Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

 

Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

 

Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Further staining of this cervical lymph node specimen revealed large atypical lymphoid cells positive for CD3, CD10, B-cell lymphoma 2 (BCL-2), BCL-6, and PD-1. There were intermixed mature B lymphocytes positive for CD20 and BCL-2. Chromogenic in situ hybridization with probes for EBV showed numerous positive cells throughout the infiltrate. Polymerase chain reaction demonstrated a T-cell population with clonally rearranged T-cell receptor genes. Primers for immunoglobulin heavy and light chains showed no evidence of a clonal B-cell population.

Additional staining of the atypical cutaneous lymphocytes revealed positivity for CD3, CD10, and PD-1. The morphologic and immunophenotypic findings of both specimens supported the diagnosis of AITL.

The patient declined further treatment and chose hospice care.

 

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Further staining of this cervical lymph node specimen revealed large atypical lymphoid cells positive for CD3, CD10, B-cell lymphoma 2 (BCL-2), BCL-6, and PD-1. There were intermixed mature B lymphocytes positive for CD20 and BCL-2. Chromogenic in situ hybridization with probes for EBV showed numerous positive cells throughout the infiltrate. Polymerase chain reaction demonstrated a T-cell population with clonally rearranged T-cell receptor genes. Primers for immunoglobulin heavy and light chains showed no evidence of a clonal B-cell population.

Additional staining of the atypical cutaneous lymphocytes revealed positivity for CD3, CD10, and PD-1. The morphologic and immunophenotypic findings of both specimens supported the diagnosis of AITL.

The patient declined further treatment and chose hospice care.

 

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Further staining of this cervical lymph node specimen revealed large atypical lymphoid cells positive for CD3, CD10, B-cell lymphoma 2 (BCL-2), BCL-6, and PD-1. There were intermixed mature B lymphocytes positive for CD20 and BCL-2. Chromogenic in situ hybridization with probes for EBV showed numerous positive cells throughout the infiltrate. Polymerase chain reaction demonstrated a T-cell population with clonally rearranged T-cell receptor genes. Primers for immunoglobulin heavy and light chains showed no evidence of a clonal B-cell population.

Additional staining of the atypical cutaneous lymphocytes revealed positivity for CD3, CD10, and PD-1. The morphologic and immunophenotypic findings of both specimens supported the diagnosis of AITL.

The patient declined further treatment and chose hospice care.

 

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

 

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

 

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

 

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.

Examining Enroll-HD Data

A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease.

Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.

Motor Symptoms More Common in Late-Onset Disease

Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.

A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.

At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.

“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”

—Erik Greb

MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.

Examining Enroll-HD Data

A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease.

Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.

Motor Symptoms More Common in Late-Onset Disease

Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.

A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.

At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.

“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”

—Erik Greb

MIAMI—The greater the age of Huntington’s disease onset, the lower the likelihood that the patient’s major symptom type at disease presentation will be behavioral or cognitive, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Increasing age at onset also is associated with a higher likelihood that motor symptoms will be the major symptom type at disease presentation.

Examining Enroll-HD Data

A patient may have subtle changes in movement, thinking, or behavior as early as 20 years before the onset of Huntington’s disease. Allison Daley, a clinical research specialist at Ohio State University in Columbus, and colleagues noted anecdotally that the severity of behavioral symptoms was decreased in older patients with newly diagnosed Huntington’s disease, compared with younger patients. The group set out to investigate the relationship between behavioral symptoms and age at onset of clinical symptoms in Huntington’s disease.

Ms. Daley and colleagues examined data for 8,714 participants registered in the Enroll-HD database as of 2016. They established three categories of patients based on age of onset. Early-onset Huntington’s disease was defined as onset at an age younger than 30. Earlier adult-onset Huntington’s disease was defined as onset between ages 30 and 59. Later adult-onset Huntington’s disease was defined as onset at an age above 59. Ms. Daley’s group examined the frequency and severity of behavioral symptoms at disease presentation in all three groups. They used the Clinical Characteristics form and the Problem Behaviors Assessment form to evaluate symptom presence and severity.

Motor Symptoms More Common in Late-Onset Disease

Of the entire sample, 4,469 participants had manifest Huntington’s disease. Motor symptoms were present in 42% of participants with early-onset Huntington’s disease, 50% of participants with earlier adult-onset Huntington’s disease, and 67% of participants with later adult-onset Huntington’s disease. Cognitive symptoms were recorded in 9% of the early-onset group, 10% of the earlier adult-onset group, and 4% of the later adult-onset group. Behavioral symptoms were observed in 26% of the early-onset group, 19% of the earlier adult-onset group, and 11% of the later adult-onset group.

A one-year increase in age at onset was associated with a 5.5% decrease in the odds of severe behavioral symptom of any type. In addition, a one-year increase in age at onset was associated with a 9.4% decrease in the odds of severe disorientation, an 8.8% decrease in the odds of severe delusions, a 6.8% decrease in the odds of severe obsessive–compulsive behavior, and a 5.8% decrease in the odds of severe apathy.

At baseline, 56% of participants had apathy, 55% had anxiety, 54% had irritability, 51% had depression, 44% had perseverative thinking, and 29% had anger or aggression.

“Specific behavioral symptoms, particularly disorientation, delusions, and obsessive–compulsive behaviors, may tend to manifest more severely in individuals with earlier age at onset. Earlier age at onset may be associated with higher severity of behavioral symptoms overall,” said Ms. Daley. “Further research exploring biologic mechanisms and environmental factors that interact with CAG repeat size to affect symptom presentation in Huntington’s disease at different ages at onset may help identify additional therapeutic strategies and individualized treatment approaches for Huntington’s disease.”

—Erik Greb

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹ Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³ Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷ Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴ Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³ Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹ Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³ Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷ Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴ Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³ Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹ Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³ Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷ Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴ Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³ Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

BALTIMORE—Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment, but a scarcity of trained clinicians has limited patients’ access to it. Telehealth and Internet-based platforms could broaden access to CBT-I, and investigators presented research on the efficacy of these methods of administration at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

CBT-I by Telehealth Is Noninferior to In-Person CBT-I

Philip Gehrman, PhD, Associate Professor of Psychology at the University of Pennsylvania and the Philadelphia VA Medical Center, and colleagues conducted a cluster-randomized trial to determine whether group CBT-I delivered by telehealth was noninferior to CBT-I delivered in person. Eligible participants were veterans with posttraumatic stress disorder (PTSD) and an Insomnia Severity Index (ISI) score of 15 or higher. The investigators randomized 95 participants in groups of six to eight to group CBT-I in person or by telehealth. The primary outcome was the change in ISI score from baseline to the three-month follow-up. Dr. Gehrman and colleagues defined treatment inferiority as a difference of greater than two points on the ISI score.

Participants’ mean age was 55.6, about 91% of the sample was male, and 42.2% of the sample was African American. The study population generally was overweight and had severe PTSD. Approximately half of the population was receiving one or more psychotropic medication. Forty-six participants were randomized to in-person CBT-I, and 49 were randomized to CBT-I delivered by telehealth.

At three months, the mean change in ISI score was 6.48 for in-person CBT-I and 4.45 for telehealth CBT-I. The difference between groups was outside of the prespecified margin of inferiority, and the researchers concluded that CBT-I delivered by telehealth was noninferior to in-person CBT-I.

The overall effectiveness of both methods of administration was modest, said Dr. Gehrman. The effect size might be greater in a group with fewer comorbidities or in a group that received more treatment sessions, he added. Nevertheless, the results “demonstrate that CBT-I can be effective even in a complex patient population,” he concluded.

SHUTi May Be Inferior to In-Person CBT-I

The online CBT-I intervention Sleep Healthy Using the Internet (SHUTi) has reduced insomnia with effect sizes similar to those of traditional CBT-I. No researchers had compared the two techniques directly, however. Håvard Kallestad, PhD, a clinical psychologist at Saint Olav’s Hospital in Trondheim, Norway, and colleagues examined whether SHUTi was a noninferior treatment for insomnia, compared with in-person CBT-I.

Eligible participants were 18 or older, had a diagnosis of insomnia, had been referred to a sleep clinic, and had access to a computer and adequate computer skills. Participants were randomized to in-person CBT-I or SHUTi. The primary outcome was ISI score, and three therapists assessed participants’ outcomes at baseline, after treatment, and at six months. They defined noninferiority as a difference between treatments of 2 or fewer points on ISI score.

Dr. Kallestad and colleagues randomized 52 participants to in-person CBT-I and 49 to SHUTi. Mean duration of insomnia was about 13 years. Approximately 60% of participants were currently using sleep medication, and about 90% had had previous treatment with sleep medication. After treatment, two patients in the in-person group and five in the SHUTi group were lost to follow-up. At six months, four participants in the in-person group and eight in the SHUTi group were lost to follow-up.

Both study arms had significantly lower ISI scores after treatment and at six months. After treatment, the mean ISI score in the in-person group was 5.1 points lower than in the SHUTi group, indicating that SHUTi was inferior at that time. At six months, mean ISI score was 3.3 points lower in the in-person group than in the SHUTi group. Because part of the confidence interval overlapped with the noninferiority margin, the result was inconclusive.

After treatment, the response rate was 70% in the in-person group and 43% in the SHUTi group. The remission rate was 52% in the in-person group and 18% in the SHUTi group. At six months, the response rate was 65% for the in-person group and 46% for the SHUTi group. The remission rate was 56% in the in-person group and 24% in the SHUTi group.

“SHUTi did not have the same effectiveness in this patient sample, compared with previous studies,” said Dr. Kallestad. One reason could be that previous studies included self-selected participants, rather than patients who had been referred to a sleep clinic. Also, the researchers interviewed all participants at baseline, and SHUTi might have seemed “more limited” in comparison with the interview, Dr. Kallestad concluded.

 

Digital CBT-I May Prevent Incident Depression

Insomnia is a modifiable risk factor for depression, and research has indicated that CBT-I reduces the severity of depression. Investigators also have shown that digitally delivered CBT-I effectively reduces insomnia and depression. Phillip C. Cheng, PhD, a researcher at the Henry Ford Health System in Detroit, and colleagues sought to determine whether digitally delivered CBT-I could prevent incident depression.

The researchers randomized 658 people with insomnia to Sleepio, an Internet-based CBT-I treatment, or to a control condition of online sleep education. The study’s primary outcome was the Quick Inventory of Depressive Symptomatology (QIDS), and Dr. Cheng’s group defined depression as a score greater than 10 on the QIDS. The researchers also examined participants’ ISI scores and functional outcomes such as work productivity, social functioning, cognitive functioning, and resilience. Assessments were performed at baseline, after treatment, and at one year.

In all, 358 participants were randomized to Sleepio, and 300 were randomized to sleep education. The patient population was predominantly female, was racially diverse, and had a diversity of educational attainment. The demographics of the study arms did not differ significantly.

After treatment, the rate of incident depression was 11% in the sleep education group and 6.5% in the Sleepio group. The difference between arms was not statistically significant. At one year, the rate of incident depression was 22% in the sleep education group and 5.1% in the Sleepio group. The difference between arms at one year was statistically significant, as was the change in depression incidence over time in the sleep education group.

Among patients who did not develop depression, ISI score decreased to a value below the cutoff for insomnia, regardless of study arm. ISI score did not change significantly among participants who developed depression, however. Work productivity, social functioning, cognitive functioning, and resilience improved more in the Sleepio group than in the sleep education group.

The results indicate that “digitally delivered CBT-I may prevent incident depression in adults with insomnia,” said Dr. Cheng. Each episode of depression increases the risk of relapse of depression, which underscores the significance of preventing incident depression, he added. Digital CBT-I also appears to reduce the economic burden associated with depression, and further studies could clarify whether it improves resilience, Dr. Cheng concluded.

—Erik Greb

Suggested Reading

Espie CA, Kyle SD, Williams C, et al. A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application. Sleep. 2012;35(6):769-781.

Gehrman P, Shah MT, Miles A, et al. Feasibility of group cognitive-behavioral treatment of insomnia delivered by clinical video telehealth. Telemed J E Health. 2016;22(12):1041-1046.

Hagatun S, Vedaa Ø, Nordgreen T, et al. The short-term efficacy of an unguided internet-based cognitive-behavioral therapy for insomnia: a randomized controlled trial with a six-month nonrandomized follow-up. Behav Sleep Med. 2017 Mar 27 [Epub ahead of print].

Ye YY, Chen NK, Chen J, et al. Internet-based cognitive-behavioural therapy for insomnia (ICBT-i): a meta-analysis of randomised controlled trials. BMJ Open. 2016;6(11):e010707.

BALTIMORE—Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment, but a scarcity of trained clinicians has limited patients’ access to it. Telehealth and Internet-based platforms could broaden access to CBT-I, and investigators presented research on the efficacy of these methods of administration at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

CBT-I by Telehealth Is Noninferior to In-Person CBT-I

Philip Gehrman, PhD, Associate Professor of Psychology at the University of Pennsylvania and the Philadelphia VA Medical Center, and colleagues conducted a cluster-randomized trial to determine whether group CBT-I delivered by telehealth was noninferior to CBT-I delivered in person. Eligible participants were veterans with posttraumatic stress disorder (PTSD) and an Insomnia Severity Index (ISI) score of 15 or higher. The investigators randomized 95 participants in groups of six to eight to group CBT-I in person or by telehealth. The primary outcome was the change in ISI score from baseline to the three-month follow-up. Dr. Gehrman and colleagues defined treatment inferiority as a difference of greater than two points on the ISI score.

Participants’ mean age was 55.6, about 91% of the sample was male, and 42.2% of the sample was African American. The study population generally was overweight and had severe PTSD. Approximately half of the population was receiving one or more psychotropic medication. Forty-six participants were randomized to in-person CBT-I, and 49 were randomized to CBT-I delivered by telehealth.

At three months, the mean change in ISI score was 6.48 for in-person CBT-I and 4.45 for telehealth CBT-I. The difference between groups was outside of the prespecified margin of inferiority, and the researchers concluded that CBT-I delivered by telehealth was noninferior to in-person CBT-I.

The overall effectiveness of both methods of administration was modest, said Dr. Gehrman. The effect size might be greater in a group with fewer comorbidities or in a group that received more treatment sessions, he added. Nevertheless, the results “demonstrate that CBT-I can be effective even in a complex patient population,” he concluded.

SHUTi May Be Inferior to In-Person CBT-I

The online CBT-I intervention Sleep Healthy Using the Internet (SHUTi) has reduced insomnia with effect sizes similar to those of traditional CBT-I. No researchers had compared the two techniques directly, however. Håvard Kallestad, PhD, a clinical psychologist at Saint Olav’s Hospital in Trondheim, Norway, and colleagues examined whether SHUTi was a noninferior treatment for insomnia, compared with in-person CBT-I.

Eligible participants were 18 or older, had a diagnosis of insomnia, had been referred to a sleep clinic, and had access to a computer and adequate computer skills. Participants were randomized to in-person CBT-I or SHUTi. The primary outcome was ISI score, and three therapists assessed participants’ outcomes at baseline, after treatment, and at six months. They defined noninferiority as a difference between treatments of 2 or fewer points on ISI score.

Dr. Kallestad and colleagues randomized 52 participants to in-person CBT-I and 49 to SHUTi. Mean duration of insomnia was about 13 years. Approximately 60% of participants were currently using sleep medication, and about 90% had had previous treatment with sleep medication. After treatment, two patients in the in-person group and five in the SHUTi group were lost to follow-up. At six months, four participants in the in-person group and eight in the SHUTi group were lost to follow-up.

Both study arms had significantly lower ISI scores after treatment and at six months. After treatment, the mean ISI score in the in-person group was 5.1 points lower than in the SHUTi group, indicating that SHUTi was inferior at that time. At six months, mean ISI score was 3.3 points lower in the in-person group than in the SHUTi group. Because part of the confidence interval overlapped with the noninferiority margin, the result was inconclusive.

After treatment, the response rate was 70% in the in-person group and 43% in the SHUTi group. The remission rate was 52% in the in-person group and 18% in the SHUTi group. At six months, the response rate was 65% for the in-person group and 46% for the SHUTi group. The remission rate was 56% in the in-person group and 24% in the SHUTi group.

“SHUTi did not have the same effectiveness in this patient sample, compared with previous studies,” said Dr. Kallestad. One reason could be that previous studies included self-selected participants, rather than patients who had been referred to a sleep clinic. Also, the researchers interviewed all participants at baseline, and SHUTi might have seemed “more limited” in comparison with the interview, Dr. Kallestad concluded.

 

Digital CBT-I May Prevent Incident Depression

Insomnia is a modifiable risk factor for depression, and research has indicated that CBT-I reduces the severity of depression. Investigators also have shown that digitally delivered CBT-I effectively reduces insomnia and depression. Phillip C. Cheng, PhD, a researcher at the Henry Ford Health System in Detroit, and colleagues sought to determine whether digitally delivered CBT-I could prevent incident depression.

The researchers randomized 658 people with insomnia to Sleepio, an Internet-based CBT-I treatment, or to a control condition of online sleep education. The study’s primary outcome was the Quick Inventory of Depressive Symptomatology (QIDS), and Dr. Cheng’s group defined depression as a score greater than 10 on the QIDS. The researchers also examined participants’ ISI scores and functional outcomes such as work productivity, social functioning, cognitive functioning, and resilience. Assessments were performed at baseline, after treatment, and at one year.

In all, 358 participants were randomized to Sleepio, and 300 were randomized to sleep education. The patient population was predominantly female, was racially diverse, and had a diversity of educational attainment. The demographics of the study arms did not differ significantly.

After treatment, the rate of incident depression was 11% in the sleep education group and 6.5% in the Sleepio group. The difference between arms was not statistically significant. At one year, the rate of incident depression was 22% in the sleep education group and 5.1% in the Sleepio group. The difference between arms at one year was statistically significant, as was the change in depression incidence over time in the sleep education group.

Among patients who did not develop depression, ISI score decreased to a value below the cutoff for insomnia, regardless of study arm. ISI score did not change significantly among participants who developed depression, however. Work productivity, social functioning, cognitive functioning, and resilience improved more in the Sleepio group than in the sleep education group.

The results indicate that “digitally delivered CBT-I may prevent incident depression in adults with insomnia,” said Dr. Cheng. Each episode of depression increases the risk of relapse of depression, which underscores the significance of preventing incident depression, he added. Digital CBT-I also appears to reduce the economic burden associated with depression, and further studies could clarify whether it improves resilience, Dr. Cheng concluded.

—Erik Greb

Suggested Reading

Espie CA, Kyle SD, Williams C, et al. A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application. Sleep. 2012;35(6):769-781.

Gehrman P, Shah MT, Miles A, et al. Feasibility of group cognitive-behavioral treatment of insomnia delivered by clinical video telehealth. Telemed J E Health. 2016;22(12):1041-1046.

Hagatun S, Vedaa Ø, Nordgreen T, et al. The short-term efficacy of an unguided internet-based cognitive-behavioral therapy for insomnia: a randomized controlled trial with a six-month nonrandomized follow-up. Behav Sleep Med. 2017 Mar 27 [Epub ahead of print].

Ye YY, Chen NK, Chen J, et al. Internet-based cognitive-behavioural therapy for insomnia (ICBT-i): a meta-analysis of randomised controlled trials. BMJ Open. 2016;6(11):e010707.

BALTIMORE—Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment, but a scarcity of trained clinicians has limited patients’ access to it. Telehealth and Internet-based platforms could broaden access to CBT-I, and investigators presented research on the efficacy of these methods of administration at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

CBT-I by Telehealth Is Noninferior to In-Person CBT-I

Philip Gehrman, PhD, Associate Professor of Psychology at the University of Pennsylvania and the Philadelphia VA Medical Center, and colleagues conducted a cluster-randomized trial to determine whether group CBT-I delivered by telehealth was noninferior to CBT-I delivered in person. Eligible participants were veterans with posttraumatic stress disorder (PTSD) and an Insomnia Severity Index (ISI) score of 15 or higher. The investigators randomized 95 participants in groups of six to eight to group CBT-I in person or by telehealth. The primary outcome was the change in ISI score from baseline to the three-month follow-up. Dr. Gehrman and colleagues defined treatment inferiority as a difference of greater than two points on the ISI score.

Participants’ mean age was 55.6, about 91% of the sample was male, and 42.2% of the sample was African American. The study population generally was overweight and had severe PTSD. Approximately half of the population was receiving one or more psychotropic medication. Forty-six participants were randomized to in-person CBT-I, and 49 were randomized to CBT-I delivered by telehealth.

At three months, the mean change in ISI score was 6.48 for in-person CBT-I and 4.45 for telehealth CBT-I. The difference between groups was outside of the prespecified margin of inferiority, and the researchers concluded that CBT-I delivered by telehealth was noninferior to in-person CBT-I.

The overall effectiveness of both methods of administration was modest, said Dr. Gehrman. The effect size might be greater in a group with fewer comorbidities or in a group that received more treatment sessions, he added. Nevertheless, the results “demonstrate that CBT-I can be effective even in a complex patient population,” he concluded.

SHUTi May Be Inferior to In-Person CBT-I

The online CBT-I intervention Sleep Healthy Using the Internet (SHUTi) has reduced insomnia with effect sizes similar to those of traditional CBT-I. No researchers had compared the two techniques directly, however. Håvard Kallestad, PhD, a clinical psychologist at Saint Olav’s Hospital in Trondheim, Norway, and colleagues examined whether SHUTi was a noninferior treatment for insomnia, compared with in-person CBT-I.

Eligible participants were 18 or older, had a diagnosis of insomnia, had been referred to a sleep clinic, and had access to a computer and adequate computer skills. Participants were randomized to in-person CBT-I or SHUTi. The primary outcome was ISI score, and three therapists assessed participants’ outcomes at baseline, after treatment, and at six months. They defined noninferiority as a difference between treatments of 2 or fewer points on ISI score.

Dr. Kallestad and colleagues randomized 52 participants to in-person CBT-I and 49 to SHUTi. Mean duration of insomnia was about 13 years. Approximately 60% of participants were currently using sleep medication, and about 90% had had previous treatment with sleep medication. After treatment, two patients in the in-person group and five in the SHUTi group were lost to follow-up. At six months, four participants in the in-person group and eight in the SHUTi group were lost to follow-up.

Both study arms had significantly lower ISI scores after treatment and at six months. After treatment, the mean ISI score in the in-person group was 5.1 points lower than in the SHUTi group, indicating that SHUTi was inferior at that time. At six months, mean ISI score was 3.3 points lower in the in-person group than in the SHUTi group. Because part of the confidence interval overlapped with the noninferiority margin, the result was inconclusive.

After treatment, the response rate was 70% in the in-person group and 43% in the SHUTi group. The remission rate was 52% in the in-person group and 18% in the SHUTi group. At six months, the response rate was 65% for the in-person group and 46% for the SHUTi group. The remission rate was 56% in the in-person group and 24% in the SHUTi group.

“SHUTi did not have the same effectiveness in this patient sample, compared with previous studies,” said Dr. Kallestad. One reason could be that previous studies included self-selected participants, rather than patients who had been referred to a sleep clinic. Also, the researchers interviewed all participants at baseline, and SHUTi might have seemed “more limited” in comparison with the interview, Dr. Kallestad concluded.

 

Digital CBT-I May Prevent Incident Depression

Insomnia is a modifiable risk factor for depression, and research has indicated that CBT-I reduces the severity of depression. Investigators also have shown that digitally delivered CBT-I effectively reduces insomnia and depression. Phillip C. Cheng, PhD, a researcher at the Henry Ford Health System in Detroit, and colleagues sought to determine whether digitally delivered CBT-I could prevent incident depression.

The researchers randomized 658 people with insomnia to Sleepio, an Internet-based CBT-I treatment, or to a control condition of online sleep education. The study’s primary outcome was the Quick Inventory of Depressive Symptomatology (QIDS), and Dr. Cheng’s group defined depression as a score greater than 10 on the QIDS. The researchers also examined participants’ ISI scores and functional outcomes such as work productivity, social functioning, cognitive functioning, and resilience. Assessments were performed at baseline, after treatment, and at one year.

In all, 358 participants were randomized to Sleepio, and 300 were randomized to sleep education. The patient population was predominantly female, was racially diverse, and had a diversity of educational attainment. The demographics of the study arms did not differ significantly.

After treatment, the rate of incident depression was 11% in the sleep education group and 6.5% in the Sleepio group. The difference between arms was not statistically significant. At one year, the rate of incident depression was 22% in the sleep education group and 5.1% in the Sleepio group. The difference between arms at one year was statistically significant, as was the change in depression incidence over time in the sleep education group.

Among patients who did not develop depression, ISI score decreased to a value below the cutoff for insomnia, regardless of study arm. ISI score did not change significantly among participants who developed depression, however. Work productivity, social functioning, cognitive functioning, and resilience improved more in the Sleepio group than in the sleep education group.

The results indicate that “digitally delivered CBT-I may prevent incident depression in adults with insomnia,” said Dr. Cheng. Each episode of depression increases the risk of relapse of depression, which underscores the significance of preventing incident depression, he added. Digital CBT-I also appears to reduce the economic burden associated with depression, and further studies could clarify whether it improves resilience, Dr. Cheng concluded.

—Erik Greb

Suggested Reading

Espie CA, Kyle SD, Williams C, et al. A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application. Sleep. 2012;35(6):769-781.

Gehrman P, Shah MT, Miles A, et al. Feasibility of group cognitive-behavioral treatment of insomnia delivered by clinical video telehealth. Telemed J E Health. 2016;22(12):1041-1046.

Hagatun S, Vedaa Ø, Nordgreen T, et al. The short-term efficacy of an unguided internet-based cognitive-behavioral therapy for insomnia: a randomized controlled trial with a six-month nonrandomized follow-up. Behav Sleep Med. 2017 Mar 27 [Epub ahead of print].

Ye YY, Chen NK, Chen J, et al. Internet-based cognitive-behavioural therapy for insomnia (ICBT-i): a meta-analysis of randomised controlled trials. BMJ Open. 2016;6(11):e010707.

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

 

Use of a smartphone application that provided daily reminders about topical treatment significantly improved adherence for patients with psoriasis, compared with those who did not use the app.

Milan_Zokic/thinkstockphotos.com

Treatment adherence remains a challenge in psoriasis, and although the field of electronic health interventions is growing, data on the effectiveness of such interventions are limited, wrote Mathias T. Svendsen, MD, of Odense University Hospital in Denmark, and his colleagues.

In a study published in the British Journal of Dermatology, 134 adults with psoriasis were randomized to use a smartphone app (68) or not (66) that provided daily medication reminders and daily information about the amount of treatment and number of product applications.

The primary outcome measure of treatment adherence was defined as once-daily application of topical medication – calcipotriol/betamethasone dipropionate cutaneous foam – for at least 80% of the days during the treatment period. A computer chip on the medication dispenser tracked patient use of the product and sent usage information to the patient’s smartphone via Bluetooth.

At 4 weeks, 65% of patients who used the app were adherent to treatment, versus 38% of those who didn’t use the app (P = .004).

In addition, patients who used the app showed significant improvement in disease severity, based on the secondary outcome measure of the Lattice System Physician’s Global Assessment (LS-PGA) at 4 weeks, with a mean change in score from baseline of 1.86 in the app group and 1.46 in the non-app group (P = .047). The LS-PGA and the Dermatology Life Quality Index (DLQI) were measured at all visits. No significant differences on the DLQI appeared between the groups.

During a 22-week follow-up completed by 122 patients, the effects were similar, but the differences were not statistically significant at weeks 8 and 26.

The study findings were limited by several factors, including the lack of knowledge of the correct amount of medication needed for the full benefit of the topical treatment and a lack of data on patient satisfaction with the app, the researchers noted. However, the results suggest that a medication reminder app improved disease severity as well as patient adherence rates in the short term, and that “there is potential for implementing patient-supporting apps in the dermatology clinic.”

The study was supported by LEO Pharma and by the Kirsten and Volmer Rask Nielsen’s Foundation; part of Dr. Svendsen’s salary during the study was paid by LEO Pharma, and several coauthors reported relationships with LEO Pharma.

SOURCE: Svendsen MT et al. Br J Dermatol. 2018 Apr 14. doi: 10.1111/bjd.16667.

 

Use of a smartphone application that provided daily reminders about topical treatment significantly improved adherence for patients with psoriasis, compared with those who did not use the app.

Milan_Zokic/thinkstockphotos.com

Treatment adherence remains a challenge in psoriasis, and although the field of electronic health interventions is growing, data on the effectiveness of such interventions are limited, wrote Mathias T. Svendsen, MD, of Odense University Hospital in Denmark, and his colleagues.

In a study published in the British Journal of Dermatology, 134 adults with psoriasis were randomized to use a smartphone app (68) or not (66) that provided daily medication reminders and daily information about the amount of treatment and number of product applications.

The primary outcome measure of treatment adherence was defined as once-daily application of topical medication – calcipotriol/betamethasone dipropionate cutaneous foam – for at least 80% of the days during the treatment period. A computer chip on the medication dispenser tracked patient use of the product and sent usage information to the patient’s smartphone via Bluetooth.

At 4 weeks, 65% of patients who used the app were adherent to treatment, versus 38% of those who didn’t use the app (P = .004).

In addition, patients who used the app showed significant improvement in disease severity, based on the secondary outcome measure of the Lattice System Physician’s Global Assessment (LS-PGA) at 4 weeks, with a mean change in score from baseline of 1.86 in the app group and 1.46 in the non-app group (P = .047). The LS-PGA and the Dermatology Life Quality Index (DLQI) were measured at all visits. No significant differences on the DLQI appeared between the groups.

During a 22-week follow-up completed by 122 patients, the effects were similar, but the differences were not statistically significant at weeks 8 and 26.

The study findings were limited by several factors, including the lack of knowledge of the correct amount of medication needed for the full benefit of the topical treatment and a lack of data on patient satisfaction with the app, the researchers noted. However, the results suggest that a medication reminder app improved disease severity as well as patient adherence rates in the short term, and that “there is potential for implementing patient-supporting apps in the dermatology clinic.”

The study was supported by LEO Pharma and by the Kirsten and Volmer Rask Nielsen’s Foundation; part of Dr. Svendsen’s salary during the study was paid by LEO Pharma, and several coauthors reported relationships with LEO Pharma.

SOURCE: Svendsen MT et al. Br J Dermatol. 2018 Apr 14. doi: 10.1111/bjd.16667.

 

Use of a smartphone application that provided daily reminders about topical treatment significantly improved adherence for patients with psoriasis, compared with those who did not use the app.

Milan_Zokic/thinkstockphotos.com

Treatment adherence remains a challenge in psoriasis, and although the field of electronic health interventions is growing, data on the effectiveness of such interventions are limited, wrote Mathias T. Svendsen, MD, of Odense University Hospital in Denmark, and his colleagues.

In a study published in the British Journal of Dermatology, 134 adults with psoriasis were randomized to use a smartphone app (68) or not (66) that provided daily medication reminders and daily information about the amount of treatment and number of product applications.

The primary outcome measure of treatment adherence was defined as once-daily application of topical medication – calcipotriol/betamethasone dipropionate cutaneous foam – for at least 80% of the days during the treatment period. A computer chip on the medication dispenser tracked patient use of the product and sent usage information to the patient’s smartphone via Bluetooth.

At 4 weeks, 65% of patients who used the app were adherent to treatment, versus 38% of those who didn’t use the app (P = .004).

In addition, patients who used the app showed significant improvement in disease severity, based on the secondary outcome measure of the Lattice System Physician’s Global Assessment (LS-PGA) at 4 weeks, with a mean change in score from baseline of 1.86 in the app group and 1.46 in the non-app group (P = .047). The LS-PGA and the Dermatology Life Quality Index (DLQI) were measured at all visits. No significant differences on the DLQI appeared between the groups.

During a 22-week follow-up completed by 122 patients, the effects were similar, but the differences were not statistically significant at weeks 8 and 26.

The study findings were limited by several factors, including the lack of knowledge of the correct amount of medication needed for the full benefit of the topical treatment and a lack of data on patient satisfaction with the app, the researchers noted. However, the results suggest that a medication reminder app improved disease severity as well as patient adherence rates in the short term, and that “there is potential for implementing patient-supporting apps in the dermatology clinic.”

The study was supported by LEO Pharma and by the Kirsten and Volmer Rask Nielsen’s Foundation; part of Dr. Svendsen’s salary during the study was paid by LEO Pharma, and several coauthors reported relationships with LEO Pharma.

SOURCE: Svendsen MT et al. Br J Dermatol. 2018 Apr 14. doi: 10.1111/bjd.16667.