Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

A significant mortality gap persists between patients with type 2 diabetes and cardiovascular disease and similarly aged patients with neither condition. Data from the Emerging Risk Factors Collaboration showed that on average, a 60-year-old female patient with type 2 diabetes and a history of myocardial infarction dies around 14 years earlier than a similarly aged patient with neither of these conditions.

Therefore, I was keen to hear the key new recommendations from the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiovascular disease in patients with diabetes. These recommendations were presented at the recent ESC 2023 congress in Amsterdam, which I was fortunate enough to attend.

The comprehensive guideline cemented the fact that our primary goal in type 2 diabetes management is a reduction in cardiovascular events and mortality, rather than the glucocentric goals that have been followed previously. Of course, good glycemic control remains important to protect against the microvascular complications of diabetes, but glycemic control has only a modest impact on macrovascular complications such as cardiovascular disease.

The updated guideline recommends that all patients with type 2 diabetes without symptomatic atherosclerotic cardiovascular disease or severe target-organ damage be screened for the risk for cardiovascular disease using a new 10-year cardiovascular risk calculator called SCORE2-Diabetes. This calculator extends the well-established SCORE2 cardiovascular risk-prediction tool with added predictors specifically related to type 2 diabetes. It also accounts for variation in risk across Europe.

Using SCORE2 Diabetes will be a change in practice for me, as I have been using QRISK3, which is a United Kingdom–based cardiovascular risk tool that has been less extensively validated in patients with type 2 diabetes. Helpfully, an ESC CVD Risk Calculation app is available and can be tailored to your geographical region to calculate a SCORE2-Diabetes risk score easily. For example, Eastern Europe has a higher cardiovascular risk profile than Western Europe.

Cardiovascular risk categories are now defined on the basis of the presence of atherosclerotic cardiovascular disease, severe target-organ damage, or the 10-year cardiovascular risk using SCORE2-Diabetes.

For patients at very high cardiovascular risk (for example, those with type 2 diabetes and established atherosclerotic cardiovascular disease), the ESC guidance recommends dual therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor to reduce cardiovascular risk independent of glucose control (that is, A1c). This dual therapy is recommended in addition to standard-of-care antiplatelet, antihypertensive, and lipid-lowering therapies.

There is no doubt that the evidence for GLP-1 receptor agonist use and reduction in atherosclerotic cardiovascular disease in type 2 diabetes is compelling, perhaps more so than the evidence for SGLT2 inhibitor use. However, this recommendation will be challenging to implement, given the current global supply issues with GLP-1 receptor agonists, which are driven by the off-label use of these medications for the management of obesity. GLP-1 receptor agonist supplies are not expected to stabilize until mid-2024.

Controversially, the updated ESC guidance suggests the use of metformin only in patients with type 2 diabetes and atherosclerotic cardiovascular disease if additional glucose control is required. This is a misstep, in my opinion, as insulin resistance is one of the key pathophysiologic abnormalities in patients with type 2 diabetes. One of the key advantages of metformin is an improvement in insulin sensitivity. This recommendation will not change my practice, and I will continue to prescribe metformin alongside GLP-1 receptor agonists or SGLT2 inhibitors for my patients at highest cardiovascular risk.

The updated ESC guidance also explicitly reminds healthcare professionals to look for significant comorbidities, such as heart failure of all subtypes and chronic kidney disease.

The ESC guidance recommends a systematic survey for heart failure symptoms and signs at each clinical encounter in all patients with type 2 diabetes. Although I agree that heart failure is underdiagnosed in this population, the recommendation will be challenging to implement and has significant workload implications, as heart failure often presents in insidious, nonspecific ways in primary care.

For patients with type 2 diabetes and heart failure with reduced ejection fraction, SGLT2 inhibitors are recommended to reduce the risk for heart failure hospitalization and cardiovascular death. Again, this recommendation is independent of glycemic control. In addition, for patients with type 2 diabetes and heart failure with mid-range ejection fraction or heart failure with preserved ejection fraction (that is, left ventricular ejection fraction > 40%), SGLT2 inhibitors are also recommended to reduce the risk for heart failure hospitalization or cardiovascular death independent of glycemic control. This recommendation is consistent with other updated global heart failure guidance. Increasingly, the pillars of heart failure therapy are being challenged with the early initiation of SGLT2 inhibitors, given their compelling evidence base, early symptomatic benefit, and ease of use, with less requirement of routine blood monitoring.

Finally, for patients with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone are now recommended to reduce the risk for kidney failure and cardiovascular disease, independent of glycemic control and in addition to standard of care.

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist with quite different pharmacokinetics and clinical effects, compared with those of spironolactone and eplerenone, which are steroidal MRAs. Specifically, finerenone does not significantly lower blood pressure and has fewer steroid-induced adverse effects such as gynecomastia, impotence, and low libido. However, like steroidal MRAs, finerenone can result in hyperkalemia.

Finerenone has demonstrated significant kidney and cardiovascular benefits across the spectrum of chronic kidney disease in patients with type 2 diabetes. It entails no significant imbalance in adverse events, hence this recommendation. This observation reinforces the importance of measuring urinary albumin–creatinine ratio in patients with type 2 diabetes and preserved kidney function.

In conclusion, the 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes are forward-thinking recommendations. They look beyond glycemia and reflect the current evidence for newer glucose-lowering therapies with proven cardiorenal benefits. Nevertheless, the implementation of these guidelines will be challenging, given their workload implications, the unstable supply of GLP-1 receptor agonists, and a persisting glucocentric approach to type 2 diabetes care in some areas. Implementation will require ongoing education for health care professionals about the risk-benefit ratios of SGLT2 inhibitors and GLP-1 receptor agonists. It also will require a re-evaluation of workforce strategy to support the development of a skilled and sustainable workforce.

Dr. Fernando is a general practitioner partner with North Berwick (Scotland) Health Centre, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education. He disclosed receiving speakers’ fees from Eli Lilly and Novo Nordisk.

A version of this article appeared on Medscape.com.

A significant mortality gap persists between patients with type 2 diabetes and cardiovascular disease and similarly aged patients with neither condition. Data from the Emerging Risk Factors Collaboration showed that on average, a 60-year-old female patient with type 2 diabetes and a history of myocardial infarction dies around 14 years earlier than a similarly aged patient with neither of these conditions.

Therefore, I was keen to hear the key new recommendations from the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiovascular disease in patients with diabetes. These recommendations were presented at the recent ESC 2023 congress in Amsterdam, which I was fortunate enough to attend.

The comprehensive guideline cemented the fact that our primary goal in type 2 diabetes management is a reduction in cardiovascular events and mortality, rather than the glucocentric goals that have been followed previously. Of course, good glycemic control remains important to protect against the microvascular complications of diabetes, but glycemic control has only a modest impact on macrovascular complications such as cardiovascular disease.

The updated guideline recommends that all patients with type 2 diabetes without symptomatic atherosclerotic cardiovascular disease or severe target-organ damage be screened for the risk for cardiovascular disease using a new 10-year cardiovascular risk calculator called SCORE2-Diabetes. This calculator extends the well-established SCORE2 cardiovascular risk-prediction tool with added predictors specifically related to type 2 diabetes. It also accounts for variation in risk across Europe.

Using SCORE2 Diabetes will be a change in practice for me, as I have been using QRISK3, which is a United Kingdom–based cardiovascular risk tool that has been less extensively validated in patients with type 2 diabetes. Helpfully, an ESC CVD Risk Calculation app is available and can be tailored to your geographical region to calculate a SCORE2-Diabetes risk score easily. For example, Eastern Europe has a higher cardiovascular risk profile than Western Europe.

Cardiovascular risk categories are now defined on the basis of the presence of atherosclerotic cardiovascular disease, severe target-organ damage, or the 10-year cardiovascular risk using SCORE2-Diabetes.

For patients at very high cardiovascular risk (for example, those with type 2 diabetes and established atherosclerotic cardiovascular disease), the ESC guidance recommends dual therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor to reduce cardiovascular risk independent of glucose control (that is, A1c). This dual therapy is recommended in addition to standard-of-care antiplatelet, antihypertensive, and lipid-lowering therapies.

There is no doubt that the evidence for GLP-1 receptor agonist use and reduction in atherosclerotic cardiovascular disease in type 2 diabetes is compelling, perhaps more so than the evidence for SGLT2 inhibitor use. However, this recommendation will be challenging to implement, given the current global supply issues with GLP-1 receptor agonists, which are driven by the off-label use of these medications for the management of obesity. GLP-1 receptor agonist supplies are not expected to stabilize until mid-2024.

Controversially, the updated ESC guidance suggests the use of metformin only in patients with type 2 diabetes and atherosclerotic cardiovascular disease if additional glucose control is required. This is a misstep, in my opinion, as insulin resistance is one of the key pathophysiologic abnormalities in patients with type 2 diabetes. One of the key advantages of metformin is an improvement in insulin sensitivity. This recommendation will not change my practice, and I will continue to prescribe metformin alongside GLP-1 receptor agonists or SGLT2 inhibitors for my patients at highest cardiovascular risk.

The updated ESC guidance also explicitly reminds healthcare professionals to look for significant comorbidities, such as heart failure of all subtypes and chronic kidney disease.

The ESC guidance recommends a systematic survey for heart failure symptoms and signs at each clinical encounter in all patients with type 2 diabetes. Although I agree that heart failure is underdiagnosed in this population, the recommendation will be challenging to implement and has significant workload implications, as heart failure often presents in insidious, nonspecific ways in primary care.

For patients with type 2 diabetes and heart failure with reduced ejection fraction, SGLT2 inhibitors are recommended to reduce the risk for heart failure hospitalization and cardiovascular death. Again, this recommendation is independent of glycemic control. In addition, for patients with type 2 diabetes and heart failure with mid-range ejection fraction or heart failure with preserved ejection fraction (that is, left ventricular ejection fraction > 40%), SGLT2 inhibitors are also recommended to reduce the risk for heart failure hospitalization or cardiovascular death independent of glycemic control. This recommendation is consistent with other updated global heart failure guidance. Increasingly, the pillars of heart failure therapy are being challenged with the early initiation of SGLT2 inhibitors, given their compelling evidence base, early symptomatic benefit, and ease of use, with less requirement of routine blood monitoring.

Finally, for patients with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone are now recommended to reduce the risk for kidney failure and cardiovascular disease, independent of glycemic control and in addition to standard of care.

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist with quite different pharmacokinetics and clinical effects, compared with those of spironolactone and eplerenone, which are steroidal MRAs. Specifically, finerenone does not significantly lower blood pressure and has fewer steroid-induced adverse effects such as gynecomastia, impotence, and low libido. However, like steroidal MRAs, finerenone can result in hyperkalemia.

Finerenone has demonstrated significant kidney and cardiovascular benefits across the spectrum of chronic kidney disease in patients with type 2 diabetes. It entails no significant imbalance in adverse events, hence this recommendation. This observation reinforces the importance of measuring urinary albumin–creatinine ratio in patients with type 2 diabetes and preserved kidney function.

In conclusion, the 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes are forward-thinking recommendations. They look beyond glycemia and reflect the current evidence for newer glucose-lowering therapies with proven cardiorenal benefits. Nevertheless, the implementation of these guidelines will be challenging, given their workload implications, the unstable supply of GLP-1 receptor agonists, and a persisting glucocentric approach to type 2 diabetes care in some areas. Implementation will require ongoing education for health care professionals about the risk-benefit ratios of SGLT2 inhibitors and GLP-1 receptor agonists. It also will require a re-evaluation of workforce strategy to support the development of a skilled and sustainable workforce.

Dr. Fernando is a general practitioner partner with North Berwick (Scotland) Health Centre, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education. He disclosed receiving speakers’ fees from Eli Lilly and Novo Nordisk.

A version of this article appeared on Medscape.com.

A significant mortality gap persists between patients with type 2 diabetes and cardiovascular disease and similarly aged patients with neither condition. Data from the Emerging Risk Factors Collaboration showed that on average, a 60-year-old female patient with type 2 diabetes and a history of myocardial infarction dies around 14 years earlier than a similarly aged patient with neither of these conditions.

Therefore, I was keen to hear the key new recommendations from the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiovascular disease in patients with diabetes. These recommendations were presented at the recent ESC 2023 congress in Amsterdam, which I was fortunate enough to attend.

The comprehensive guideline cemented the fact that our primary goal in type 2 diabetes management is a reduction in cardiovascular events and mortality, rather than the glucocentric goals that have been followed previously. Of course, good glycemic control remains important to protect against the microvascular complications of diabetes, but glycemic control has only a modest impact on macrovascular complications such as cardiovascular disease.

The updated guideline recommends that all patients with type 2 diabetes without symptomatic atherosclerotic cardiovascular disease or severe target-organ damage be screened for the risk for cardiovascular disease using a new 10-year cardiovascular risk calculator called SCORE2-Diabetes. This calculator extends the well-established SCORE2 cardiovascular risk-prediction tool with added predictors specifically related to type 2 diabetes. It also accounts for variation in risk across Europe.

Using SCORE2 Diabetes will be a change in practice for me, as I have been using QRISK3, which is a United Kingdom–based cardiovascular risk tool that has been less extensively validated in patients with type 2 diabetes. Helpfully, an ESC CVD Risk Calculation app is available and can be tailored to your geographical region to calculate a SCORE2-Diabetes risk score easily. For example, Eastern Europe has a higher cardiovascular risk profile than Western Europe.

Cardiovascular risk categories are now defined on the basis of the presence of atherosclerotic cardiovascular disease, severe target-organ damage, or the 10-year cardiovascular risk using SCORE2-Diabetes.

For patients at very high cardiovascular risk (for example, those with type 2 diabetes and established atherosclerotic cardiovascular disease), the ESC guidance recommends dual therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor to reduce cardiovascular risk independent of glucose control (that is, A1c). This dual therapy is recommended in addition to standard-of-care antiplatelet, antihypertensive, and lipid-lowering therapies.

There is no doubt that the evidence for GLP-1 receptor agonist use and reduction in atherosclerotic cardiovascular disease in type 2 diabetes is compelling, perhaps more so than the evidence for SGLT2 inhibitor use. However, this recommendation will be challenging to implement, given the current global supply issues with GLP-1 receptor agonists, which are driven by the off-label use of these medications for the management of obesity. GLP-1 receptor agonist supplies are not expected to stabilize until mid-2024.

Controversially, the updated ESC guidance suggests the use of metformin only in patients with type 2 diabetes and atherosclerotic cardiovascular disease if additional glucose control is required. This is a misstep, in my opinion, as insulin resistance is one of the key pathophysiologic abnormalities in patients with type 2 diabetes. One of the key advantages of metformin is an improvement in insulin sensitivity. This recommendation will not change my practice, and I will continue to prescribe metformin alongside GLP-1 receptor agonists or SGLT2 inhibitors for my patients at highest cardiovascular risk.

The updated ESC guidance also explicitly reminds healthcare professionals to look for significant comorbidities, such as heart failure of all subtypes and chronic kidney disease.

The ESC guidance recommends a systematic survey for heart failure symptoms and signs at each clinical encounter in all patients with type 2 diabetes. Although I agree that heart failure is underdiagnosed in this population, the recommendation will be challenging to implement and has significant workload implications, as heart failure often presents in insidious, nonspecific ways in primary care.

For patients with type 2 diabetes and heart failure with reduced ejection fraction, SGLT2 inhibitors are recommended to reduce the risk for heart failure hospitalization and cardiovascular death. Again, this recommendation is independent of glycemic control. In addition, for patients with type 2 diabetes and heart failure with mid-range ejection fraction or heart failure with preserved ejection fraction (that is, left ventricular ejection fraction > 40%), SGLT2 inhibitors are also recommended to reduce the risk for heart failure hospitalization or cardiovascular death independent of glycemic control. This recommendation is consistent with other updated global heart failure guidance. Increasingly, the pillars of heart failure therapy are being challenged with the early initiation of SGLT2 inhibitors, given their compelling evidence base, early symptomatic benefit, and ease of use, with less requirement of routine blood monitoring.

Finally, for patients with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone are now recommended to reduce the risk for kidney failure and cardiovascular disease, independent of glycemic control and in addition to standard of care.

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist with quite different pharmacokinetics and clinical effects, compared with those of spironolactone and eplerenone, which are steroidal MRAs. Specifically, finerenone does not significantly lower blood pressure and has fewer steroid-induced adverse effects such as gynecomastia, impotence, and low libido. However, like steroidal MRAs, finerenone can result in hyperkalemia.

Finerenone has demonstrated significant kidney and cardiovascular benefits across the spectrum of chronic kidney disease in patients with type 2 diabetes. It entails no significant imbalance in adverse events, hence this recommendation. This observation reinforces the importance of measuring urinary albumin–creatinine ratio in patients with type 2 diabetes and preserved kidney function.

In conclusion, the 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes are forward-thinking recommendations. They look beyond glycemia and reflect the current evidence for newer glucose-lowering therapies with proven cardiorenal benefits. Nevertheless, the implementation of these guidelines will be challenging, given their workload implications, the unstable supply of GLP-1 receptor agonists, and a persisting glucocentric approach to type 2 diabetes care in some areas. Implementation will require ongoing education for health care professionals about the risk-benefit ratios of SGLT2 inhibitors and GLP-1 receptor agonists. It also will require a re-evaluation of workforce strategy to support the development of a skilled and sustainable workforce.

Dr. Fernando is a general practitioner partner with North Berwick (Scotland) Health Centre, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education. He disclosed receiving speakers’ fees from Eli Lilly and Novo Nordisk.

A version of this article appeared on Medscape.com.

Widely used billing codes have been updated for 2024, including new ones for respiratory syncytial virus (RSV) vaccines and medications, and new Spanish translations.

The American Medical Association recently released the Current Procedural Terminology (CPT) 2024 Code Set. The update included 349 editorial changes, including 230 additions, 49 deletions, and 70 revisions. With more than 11,100 codes in use, the CPT system continues “to grow and evolve with the rapid pace of innovation in medical science and health technology,” AMA said.

The AMA said the CPT update includes five new codes created to report product-specific RSV products (90380, 90381, 90683, 90679, and 90678) for better tracking, reporting and analysis that supports data-driven planning and allocation, AMA said.

There’s been a flurry of new U.S. vaccines and drugs to address RSV. The Food and Drug Administration in May granted the first U.S. approval of an RSV vaccine to Arexy, manufactured by GSK. The FDA cleared it for prevention of lower respiratory tract disease caused by RSV in adults age 60 years and older.

In June, Pfizer won FDA approval of Abrysvo, another vaccine meant to protect adults older than 60 years from RSV. The following month, the FDA approved nirsevimab (Beyfortus, AstraZeneca/Sanofi), for the prevention of RSV in neonates and infants entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. (This is not a vaccine, but a monoclonal antibody used for prevention. There has been confusion on this issue in part because monoclonal antibodies are often used for treatment rather than prevention.)

The FDA also has approved Abrysvo for use in pregnant individuals.

In addition, new CPT codes aim to streamline COVID-19 immunizations reporting. A new code (90480) was approved for reporting the administration of any COVID-19 vaccine for any patient. New provisional codes (91318-91322) will identify monovalent vaccine products from Moderna and Pfizer for immunization against COVID-19.

These provisional codes will be effective for use when the monovalent vaccine products from Moderna and Pfizer receive FDA approval, AMA said.
 

More codes explained in Spanish

The 2024 update includes more code descriptions in Spanish. Many hospitals, health plans, and medical offices already incorporate CPT descriptors in English-language medical documents, insurance forms, price sheets, and patient portals. This expansion is intended to help patients who may not read English well or at all.

“Providing approximately 41 million Spanish-speaking individuals in the United States with an easy-to-understand description of medical procedures and services can help build a more inclusive health care environment, where language is no longer a barrier and patients can actively engage in their own care,” Lori Prestesater, AMA’s senior vice president of health solutions, said in a statement.

In addition, the 2024 update includes clarifications sought by the Centers for Medicare & Medicaid Services about the reporting of evaluation and management (E/M) services. The revisions include:

• Removal of time ranges from office or other outpatient visit codes (99202-99205, 99212-99215) and format alignment with other E/M codes.
• Definition of the “substantive portion” of a split/shared E/M visit in which a physician and a nonphysician practitioner work jointly to furnish all the work related to the visit.
• Instructions for reporting hospital inpatient or observation care services and admission and discharge services for the use of codes. 99234-99236 when the patient stay crosses over two calendar dates.

A version of this article appeared on Medscape.com.

Widely used billing codes have been updated for 2024, including new ones for respiratory syncytial virus (RSV) vaccines and medications, and new Spanish translations.

The American Medical Association recently released the Current Procedural Terminology (CPT) 2024 Code Set. The update included 349 editorial changes, including 230 additions, 49 deletions, and 70 revisions. With more than 11,100 codes in use, the CPT system continues “to grow and evolve with the rapid pace of innovation in medical science and health technology,” AMA said.

The AMA said the CPT update includes five new codes created to report product-specific RSV products (90380, 90381, 90683, 90679, and 90678) for better tracking, reporting and analysis that supports data-driven planning and allocation, AMA said.

There’s been a flurry of new U.S. vaccines and drugs to address RSV. The Food and Drug Administration in May granted the first U.S. approval of an RSV vaccine to Arexy, manufactured by GSK. The FDA cleared it for prevention of lower respiratory tract disease caused by RSV in adults age 60 years and older.

In June, Pfizer won FDA approval of Abrysvo, another vaccine meant to protect adults older than 60 years from RSV. The following month, the FDA approved nirsevimab (Beyfortus, AstraZeneca/Sanofi), for the prevention of RSV in neonates and infants entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. (This is not a vaccine, but a monoclonal antibody used for prevention. There has been confusion on this issue in part because monoclonal antibodies are often used for treatment rather than prevention.)

The FDA also has approved Abrysvo for use in pregnant individuals.

In addition, new CPT codes aim to streamline COVID-19 immunizations reporting. A new code (90480) was approved for reporting the administration of any COVID-19 vaccine for any patient. New provisional codes (91318-91322) will identify monovalent vaccine products from Moderna and Pfizer for immunization against COVID-19.

These provisional codes will be effective for use when the monovalent vaccine products from Moderna and Pfizer receive FDA approval, AMA said.
 

More codes explained in Spanish

The 2024 update includes more code descriptions in Spanish. Many hospitals, health plans, and medical offices already incorporate CPT descriptors in English-language medical documents, insurance forms, price sheets, and patient portals. This expansion is intended to help patients who may not read English well or at all.

“Providing approximately 41 million Spanish-speaking individuals in the United States with an easy-to-understand description of medical procedures and services can help build a more inclusive health care environment, where language is no longer a barrier and patients can actively engage in their own care,” Lori Prestesater, AMA’s senior vice president of health solutions, said in a statement.

In addition, the 2024 update includes clarifications sought by the Centers for Medicare & Medicaid Services about the reporting of evaluation and management (E/M) services. The revisions include:

• Removal of time ranges from office or other outpatient visit codes (99202-99205, 99212-99215) and format alignment with other E/M codes.
• Definition of the “substantive portion” of a split/shared E/M visit in which a physician and a nonphysician practitioner work jointly to furnish all the work related to the visit.
• Instructions for reporting hospital inpatient or observation care services and admission and discharge services for the use of codes. 99234-99236 when the patient stay crosses over two calendar dates.

A version of this article appeared on Medscape.com.

Widely used billing codes have been updated for 2024, including new ones for respiratory syncytial virus (RSV) vaccines and medications, and new Spanish translations.

The American Medical Association recently released the Current Procedural Terminology (CPT) 2024 Code Set. The update included 349 editorial changes, including 230 additions, 49 deletions, and 70 revisions. With more than 11,100 codes in use, the CPT system continues “to grow and evolve with the rapid pace of innovation in medical science and health technology,” AMA said.

The AMA said the CPT update includes five new codes created to report product-specific RSV products (90380, 90381, 90683, 90679, and 90678) for better tracking, reporting and analysis that supports data-driven planning and allocation, AMA said.

There’s been a flurry of new U.S. vaccines and drugs to address RSV. The Food and Drug Administration in May granted the first U.S. approval of an RSV vaccine to Arexy, manufactured by GSK. The FDA cleared it for prevention of lower respiratory tract disease caused by RSV in adults age 60 years and older.

In June, Pfizer won FDA approval of Abrysvo, another vaccine meant to protect adults older than 60 years from RSV. The following month, the FDA approved nirsevimab (Beyfortus, AstraZeneca/Sanofi), for the prevention of RSV in neonates and infants entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. (This is not a vaccine, but a monoclonal antibody used for prevention. There has been confusion on this issue in part because monoclonal antibodies are often used for treatment rather than prevention.)

The FDA also has approved Abrysvo for use in pregnant individuals.

In addition, new CPT codes aim to streamline COVID-19 immunizations reporting. A new code (90480) was approved for reporting the administration of any COVID-19 vaccine for any patient. New provisional codes (91318-91322) will identify monovalent vaccine products from Moderna and Pfizer for immunization against COVID-19.

These provisional codes will be effective for use when the monovalent vaccine products from Moderna and Pfizer receive FDA approval, AMA said.
 

More codes explained in Spanish

The 2024 update includes more code descriptions in Spanish. Many hospitals, health plans, and medical offices already incorporate CPT descriptors in English-language medical documents, insurance forms, price sheets, and patient portals. This expansion is intended to help patients who may not read English well or at all.

“Providing approximately 41 million Spanish-speaking individuals in the United States with an easy-to-understand description of medical procedures and services can help build a more inclusive health care environment, where language is no longer a barrier and patients can actively engage in their own care,” Lori Prestesater, AMA’s senior vice president of health solutions, said in a statement.

In addition, the 2024 update includes clarifications sought by the Centers for Medicare & Medicaid Services about the reporting of evaluation and management (E/M) services. The revisions include:

• Removal of time ranges from office or other outpatient visit codes (99202-99205, 99212-99215) and format alignment with other E/M codes.
• Definition of the “substantive portion” of a split/shared E/M visit in which a physician and a nonphysician practitioner work jointly to furnish all the work related to the visit.
• Instructions for reporting hospital inpatient or observation care services and admission and discharge services for the use of codes. 99234-99236 when the patient stay crosses over two calendar dates.

A version of this article appeared on Medscape.com.

MILAN – Numerous unresolved questions surround progressive pulmonary fibrosis (PPF) treatment, according to Elisabeth Bendstrup, MD, PhD, a researcher and clinical professor in the department of clinical medicine – department of respiratory diseases and allergy, Aarhus (Denmark) University, Denmark. These questions regard the optimal timing for treatment initiation, the role of available medications, either as monotherapy or in combination, and nonpharmacologic support options.

What’s in the toolbox?

Pulmonologists who manage PPF have a range of treatment options at their disposal. This includes careful patient observation, with treatment initiation based on clinical necessity. The therapeutic arsenal comprises immunomodulatory treatments, antifibrotic agents, palliative and supportive care, and, for a minority of patients, lung transplantation.

“Once a patient is diagnosed with PPF, it is important to remember that the diagnostic criteria from the guidelines are not exactly the same of those accepted for the reimbursement of antifibrotic treatments in different countries,” Dr. Bendstrup said, suggesting that nonclinical considerations could also potentially influence the treatment choice. She spoke at the annual congress of the European Respiratory Society.

Michael Kreuter, MD, director of the Lung Center at the University Hospital in Mainz, Germany, provided insight into the introduction of antifibrotic drugs for the treatment of PPF. Drawing from nearly a decade ago when the first antifibrotic medication was approved for idiopathic pulmonary fibrosis (IPF), Dr. Kreuter noted its effectiveness in slowing disease progression, although it does not reverse it. Subsequently, the discovery that non-IPF diseases, such as rheumatoid arthritis, exhibited IPF-like behavior led to the exploration of the use of the same drugs for similar conditions, even if not IPF.

“That’s how antifibrotic treatments came into place. Now we have more trials and data to be discussed in the future,” Dr. Kreuter added. He highlighted that antifibrotic drugs are effective for several diseases. Most of those diseases are treated with different anti-inflammatory drugs, which makes it difficult to decide when to start antifibrotic therapy and how to eventually combine it with different pharmacologic approaches.
 

A pivotal starting point

One of the primary challenges faced by pulmonologists in the management of PPF is determining the appropriate timing for initiating treatment, a question only partially addressed by existing guidelines. Dr. Bendstrup advocated for a comprehensive baseline evaluation. Factors to be considered include symptom burden, the severity of lung decline, radiologic characteristics, signs of alveolar inflammation, progression risk factors, quality of life, patient preferences, and medical history. “All these should be best discussed in a multidisciplinary team, including pulmonologists, nurses, experts in palliative care, occupational physicians, and more,” she said.

Current guidelines recommend nintedanib for PPF treatment for patients who have failed standard management for fibrotic interstitial lung disease (ILD) other than IPF. However, the definition of “standard management” remains a topic of debate, and it is acknowledged that evidence-based guidance for a standard of care varies among patients. Dr. Bendstrup pointed out the limited guidance clinicians receive from these guidelines. “As clinicians, we are not left with very much help from here.”
 

Choosing the right approach

Dr. Bendstrup delved into the factors influencing the choice between antifibrotic and anti-inflammatory therapies. This decision hinges on whether the patient presents with a predominantly inflammatory or a fibrotic progressive phenotype. Certain clinical characteristics contribute to the decision. Factors such as younger age, female gender, and the presence of connective tissue disease lean toward an inflammatory phenotype. Radiologic patterns, such as organized pneumonia, hypersensitivity pneumonia, or usual interstitial pneumonia–like patterns also provide valuable clues. Additionally, genetics plays a role, with shorter telomeres indicating a more fibrotic phenotype and an increased risk of immunomodulatory treatment side effects in non-IPF ILDs.

Bendstrup referred to a recent position paper on treatment recommendations and many other studies that support the use of different treatments for patients with PPF. The authors highlighted limited evidence for immunomodulation in fibrotic ILD, though such treatment is generally used except for ILD associated with systemic sclerosis. Moreover, the guidelines conditionally recommend nintedanib and call for further research on pirfenidone in PPF.

“We need intelligent, well-designed trials looking at subgroups of patients at higher risk, maybe based on molecular identification. We also need to have good biomarkers to better classify our patients based on disease behavior and treatment response. There’s a lot of discussion of biomarkers for progression, much less – if any – on biomarkers for the response to treatment. And we need them as well,” Dr. Bendstrup said in an interview.
 

The role of supportive care

Effective PPF treatment extends beyond pharmacologic interventions. It encompasses symptom management, patient education on vaccination and smoking cessation, and fostering social support networks. Psychological support, supplemental oxygen therapy, and pulmonary rehabilitation are integral components of care.

Elisabeth Robertson, a PPF patient representative from the United Kingdom, emphasized the importance of palliative care, not just in end-of-life scenarios but throughout the patient’s journey. Palliative care encompasses symptom alleviation, enabling patients to stay at home when possible, addressing mental health, and preparing for the end of life. Such holistic care can significantly enhance the patient’s quality of life.

The cochair of the session, Marlies S. Wijsenbeek, MD, PhD, pulmonary physician and head of the ILD Centre at the Erasmus University Medical Centre, Rotterdam, the Netherlands, underscored that palliative care begins at diagnosis and involves managing symptom burdens. “Supportive care also includes nurses, as they are precious for the patients while answering their questions and can help save time for the doctors,” she said in an interview.

In the discussion on treatment decisions, experts agreed on the pivotal role of patients in decision-making. However, Dr. Kreuter highlighted two critical factors that influence successful patient-doctor interactions: the cultural backgrounds of patients and their relatives, and the attitudes of health care providers.

Dr. Bendstrup has received honoraria or consultation fees from Boehringer Ingelheim, Roche, Astra Zeneca, Chiesi, and Daiichi Sankyo. Ms. Robertson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MILAN – Numerous unresolved questions surround progressive pulmonary fibrosis (PPF) treatment, according to Elisabeth Bendstrup, MD, PhD, a researcher and clinical professor in the department of clinical medicine – department of respiratory diseases and allergy, Aarhus (Denmark) University, Denmark. These questions regard the optimal timing for treatment initiation, the role of available medications, either as monotherapy or in combination, and nonpharmacologic support options.

What’s in the toolbox?

Pulmonologists who manage PPF have a range of treatment options at their disposal. This includes careful patient observation, with treatment initiation based on clinical necessity. The therapeutic arsenal comprises immunomodulatory treatments, antifibrotic agents, palliative and supportive care, and, for a minority of patients, lung transplantation.

“Once a patient is diagnosed with PPF, it is important to remember that the diagnostic criteria from the guidelines are not exactly the same of those accepted for the reimbursement of antifibrotic treatments in different countries,” Dr. Bendstrup said, suggesting that nonclinical considerations could also potentially influence the treatment choice. She spoke at the annual congress of the European Respiratory Society.

Michael Kreuter, MD, director of the Lung Center at the University Hospital in Mainz, Germany, provided insight into the introduction of antifibrotic drugs for the treatment of PPF. Drawing from nearly a decade ago when the first antifibrotic medication was approved for idiopathic pulmonary fibrosis (IPF), Dr. Kreuter noted its effectiveness in slowing disease progression, although it does not reverse it. Subsequently, the discovery that non-IPF diseases, such as rheumatoid arthritis, exhibited IPF-like behavior led to the exploration of the use of the same drugs for similar conditions, even if not IPF.

“That’s how antifibrotic treatments came into place. Now we have more trials and data to be discussed in the future,” Dr. Kreuter added. He highlighted that antifibrotic drugs are effective for several diseases. Most of those diseases are treated with different anti-inflammatory drugs, which makes it difficult to decide when to start antifibrotic therapy and how to eventually combine it with different pharmacologic approaches.
 

A pivotal starting point

One of the primary challenges faced by pulmonologists in the management of PPF is determining the appropriate timing for initiating treatment, a question only partially addressed by existing guidelines. Dr. Bendstrup advocated for a comprehensive baseline evaluation. Factors to be considered include symptom burden, the severity of lung decline, radiologic characteristics, signs of alveolar inflammation, progression risk factors, quality of life, patient preferences, and medical history. “All these should be best discussed in a multidisciplinary team, including pulmonologists, nurses, experts in palliative care, occupational physicians, and more,” she said.

Current guidelines recommend nintedanib for PPF treatment for patients who have failed standard management for fibrotic interstitial lung disease (ILD) other than IPF. However, the definition of “standard management” remains a topic of debate, and it is acknowledged that evidence-based guidance for a standard of care varies among patients. Dr. Bendstrup pointed out the limited guidance clinicians receive from these guidelines. “As clinicians, we are not left with very much help from here.”
 

Choosing the right approach

Dr. Bendstrup delved into the factors influencing the choice between antifibrotic and anti-inflammatory therapies. This decision hinges on whether the patient presents with a predominantly inflammatory or a fibrotic progressive phenotype. Certain clinical characteristics contribute to the decision. Factors such as younger age, female gender, and the presence of connective tissue disease lean toward an inflammatory phenotype. Radiologic patterns, such as organized pneumonia, hypersensitivity pneumonia, or usual interstitial pneumonia–like patterns also provide valuable clues. Additionally, genetics plays a role, with shorter telomeres indicating a more fibrotic phenotype and an increased risk of immunomodulatory treatment side effects in non-IPF ILDs.

Bendstrup referred to a recent position paper on treatment recommendations and many other studies that support the use of different treatments for patients with PPF. The authors highlighted limited evidence for immunomodulation in fibrotic ILD, though such treatment is generally used except for ILD associated with systemic sclerosis. Moreover, the guidelines conditionally recommend nintedanib and call for further research on pirfenidone in PPF.

“We need intelligent, well-designed trials looking at subgroups of patients at higher risk, maybe based on molecular identification. We also need to have good biomarkers to better classify our patients based on disease behavior and treatment response. There’s a lot of discussion of biomarkers for progression, much less – if any – on biomarkers for the response to treatment. And we need them as well,” Dr. Bendstrup said in an interview.
 

The role of supportive care

Effective PPF treatment extends beyond pharmacologic interventions. It encompasses symptom management, patient education on vaccination and smoking cessation, and fostering social support networks. Psychological support, supplemental oxygen therapy, and pulmonary rehabilitation are integral components of care.

Elisabeth Robertson, a PPF patient representative from the United Kingdom, emphasized the importance of palliative care, not just in end-of-life scenarios but throughout the patient’s journey. Palliative care encompasses symptom alleviation, enabling patients to stay at home when possible, addressing mental health, and preparing for the end of life. Such holistic care can significantly enhance the patient’s quality of life.

The cochair of the session, Marlies S. Wijsenbeek, MD, PhD, pulmonary physician and head of the ILD Centre at the Erasmus University Medical Centre, Rotterdam, the Netherlands, underscored that palliative care begins at diagnosis and involves managing symptom burdens. “Supportive care also includes nurses, as they are precious for the patients while answering their questions and can help save time for the doctors,” she said in an interview.

In the discussion on treatment decisions, experts agreed on the pivotal role of patients in decision-making. However, Dr. Kreuter highlighted two critical factors that influence successful patient-doctor interactions: the cultural backgrounds of patients and their relatives, and the attitudes of health care providers.

Dr. Bendstrup has received honoraria or consultation fees from Boehringer Ingelheim, Roche, Astra Zeneca, Chiesi, and Daiichi Sankyo. Ms. Robertson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MILAN – Numerous unresolved questions surround progressive pulmonary fibrosis (PPF) treatment, according to Elisabeth Bendstrup, MD, PhD, a researcher and clinical professor in the department of clinical medicine – department of respiratory diseases and allergy, Aarhus (Denmark) University, Denmark. These questions regard the optimal timing for treatment initiation, the role of available medications, either as monotherapy or in combination, and nonpharmacologic support options.

What’s in the toolbox?

Pulmonologists who manage PPF have a range of treatment options at their disposal. This includes careful patient observation, with treatment initiation based on clinical necessity. The therapeutic arsenal comprises immunomodulatory treatments, antifibrotic agents, palliative and supportive care, and, for a minority of patients, lung transplantation.

“Once a patient is diagnosed with PPF, it is important to remember that the diagnostic criteria from the guidelines are not exactly the same of those accepted for the reimbursement of antifibrotic treatments in different countries,” Dr. Bendstrup said, suggesting that nonclinical considerations could also potentially influence the treatment choice. She spoke at the annual congress of the European Respiratory Society.

Michael Kreuter, MD, director of the Lung Center at the University Hospital in Mainz, Germany, provided insight into the introduction of antifibrotic drugs for the treatment of PPF. Drawing from nearly a decade ago when the first antifibrotic medication was approved for idiopathic pulmonary fibrosis (IPF), Dr. Kreuter noted its effectiveness in slowing disease progression, although it does not reverse it. Subsequently, the discovery that non-IPF diseases, such as rheumatoid arthritis, exhibited IPF-like behavior led to the exploration of the use of the same drugs for similar conditions, even if not IPF.

“That’s how antifibrotic treatments came into place. Now we have more trials and data to be discussed in the future,” Dr. Kreuter added. He highlighted that antifibrotic drugs are effective for several diseases. Most of those diseases are treated with different anti-inflammatory drugs, which makes it difficult to decide when to start antifibrotic therapy and how to eventually combine it with different pharmacologic approaches.
 

A pivotal starting point

One of the primary challenges faced by pulmonologists in the management of PPF is determining the appropriate timing for initiating treatment, a question only partially addressed by existing guidelines. Dr. Bendstrup advocated for a comprehensive baseline evaluation. Factors to be considered include symptom burden, the severity of lung decline, radiologic characteristics, signs of alveolar inflammation, progression risk factors, quality of life, patient preferences, and medical history. “All these should be best discussed in a multidisciplinary team, including pulmonologists, nurses, experts in palliative care, occupational physicians, and more,” she said.

Current guidelines recommend nintedanib for PPF treatment for patients who have failed standard management for fibrotic interstitial lung disease (ILD) other than IPF. However, the definition of “standard management” remains a topic of debate, and it is acknowledged that evidence-based guidance for a standard of care varies among patients. Dr. Bendstrup pointed out the limited guidance clinicians receive from these guidelines. “As clinicians, we are not left with very much help from here.”
 

Choosing the right approach

Dr. Bendstrup delved into the factors influencing the choice between antifibrotic and anti-inflammatory therapies. This decision hinges on whether the patient presents with a predominantly inflammatory or a fibrotic progressive phenotype. Certain clinical characteristics contribute to the decision. Factors such as younger age, female gender, and the presence of connective tissue disease lean toward an inflammatory phenotype. Radiologic patterns, such as organized pneumonia, hypersensitivity pneumonia, or usual interstitial pneumonia–like patterns also provide valuable clues. Additionally, genetics plays a role, with shorter telomeres indicating a more fibrotic phenotype and an increased risk of immunomodulatory treatment side effects in non-IPF ILDs.

Bendstrup referred to a recent position paper on treatment recommendations and many other studies that support the use of different treatments for patients with PPF. The authors highlighted limited evidence for immunomodulation in fibrotic ILD, though such treatment is generally used except for ILD associated with systemic sclerosis. Moreover, the guidelines conditionally recommend nintedanib and call for further research on pirfenidone in PPF.

“We need intelligent, well-designed trials looking at subgroups of patients at higher risk, maybe based on molecular identification. We also need to have good biomarkers to better classify our patients based on disease behavior and treatment response. There’s a lot of discussion of biomarkers for progression, much less – if any – on biomarkers for the response to treatment. And we need them as well,” Dr. Bendstrup said in an interview.
 

The role of supportive care

Effective PPF treatment extends beyond pharmacologic interventions. It encompasses symptom management, patient education on vaccination and smoking cessation, and fostering social support networks. Psychological support, supplemental oxygen therapy, and pulmonary rehabilitation are integral components of care.

Elisabeth Robertson, a PPF patient representative from the United Kingdom, emphasized the importance of palliative care, not just in end-of-life scenarios but throughout the patient’s journey. Palliative care encompasses symptom alleviation, enabling patients to stay at home when possible, addressing mental health, and preparing for the end of life. Such holistic care can significantly enhance the patient’s quality of life.

The cochair of the session, Marlies S. Wijsenbeek, MD, PhD, pulmonary physician and head of the ILD Centre at the Erasmus University Medical Centre, Rotterdam, the Netherlands, underscored that palliative care begins at diagnosis and involves managing symptom burdens. “Supportive care also includes nurses, as they are precious for the patients while answering their questions and can help save time for the doctors,” she said in an interview.

In the discussion on treatment decisions, experts agreed on the pivotal role of patients in decision-making. However, Dr. Kreuter highlighted two critical factors that influence successful patient-doctor interactions: the cultural backgrounds of patients and their relatives, and the attitudes of health care providers.

Dr. Bendstrup has received honoraria or consultation fees from Boehringer Ingelheim, Roche, Astra Zeneca, Chiesi, and Daiichi Sankyo. Ms. Robertson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Key clinical point: Uveitis is far more prevalent in patients with axial spondylarthritis (axSpA) than in those with psoriatic arthritis (PsA). A family history of SpA, axial disease at diagnosis, and disease duration were important factors associated with the occurrence of uveitis in PsA.

Major finding: Uveitis was more frequent in patients with axSpA vs PsA (11.7% vs 2.7%), with a median uveitis recurrence rate of 0.205 episodes per year and 0.285 episodes per year for axSpA and PsA, respectively. Family history of SpA (odds ratio [OR] 6.35; P = .023), axial disease at diagnosis (OR 5.61; P = .038), and disease duration (OR 1.12; P = .004) were associated with the occurrence of uveitis in PsA.

Study details: Findings are from a retrospective study including 264 patients with axSpA and 369 patients with PsA.

Disclosures: This study did not receive any specific funding except open access funding by HEAL-Link Greece. The authors declared no conflicts of interest.

Source: Kougkas N et al. Higher frequency but similar recurrence rate of uveitis episodes in axial spondylarthritis compared to psoriatic arthritis. A multicentre retrospective study. Rheumatol Int. 2023;43:2081-2088 (Aug 23). doi: 10.1007/s00296-023-05424-0

Key clinical point: Uveitis is far more prevalent in patients with axial spondylarthritis (axSpA) than in those with psoriatic arthritis (PsA). A family history of SpA, axial disease at diagnosis, and disease duration were important factors associated with the occurrence of uveitis in PsA.

Major finding: Uveitis was more frequent in patients with axSpA vs PsA (11.7% vs 2.7%), with a median uveitis recurrence rate of 0.205 episodes per year and 0.285 episodes per year for axSpA and PsA, respectively. Family history of SpA (odds ratio [OR] 6.35; P = .023), axial disease at diagnosis (OR 5.61; P = .038), and disease duration (OR 1.12; P = .004) were associated with the occurrence of uveitis in PsA.

Study details: Findings are from a retrospective study including 264 patients with axSpA and 369 patients with PsA.

Disclosures: This study did not receive any specific funding except open access funding by HEAL-Link Greece. The authors declared no conflicts of interest.

Source: Kougkas N et al. Higher frequency but similar recurrence rate of uveitis episodes in axial spondylarthritis compared to psoriatic arthritis. A multicentre retrospective study. Rheumatol Int. 2023;43:2081-2088 (Aug 23). doi: 10.1007/s00296-023-05424-0

Key clinical point: Uveitis is far more prevalent in patients with axial spondylarthritis (axSpA) than in those with psoriatic arthritis (PsA). A family history of SpA, axial disease at diagnosis, and disease duration were important factors associated with the occurrence of uveitis in PsA.

Major finding: Uveitis was more frequent in patients with axSpA vs PsA (11.7% vs 2.7%), with a median uveitis recurrence rate of 0.205 episodes per year and 0.285 episodes per year for axSpA and PsA, respectively. Family history of SpA (odds ratio [OR] 6.35; P = .023), axial disease at diagnosis (OR 5.61; P = .038), and disease duration (OR 1.12; P = .004) were associated with the occurrence of uveitis in PsA.

Study details: Findings are from a retrospective study including 264 patients with axSpA and 369 patients with PsA.

Disclosures: This study did not receive any specific funding except open access funding by HEAL-Link Greece. The authors declared no conflicts of interest.

Source: Kougkas N et al. Higher frequency but similar recurrence rate of uveitis episodes in axial spondylarthritis compared to psoriatic arthritis. A multicentre retrospective study. Rheumatol Int. 2023;43:2081-2088 (Aug 23). doi: 10.1007/s00296-023-05424-0

Key clinical point: Compared with placebo, tofacitinib demonstrated greater improvement in enthesitis in patients with psoriatic arthritis (PsA), irrespective of enthesitis location and severity.

Major finding: Tofacitinib vs placebo led to greater changes in the Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada Enthesitis Index scores up to month 3, irrespective of baseline enthesitis locations and severities, with all improvements with tofacitinib being maintained and continued through month 6. Among patients with baseline LEI >0 whose enthesitis had resolved at month 1, relapse at month 3 was experienced by 26.3% and 15.6% vs 30.8% of patients treated with 5 mg tofacitinib and 10 mg tofacitinib vs placebo, respectively.

Study details: This post hoc analysis of pooled data from 2 phase 3 studies (OPAL Broaden and OPAL Beyond) and included 710 patients with PsA who received tofacitinib for 6 months or placebo for 3 months.

Disclosures: This study was sponsored by Pfizer Inc. Three authors declared being employees and shareholders of Pfizer Inc. Five authors declared receiving grants, research support, or consulting fees from or having ties with various sources, including Pfizer.

Source: Mease PJ et al. Efficacy of tofacitinib on enthesitis in patients with active psoriatic arthritis: Analysis of pooled data from two phase 3 studies. Arthritis Res Ther. 2023;25:153 (Aug 22). doi: 10.1186/s13075-023-03108-5

Key clinical point: Compared with placebo, tofacitinib demonstrated greater improvement in enthesitis in patients with psoriatic arthritis (PsA), irrespective of enthesitis location and severity.

Major finding: Tofacitinib vs placebo led to greater changes in the Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada Enthesitis Index scores up to month 3, irrespective of baseline enthesitis locations and severities, with all improvements with tofacitinib being maintained and continued through month 6. Among patients with baseline LEI >0 whose enthesitis had resolved at month 1, relapse at month 3 was experienced by 26.3% and 15.6% vs 30.8% of patients treated with 5 mg tofacitinib and 10 mg tofacitinib vs placebo, respectively.

Study details: This post hoc analysis of pooled data from 2 phase 3 studies (OPAL Broaden and OPAL Beyond) and included 710 patients with PsA who received tofacitinib for 6 months or placebo for 3 months.

Disclosures: This study was sponsored by Pfizer Inc. Three authors declared being employees and shareholders of Pfizer Inc. Five authors declared receiving grants, research support, or consulting fees from or having ties with various sources, including Pfizer.

Source: Mease PJ et al. Efficacy of tofacitinib on enthesitis in patients with active psoriatic arthritis: Analysis of pooled data from two phase 3 studies. Arthritis Res Ther. 2023;25:153 (Aug 22). doi: 10.1186/s13075-023-03108-5

Key clinical point: Compared with placebo, tofacitinib demonstrated greater improvement in enthesitis in patients with psoriatic arthritis (PsA), irrespective of enthesitis location and severity.

Major finding: Tofacitinib vs placebo led to greater changes in the Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada Enthesitis Index scores up to month 3, irrespective of baseline enthesitis locations and severities, with all improvements with tofacitinib being maintained and continued through month 6. Among patients with baseline LEI >0 whose enthesitis had resolved at month 1, relapse at month 3 was experienced by 26.3% and 15.6% vs 30.8% of patients treated with 5 mg tofacitinib and 10 mg tofacitinib vs placebo, respectively.

Study details: This post hoc analysis of pooled data from 2 phase 3 studies (OPAL Broaden and OPAL Beyond) and included 710 patients with PsA who received tofacitinib for 6 months or placebo for 3 months.

Disclosures: This study was sponsored by Pfizer Inc. Three authors declared being employees and shareholders of Pfizer Inc. Five authors declared receiving grants, research support, or consulting fees from or having ties with various sources, including Pfizer.

Source: Mease PJ et al. Efficacy of tofacitinib on enthesitis in patients with active psoriatic arthritis: Analysis of pooled data from two phase 3 studies. Arthritis Res Ther. 2023;25:153 (Aug 22). doi: 10.1186/s13075-023-03108-5

Key clinical point: Patients with active psoriatic arthritis (PsA) who initiated secukinumab treatment had stable improvements in synovitis and sustained clinical improvements in enthesitis up to week 52.

Major finding: At week 12, secukinumab vs placebo led to significant improvements in power Doppler ultrasound (PDUS)-assessed synovitis (Global EULAR-OMERACT Synovitis Score: −9 vs −6; one-sided P = .004) and PDUS-assessed enthesitis (Spondyloarthritis Research Consortium of Canada enthesitis index score: −2.2 vs −1.6; one-sided P = .03), with the improvements being sustained up to week 52.

Study details: This 52-week, phase 3 ULTIMATE study included 166 patients with active PsA, who were naive to biologics and intolerant to conventional synthetic disease-modifying anti-rheumatic drugs and were randomly assigned to receive secukinumab or placebo.

Disclosures: This study was funded by Novartis Pharma AG, Basel, Switzerland. Three authors declared being employees or stockholders of Novartis. Several authors declared ties with various sources, including Novartis. Three authors declared no conflicts of interest.

Source: D’Agostino MA et al. Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension. Semin Arthritis Rheum. 2023;63:152259 (Aug 19). doi: 10.1016/j.semarthrit.2023.152259

Key clinical point: Patients with active psoriatic arthritis (PsA) who initiated secukinumab treatment had stable improvements in synovitis and sustained clinical improvements in enthesitis up to week 52.

Major finding: At week 12, secukinumab vs placebo led to significant improvements in power Doppler ultrasound (PDUS)-assessed synovitis (Global EULAR-OMERACT Synovitis Score: −9 vs −6; one-sided P = .004) and PDUS-assessed enthesitis (Spondyloarthritis Research Consortium of Canada enthesitis index score: −2.2 vs −1.6; one-sided P = .03), with the improvements being sustained up to week 52.

Study details: This 52-week, phase 3 ULTIMATE study included 166 patients with active PsA, who were naive to biologics and intolerant to conventional synthetic disease-modifying anti-rheumatic drugs and were randomly assigned to receive secukinumab or placebo.

Disclosures: This study was funded by Novartis Pharma AG, Basel, Switzerland. Three authors declared being employees or stockholders of Novartis. Several authors declared ties with various sources, including Novartis. Three authors declared no conflicts of interest.

Source: D’Agostino MA et al. Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension. Semin Arthritis Rheum. 2023;63:152259 (Aug 19). doi: 10.1016/j.semarthrit.2023.152259

Key clinical point: Patients with active psoriatic arthritis (PsA) who initiated secukinumab treatment had stable improvements in synovitis and sustained clinical improvements in enthesitis up to week 52.

Major finding: At week 12, secukinumab vs placebo led to significant improvements in power Doppler ultrasound (PDUS)-assessed synovitis (Global EULAR-OMERACT Synovitis Score: −9 vs −6; one-sided P = .004) and PDUS-assessed enthesitis (Spondyloarthritis Research Consortium of Canada enthesitis index score: −2.2 vs −1.6; one-sided P = .03), with the improvements being sustained up to week 52.

Study details: This 52-week, phase 3 ULTIMATE study included 166 patients with active PsA, who were naive to biologics and intolerant to conventional synthetic disease-modifying anti-rheumatic drugs and were randomly assigned to receive secukinumab or placebo.

Disclosures: This study was funded by Novartis Pharma AG, Basel, Switzerland. Three authors declared being employees or stockholders of Novartis. Several authors declared ties with various sources, including Novartis. Three authors declared no conflicts of interest.

Source: D’Agostino MA et al. Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension. Semin Arthritis Rheum. 2023;63:152259 (Aug 19). doi: 10.1016/j.semarthrit.2023.152259

Key clinical point: Secukinumab demonstrated sustained efficacy, high retention rates, and a consistent safety profile in patients with active psoriatic arthritis (PsA) who were followed for ≥ 2 years.

Major finding: The treatment retention rate with secukinumab was 78.2% in PsA. The mean swollen joint counts (enrolment vs 2 years: 4.5 vs 3.6) and tender joint counts (enrolment vs 2 years: 12.8 vs 9.2) remained stable over 2 years of treatment. Serious adverse events occurred in 13.6% of patients, but no deaths related to treatment-emergent adverse events were reported.

Study details: Findings are from an interim analysis of the ongoing SERENA study including patients with active PsA (n = 81) or radiographic axial spondyloarthritis (n = 108) who had received secukinumab for ≥16 weeks prior to enrolment.

Disclosures: This study was supported by Novartis Pharma AG. Two authors declared being employees of Novartis Pharmaceuticals U.K. Ltd. Three authors declared ties with various sources, including Novartis.

Source: Gaffney K et al. Real-world evidence for secukinumab in UK patients with psoriatic arthritis or radiographic axial spondyloarthritis: Interim 2-year analysis from SERENA. Rheumatol Adv Pract. 2023;7(3):rkad055 (Aug 21). doi: 10.1093/rap/rkad055

Key clinical point: Secukinumab demonstrated sustained efficacy, high retention rates, and a consistent safety profile in patients with active psoriatic arthritis (PsA) who were followed for ≥ 2 years.

Major finding: The treatment retention rate with secukinumab was 78.2% in PsA. The mean swollen joint counts (enrolment vs 2 years: 4.5 vs 3.6) and tender joint counts (enrolment vs 2 years: 12.8 vs 9.2) remained stable over 2 years of treatment. Serious adverse events occurred in 13.6% of patients, but no deaths related to treatment-emergent adverse events were reported.

Study details: Findings are from an interim analysis of the ongoing SERENA study including patients with active PsA (n = 81) or radiographic axial spondyloarthritis (n = 108) who had received secukinumab for ≥16 weeks prior to enrolment.

Disclosures: This study was supported by Novartis Pharma AG. Two authors declared being employees of Novartis Pharmaceuticals U.K. Ltd. Three authors declared ties with various sources, including Novartis.

Source: Gaffney K et al. Real-world evidence for secukinumab in UK patients with psoriatic arthritis or radiographic axial spondyloarthritis: Interim 2-year analysis from SERENA. Rheumatol Adv Pract. 2023;7(3):rkad055 (Aug 21). doi: 10.1093/rap/rkad055

Key clinical point: Secukinumab demonstrated sustained efficacy, high retention rates, and a consistent safety profile in patients with active psoriatic arthritis (PsA) who were followed for ≥ 2 years.

Major finding: The treatment retention rate with secukinumab was 78.2% in PsA. The mean swollen joint counts (enrolment vs 2 years: 4.5 vs 3.6) and tender joint counts (enrolment vs 2 years: 12.8 vs 9.2) remained stable over 2 years of treatment. Serious adverse events occurred in 13.6% of patients, but no deaths related to treatment-emergent adverse events were reported.

Study details: Findings are from an interim analysis of the ongoing SERENA study including patients with active PsA (n = 81) or radiographic axial spondyloarthritis (n = 108) who had received secukinumab for ≥16 weeks prior to enrolment.

Disclosures: This study was supported by Novartis Pharma AG. Two authors declared being employees of Novartis Pharmaceuticals U.K. Ltd. Three authors declared ties with various sources, including Novartis.

Source: Gaffney K et al. Real-world evidence for secukinumab in UK patients with psoriatic arthritis or radiographic axial spondyloarthritis: Interim 2-year analysis from SERENA. Rheumatol Adv Pract. 2023;7(3):rkad055 (Aug 21). doi: 10.1093/rap/rkad055