread. Patients with thinner tumors may undergo wide local excision without SLNB.

In this case, National Comprehensive Cancer Network guidelines would dictate a 2-cm margin for a wide local incision; the patient underwent a modified version of this with Surgical Oncology to accommodate maintenance of hand function. This patient’s SLNB was negative, so the melanoma was classified as Stage IIC.

In the recent past, there were no additional treatments for patients with late Stage II disease (thick tumors without evidence of metastasis). However, in December 2021, the US Food and Drug Administration approved the use of immunotherapy with pembrolizumab in patients with node-negative late Stage II melanoma after demonstration of improved recurrence-free survival in the KEYNOTE trial.² Evidence of improved long-term survival is mixed with adjuvant therapy, and studies evaluating the best role of adjuvant therapy are ongoing.

This patient was started on a regimen of pembrolizumab 200 mg IV every 3 weeks, which he will continue for as long as 1 year. He has tolerated this regimen without difficulty and has no evidence of disease.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A broad shave biopsy was performed at the base of the lesion and the results were consistent with a thick nodular melanoma with a Breslow depth of 5.5 mm.

Melanoma is the deadliest skin cancer in the United States with mortality risk corresponding with the depth of the tumor.¹ Nodular melanomas grow faster than all other types of melanoma. For this reason, a concerning raised lesion with a risk of melanoma should not be observed for change over time; it should be biopsied promptly. In this case, a depth of 5.5 mm was cause for quick action. Patients with tumors > 1 mm in depth (and some tumors > 0.8 mm) should be offered sentinel lymph node biopsy (SLNB) along with wide local excision to evaluate for lymphatic spread. Patients with thinner tumors may undergo wide local excision without SLNB.

In this case, National Comprehensive Cancer Network guidelines would dictate a 2-cm margin for a wide local incision; the patient underwent a modified version of this with Surgical Oncology to accommodate maintenance of hand function. This patient’s SLNB was negative, so the melanoma was classified as Stage IIC.

In the recent past, there were no additional treatments for patients with late Stage II disease (thick tumors without evidence of metastasis). However, in December 2021, the US Food and Drug Administration approved the use of immunotherapy with pembrolizumab in patients with node-negative late Stage II melanoma after demonstration of improved recurrence-free survival in the KEYNOTE trial.² Evidence of improved long-term survival is mixed with adjuvant therapy, and studies evaluating the best role of adjuvant therapy are ongoing.

This patient was started on a regimen of pembrolizumab 200 mg IV every 3 weeks, which he will continue for as long as 1 year. He has tolerated this regimen without difficulty and has no evidence of disease.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The biopsy revealed abundant lymphocytes, neutrophils, and eosinophils consistent with a diagnosis of cutaneous B cell pseudolymphoma. The pseudolymphoma was caused by an exaggerated response to a tick bite.

As the name implies, B cell pseudolymphomas clinically and histologically mimic the various patterns of cutaneous lymphoma, often appearing as a firm, pink to dark violet nodule. A biopsy is mandatory to distinguish between pseudolymphoma and true lymphoma. There is an association between pseudolymphomas and Borrelia burgdorferi, the organism responsible for Lyme disease. Thus, testing for Lyme disease is recommended for patients with pseudolymphomas who live in endemic areas. Patients who test positive should be treated with doxycycline 100 mg bid for 10 days.

In the absence of Lyme disease, a pseudolymphoma may resolve spontaneously over weeks or months. Resolution can be hastened with topical superpotent steroids, intralesional steroids, or systemic steroids. Treatment can begin with topical clobetasol 0.05% bid. If the lesion does not resolve, the next step would be intralesional triamcinolone 10 mg/mL injected directly into the nodule until it blanches slightly. Injections should be repeated every 3 to 4 weeks for a total of 2 to 3 injections.

The patient in this case had negative Lyme serology and was treated with 2 injections of triamcinolone 10 mg/mL administered 3 weeks apart. She experienced complete resolution.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The biopsy revealed abundant lymphocytes, neutrophils, and eosinophils consistent with a diagnosis of cutaneous B cell pseudolymphoma. The pseudolymphoma was caused by an exaggerated response to a tick bite.

As the name implies, B cell pseudolymphomas clinically and histologically mimic the various patterns of cutaneous lymphoma, often appearing as a firm, pink to dark violet nodule. A biopsy is mandatory to distinguish between pseudolymphoma and true lymphoma. There is an association between pseudolymphomas and Borrelia burgdorferi, the organism responsible for Lyme disease. Thus, testing for Lyme disease is recommended for patients with pseudolymphomas who live in endemic areas. Patients who test positive should be treated with doxycycline 100 mg bid for 10 days.

In the absence of Lyme disease, a pseudolymphoma may resolve spontaneously over weeks or months. Resolution can be hastened with topical superpotent steroids, intralesional steroids, or systemic steroids. Treatment can begin with topical clobetasol 0.05% bid. If the lesion does not resolve, the next step would be intralesional triamcinolone 10 mg/mL injected directly into the nodule until it blanches slightly. Injections should be repeated every 3 to 4 weeks for a total of 2 to 3 injections.

The patient in this case had negative Lyme serology and was treated with 2 injections of triamcinolone 10 mg/mL administered 3 weeks apart. She experienced complete resolution.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The biopsy revealed abundant lymphocytes, neutrophils, and eosinophils consistent with a diagnosis of cutaneous B cell pseudolymphoma. The pseudolymphoma was caused by an exaggerated response to a tick bite.

As the name implies, B cell pseudolymphomas clinically and histologically mimic the various patterns of cutaneous lymphoma, often appearing as a firm, pink to dark violet nodule. A biopsy is mandatory to distinguish between pseudolymphoma and true lymphoma. There is an association between pseudolymphomas and Borrelia burgdorferi, the organism responsible for Lyme disease. Thus, testing for Lyme disease is recommended for patients with pseudolymphomas who live in endemic areas. Patients who test positive should be treated with doxycycline 100 mg bid for 10 days.

In the absence of Lyme disease, a pseudolymphoma may resolve spontaneously over weeks or months. Resolution can be hastened with topical superpotent steroids, intralesional steroids, or systemic steroids. Treatment can begin with topical clobetasol 0.05% bid. If the lesion does not resolve, the next step would be intralesional triamcinolone 10 mg/mL injected directly into the nodule until it blanches slightly. Injections should be repeated every 3 to 4 weeks for a total of 2 to 3 injections.

The patient in this case had negative Lyme serology and was treated with 2 injections of triamcinolone 10 mg/mL administered 3 weeks apart. She experienced complete resolution.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

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

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

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

The history and findings in this case are suggestive of Alzheimer's disease (AD). 

AD is the most common type of dementia. It is characterized by cognitive and behavioral impairment that significantly impairs a patient's social and occupational functioning. The predominant AD pathogenesis hypothesis suggests that AD is largely caused by the accumulation of insoluble amyloid beta deposits and neurofibrillary tangles induced by highly phosphorylated tau proteins in the neocortex, hippocampus, and amygdala, as well as significant loss of neurons and synapses, which leads to brain atrophy. Estimates suggest that approximately 6.2 million people ≥ 65 years of age have AD and that by 2060, the number of Americans with AD may increase to 13.8 million, the result of an aging population and the lack of effective prevention and treatment strategies. AD is a chronic disease that confers tremendous emotional and economic burdens to individuals, families, and society. 

Insidiously progressive memory loss is commonly seen in patients presenting with AD. As the disease progresses over the course of several years, other areas of cognition are impaired. Patients may develop language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. Slowly progressive behavioral changes are also observed in many individuals with AD.

Criteria for the clinical diagnosis of AD (eg, insidious onset of cognitive impairment, clear history of worsening symptoms) have been developed and are frequently employed. Among individuals who meet the core clinical criteria for probable AD dementia, biomarker evidence may help to increase the certainty that AD is the basis of the clinical dementia syndrome. Several cerebrospinal fluid and blood biomarkers have shown excellent diagnostic ability by identifying tau pathology and cerebral amyloid beta for AD. Neuroimaging is becoming increasingly important for identifying the underlying causes of cognitive impairment. Currently, MRI is considered the preferred neuroimaging modality for AD as it enables accurate measurement of the three-dimensional volume of brain structures, particularly the size of the hippocampus and related regions. CT may be used when MRI is not possible, such as in a patient with a pacemaker. 

PET is increasingly being used as a noninvasive method for depicting tau pathology deposition and distribution in patients with cognitive impairment. In 2020, the US Food and Drug Administration approved the first tau PET tracer, ¹⁸F-flortaucipir, a significant achievement in improving AD diagnosis. 

Currently, the only therapies available for AD are symptomatic therapies. Cholinesterase inhibitors and a partial N-methyl-d-aspartate antagonist are the standard medical treatment for AD. Recently approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021; and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents are often used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and/or sleep disorders, which can be problematic. Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Behavioral interventions, including patient-centered approaches and caregiver training, may also be beneficial for managing the cognitive and behavioral manifestations of AD. These modalities are often used in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Regular physical activity and exercise is also emerging as a potential strategy for delaying AD progression and possibly conferring a protective effect on brain health.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

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

Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring). Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

 

 

The future of a “referral bridge”

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; dkraus@outcomereferrals.com

Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring). Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

 

 

The future of a “referral bridge”

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; dkraus@outcomereferrals.com

Approximately 1 in 4 people ages 18 years and older and 1 in 3 people ages 18 to 25 years had a mental illness in the past year, according to the 2021 National Survey of Drug Use and Health.¹ The survey also found that adults ages 18 to 25 years had the highest rate of serious mental illness but the lowest treatment rate compared to other adult age groups.¹ Unfortunately, more than 60% of patients receiving mental health treatment fail to benefit to a clinically meaningful degree.²

However, there is growing evidence that referring patients to behavioral health practitioners (BHPs) with outcome-measured skills that meet the patient’s specific needs can have a dramatic and positive impact. There are 2 main steps to pairing patients with an appropriate BHP: (1) use of measurement-based care data that can be analyzed at the patient and therapist level, and (2) data-driven referrals that pair patients with BHPs based on such routine outcome monitoring data (paired-on outcome data).

Psychotherapy’s slow road toward measurement-based care

Routine outcome monitoring is the systematic measurement of symptoms and functioning during treatment. It serves multiple functions, including program evaluation and benchmarking of patient improvement rates. Moreover, routine outcome monitoring–­derived feedback (based on repeated patient outcome measurements) can inform personalized and responsive care decisions throughout treatment.

For all intents and purposes, routine outcome monitoring plus feedback is synonymous with measurement-based care, which is becoming the preferred term in psychotherapy.³ Although measurement-based care is often the standard of practice for treating physical health conditions, the adoption of measurement-based care practices for treating mental health conditions remains low.³ The implementation of routine outcome monitoring is the lynchpin of measurement-based care, which in psychotherapy includes³:

• routinely administered symptom/functioning measure, ideally before each clinical encounter,
• practitioner review of these patient-level data,
• patient review of these data with their practitioner, and
• collaborative reevaluation of the person-specific treatment plan informed by these data.

CASE SCENARIO

Violeta W is a 33-year-old woman who presented to her family physician for her annual wellness exam. Prior to the exam, the medical assistant administered a Patient Health ­Questionnaire-9 (PHQ-9) to screen for depressive symptoms. Ms. W’s score was 20 out of 27, suggestive of depression. To further assess the severity of depressive symptoms and their effect on daily function, the physician reviewed responses to the questionnaire with her and discussed treatment options. Ms. W was most interested in trying a low-dose selective serotonin reuptake inhibitor (SSRI).

At her follow-up visit 4 weeks later, the medical assistant re-administered the PHQ-9. The physician then reviewed Ms. W’s responses­ with her and, based on Ms. W’s subjective report and objective symptoms (still a score of 20 out of 27 on the PHQ-9), increased her SSRI dose. At each subsequent visit, Ms. W completed a PHQ-9 and reviewed responses and depressive symptoms with her physician.

The value of measurement-based care in mental health care

A narrative review by Lewis et al³ of 21 randomized controlled clinical trials (RCTs) across a range of age groups (eg, adolescents, young adults, adults), disorders (eg, anxiety, mood), and settings (eg, outpatient, inpatient) found that in at least 9 review articles, measurement-based care was associated with significantly improved outcomes vs usual care (ie, treatment without routine outcome monitoring plus feedback). The average increase in treatment effect size was about 30% when treatment was accompanied by measurement-based care.³

Continue to: Moreover, a recent within-patient meta-analysis...

Routine outcome monitoring– derived feedback can inform personalized and responsive care decisions throughout treatment.

Moreover, a recent within-patient meta-analysis by de Jong et al⁴ shows that ­measurement-based care yields a small but significant increase in therapeutic outcomes (d = .15). Use of measurement-based care also is associated with improved communication between the patient and therapist.⁵ In pharmacotherapy practice, measurement-based care has been shown to predict rapid dose increases and changes in medication, when necessary; faster recovery rates; higher response rates to treatment³; and fewer ­dropouts.⁴

Perhaps one of the best-studied benefits of measurement-based mental health care is the ability to predict deterioration in care (ie, patients who are off-track in a way that practitioners often miss without the help of routine outcome monitoring data).^6,7 Studies show that without a data-informed approach to care, some forms of psychotherapy or therapy with BHPs who are not sufficiently skilled in treating a given diagnosis increase symptoms or create significant harmful and iatrogenic effects.^8-10 Conversely, the meta-analysis by de Jong et al⁴ found a lower percentage of deterioration in patients receiving ­measurement-based care. The difference in deterioration was significant: An average of 5.4% of patients in control conditions deteriorated compared to an average of 4.6% in feedback (measurement-based care) groups. There were even larger effect sizes when therapists received training in the feedback system.⁴

Routine outcome monitoring without a dialogue between patient and practitioner about the assessments (eg, ignoring complete measurement-based care requirements) may be inadequate. A recent review by Muir et al⁶ found no differences in patient outcomes when data were used solely for aggregate quality improvement activities, suggesting the need for practitioners to review results of routine outcome monitoring assessments with patients and use data to alter care when necessary.

Measurement-based care is believed to deliver benefits and reduce harm by enhancing and encouraging active patient involvement, improving patient understanding of symptoms, promoting better communication, and facilitating better care coordination.³ The benefits of measurement-based care can be enhanced with a comprehensive core routine outcome monitoring tool and the level of monitoring-generated information delivered for multiple stakeholders (eg, patient, therapist, clinic).¹¹

A look at multidimensional assessment

The features of routine outcome monitoring tools vary significantly.¹² Some measures assess single-symptom or problem domains (eg, PHQ-9 for depression or Generalized Anxiety Disorder-7 [GAD-7] scale for anxiety) or multiple dimensions (multidimensional routine outcome monitoring). Multidimensional routine outcome monitoring may have benefits over single-domain measures. Single­-domain measures and the subscales or factors of more comprehensive multidimensional routine outcome monitoring assessments should possess adequate specificity and sensitivity.

Continue to: Some recent research findings...

Some recent research findings question the construct validity of brief single-domain measures of common presenting problems, such as depression and anxiety. For example, results from a factor analysis of the PHQ-9 and GAD-7 scale in patients with traumatic brain injury suggest these tools measure 1 psychological construct that includes depression and the cognitive components of anxiety (eg, worry)¹³—a finding consistent with those of other tools.¹⁴ Similarly, a larger study of 7763 BH patients found that a single factor accounted for most of the variance of the 2 combined measures, with no set of factors meeting the exacting standards used to develop multidimensional routine outcome monitoring.¹⁵ These findings suggest that the PHQ-9 and GAD-7 largely overlap and are not measuring different aspects of health as most practitioners believe (eg, depression and anxiety).

In commonly used assessments, ­multiple-factor analytic studies with high standards have supported the construct validity of domain-specific subscales, indicating that the various questions tap into different constructs of psychological health.^14,16,17

Perhaps one of the best-studied benefits of mental health measurementbased care is the ability to predict deterioration in care.

Beyond multiple domain–specific indicators, multidimensional routine outcome measurements provide a global total score that minimizes Type I (false-positive conclusion) and Type II (false-negative conclusion) errors in tracking patient improvement or deterioration.¹⁸ As one would expect, multidimensional routine outcome monitoring generally includes more items than single-domain measures; however, this comes with a trade-off. If there are specificity and sensitivity concerns with an ultra-brief single-domain measure, an alternative to a core multidimensional routine outcome measurement is to aggregate a series of single-domain measures into a battery of patient self-reports. However, this approach may take longer for patients to complete since they would have to shift among the varying response sets and wording across the unique single-domain measures.

In addition, the standardization/­normalization of multidimensional routine outcome monitoring likely makes interpretation easier than referring to norms and clinical severity cutoffs for many distinct measures. Furthermore, increased specificity enhances predictive power and allows BHPs to screen and track other conditions besides depression and anxiety. (It is worth noting that there are no known studies that have looked at the difference in time to administer or ease of interpretation of multidimensional routine outcome monitoring tools vs multiple single-domain measures.)

Two multidimensional routine outcome monitoring tools that cover a comprehensive series of discrete symptom and functional domains are the Treatment Outcome Package¹² and Counseling Center ­Assessment of Psychological Symptoms.¹⁶ These tools, which include subscales beyond general depression and anxiety (eg, sleep, substance misuse, social conflict), take 7 to 10 minutes to complete and provide outcome results across 12 symptom and 8 functional dimensions. As an example, the Treatment Outcome Package has good psychometric qualities (eg, reliability, construct and concurrent validity) for adults,¹² children,^14,19 and adolescents,¹⁹ and can be administered through a secure online data collection portal. The Counseling Center Assessment of Psychological Symptoms has demonstrated high construct validity and good convergent validity.¹⁶ These assessments can be administered in paper or digital (eg, electronic medical record portal, smartphone) format.²⁰

Continue to: CASE SCENARIO

CASE SCENARIO

Ms. W’s physician asked her to go online using her phone and answer the questions in the Treatment Outcome Package. Her results, which she viewed with her physician, were displayed in graph form (FIGURE). Her scores were represented in Z scores normalized to the general population, with “0” representing the general, nontreatment-seeking population average and positive scores representing the number of standard deviations (SDs) more severe than the general population average.

Although this assessment scored Ms. W’s clinically elevated depression as mild, it revealed abnormalities in 3 other domains. Sexual functioning issues represented the most abnormal domain at greater than 3 SDs (more severe than the general population), followed by poor life quality and school/work functioning.

After reviewing Ms. W’s report, her physician decided that pharmacologic management alone (for depression) was not the most appropriate treatment course. Therefore, her physician recommended psychotherapy in addition to the SSRI she was taking. Ms. W agreed to a customized referral for psychotherapy.

Data-driven referrals

When psychotherapy is chosen as a treatment, the individual BHP is an active component of that treatment. Consequently, it is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains. It is rare for a BHP to be skilled in treating every mental health domain.⁹ Multiple studies have shown that BHPs have identifiable treatment skills in specific domains, which physicians should consider when making referrals.^9,21,22 These studies demonstrate the utility of aggregating patient-level routine outcome monitoring data to better understand therapist-level (and ultimately clinic- and system-level) outcomes.

It is essential to customize referrals to match a patient’s most elevated mental health concerns with a therapist who will most effectively treat those domains.

Additionally, recent research has tested this idea prospectively. An RCT funded by the Patient-Centered Outcome Research Institute and published in JAMA Psychiatry showed a significant and positive effect on patient outcomes (ie, reductions in general impairment, impairment involving a patient’s most elevated domain, and global distress) using paired-on outcome data matching vs as-usual matching protocols (eg, therapist self-defined areas of specialty).²² In the RCT, the most effective matching protocol was a combination of eliminating harm and matching the patient on their 3 most problematic domains (the highest match level). These patients ended care as healthy as the general population after 16 weeks of treatment. A random 1-year follow-up assessment from the original RCT showed that most patients who had been matched had maintained their improvement.²³

Continue to: Therefore, a multidimensional routine outcome...

Therefore, a multidimensional routine outcome monitoring tool can be used to identify a BHP’s relative strengths and weaknesses across multiple outcome domains. Within a system of care, a sample of BHPs will possess varying outcome-domain profiles. When a new patient is seeking a referral to a BHP, these profiles (or domain-specific outcome track records) can be used to support paired-on outcome data matching. Specifically, a new patient completes the multidimensional routine outcome monitoring tool at pretreatment, and the results reveal the outcome domains on which the patient is most clinically severe. This pattern of domain-specific severity then can be used to pair the new patient with a BHP who has demonstrated success in addressing the same outcome domain(s). This approach matches a new patient to a BHP with established expertise based on routine outcome monitoring.

Retrospective and prospective studies have found that most BHPs have stable performance in their strengths and weaknesses.^11,21 One study found that assessing BHP performance with their most recent 30 patients can reliably predict future performance with their next 30 patients.²⁴ This predictability in a practitioner’s outcomes suggests report cards that are updated frequently can be utilized to make case assignments within BH or referrals to a specific BHP from primary care.

Making a paired-on outcome data–matched referral

Making customized BH referrals requires access to information about a practitioner’s previous routine outcome monitoring data per clinical domain (eg, suicidality, violence, quality of life) from their most recent patients. Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses (ie, effectiveness “report card”) per clinical ­domain.²⁴

Previous research suggests that follow-up data from a minimum of 15 patients is necessary to make a reliable evaluation of a practitioner’s strengths and weaknesses.

Few, if any, physicians have access to this level of updated outcome data from their referral network. To facilitate widespread use of paired-on outcome data matching, a new Web system (MatchedTherapists.com) will allow the general public and PCPs to access these grades. As a public service option, this site currently allows for a self-assessment using the Treatment Outcome Package. Pending versions will generate paired-on outcome data grades, and users will receive a list of local therapists available for in-person appointments as well as therapists available for virtual appointments. The paired-on outcome data grades are delivered in school-based letter grades. An “A+,” for example, represents the best matching grade. Users also will be able to sort and filter results for other criteria such as telemedicine, insurance, age, gender, and appointment availability. Currently, there are more than 77,000 therapists listed on the site nationwide. A basic listing is free.

CASE SCENARIO

After Ms. W took the multidimensional routine outcome assessment online, she received a list of therapists rank-ordered by paired-on outcome data grade, with the “A+” matches listed first. Three of the best-matched referrals accepted her insurance and were willing to see her through telemedicine. Therapists with available in-person appointments had a “B” grade. After discussing the options with her physician, Ms. W opted for telehealth counseling with the therapist whose profile she liked best. The therapist and PCP tracked her progress through routine outcome monitoring reporting until all her symptoms became subclinical.

Continue to: The future of a "referral bridge"

 

 

The future of a “referral bridge”

In this article, we present a solution to a common issue faced by mental health care patients: failure to benefit meaningfully from mental health treatment. Matching patients to specific BHPs based on effectiveness data regarding the therapist’s strengths and skills can improve patient outcomes and reduce harm. In addition, patients appear to value this approach. A Robert Wood Johnson Foundation–­funded study demonstrated that patients value seeing practitioners who have a track record of successfully treating previous patients with similar issues.^25,26 In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience or the same demographic characteristics as the patient.^25,26

In many cases, patients indicated they would prioritize this matching process over other factors such as practitioners with a higher number of years of experience.

These findings may represent a new area in the science of health care. Over the past century, major advances in diagnosis and treatment—the 2 primary pillars of health care—have turned the art of medicine into a science. However, the art of making referrals has not advanced commensurately, as there has been little attention focused on the “referral bridge” between these 2 pillars. As the studies reviewed in this paper demonstrate, a referral bridge deserves exploration in all fields of medicine.

CORRESPONDENCE
David R. Kraus, PhD, 1 Speen Street, Framingham, MA 01701; dkraus@outcomereferrals.com