LIVERPOOL, ENGLAND – Very few patients with idiopathic pulmonary fibrosis have connective tissue disease antibodies, suggesting that IPF is a “robust diagnosis” when made on the basis of standard diagnostic tests, it was reported at the British Society for Rheumatology annual conference.

“The results were perhaps not what we’d expected,” said Caroline V. Cotton, PhD, of the Institute of Ageing and Chronic Disease at the University of Liverpool, England.

Sarah Freeman/MDedge News

SOURCE: Cotton CV et al. Rheumatology. 2018;57[Suppl. 3]:key075.206.
 

LIVERPOOL, ENGLAND – Very few patients with idiopathic pulmonary fibrosis have connective tissue disease antibodies, suggesting that IPF is a “robust diagnosis” when made on the basis of standard diagnostic tests, it was reported at the British Society for Rheumatology annual conference.

“The results were perhaps not what we’d expected,” said Caroline V. Cotton, PhD, of the Institute of Ageing and Chronic Disease at the University of Liverpool, England.

Sarah Freeman/MDedge News

SOURCE: Cotton CV et al. Rheumatology. 2018;57[Suppl. 3]:key075.206.
 

LIVERPOOL, ENGLAND – Very few patients with idiopathic pulmonary fibrosis have connective tissue disease antibodies, suggesting that IPF is a “robust diagnosis” when made on the basis of standard diagnostic tests, it was reported at the British Society for Rheumatology annual conference.

“The results were perhaps not what we’d expected,” said Caroline V. Cotton, PhD, of the Institute of Ageing and Chronic Disease at the University of Liverpool, England.

Sarah Freeman/MDedge News

SOURCE: Cotton CV et al. Rheumatology. 2018;57[Suppl. 3]:key075.206.
 

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Case Report

A 67-year-old woman with a history of allergic rhinitis presented in the spring with a pruritic eruption of 2 days’ duration that began on the abdomen and spread to the chest, back, and bilateral arms. Six days prior to the onset of the symptoms she underwent computed tomography (CT) of the abdomen and pelvis to evaluate abdominal pain and peripheral eosinophilia. Two iodinated contrast (IC) agents were used: intravenous iohexol and oral diatrizoate meglumine–diatrizoate sodium. The eruption was not preceded by fever, malaise, sore throat, rhinorrhea, cough, arthralgia, headache, diarrhea, or new medication or supplement use. The patient denied any history of drug allergy or cutaneous eruptions. Her current medications, which she had been taking long-term, were aspirin, lisinopril, diltiazem, levothyroxine, esomeprazole, paroxetine, gabapentin, and diphenhydramine.

Physical examination was notable for erythematous, blanchable, nontender macules coalescing into patches on the trunk and bilateral arms (Figure). There was slight erythema on the nasolabial folds and ears. The mucosal surfaces and distal legs were clear. The patient was afebrile. Her white blood cell count was 12.5×10⁹/L with 32.3% eosinophils (baseline: white blood cell count, 14.8×10⁹/L; 22% eosinophils)(reference range, 4.8–10.8×10⁹/L; 1%–4% eosinophils). Her comprehensive metabolic panel was within reference range. The human immunodeficiency virus 1/2 antibody immunoassay was nonreactive.

The patient was diagnosed with an exanthematous eruption caused by IC and was treated with oral hydroxyzine and triamcinolone acetonide cream 0.1%. The eruption resolved within 2 weeks without recurrence at 3-month follow-up.

Comment

Delayed cutaneous eruptions caused by IC are underrecognized in medicine and are infrequently described in the dermatology literature.¹ Unlike urticaria and other well-known immediate reactions to IC, delayed reactions develop when patients are less likely to be under medical supervision.² Moreover, only 12% to 33% of patients with delayed reactions to IC seek medical attention.^3-6 As a result, these delayed reactions often are attributed to other causes.¹ Patients may then be unknowingly reexposed to the offending contrast agent and experience recurrent eruptions, such as in one fatal case of toxic epidermal necrolysis (TEN).^7-11 Given the role of dermatologists in the diagnosis and prevention of cutaneous drug reactions, it is important to be mindful of delayed cutaneous eruptions caused by IC.

Clinical Presentation of Delayed Reactions
Most delayed cutaneous reactions to IC present as exanthematous eruptions in the week following a contrast-enhanced CT scan or coronary angiogram.^2,12 The reactions tend to resolve within 2 weeks of onset, and the treatment is largely supportive with antihistamines and/or corticosteroids for the associated pruritus.^2,5,6 In a study of 98 patients with a history of delayed reactions to IC, delayed-onset urticaria and angioedema also have been reported with incidence rates of 19% and 24%, respectively.² Other reactions are less common. In the same study, 7% of patients developed palpable purpura; acute generalized exanthematous pustulosis; bullous, flexural, or psoriasislike exanthema; exfoliative eruptions; or purpura and a maculopapular eruption combined with eosinophilia.² There also have been reports of IC-induced erythema multiforme,³ fixed drug eruptions,^10,11 symmetrical drug-related intertriginous and flexural exanthema,¹³ cutaneous vasculitis,¹⁴ drug reactions with eosinophilia and systemic symptoms,¹⁵ Stevens-Johnson syndrome/TEN,^7,8,16,17 and iododerma.¹⁸

IC Agents
Virtually all delayed cutaneous reactions to IC reportedly are due to intravascular rather than oral agents,^1,2,19 with the exception of iododerma¹⁸ and 1 reported case of TEN.¹⁷ Intravenous iohexol was most likely the offending drug in our case. In a prospective cohort study of 539 patients undergoing CT scans, the absolute risk for developing a delayed cutaneous reaction (defined as rash, itching, or skin redness or swelling) to intravascular iohexol was 9.4%.²⁰ Randomized, double-blind studies have found that the risk for delayed cutaneous eruptions is similar among various types of IC, except for iodixanol, which confers a higher risk.^5,6,21

Risk Factors
Interestingly, analyses have shown that delayed reactions to IC are more common in atopic patients and during high pollen season.²² Our patient displayed these risk factors, as she had allergic rhinitis and presented for evaluation in late spring when local pollen counts were high. Additionally, patients who develop delayed reactions to IC are notably more likely than controls to have a history of other cutaneous drug reactions, serum creatinine levels greater than 2.0 mg/dL (reference range, 0.6–1.2 mg/dL),³ or history of treatment with recombinant interleukin 2.¹⁹

Patients with a history of delayed reactions to IC are not at increased risk for immediate reactions and vice versa.^2,3 This finding is consistent with the evidence that delayed and immediate reactions to IC are mechanistically unrelated.²³ Additionally, seafood allergy is not a risk factor for either immediate or delayed reactions to IC, despite a common misconception among physicians and patients because seafood is iodinated.^24,25

Reexposure to IC
Patients who have had delayed cutaneous reactions to IC are at risk for similar eruptions upon reexposure. Although the reactions are believed to be cell mediated, skin testing with IC is not sensitive enough to reliably identify tolerable alternatives.¹² Consequently, gadolinium-based agents have been recommended in patients with a history of reactions to IC if additional contrast-enhanced studies are needed.^13,26 Iodinated and gadolinium-based contrast agents do not cross-react, and gadolinium is compatible with studies other than magnetic resonance imaging.^1,27

Premedication
Despite the absence of cross-reactivity, the American College of Radiology considers patients with hypersensitivity reactions to IC to be at increased risk for reactions to gadolinium but does not make specific recommendations regarding premedication given the dearth of data.¹ As a result, premedication may be considered prior to gadolinium administration depending on the severity of the delayed reaction to IC. Additionally, premedication may be beneficial in cases in which gadolinium is contraindicated and IC must be reused. In a retrospective study, all patients with suspected delayed reactions to IC tolerated IC or gadolinium contrast when pretreated with corticosteroids with or without antihistamines.²⁸ Regimens with corticosteroids and either cyclosporine or intravenous immunoglobulin also have prevented the recurrence of IC-induced exanthematous eruptions and Stevens-Johnson syndrome.^29,30 Despite these reports, delayed cutaneous reactions to IC have recurred in other patients receiving corticosteroids, antihistamines, and/or cyclosporine for premedication or concurrent treatment of an underlying condition.^16,29-31

Conclusion

It is important for dermatologists to recognize IC as a cause of delayed drug reactions. Current awareness is limited, and as a result, patients often are reexposed to the offending contrast agents unsuspectingly. In addition to diagnosing these eruptions, dermatologists may help prevent their recurrence if future contrast-enhanced studies are required by recommending gadolinium-based agents and/or premedication.

Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Vidyard Video

Read Dr. Lio’s guest editorial “Updated Guidelines on Peanut Allergy Prevention in Infants With Atopic Dermatitis” for more information

Vidyard Video

Read Dr. Lio’s guest editorial “Updated Guidelines on Peanut Allergy Prevention in Infants With Atopic Dermatitis” for more information

Vidyard Video

Read Dr. Lio’s guest editorial “Updated Guidelines on Peanut Allergy Prevention in Infants With Atopic Dermatitis” for more information

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.