Psoriasis

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

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Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

jancin

Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

jancin

Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/

The Pearls in Dermatology collection consists of our popular pearls from the year in one convenient file. Topics include:

• Nail psoriasis and psoriasis on the hands and feet
• Genital wart treatment
• Isotretinoin for acne
• Cosmeceuticals for rosacea
• Surgical technique with the flexible scalpel blade

Editor’s Commentary provided by Vincent A. DeLeo, MD, Editor-in-Chief, Cutis.

Save this collection, print it, and/or share it with your colleagues. We hope this comprehensive collection will positively impact how you manage patients.

The Pearls in Dermatology collection consists of our popular pearls from the year in one convenient file. Topics include:

• Nail psoriasis and psoriasis on the hands and feet
• Genital wart treatment
• Isotretinoin for acne
• Cosmeceuticals for rosacea
• Surgical technique with the flexible scalpel blade

Editor’s Commentary provided by Vincent A. DeLeo, MD, Editor-in-Chief, Cutis.

Save this collection, print it, and/or share it with your colleagues. We hope this comprehensive collection will positively impact how you manage patients.

The Pearls in Dermatology collection consists of our popular pearls from the year in one convenient file. Topics include:

• Nail psoriasis and psoriasis on the hands and feet
• Genital wart treatment
• Isotretinoin for acne
• Cosmeceuticals for rosacea
• Surgical technique with the flexible scalpel blade

Editor’s Commentary provided by Vincent A. DeLeo, MD, Editor-in-Chief, Cutis.

Save this collection, print it, and/or share it with your colleagues. We hope this comprehensive collection will positively impact how you manage patients.

Mood changes are a rare side effect of methotrexate therapy, but ask about psychiatric side effects when using the drug, as when treating dermatologic disease, said Trisha Bhat and Carrie C. Coughlin, MD, both of Washington University, St. Louis.

Neurotoxicity with low-dose methotrexate often has been described when used to treat rheumatologic disease, the investigators said, but not in the dermatologic literature – although CNS symptoms such as dizziness and headache have been described in both.

KatarzynaBialasiewicz/Thinkstock

[email protected]

Mood changes are a rare side effect of methotrexate therapy, but ask about psychiatric side effects when using the drug, as when treating dermatologic disease, said Trisha Bhat and Carrie C. Coughlin, MD, both of Washington University, St. Louis.

Neurotoxicity with low-dose methotrexate often has been described when used to treat rheumatologic disease, the investigators said, but not in the dermatologic literature – although CNS symptoms such as dizziness and headache have been described in both.

KatarzynaBialasiewicz/Thinkstock

[email protected]

Mood changes are a rare side effect of methotrexate therapy, but ask about psychiatric side effects when using the drug, as when treating dermatologic disease, said Trisha Bhat and Carrie C. Coughlin, MD, both of Washington University, St. Louis.

Neurotoxicity with low-dose methotrexate often has been described when used to treat rheumatologic disease, the investigators said, but not in the dermatologic literature – although CNS symptoms such as dizziness and headache have been described in both.

KatarzynaBialasiewicz/Thinkstock

[email protected]

REPORTING FROM THE EADV CONGRESS

GENEVA – Psoriasis patients switched to ixekizumab after previous exposure to another interleukin-17 inhibitor respond as well as those who are IL-17 antagonist naive, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This finding is of importance in real-world clinical practice because it’s not at all uncommon for psoriasis patients on one biologic to have to switch to another because of insufficient efficacy, side effects, or a change in insurance coverage. Physicians would like to know what sort of responses can be expected to whatever agent they prescribe next.

[email protected]

REPORTING FROM THE EADV CONGRESS

GENEVA – Psoriasis patients switched to ixekizumab after previous exposure to another interleukin-17 inhibitor respond as well as those who are IL-17 antagonist naive, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This finding is of importance in real-world clinical practice because it’s not at all uncommon for psoriasis patients on one biologic to have to switch to another because of insufficient efficacy, side effects, or a change in insurance coverage. Physicians would like to know what sort of responses can be expected to whatever agent they prescribe next.

[email protected]

REPORTING FROM THE EADV CONGRESS

GENEVA – Psoriasis patients switched to ixekizumab after previous exposure to another interleukin-17 inhibitor respond as well as those who are IL-17 antagonist naive, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This finding is of importance in real-world clinical practice because it’s not at all uncommon for psoriasis patients on one biologic to have to switch to another because of insufficient efficacy, side effects, or a change in insurance coverage. Physicians would like to know what sort of responses can be expected to whatever agent they prescribe next.

[email protected]

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.