Immunology

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

The Journal generally does not publish articles on topics not yet clinically relevant. But since the topic of immunization is so often in the news, and since immunotherapeutic strategies against cancer continue to be tested in clinical trials, we decided to include in this issue an edited transcript of a Medicine Grand Rounds presentation at Cleveland Clinic by Dr. Vincent Tuohy on a novel strategy to develop a vaccine against a particularly virulent form of breast cancer.

The immune system’s response to cancer is complex. Melanoma and renal cell carcinoma seem particularly susceptible to suppression by the native or augmented immune response. But most cancers seem to grow—and many metastasize—seemingly unaffected by our immune system, and sometimes even in the presence of detectable antitumor cell-directed lymphocytes and antibodies. Many attempts at devising human antitumor vaccines and immunotherapies have failed. On the other hand, we have seen the successful development of effective monoclonal antibody therapies (eg, rituximab for B cell lymphoma), immunomodulatory treatments for patients with advanced disease, and vaccines against viruses that cause cancer, ie, human papillomavirus and hepatitis B.

To fully appreciate the nuances of Dr. Tuohy’s proposed strategy, which has not yet been tested in clinical trials, and the complexities of tumor immunology, a very brief primer on the challenges is in order.

CHALLENGES TO DEVELOPING CANCER IMMUNOTHERAPY

Solid tumors can be triggered by multiple mechanisms, alone or in combination, including viruses, spontaneous mutations, overexpression of tumor promoters, and underexpression of tumor suppressors. Once growing, the solid tumor establishes its own rogue growth community, complete with a new infrastructure to supply nutrition and oxygen, potential means for expansion locally and distally, and a system to defend itself from the body’s immune system. The last of these poses specific challenges to successful spontaneous immune surveillance and to immunotherapy designed to kill cancer cells.

Microbial pathogens trigger both a nonspecific (innate) and a specific immune response in the human body. Initially, the immune system is nonspecifically “revved up,” triggered by shared “danger signals” associated with the perceived pathogen and its specific antigens. Then, specialized cells including dendritic cells locally and in proximate lymph nodes are primed to present the de novo antigens in a way that generates a specific and maturing immune response capable of getting rid of the pathogen. Tumors are also pathogenic and in some ways “foreign.” However, they are also similar to normal tissue and interact quite differently with the immune response in ways that enhance their likelihood of growth and survival. Tumor cells often do not send a danger signal to the immune system akin to what is generated by a staphylococcal or mycobacterial invader.

Tumor cells express specific antigens on their surface, such as viral proteins, cancer-associated mutated proteins, and overexpressed differentiated or undifferentiated antigens, including in some cases what Dr. Tuohy discusses as “retired proteins.” But some of these antigens may also be expressed in normal tissues, especially in an environment of resolving inflammation. Some signal the immune system to down-regulate what could otherwise be a vigorous self-destructive response every time there was inflammation.

The dendritic cell activation of the potential antitumor T-cell response and the antitumor T-cell response itself seem to be systematically blunted by many tumors. Reversal of this blunting represents one strategy currently used with very modest clinical success in treating advanced melanoma. Some newly generated tumor-antigen–recognizing T cells may in fact exert suppressor (or regulator) and not cytotoxic activity. Some tumors exhibit systemic immunosuppressive activity; this can be manifested not only by unchecked tumor growth, but also by an increased susceptibility to certain infections.

PITFALLS OF MESSING WITH THE IMMUNE SYSTEM

Messing with the immune system is not without pitfalls. Not all toxicities will be predicted by preclinical animal studies, and human immunity is not a mirror image of rodents’ or even other primates’ immune systems. Augmentation of an antitumor response, in part from the interplay of the complexities noted above, may lead to destruction of normal tissue elsewhere, or even to disruption of tolerance with the expression of autoimmunity. The toxicities will be different than the somewhat predictable toxicities from traditional antiproliferative chemotherapies—witness the striking systemic toxicity from interleukin 2-based therapies.

Whether Dr. Tuohy’s approach to developing a tumor vaccine will ultimately reach our formularies remains to be seen. The work is in an extremely preliminary phase. But the concept of immunotherapy for cancer remains an active area of research that is worth keeping an eye on.

The most proven, effective way to control disease is through prophylactic vaccination. The childhood vaccination program is a testament to this disease prevention approach, and in its current form protects us from diseases caused by 16 different pathogens.¹

Childhood immunization ends in the teen years with recommended vaccination against multiple strains of human papillomavirus that are associated with several cancers, most notably cervical carcinoma.² However, even though we have known for over 30 years that the immune system can provide considerable vaccine-induced protection against the development of cancer,³ we have not produced any vaccines that prevent cancers that commonly occur with age, such as breast and prostate cancer, which afflict 1 of 8 women and 1 of 6 men, respectively.^4,5

The lack of an adult vaccine program that provides protection against such commonly occurring adult-onset cancers represents a glaring health care deficiency and a challenge for this current generation to protect coming generations.

THE ‘RETIRED’ PROTEIN HYPOTHESIS

Given that most cancers are not associated with any disease-inducing pathogens, at what targets can we aim our immune system to induce safe and effective protection against these commonly occurring adult-onset cancers?

Perhaps an understanding of the natural aging process may provide us with insights regarding possible vaccine targets. As we age, there is a decline in expression of many tissue-specific proteins, often to the point where they may be considered “retired” and no longer found at detectable or immunogenic levels in normal cells. Examples of this natural aging process include the pigment proteins as our hair whitens, certain lactation proteins when breastfeeding ceases, and some ovarian proteins as menopause begins and production of mature egg follicles ceases. If these retired proteins are expressed in invigorated emerging tumors, then preemptive immunity directed against these retired proteins would attack and destroy the emerging tumors and ignore normal tissues, thereby avoiding any complicating collateral autoimmune damage.

Thus, we propose that retired tissue-specific self-proteins may substitute for unavailable pathogens as targets for mediating safe and effective immune protection against adult-onset cancers such as breast cancer.

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

• Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
• Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

We found that alpha-lactalbumin vaccination consistently inhibited the formation and growth of breast tumors in three different mouse models commonly used in breast cancer research.¹³ More importantly, the observed immune protection against the development of breast cancer in mice occurred in the absence of any detectable autoimmune inflammatory damage in any normal tissues examined. Thus, we concluded that alpha-lactalbumin vaccination could provide healthy women with safe and effective immune protection against the more malignant forms of breast cancer.

FROM BENCH TO BEDSIDE

How then do we determine whether alpha-lactalbumin vaccination prevents the development of TNBC in otherwise healthy cancer-free women, and whether it prevents recurrence of TNBC in women already diagnosed with TNBC? Our initial approach will involve two phase 1 clinical trials designed to determine the safety of the vaccine as well as the dose and number of vaccinations needed to induce optimum tumor immunity.

The first (phase 1a) trial will involve vaccination of women recently diagnosed with TNBC who have recovered with the current standard of care. These women will be vaccinated in groups receiving various doses of both recombinant human alpha-lactalbumin and an appropriate immune adjuvant that activates the immune system so it responds aggressively to the alpha-lactalbumin and creates the proinflammatory T-cell response needed for effective tumor immunity. This trial will simply provide dosage and safety profiles of the vaccine and will thereby lay the groundwork for subsequent (phase 2 and 3) trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing recurrence of TNBC in women already diagnosed with this disease.

The dosage and number of immunizations shown to provide optimum immunity in the phase 1a trial will be used in a second (phase 1b) trial designed primarily to determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women who have elected to undergo voluntary prophylactic mastectomy to reduce their breast cancer risk. Most of the women who elect to have this surgery have an established family history of breast cancer or a known BRCA1 mutation associated with high breast cancer risk, or both.^11,12 Consenting women will be vaccinated against alpha-lactalbumin several months before their mastectomy, and their surgically removed breast tissues will be examined extensively for signs of vaccine-induced autoimmune damage. Thus, this trial will determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women and will lay the groundwork for subsequent phase 2 and 3 trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing TNBC in women at high risk of developing this form of breast cancer.

We estimate that completing our preclinical studies, obtaining permission from the US Food and Drug Administration to test our investigational new drug, and completing both phase 1 clinical trials will require about 5 years. Thereafter, completion of phase 2 and 3 trials designed to prevent both recurrence of TNBC in women already diagnosed with this disease and occurrence of TNBC in otherwise healthy, cancer-free women will likely take at least another 5 years, so that this vaccine will likely not be available to the general public before 2024.

TO SUM UP

Although our immune system is potentially capable of protecting us from some cancers, we currently have no immune protection against cancers we commonly confront as we age. We propose that tissue-specific self proteins that are retired from expression with age in normal tissues but are expressed at immunogenic levels in emerging tumors may substitute for unavailable pathogens as targets for immunoprevention of adult-onset cancers that commonly occur with age. We know that the retired breast-specific protein, alpha-lactalbumin, is overexpressed in TNBC and that vaccination with alpha-lactalbumin provides safe and effective protection from breast cancer in preclinical mouse studies. Clinical trials are planned to ultimately determine whether alpha-lactalbumin vaccination can prevent recurrence of TNBC in women already diagnosed with this disease and prevent the initiation of TNBC in women at high risk of developing this most aggressive and lethal form of breast cancer.
 

Acknowledgment: This work was supported by a grant from Shield Biotech, Inc., Cleveland, OH. In addition, the author wishes to recognize and express his sincere gratitude for the support and encouragement received from numerous organizations that have been instrumental in making this work possible, including November Philanthropy, Brakes for Breasts, the Breast Health and Healing Foundation, the Toni Turchi Foundation, the Coalition of Women Who Care About Breast Cancer, the Sisters for Prevention, the Previvors and Survivors, the Champions of the Pink Vaccine, the Race at Legacy Village, the National Greek Orthodox Ladies Philopto-chos Society, the Daughters of Penelope Icarus Chapter 321, Can’t Stop Won’t Stop, the Babylon Breast Cancer Coalition, and Walk With A Doc.

The most proven, effective way to control disease is through prophylactic vaccination. The childhood vaccination program is a testament to this disease prevention approach, and in its current form protects us from diseases caused by 16 different pathogens.¹

Childhood immunization ends in the teen years with recommended vaccination against multiple strains of human papillomavirus that are associated with several cancers, most notably cervical carcinoma.² However, even though we have known for over 30 years that the immune system can provide considerable vaccine-induced protection against the development of cancer,³ we have not produced any vaccines that prevent cancers that commonly occur with age, such as breast and prostate cancer, which afflict 1 of 8 women and 1 of 6 men, respectively.^4,5

The lack of an adult vaccine program that provides protection against such commonly occurring adult-onset cancers represents a glaring health care deficiency and a challenge for this current generation to protect coming generations.

THE ‘RETIRED’ PROTEIN HYPOTHESIS

Given that most cancers are not associated with any disease-inducing pathogens, at what targets can we aim our immune system to induce safe and effective protection against these commonly occurring adult-onset cancers?

Perhaps an understanding of the natural aging process may provide us with insights regarding possible vaccine targets. As we age, there is a decline in expression of many tissue-specific proteins, often to the point where they may be considered “retired” and no longer found at detectable or immunogenic levels in normal cells. Examples of this natural aging process include the pigment proteins as our hair whitens, certain lactation proteins when breastfeeding ceases, and some ovarian proteins as menopause begins and production of mature egg follicles ceases. If these retired proteins are expressed in invigorated emerging tumors, then preemptive immunity directed against these retired proteins would attack and destroy the emerging tumors and ignore normal tissues, thereby avoiding any complicating collateral autoimmune damage.

Thus, we propose that retired tissue-specific self-proteins may substitute for unavailable pathogens as targets for mediating safe and effective immune protection against adult-onset cancers such as breast cancer.

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

• Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
• Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

We found that alpha-lactalbumin vaccination consistently inhibited the formation and growth of breast tumors in three different mouse models commonly used in breast cancer research.¹³ More importantly, the observed immune protection against the development of breast cancer in mice occurred in the absence of any detectable autoimmune inflammatory damage in any normal tissues examined. Thus, we concluded that alpha-lactalbumin vaccination could provide healthy women with safe and effective immune protection against the more malignant forms of breast cancer.

FROM BENCH TO BEDSIDE

How then do we determine whether alpha-lactalbumin vaccination prevents the development of TNBC in otherwise healthy cancer-free women, and whether it prevents recurrence of TNBC in women already diagnosed with TNBC? Our initial approach will involve two phase 1 clinical trials designed to determine the safety of the vaccine as well as the dose and number of vaccinations needed to induce optimum tumor immunity.

The first (phase 1a) trial will involve vaccination of women recently diagnosed with TNBC who have recovered with the current standard of care. These women will be vaccinated in groups receiving various doses of both recombinant human alpha-lactalbumin and an appropriate immune adjuvant that activates the immune system so it responds aggressively to the alpha-lactalbumin and creates the proinflammatory T-cell response needed for effective tumor immunity. This trial will simply provide dosage and safety profiles of the vaccine and will thereby lay the groundwork for subsequent (phase 2 and 3) trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing recurrence of TNBC in women already diagnosed with this disease.

The dosage and number of immunizations shown to provide optimum immunity in the phase 1a trial will be used in a second (phase 1b) trial designed primarily to determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women who have elected to undergo voluntary prophylactic mastectomy to reduce their breast cancer risk. Most of the women who elect to have this surgery have an established family history of breast cancer or a known BRCA1 mutation associated with high breast cancer risk, or both.^11,12 Consenting women will be vaccinated against alpha-lactalbumin several months before their mastectomy, and their surgically removed breast tissues will be examined extensively for signs of vaccine-induced autoimmune damage. Thus, this trial will determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women and will lay the groundwork for subsequent phase 2 and 3 trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing TNBC in women at high risk of developing this form of breast cancer.

We estimate that completing our preclinical studies, obtaining permission from the US Food and Drug Administration to test our investigational new drug, and completing both phase 1 clinical trials will require about 5 years. Thereafter, completion of phase 2 and 3 trials designed to prevent both recurrence of TNBC in women already diagnosed with this disease and occurrence of TNBC in otherwise healthy, cancer-free women will likely take at least another 5 years, so that this vaccine will likely not be available to the general public before 2024.

TO SUM UP

Although our immune system is potentially capable of protecting us from some cancers, we currently have no immune protection against cancers we commonly confront as we age. We propose that tissue-specific self proteins that are retired from expression with age in normal tissues but are expressed at immunogenic levels in emerging tumors may substitute for unavailable pathogens as targets for immunoprevention of adult-onset cancers that commonly occur with age. We know that the retired breast-specific protein, alpha-lactalbumin, is overexpressed in TNBC and that vaccination with alpha-lactalbumin provides safe and effective protection from breast cancer in preclinical mouse studies. Clinical trials are planned to ultimately determine whether alpha-lactalbumin vaccination can prevent recurrence of TNBC in women already diagnosed with this disease and prevent the initiation of TNBC in women at high risk of developing this most aggressive and lethal form of breast cancer.
 

Acknowledgment: This work was supported by a grant from Shield Biotech, Inc., Cleveland, OH. In addition, the author wishes to recognize and express his sincere gratitude for the support and encouragement received from numerous organizations that have been instrumental in making this work possible, including November Philanthropy, Brakes for Breasts, the Breast Health and Healing Foundation, the Toni Turchi Foundation, the Coalition of Women Who Care About Breast Cancer, the Sisters for Prevention, the Previvors and Survivors, the Champions of the Pink Vaccine, the Race at Legacy Village, the National Greek Orthodox Ladies Philopto-chos Society, the Daughters of Penelope Icarus Chapter 321, Can’t Stop Won’t Stop, the Babylon Breast Cancer Coalition, and Walk With A Doc.

The most proven, effective way to control disease is through prophylactic vaccination. The childhood vaccination program is a testament to this disease prevention approach, and in its current form protects us from diseases caused by 16 different pathogens.¹

Childhood immunization ends in the teen years with recommended vaccination against multiple strains of human papillomavirus that are associated with several cancers, most notably cervical carcinoma.² However, even though we have known for over 30 years that the immune system can provide considerable vaccine-induced protection against the development of cancer,³ we have not produced any vaccines that prevent cancers that commonly occur with age, such as breast and prostate cancer, which afflict 1 of 8 women and 1 of 6 men, respectively.^4,5

The lack of an adult vaccine program that provides protection against such commonly occurring adult-onset cancers represents a glaring health care deficiency and a challenge for this current generation to protect coming generations.

THE ‘RETIRED’ PROTEIN HYPOTHESIS

Given that most cancers are not associated with any disease-inducing pathogens, at what targets can we aim our immune system to induce safe and effective protection against these commonly occurring adult-onset cancers?

Perhaps an understanding of the natural aging process may provide us with insights regarding possible vaccine targets. As we age, there is a decline in expression of many tissue-specific proteins, often to the point where they may be considered “retired” and no longer found at detectable or immunogenic levels in normal cells. Examples of this natural aging process include the pigment proteins as our hair whitens, certain lactation proteins when breastfeeding ceases, and some ovarian proteins as menopause begins and production of mature egg follicles ceases. If these retired proteins are expressed in invigorated emerging tumors, then preemptive immunity directed against these retired proteins would attack and destroy the emerging tumors and ignore normal tissues, thereby avoiding any complicating collateral autoimmune damage.

Thus, we propose that retired tissue-specific self-proteins may substitute for unavailable pathogens as targets for mediating safe and effective immune protection against adult-onset cancers such as breast cancer.

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

• Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.^6–8
• Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),^9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).^11,12

We found that alpha-lactalbumin vaccination consistently inhibited the formation and growth of breast tumors in three different mouse models commonly used in breast cancer research.¹³ More importantly, the observed immune protection against the development of breast cancer in mice occurred in the absence of any detectable autoimmune inflammatory damage in any normal tissues examined. Thus, we concluded that alpha-lactalbumin vaccination could provide healthy women with safe and effective immune protection against the more malignant forms of breast cancer.

FROM BENCH TO BEDSIDE

How then do we determine whether alpha-lactalbumin vaccination prevents the development of TNBC in otherwise healthy cancer-free women, and whether it prevents recurrence of TNBC in women already diagnosed with TNBC? Our initial approach will involve two phase 1 clinical trials designed to determine the safety of the vaccine as well as the dose and number of vaccinations needed to induce optimum tumor immunity.

The first (phase 1a) trial will involve vaccination of women recently diagnosed with TNBC who have recovered with the current standard of care. These women will be vaccinated in groups receiving various doses of both recombinant human alpha-lactalbumin and an appropriate immune adjuvant that activates the immune system so it responds aggressively to the alpha-lactalbumin and creates the proinflammatory T-cell response needed for effective tumor immunity. This trial will simply provide dosage and safety profiles of the vaccine and will thereby lay the groundwork for subsequent (phase 2 and 3) trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing recurrence of TNBC in women already diagnosed with this disease.

The dosage and number of immunizations shown to provide optimum immunity in the phase 1a trial will be used in a second (phase 1b) trial designed primarily to determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women who have elected to undergo voluntary prophylactic mastectomy to reduce their breast cancer risk. Most of the women who elect to have this surgery have an established family history of breast cancer or a known BRCA1 mutation associated with high breast cancer risk, or both.^11,12 Consenting women will be vaccinated against alpha-lactalbumin several months before their mastectomy, and their surgically removed breast tissues will be examined extensively for signs of vaccine-induced autoimmune damage. Thus, this trial will determine the safety of alpha-lactalbumin vaccination in healthy cancer-free women and will lay the groundwork for subsequent phase 2 and 3 trials designed to determine whether alpha-lactalbumin vaccination is effective in preventing TNBC in women at high risk of developing this form of breast cancer.

We estimate that completing our preclinical studies, obtaining permission from the US Food and Drug Administration to test our investigational new drug, and completing both phase 1 clinical trials will require about 5 years. Thereafter, completion of phase 2 and 3 trials designed to prevent both recurrence of TNBC in women already diagnosed with this disease and occurrence of TNBC in otherwise healthy, cancer-free women will likely take at least another 5 years, so that this vaccine will likely not be available to the general public before 2024.

TO SUM UP

Although our immune system is potentially capable of protecting us from some cancers, we currently have no immune protection against cancers we commonly confront as we age. We propose that tissue-specific self proteins that are retired from expression with age in normal tissues but are expressed at immunogenic levels in emerging tumors may substitute for unavailable pathogens as targets for immunoprevention of adult-onset cancers that commonly occur with age. We know that the retired breast-specific protein, alpha-lactalbumin, is overexpressed in TNBC and that vaccination with alpha-lactalbumin provides safe and effective protection from breast cancer in preclinical mouse studies. Clinical trials are planned to ultimately determine whether alpha-lactalbumin vaccination can prevent recurrence of TNBC in women already diagnosed with this disease and prevent the initiation of TNBC in women at high risk of developing this most aggressive and lethal form of breast cancer.
 

Acknowledgment: This work was supported by a grant from Shield Biotech, Inc., Cleveland, OH. In addition, the author wishes to recognize and express his sincere gratitude for the support and encouragement received from numerous organizations that have been instrumental in making this work possible, including November Philanthropy, Brakes for Breasts, the Breast Health and Healing Foundation, the Toni Turchi Foundation, the Coalition of Women Who Care About Breast Cancer, the Sisters for Prevention, the Previvors and Survivors, the Champions of the Pink Vaccine, the Race at Legacy Village, the National Greek Orthodox Ladies Philopto-chos Society, the Daughters of Penelope Icarus Chapter 321, Can’t Stop Won’t Stop, the Babylon Breast Cancer Coalition, and Walk With A Doc.

ANSWER

The correct answer is an allergic reaction to a contactant, most likely the triple-antibiotic ointment (choice “d”).

Irritant reactions to tape adhesive (choice “a”) are extremely common. However, the resultant rash would have been confined to the linear areas where the tape touched his skin.

Dissolving sutures, such as those used in this case, can provoke a “suture granuloma”—essentially a foreign body reaction to the suture material (choice “b”). But this would have caused a focal area of swelling and redness, and very possibly a show of pus.

Postop wound infections (choice “c”) are also quite common. However, they would not manifest solely with itching in a papulovesicular rash surrounding the wound. Had infection developed, the redness would have been broad-based, with ill-defined margins, and the patient’s complaint would have been of pain, not itching. No vesicles would have been seen with bacterial infection.

DISCUSSION

This case illustrates the phenomenon of “treatment as problem,” in which the medication the patient applies becomes more problematic than the condition being addressed. Reactions to the neomycin in triple-antibiotic ointment are common but still provoke considerable worry on the part of patients and providers alike, especially when mistaken for “infection.”

This patient, like many, was dubious of the diagnosis, pointing out that he had used this same topical medication on many occasions without incident (though not recently). What he didn’t know is that it takes repeated exposure to a given allergen to develop T-memory cells that eventually begin to react. This same phenomenon is seen with poison ivy; patients will recall the ability, as a child, to practically wallow in poison ivy with impunity, making them doubtful about being allergic to it as an adult.

Neomycin, an aminoglycoside with a fairly wide spectrum of antibacterial activity, was first noted as a contact allergen in 1952. It is such a notorious offender that it was named Allergen of the Year in 2010 by the American Contact Dermatology Society.

For the past 20 years, 7% to 13% of patch tests surveyed were positive for neomycin. For reasons not entirely clear, Americans older than 60 are 150% more likely to experience a reaction to neomycin than are younger patients. (It could simply be that they’ve had more chances for exposure.)

In another interesting twist, the ointment vehicle appears to play a role. A reaction to this preparation is considerably more likely than to the same drug in other forms (eg, powders, solutions, creams). This is true of most medications, such as topical steroids, which are effectively self-occluded by this vehicle.

Persons with impaired barrier function, such as those with atopic dermatitis or whose skin has been prepped for surgery, appear to be at increased risk for these types of contact dermatoses.

Though there are other items in the differential, the configuration of the papulovesicular rash and the sole symptom of itching are essentially pathognomic for contact dermatitis. Besides the use of potent topical steroids for a few days, the real “cure” for this problem is for the patient to switch to “double-antibiotic” creams or ointments that do not include neomycin. 

ANSWER

The correct answer is an allergic reaction to a contactant, most likely the triple-antibiotic ointment (choice “d”).

Irritant reactions to tape adhesive (choice “a”) are extremely common. However, the resultant rash would have been confined to the linear areas where the tape touched his skin.

Dissolving sutures, such as those used in this case, can provoke a “suture granuloma”—essentially a foreign body reaction to the suture material (choice “b”). But this would have caused a focal area of swelling and redness, and very possibly a show of pus.

Postop wound infections (choice “c”) are also quite common. However, they would not manifest solely with itching in a papulovesicular rash surrounding the wound. Had infection developed, the redness would have been broad-based, with ill-defined margins, and the patient’s complaint would have been of pain, not itching. No vesicles would have been seen with bacterial infection.

DISCUSSION

This case illustrates the phenomenon of “treatment as problem,” in which the medication the patient applies becomes more problematic than the condition being addressed. Reactions to the neomycin in triple-antibiotic ointment are common but still provoke considerable worry on the part of patients and providers alike, especially when mistaken for “infection.”

This patient, like many, was dubious of the diagnosis, pointing out that he had used this same topical medication on many occasions without incident (though not recently). What he didn’t know is that it takes repeated exposure to a given allergen to develop T-memory cells that eventually begin to react. This same phenomenon is seen with poison ivy; patients will recall the ability, as a child, to practically wallow in poison ivy with impunity, making them doubtful about being allergic to it as an adult.

Neomycin, an aminoglycoside with a fairly wide spectrum of antibacterial activity, was first noted as a contact allergen in 1952. It is such a notorious offender that it was named Allergen of the Year in 2010 by the American Contact Dermatology Society.

For the past 20 years, 7% to 13% of patch tests surveyed were positive for neomycin. For reasons not entirely clear, Americans older than 60 are 150% more likely to experience a reaction to neomycin than are younger patients. (It could simply be that they’ve had more chances for exposure.)

In another interesting twist, the ointment vehicle appears to play a role. A reaction to this preparation is considerably more likely than to the same drug in other forms (eg, powders, solutions, creams). This is true of most medications, such as topical steroids, which are effectively self-occluded by this vehicle.

Persons with impaired barrier function, such as those with atopic dermatitis or whose skin has been prepped for surgery, appear to be at increased risk for these types of contact dermatoses.

Though there are other items in the differential, the configuration of the papulovesicular rash and the sole symptom of itching are essentially pathognomic for contact dermatitis. Besides the use of potent topical steroids for a few days, the real “cure” for this problem is for the patient to switch to “double-antibiotic” creams or ointments that do not include neomycin. 

ANSWER

The correct answer is an allergic reaction to a contactant, most likely the triple-antibiotic ointment (choice “d”).

Irritant reactions to tape adhesive (choice “a”) are extremely common. However, the resultant rash would have been confined to the linear areas where the tape touched his skin.

Dissolving sutures, such as those used in this case, can provoke a “suture granuloma”—essentially a foreign body reaction to the suture material (choice “b”). But this would have caused a focal area of swelling and redness, and very possibly a show of pus.

Postop wound infections (choice “c”) are also quite common. However, they would not manifest solely with itching in a papulovesicular rash surrounding the wound. Had infection developed, the redness would have been broad-based, with ill-defined margins, and the patient’s complaint would have been of pain, not itching. No vesicles would have been seen with bacterial infection.

DISCUSSION

This case illustrates the phenomenon of “treatment as problem,” in which the medication the patient applies becomes more problematic than the condition being addressed. Reactions to the neomycin in triple-antibiotic ointment are common but still provoke considerable worry on the part of patients and providers alike, especially when mistaken for “infection.”

This patient, like many, was dubious of the diagnosis, pointing out that he had used this same topical medication on many occasions without incident (though not recently). What he didn’t know is that it takes repeated exposure to a given allergen to develop T-memory cells that eventually begin to react. This same phenomenon is seen with poison ivy; patients will recall the ability, as a child, to practically wallow in poison ivy with impunity, making them doubtful about being allergic to it as an adult.

Neomycin, an aminoglycoside with a fairly wide spectrum of antibacterial activity, was first noted as a contact allergen in 1952. It is such a notorious offender that it was named Allergen of the Year in 2010 by the American Contact Dermatology Society.

For the past 20 years, 7% to 13% of patch tests surveyed were positive for neomycin. For reasons not entirely clear, Americans older than 60 are 150% more likely to experience a reaction to neomycin than are younger patients. (It could simply be that they’ve had more chances for exposure.)

In another interesting twist, the ointment vehicle appears to play a role. A reaction to this preparation is considerably more likely than to the same drug in other forms (eg, powders, solutions, creams). This is true of most medications, such as topical steroids, which are effectively self-occluded by this vehicle.

Persons with impaired barrier function, such as those with atopic dermatitis or whose skin has been prepped for surgery, appear to be at increased risk for these types of contact dermatoses.

Though there are other items in the differential, the configuration of the papulovesicular rash and the sole symptom of itching are essentially pathognomic for contact dermatitis. Besides the use of potent topical steroids for a few days, the real “cure” for this problem is for the patient to switch to “double-antibiotic” creams or ointments that do not include neomycin.