LOS ANGELES – A peanut protein–bearing skin patch known as the Viaskin Peanut gave a continued strong performance for treatment of peanut allergy in children during the second year of an international study of this novel form of epicutaneous immunotherapy.

The clinical response rate in 6- to 11-year-olds after 1 year of treatment with the 250-mcg dose of peanut protein in the medical device was 57% in the phase IIb, double-blind, 22-site, international VIPES trial, as reported last year.

©mates/Fotolia.com

After an additional year of treatment with the 250-mcg Viaskin Peanut in the open-label extension study known as OLFUS-VIPES, this rate climbed to 80%. Safety and tolerability of the device therapy remained excellent, Dr. Hugh A. Sampson said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In adolescents and adults, however, the clinical response – while significantly better than placebo in VIPES – was less robust than in children, and it remained stable from year 1 to year 2. This is believed to be due to the greater plasticity of the immune system in children, observed Dr. Sampson, director of the Jaffe Food Allergy Institute at Kravis Children’s Hospital at Mount Sinai in New York and chief scientific officer at DBV Technologies, which is developing the Viaskin Peanut.

The ongoing phase III trial uses the 250-mcg dose of peanut protein – the highest of several doses studied in VIPES and OLFUS-VIPES – and is restricted to peanut-allergic children ages 4-11 years. Doses of peanut protein greater than 250 mcg will be explored in separate studies of adolescents and adults.

The clinical response rate in children on the 250-mcg Viaskin Peanut rose from 57% after 1 year to 80% – that is, 16 of 20 subjects – after 2 years. A clinical response in VIPES and OLFUS-VIPES was defined as nonreactivity to a dose of at least 1,000 mg of peanut protein – the equivalent of four peanuts – during a formal double-blind food challenge or at least a tenfold increase in the eliciting dose, compared to the original eliciting dose.

In VIPES, one-third of children on the 250-mcg device therapy for 1 year could tolerate at least 1,000 mg of peanut protein; after an additional year of open-label therapy, 60% of children were able to do so.

Among 6- to 11-year-olds, the median cumulative reactive dose of peanut protein was 44 mg at baseline, 444 mg after 12 months of using the 250-mcg Viaskin Peanut, and 1,444 mg at 2 years.

The children’s immunologic response to the Viaskin Peanut was impressive: A 40% reduction from baseline in peanut IgE at 2 years, along with a ninefold increase in protective peanut-specific IgG4.

The skin patch consists of a dried allergen – in this case, peanut protein – which is made electrostatically adherent to a membrane on a Band-Aid–like chamber. A set of patches is placed on noneczematous skin on a child’s back and on the inner upper arm of older patients. Moisture emitted from the skin gradually causes the protein allergen to solubilize and get absorbed into the outer layer of the skin. It is then picked up by antigen-presenting Langerhans cells and transported to regional lymph nodes for deactivation. The patches are changed daily.

“It appears that we need to look at the skin as a tolerogenic organ when it’s uninflamed,” Dr. Sampson observed.

Compliance with treatment was in excess of 96% in both VIPES and OLFUS-VIPES. There have been no serious treatment-related adverse events and no need for the use of epinephrine. Side effects have been limited to occasional mild to moderate application site reactions easily managed with antihistamines and/or topical steroids, according to Dr. Sampson.

The double-blind VIPES study included 207 subjects with documented peanut allergy. OLFUS-VIPES, which will continue for 1 additional year of open-label therapy, includes 171 of the original 207, including 97 children, 49 adolescents, and 25 adults up to age 55 years.

“We’ll see if there’s continued improvement in children through the third year or it levels off, but based upon the immunologic parameters I think it’s having continued effect,” the pediatric allergist said.

[email protected]

LOS ANGELES – A peanut protein–bearing skin patch known as the Viaskin Peanut gave a continued strong performance for treatment of peanut allergy in children during the second year of an international study of this novel form of epicutaneous immunotherapy.

The clinical response rate in 6- to 11-year-olds after 1 year of treatment with the 250-mcg dose of peanut protein in the medical device was 57% in the phase IIb, double-blind, 22-site, international VIPES trial, as reported last year.

©mates/Fotolia.com

After an additional year of treatment with the 250-mcg Viaskin Peanut in the open-label extension study known as OLFUS-VIPES, this rate climbed to 80%. Safety and tolerability of the device therapy remained excellent, Dr. Hugh A. Sampson said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In adolescents and adults, however, the clinical response – while significantly better than placebo in VIPES – was less robust than in children, and it remained stable from year 1 to year 2. This is believed to be due to the greater plasticity of the immune system in children, observed Dr. Sampson, director of the Jaffe Food Allergy Institute at Kravis Children’s Hospital at Mount Sinai in New York and chief scientific officer at DBV Technologies, which is developing the Viaskin Peanut.

The ongoing phase III trial uses the 250-mcg dose of peanut protein – the highest of several doses studied in VIPES and OLFUS-VIPES – and is restricted to peanut-allergic children ages 4-11 years. Doses of peanut protein greater than 250 mcg will be explored in separate studies of adolescents and adults.

The clinical response rate in children on the 250-mcg Viaskin Peanut rose from 57% after 1 year to 80% – that is, 16 of 20 subjects – after 2 years. A clinical response in VIPES and OLFUS-VIPES was defined as nonreactivity to a dose of at least 1,000 mg of peanut protein – the equivalent of four peanuts – during a formal double-blind food challenge or at least a tenfold increase in the eliciting dose, compared to the original eliciting dose.

In VIPES, one-third of children on the 250-mcg device therapy for 1 year could tolerate at least 1,000 mg of peanut protein; after an additional year of open-label therapy, 60% of children were able to do so.

Among 6- to 11-year-olds, the median cumulative reactive dose of peanut protein was 44 mg at baseline, 444 mg after 12 months of using the 250-mcg Viaskin Peanut, and 1,444 mg at 2 years.

The children’s immunologic response to the Viaskin Peanut was impressive: A 40% reduction from baseline in peanut IgE at 2 years, along with a ninefold increase in protective peanut-specific IgG4.

The skin patch consists of a dried allergen – in this case, peanut protein – which is made electrostatically adherent to a membrane on a Band-Aid–like chamber. A set of patches is placed on noneczematous skin on a child’s back and on the inner upper arm of older patients. Moisture emitted from the skin gradually causes the protein allergen to solubilize and get absorbed into the outer layer of the skin. It is then picked up by antigen-presenting Langerhans cells and transported to regional lymph nodes for deactivation. The patches are changed daily.

“It appears that we need to look at the skin as a tolerogenic organ when it’s uninflamed,” Dr. Sampson observed.

Compliance with treatment was in excess of 96% in both VIPES and OLFUS-VIPES. There have been no serious treatment-related adverse events and no need for the use of epinephrine. Side effects have been limited to occasional mild to moderate application site reactions easily managed with antihistamines and/or topical steroids, according to Dr. Sampson.

The double-blind VIPES study included 207 subjects with documented peanut allergy. OLFUS-VIPES, which will continue for 1 additional year of open-label therapy, includes 171 of the original 207, including 97 children, 49 adolescents, and 25 adults up to age 55 years.

“We’ll see if there’s continued improvement in children through the third year or it levels off, but based upon the immunologic parameters I think it’s having continued effect,” the pediatric allergist said.

[email protected]

LOS ANGELES – A peanut protein–bearing skin patch known as the Viaskin Peanut gave a continued strong performance for treatment of peanut allergy in children during the second year of an international study of this novel form of epicutaneous immunotherapy.

The clinical response rate in 6- to 11-year-olds after 1 year of treatment with the 250-mcg dose of peanut protein in the medical device was 57% in the phase IIb, double-blind, 22-site, international VIPES trial, as reported last year.

©mates/Fotolia.com

After an additional year of treatment with the 250-mcg Viaskin Peanut in the open-label extension study known as OLFUS-VIPES, this rate climbed to 80%. Safety and tolerability of the device therapy remained excellent, Dr. Hugh A. Sampson said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In adolescents and adults, however, the clinical response – while significantly better than placebo in VIPES – was less robust than in children, and it remained stable from year 1 to year 2. This is believed to be due to the greater plasticity of the immune system in children, observed Dr. Sampson, director of the Jaffe Food Allergy Institute at Kravis Children’s Hospital at Mount Sinai in New York and chief scientific officer at DBV Technologies, which is developing the Viaskin Peanut.

The ongoing phase III trial uses the 250-mcg dose of peanut protein – the highest of several doses studied in VIPES and OLFUS-VIPES – and is restricted to peanut-allergic children ages 4-11 years. Doses of peanut protein greater than 250 mcg will be explored in separate studies of adolescents and adults.

The clinical response rate in children on the 250-mcg Viaskin Peanut rose from 57% after 1 year to 80% – that is, 16 of 20 subjects – after 2 years. A clinical response in VIPES and OLFUS-VIPES was defined as nonreactivity to a dose of at least 1,000 mg of peanut protein – the equivalent of four peanuts – during a formal double-blind food challenge or at least a tenfold increase in the eliciting dose, compared to the original eliciting dose.

In VIPES, one-third of children on the 250-mcg device therapy for 1 year could tolerate at least 1,000 mg of peanut protein; after an additional year of open-label therapy, 60% of children were able to do so.

Among 6- to 11-year-olds, the median cumulative reactive dose of peanut protein was 44 mg at baseline, 444 mg after 12 months of using the 250-mcg Viaskin Peanut, and 1,444 mg at 2 years.

The children’s immunologic response to the Viaskin Peanut was impressive: A 40% reduction from baseline in peanut IgE at 2 years, along with a ninefold increase in protective peanut-specific IgG4.

The skin patch consists of a dried allergen – in this case, peanut protein – which is made electrostatically adherent to a membrane on a Band-Aid–like chamber. A set of patches is placed on noneczematous skin on a child’s back and on the inner upper arm of older patients. Moisture emitted from the skin gradually causes the protein allergen to solubilize and get absorbed into the outer layer of the skin. It is then picked up by antigen-presenting Langerhans cells and transported to regional lymph nodes for deactivation. The patches are changed daily.

“It appears that we need to look at the skin as a tolerogenic organ when it’s uninflamed,” Dr. Sampson observed.

Compliance with treatment was in excess of 96% in both VIPES and OLFUS-VIPES. There have been no serious treatment-related adverse events and no need for the use of epinephrine. Side effects have been limited to occasional mild to moderate application site reactions easily managed with antihistamines and/or topical steroids, according to Dr. Sampson.

The double-blind VIPES study included 207 subjects with documented peanut allergy. OLFUS-VIPES, which will continue for 1 additional year of open-label therapy, includes 171 of the original 207, including 97 children, 49 adolescents, and 25 adults up to age 55 years.

“We’ll see if there’s continued improvement in children through the third year or it levels off, but based upon the immunologic parameters I think it’s having continued effect,” the pediatric allergist said.

[email protected]

Lymphomatoid papulosis (LyP) is a clinicopathologic variant of CD30⁺ primary cutaneous T-cell lymphoproliferative disorder characterized by a chronic, recurrent, self-healing eruption of papules and small nodules. From a clinical point of view, LyP is not considered a malignant disorder despite demonstration of clonality in most cases.¹ From a histopathologic point of view, there are 5 types of LyP: (1) type A, the most common type, which is characterized by a wedge-shaped infiltrate composed of clustered large atypical cells admixed with neutrophils, eosinophils, histiocytes, and small lymphocytes; (2) type B, a rare variant characterized by a bandlike infiltrate of small- to medium-sized pleomorphic and hyperchromatic lymphocytes involving the superficial dermis with epidermotropism; (3) type C, which consists of a nodular infiltrate of large atypical cells with a cohesive arrangement closely similar to anaplastic large-cell lymphoma; (4) type D, a variant with histopathologic features that resemble primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, but neoplastic cells express CD30 and a T-cell cytotoxic phenotype (βF1⁺, CD3+, CD4^‒, CD8⁺), and follow-up usually does not reveal development of systemic involvement or signs of other cutaneous lymphomas²; and (5) type E, which is characterized by oligolesional papules that rapidly ulcerate and evolve into large, necrotic, escharlike lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small- to medium-sized atypical lymphocytes expressing CD30 and frequently CD8.³

The clinical appearance of LyP usually is polymorphic, with lesions in different stages of evolution scattered all over the skin; however, the lesions are occasionally localized only to one area of the skin, the so-called regional or agminated LyP.^4-14 We report a case of regional LyP that exclusively involved the skin of the left breast, which had previously received radiotherapy for treatment of breast carcinoma. Lymphomatoid papulosis with cutaneous lesions involving only an area of irradiated skin is rare.

Case Report

A 59-year-old woman presented with new-onset cutaneous lesions on the left breast. The patient had a history of invasive ductal carcinoma of the left breast, which had been treated 5 years prior with a partial mastectomy and radiotherapy (10 Gy per week for 5 consecutive weeks [50 Gy total]). Physical examination revealed a large nodular lesion with a necrotic surface on the upper half of the left breast as well as 3 small papular lesions with eroded surfaces on the lower half of the breast (Figure 1). A clinical diagnosis of cutaneous metastases from breast carcinoma was suspected.

Biopsies from one small papule and the large nodular lesion showed similar findings consisting of a necrotic epidermis covered by crusts and a wedge-shaped infiltrate involving the superficial dermis (Figure 2A). The infiltrate was mostly composed of large atypical mononuclear cells with oval to kidney-shaped nuclei, prominent nucleoli, and ample basophilic cytoplasm. Many mitotic figures were seen within the infiltrate (Figure 2B). The infiltrate of atypical cells was admixed with small lymphocytes, histiocytes, and some eosinophils. Immunohistochemically, the large atypical cells expressed CD2, CD3, CD4, CD45, CD30, and epithelial membrane antigen (Figures 2C and 2D). A few atypical cells also expressed CD8 and T-cell intracellular antigen 1. Approximately 60% of the nuclei of the atypical cells showed MIB-1 positivity, while CD20, CD56, AE1/AE3, S-100 protein, CD34, and CD31 were negative. The anaplastic lymphoma kinase was not expressed in atypical cells. Monoclonal rearrangement of the γ T-cell receptor was demonstrated on polymerase chain reaction. Physical examination showed no lymphadenopathy in any lymph node chains. Computed tomography of the chest and abdomen failed to demonstrate systemic involvement. On the basis of these clinical, histologic, immunohistochemical, and molecular results, a diagnosis of type A regional LyP was established.

The patient was treated with 2 daily applications of clobetasol propionate cream 0.5 mg/g and 10 mg of oral methotrexate per week for 4 weeks. After 4 weeks of treatment, the lesions on the left breast had resolved leaving slightly atrophic scars. Six months later, an episode of recurrent papular lesions occurred in the same area and responded to the same treatment, but no systemic involvement had been found.

Comment

Regional LyP is a rare variant, with only a few reported cases in the literature.^4-18 Scarisbrick et al⁴ originally reported 4 patients with LyP limited to specific regions. Interestingly, one of the patients had mycosis fungoides and the LyP lesions were confined to the same region where the mycosis fungoides lesions were observed.⁴ In a review of LyP in patients from the Netherlands (n=118), lesions limited to a specific region of the body were observed in 13% of cases.⁵ Cases of LyP limited to acral skin also have been reported.^6-8 Heald et al⁹ described 7 patients who had continuing eruptions of papulonodules with histopathologic features of LyP within well-circumscribed areas of the skin. The investigators interpreted this localized variant of LyP as an equivalent of the limited plaque stage of mycosis fungoides. Interestingly, one of the patients with LyP eventually developed plaques of mycosis fungoides in other areas of the skin not involved by LyP.⁹ Sharma et al¹⁰ described an additional example of regional LyP, and Nakahigashi et al¹¹ described a patient with tumor-stage mycosis fungoides who subsequently developed regional LyP involving the right side of the chest. Kim et al¹² described a patient with recurrent episodes of regional LyP exclusively involving the periorbital skin, and Torrelo et al¹³ reported a 12-year-old boy with persistent lesions of LyP involving the skin of the right side of the abdomen. Coelho et al¹⁴ reported a 13-year-old adolescent girl who presented with recurrent papules of LyP exclusively involving the left upper arm. Buder et al¹⁵ reported a case of LyP limited to Becker melanosis. Shang et al¹⁶ described an additional caseof regional LyP that was successfully controlled by interferon alfa-2b and nitrogen mustard solution. Haus et al¹⁷ reported type A LyP confined to the cutaneous area within a red tattoo. Finally, Wang et al¹⁸ reported a case of regional LyP in association with pseudoepitheliomatous hyperplasia

Several dermatoses may appear as specific isomorphic responses to various external stimuli, and it is possible that radiotherapy induces some damage that favors the location of the lesions because the irradiated skin behaves as a locus minoris resistentiae. Pemphigus vulgaris,^19,20 Sweet syndrome,²¹ cutaneous angiosarcoma,^22-32 and cutaneous metastases from malignant melanoma also have been reported to be confined to irradiated skin.³³ However, in our PubMed search of articles indexed for MEDLINE using the terms lymphomatoid papules and regional, none of the previously reported cases of regional LyP had a history of radiotherapy, and in no instance did the lesions develop on a previously irradiated area of the skin.^4-18 The localization of the lesions in our patient could have been the result of the so-called radiation recall phenomenon. Recall dermatitis is defined as a skin reaction in a previously irradiated field, usually subsequent to the administration of cytotoxic drugs or antibiotics.³⁴ It may appear days to years after exposure to ionizing radiation and has mostly been associated with chemotherapy drugs, but recall dermatitis is neither exclusive of chemotherapy medications nor strictly radiotherapy induced. The concept of recall dermatitis has been expanded beyond radiation recall dermatitis to include dermatitis induced by other stimuli, including other drugs, contact irritants, and UV radiation, as well as residual herpes zoster. Nevertheless, in recall dermatitis the triggering drug or agent recalls a prior dermatitis in the involved area, such as sunburn or radiodermatitis. In our patient, there was no history of LyP prior to irradiation of the left breast; therefore, the most plausible interpretation of the peculiar localization of the lesions in our patient seems to be that the eruption resulted as expression of a locus minoris resistentiae.

Distinction between primary cutaneous anaplastic large-cell lymphoma and LyP may be difficult because the histopathologic and immunophenotypic features may overlap. In our case, the presence of several papular lesions and one large nodule are more consistent, from a clinical point of view, with a diagnosis of LyP rather than primary cutaneous anaplastic large-cell lymphoma, which usually presents with a solitary and often large, ulcerated, reddish brown tumor. In our patient, the absence of lymphadenopathy, negative results of the computed tomography of the chest and abdomen, and lack of expression for anaplastic lymphoma kinase in atypical cells of the infiltrate militate against a diagnosis of secondary cutaneous involvement from nodal disease.

The histopathologic differential diagnosis of the current case also included cutaneous CD30⁺ epithelioid angiosarcoma of the breast. Weed and Folpe³⁵ reported the case of an 85-year-old woman who developed a CD30⁺ epithelioid angiosarcoma on the breast after undergoing breast-conserving surgery and adjuvant radiotherapy for treatment of an infiltrating ductal carcinoma of the breast. Histopathology showed a diffuse replacement of the dermis by a highly malignant-appearing epithelioid neoplasm growing in a solid sheet. Neoplastic cells expressed strong CD30 immunoreactivity with absence of immunoexpression for cytokeratins, S-100 protein, and CD45. Additional immunostaining demonstrated that neoplastic cells also expressed strong immunoreactivity for CD31 and the friend leukemia virus integration 1 gene, FLI-1, and focal positivity for von Willebrand factor, supporting a diagnosis of epithelioid angiosarcoma.³⁵ In our patient, CD34 and CD31 were negative, which ruled out the endothelial nature of neoplastic cells.

Conclusion

In summary, we report an example of regional LyP limited to the left breast of a woman with a history of partial mastectomy and adjuvant radiotherapy for treatment of invasive ductal breast carcinoma. It is a rare case of regional LyP exclusively involving an irradiated area of the skin.

Lymphomatoid papulosis (LyP) is a clinicopathologic variant of CD30⁺ primary cutaneous T-cell lymphoproliferative disorder characterized by a chronic, recurrent, self-healing eruption of papules and small nodules. From a clinical point of view, LyP is not considered a malignant disorder despite demonstration of clonality in most cases.¹ From a histopathologic point of view, there are 5 types of LyP: (1) type A, the most common type, which is characterized by a wedge-shaped infiltrate composed of clustered large atypical cells admixed with neutrophils, eosinophils, histiocytes, and small lymphocytes; (2) type B, a rare variant characterized by a bandlike infiltrate of small- to medium-sized pleomorphic and hyperchromatic lymphocytes involving the superficial dermis with epidermotropism; (3) type C, which consists of a nodular infiltrate of large atypical cells with a cohesive arrangement closely similar to anaplastic large-cell lymphoma; (4) type D, a variant with histopathologic features that resemble primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, but neoplastic cells express CD30 and a T-cell cytotoxic phenotype (βF1⁺, CD3+, CD4^‒, CD8⁺), and follow-up usually does not reveal development of systemic involvement or signs of other cutaneous lymphomas²; and (5) type E, which is characterized by oligolesional papules that rapidly ulcerate and evolve into large, necrotic, escharlike lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small- to medium-sized atypical lymphocytes expressing CD30 and frequently CD8.³

The clinical appearance of LyP usually is polymorphic, with lesions in different stages of evolution scattered all over the skin; however, the lesions are occasionally localized only to one area of the skin, the so-called regional or agminated LyP.^4-14 We report a case of regional LyP that exclusively involved the skin of the left breast, which had previously received radiotherapy for treatment of breast carcinoma. Lymphomatoid papulosis with cutaneous lesions involving only an area of irradiated skin is rare.

Case Report

A 59-year-old woman presented with new-onset cutaneous lesions on the left breast. The patient had a history of invasive ductal carcinoma of the left breast, which had been treated 5 years prior with a partial mastectomy and radiotherapy (10 Gy per week for 5 consecutive weeks [50 Gy total]). Physical examination revealed a large nodular lesion with a necrotic surface on the upper half of the left breast as well as 3 small papular lesions with eroded surfaces on the lower half of the breast (Figure 1). A clinical diagnosis of cutaneous metastases from breast carcinoma was suspected.

Biopsies from one small papule and the large nodular lesion showed similar findings consisting of a necrotic epidermis covered by crusts and a wedge-shaped infiltrate involving the superficial dermis (Figure 2A). The infiltrate was mostly composed of large atypical mononuclear cells with oval to kidney-shaped nuclei, prominent nucleoli, and ample basophilic cytoplasm. Many mitotic figures were seen within the infiltrate (Figure 2B). The infiltrate of atypical cells was admixed with small lymphocytes, histiocytes, and some eosinophils. Immunohistochemically, the large atypical cells expressed CD2, CD3, CD4, CD45, CD30, and epithelial membrane antigen (Figures 2C and 2D). A few atypical cells also expressed CD8 and T-cell intracellular antigen 1. Approximately 60% of the nuclei of the atypical cells showed MIB-1 positivity, while CD20, CD56, AE1/AE3, S-100 protein, CD34, and CD31 were negative. The anaplastic lymphoma kinase was not expressed in atypical cells. Monoclonal rearrangement of the γ T-cell receptor was demonstrated on polymerase chain reaction. Physical examination showed no lymphadenopathy in any lymph node chains. Computed tomography of the chest and abdomen failed to demonstrate systemic involvement. On the basis of these clinical, histologic, immunohistochemical, and molecular results, a diagnosis of type A regional LyP was established.

The patient was treated with 2 daily applications of clobetasol propionate cream 0.5 mg/g and 10 mg of oral methotrexate per week for 4 weeks. After 4 weeks of treatment, the lesions on the left breast had resolved leaving slightly atrophic scars. Six months later, an episode of recurrent papular lesions occurred in the same area and responded to the same treatment, but no systemic involvement had been found.

Comment

Regional LyP is a rare variant, with only a few reported cases in the literature.^4-18 Scarisbrick et al⁴ originally reported 4 patients with LyP limited to specific regions. Interestingly, one of the patients had mycosis fungoides and the LyP lesions were confined to the same region where the mycosis fungoides lesions were observed.⁴ In a review of LyP in patients from the Netherlands (n=118), lesions limited to a specific region of the body were observed in 13% of cases.⁵ Cases of LyP limited to acral skin also have been reported.^6-8 Heald et al⁹ described 7 patients who had continuing eruptions of papulonodules with histopathologic features of LyP within well-circumscribed areas of the skin. The investigators interpreted this localized variant of LyP as an equivalent of the limited plaque stage of mycosis fungoides. Interestingly, one of the patients with LyP eventually developed plaques of mycosis fungoides in other areas of the skin not involved by LyP.⁹ Sharma et al¹⁰ described an additional example of regional LyP, and Nakahigashi et al¹¹ described a patient with tumor-stage mycosis fungoides who subsequently developed regional LyP involving the right side of the chest. Kim et al¹² described a patient with recurrent episodes of regional LyP exclusively involving the periorbital skin, and Torrelo et al¹³ reported a 12-year-old boy with persistent lesions of LyP involving the skin of the right side of the abdomen. Coelho et al¹⁴ reported a 13-year-old adolescent girl who presented with recurrent papules of LyP exclusively involving the left upper arm. Buder et al¹⁵ reported a case of LyP limited to Becker melanosis. Shang et al¹⁶ described an additional caseof regional LyP that was successfully controlled by interferon alfa-2b and nitrogen mustard solution. Haus et al¹⁷ reported type A LyP confined to the cutaneous area within a red tattoo. Finally, Wang et al¹⁸ reported a case of regional LyP in association with pseudoepitheliomatous hyperplasia

Several dermatoses may appear as specific isomorphic responses to various external stimuli, and it is possible that radiotherapy induces some damage that favors the location of the lesions because the irradiated skin behaves as a locus minoris resistentiae. Pemphigus vulgaris,^19,20 Sweet syndrome,²¹ cutaneous angiosarcoma,^22-32 and cutaneous metastases from malignant melanoma also have been reported to be confined to irradiated skin.³³ However, in our PubMed search of articles indexed for MEDLINE using the terms lymphomatoid papules and regional, none of the previously reported cases of regional LyP had a history of radiotherapy, and in no instance did the lesions develop on a previously irradiated area of the skin.^4-18 The localization of the lesions in our patient could have been the result of the so-called radiation recall phenomenon. Recall dermatitis is defined as a skin reaction in a previously irradiated field, usually subsequent to the administration of cytotoxic drugs or antibiotics.³⁴ It may appear days to years after exposure to ionizing radiation and has mostly been associated with chemotherapy drugs, but recall dermatitis is neither exclusive of chemotherapy medications nor strictly radiotherapy induced. The concept of recall dermatitis has been expanded beyond radiation recall dermatitis to include dermatitis induced by other stimuli, including other drugs, contact irritants, and UV radiation, as well as residual herpes zoster. Nevertheless, in recall dermatitis the triggering drug or agent recalls a prior dermatitis in the involved area, such as sunburn or radiodermatitis. In our patient, there was no history of LyP prior to irradiation of the left breast; therefore, the most plausible interpretation of the peculiar localization of the lesions in our patient seems to be that the eruption resulted as expression of a locus minoris resistentiae.

Distinction between primary cutaneous anaplastic large-cell lymphoma and LyP may be difficult because the histopathologic and immunophenotypic features may overlap. In our case, the presence of several papular lesions and one large nodule are more consistent, from a clinical point of view, with a diagnosis of LyP rather than primary cutaneous anaplastic large-cell lymphoma, which usually presents with a solitary and often large, ulcerated, reddish brown tumor. In our patient, the absence of lymphadenopathy, negative results of the computed tomography of the chest and abdomen, and lack of expression for anaplastic lymphoma kinase in atypical cells of the infiltrate militate against a diagnosis of secondary cutaneous involvement from nodal disease.

The histopathologic differential diagnosis of the current case also included cutaneous CD30⁺ epithelioid angiosarcoma of the breast. Weed and Folpe³⁵ reported the case of an 85-year-old woman who developed a CD30⁺ epithelioid angiosarcoma on the breast after undergoing breast-conserving surgery and adjuvant radiotherapy for treatment of an infiltrating ductal carcinoma of the breast. Histopathology showed a diffuse replacement of the dermis by a highly malignant-appearing epithelioid neoplasm growing in a solid sheet. Neoplastic cells expressed strong CD30 immunoreactivity with absence of immunoexpression for cytokeratins, S-100 protein, and CD45. Additional immunostaining demonstrated that neoplastic cells also expressed strong immunoreactivity for CD31 and the friend leukemia virus integration 1 gene, FLI-1, and focal positivity for von Willebrand factor, supporting a diagnosis of epithelioid angiosarcoma.³⁵ In our patient, CD34 and CD31 were negative, which ruled out the endothelial nature of neoplastic cells.

Conclusion

In summary, we report an example of regional LyP limited to the left breast of a woman with a history of partial mastectomy and adjuvant radiotherapy for treatment of invasive ductal breast carcinoma. It is a rare case of regional LyP exclusively involving an irradiated area of the skin.

Lymphomatoid papulosis (LyP) is a clinicopathologic variant of CD30⁺ primary cutaneous T-cell lymphoproliferative disorder characterized by a chronic, recurrent, self-healing eruption of papules and small nodules. From a clinical point of view, LyP is not considered a malignant disorder despite demonstration of clonality in most cases.¹ From a histopathologic point of view, there are 5 types of LyP: (1) type A, the most common type, which is characterized by a wedge-shaped infiltrate composed of clustered large atypical cells admixed with neutrophils, eosinophils, histiocytes, and small lymphocytes; (2) type B, a rare variant characterized by a bandlike infiltrate of small- to medium-sized pleomorphic and hyperchromatic lymphocytes involving the superficial dermis with epidermotropism; (3) type C, which consists of a nodular infiltrate of large atypical cells with a cohesive arrangement closely similar to anaplastic large-cell lymphoma; (4) type D, a variant with histopathologic features that resemble primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, but neoplastic cells express CD30 and a T-cell cytotoxic phenotype (βF1⁺, CD3+, CD4^‒, CD8⁺), and follow-up usually does not reveal development of systemic involvement or signs of other cutaneous lymphomas²; and (5) type E, which is characterized by oligolesional papules that rapidly ulcerate and evolve into large, necrotic, escharlike lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small- to medium-sized atypical lymphocytes expressing CD30 and frequently CD8.³

The clinical appearance of LyP usually is polymorphic, with lesions in different stages of evolution scattered all over the skin; however, the lesions are occasionally localized only to one area of the skin, the so-called regional or agminated LyP.^4-14 We report a case of regional LyP that exclusively involved the skin of the left breast, which had previously received radiotherapy for treatment of breast carcinoma. Lymphomatoid papulosis with cutaneous lesions involving only an area of irradiated skin is rare.

Case Report

A 59-year-old woman presented with new-onset cutaneous lesions on the left breast. The patient had a history of invasive ductal carcinoma of the left breast, which had been treated 5 years prior with a partial mastectomy and radiotherapy (10 Gy per week for 5 consecutive weeks [50 Gy total]). Physical examination revealed a large nodular lesion with a necrotic surface on the upper half of the left breast as well as 3 small papular lesions with eroded surfaces on the lower half of the breast (Figure 1). A clinical diagnosis of cutaneous metastases from breast carcinoma was suspected.

Biopsies from one small papule and the large nodular lesion showed similar findings consisting of a necrotic epidermis covered by crusts and a wedge-shaped infiltrate involving the superficial dermis (Figure 2A). The infiltrate was mostly composed of large atypical mononuclear cells with oval to kidney-shaped nuclei, prominent nucleoli, and ample basophilic cytoplasm. Many mitotic figures were seen within the infiltrate (Figure 2B). The infiltrate of atypical cells was admixed with small lymphocytes, histiocytes, and some eosinophils. Immunohistochemically, the large atypical cells expressed CD2, CD3, CD4, CD45, CD30, and epithelial membrane antigen (Figures 2C and 2D). A few atypical cells also expressed CD8 and T-cell intracellular antigen 1. Approximately 60% of the nuclei of the atypical cells showed MIB-1 positivity, while CD20, CD56, AE1/AE3, S-100 protein, CD34, and CD31 were negative. The anaplastic lymphoma kinase was not expressed in atypical cells. Monoclonal rearrangement of the γ T-cell receptor was demonstrated on polymerase chain reaction. Physical examination showed no lymphadenopathy in any lymph node chains. Computed tomography of the chest and abdomen failed to demonstrate systemic involvement. On the basis of these clinical, histologic, immunohistochemical, and molecular results, a diagnosis of type A regional LyP was established.

The patient was treated with 2 daily applications of clobetasol propionate cream 0.5 mg/g and 10 mg of oral methotrexate per week for 4 weeks. After 4 weeks of treatment, the lesions on the left breast had resolved leaving slightly atrophic scars. Six months later, an episode of recurrent papular lesions occurred in the same area and responded to the same treatment, but no systemic involvement had been found.

Comment

Regional LyP is a rare variant, with only a few reported cases in the literature.^4-18 Scarisbrick et al⁴ originally reported 4 patients with LyP limited to specific regions. Interestingly, one of the patients had mycosis fungoides and the LyP lesions were confined to the same region where the mycosis fungoides lesions were observed.⁴ In a review of LyP in patients from the Netherlands (n=118), lesions limited to a specific region of the body were observed in 13% of cases.⁵ Cases of LyP limited to acral skin also have been reported.^6-8 Heald et al⁹ described 7 patients who had continuing eruptions of papulonodules with histopathologic features of LyP within well-circumscribed areas of the skin. The investigators interpreted this localized variant of LyP as an equivalent of the limited plaque stage of mycosis fungoides. Interestingly, one of the patients with LyP eventually developed plaques of mycosis fungoides in other areas of the skin not involved by LyP.⁹ Sharma et al¹⁰ described an additional example of regional LyP, and Nakahigashi et al¹¹ described a patient with tumor-stage mycosis fungoides who subsequently developed regional LyP involving the right side of the chest. Kim et al¹² described a patient with recurrent episodes of regional LyP exclusively involving the periorbital skin, and Torrelo et al¹³ reported a 12-year-old boy with persistent lesions of LyP involving the skin of the right side of the abdomen. Coelho et al¹⁴ reported a 13-year-old adolescent girl who presented with recurrent papules of LyP exclusively involving the left upper arm. Buder et al¹⁵ reported a case of LyP limited to Becker melanosis. Shang et al¹⁶ described an additional caseof regional LyP that was successfully controlled by interferon alfa-2b and nitrogen mustard solution. Haus et al¹⁷ reported type A LyP confined to the cutaneous area within a red tattoo. Finally, Wang et al¹⁸ reported a case of regional LyP in association with pseudoepitheliomatous hyperplasia

Several dermatoses may appear as specific isomorphic responses to various external stimuli, and it is possible that radiotherapy induces some damage that favors the location of the lesions because the irradiated skin behaves as a locus minoris resistentiae. Pemphigus vulgaris,^19,20 Sweet syndrome,²¹ cutaneous angiosarcoma,^22-32 and cutaneous metastases from malignant melanoma also have been reported to be confined to irradiated skin.³³ However, in our PubMed search of articles indexed for MEDLINE using the terms lymphomatoid papules and regional, none of the previously reported cases of regional LyP had a history of radiotherapy, and in no instance did the lesions develop on a previously irradiated area of the skin.^4-18 The localization of the lesions in our patient could have been the result of the so-called radiation recall phenomenon. Recall dermatitis is defined as a skin reaction in a previously irradiated field, usually subsequent to the administration of cytotoxic drugs or antibiotics.³⁴ It may appear days to years after exposure to ionizing radiation and has mostly been associated with chemotherapy drugs, but recall dermatitis is neither exclusive of chemotherapy medications nor strictly radiotherapy induced. The concept of recall dermatitis has been expanded beyond radiation recall dermatitis to include dermatitis induced by other stimuli, including other drugs, contact irritants, and UV radiation, as well as residual herpes zoster. Nevertheless, in recall dermatitis the triggering drug or agent recalls a prior dermatitis in the involved area, such as sunburn or radiodermatitis. In our patient, there was no history of LyP prior to irradiation of the left breast; therefore, the most plausible interpretation of the peculiar localization of the lesions in our patient seems to be that the eruption resulted as expression of a locus minoris resistentiae.

Distinction between primary cutaneous anaplastic large-cell lymphoma and LyP may be difficult because the histopathologic and immunophenotypic features may overlap. In our case, the presence of several papular lesions and one large nodule are more consistent, from a clinical point of view, with a diagnosis of LyP rather than primary cutaneous anaplastic large-cell lymphoma, which usually presents with a solitary and often large, ulcerated, reddish brown tumor. In our patient, the absence of lymphadenopathy, negative results of the computed tomography of the chest and abdomen, and lack of expression for anaplastic lymphoma kinase in atypical cells of the infiltrate militate against a diagnosis of secondary cutaneous involvement from nodal disease.

The histopathologic differential diagnosis of the current case also included cutaneous CD30⁺ epithelioid angiosarcoma of the breast. Weed and Folpe³⁵ reported the case of an 85-year-old woman who developed a CD30⁺ epithelioid angiosarcoma on the breast after undergoing breast-conserving surgery and adjuvant radiotherapy for treatment of an infiltrating ductal carcinoma of the breast. Histopathology showed a diffuse replacement of the dermis by a highly malignant-appearing epithelioid neoplasm growing in a solid sheet. Neoplastic cells expressed strong CD30 immunoreactivity with absence of immunoexpression for cytokeratins, S-100 protein, and CD45. Additional immunostaining demonstrated that neoplastic cells also expressed strong immunoreactivity for CD31 and the friend leukemia virus integration 1 gene, FLI-1, and focal positivity for von Willebrand factor, supporting a diagnosis of epithelioid angiosarcoma.³⁵ In our patient, CD34 and CD31 were negative, which ruled out the endothelial nature of neoplastic cells.

Conclusion

In summary, we report an example of regional LyP limited to the left breast of a woman with a history of partial mastectomy and adjuvant radiotherapy for treatment of invasive ductal breast carcinoma. It is a rare case of regional LyP exclusively involving an irradiated area of the skin.

To the Editor:

Onychomadesis is characterized by separation of the nail plate from the matrix due to a temporary arrest in nail matrix activity. Hand-foot-and-mouth disease (HFMD) is a relatively common viral infection, especially in children. Although the relationship between onychomadesis and HFMD has been noted, there are few reports in the literature.^1-9 We present 2 cases of onychomadesis following HFMD in Taiwanese siblings.

A 3-year-old girl presented with proximal nail plate detachment from the proximal nail fold on the bilateral great toenails (Figure 1) and a transverse whole-thickness sulcus on the bilateral thumbnails (Figure 2) of several weeks’ duration. Her 6-year-old sister had similar nail changes. Hand-foot-and-mouth disease was diagnosed about 4 weeks prior to nail changes. The mother reported that only the younger sister experienced fever. There was no history of notable medication intake, nail trauma, periungual erythema, vesicular lesion, or dermatitis. In both patients, the nail changes were temporary with spontaneous normal nail plate regrowth several months later. A diagnosis of onychomadesis was made.

The etiology of onychomadesis includes drug ingestion, especially chemotherapy; severe systemic diseases; high fever; infection, including viral illnesses such as influenza, measles, and HFMD; and idiopathic onychomadesis.^1,2,5,10 In 2000, Clementz and Mancini¹ reported 5 children with nail matrix arrest following HFMD and suggested an epidemic caused by the same virus strain. Bernier et al² reported another 4 cases and suggested more than one viral strain may have been implicated in the nail matrix arrest. Although these authors list HFMD as one of the causes of onychomadesis,^1,2 the number of cases reported was small; however, studies with a larger number of cases and even outbreak have been reported more recently.^3-8 Salazar et al³ reported an onychomadesis outbreak associated with HFMD in Valencia, Spain, in 2008 (N=298). This outbreak primarily was caused by coxsackievirus (CV) A10 (49% of cases).⁵ Another onychomadesis outbreak occurred in Saragossa, Spain, in 2008, and CV B1, B2, and unidentified nonpoliovirus enterovirus were isolated.⁶ Outbreaks also occurred in Finland in 2008, and the causative agents were identified as CV A6 and A10.^7,8 The latency period for onychomadesis following HFMD was 1 to 2 months (mean, 40 days), and the majority of cases occurred in patients younger than 6 years.^1-5 Not all of the nails were involved; in one report, each patient shed only 4 nails on average.⁶

Although there is a definite relationship between HFMD and onychomadesis, the mechanism is still unclear. Some authors claim that nail matrix arrest is caused by high fever¹⁰; however, we found that 40% (2/5)¹ to 63% (10/16)⁴ of reported cases did not have a fever. Additionally, only 1 of our patients had fever. Therefore high fever–induced nail matrix arrest is not a reasonable explanation. Davia et al⁵ observed no relationship between onychomadesis and the severity of HFMD. In addition, no serious complications of HFMD were mentioned in prior reports.

We propose that HFMD-related onychomadesis is caused by the viral infection itself, rather than by severe systemic disease.^1-5,7 Certain viral strains associated with HFMD can induce arrest of nail matrix activity. Osterback et al⁷ detected CV A6 in shed nail fragments and suggested that virus replication damaged the nail matrix and resulted in temporary nail dystrophy. This hypothesis can explain that only some nails, not all, were involved. In our cases, we noted an incomplete and slanted cleft on the thumbnail (Figure 2). We also found that incomplete onychomadesis appeared in the clinical photograph from a prior report.⁵ The slanted cleft in our case may be caused by secondary external force after original incomplete onychomadesis or a different rate of nail regrowth because of different intensity of nail matrix damage. The phenomenon of incomplete onychomadesis in the same nail further suggests the mechanism of onychomadesis following HFMD is localized nail matrix damage.

In conclusion, we report 2 cases of onychomadesis associated with HFMD. Our report highlights that there is no racial difference in post-HFMD onychomadesis. These cases highlight that HFMD is an important cause of onychomadesis, especially in children. We suggest that certain viral strains associated with HFMD may specifically arrest nail matrix growth activity, regardless of fever or disease severity.

To the Editor:

Onychomadesis is characterized by separation of the nail plate from the matrix due to a temporary arrest in nail matrix activity. Hand-foot-and-mouth disease (HFMD) is a relatively common viral infection, especially in children. Although the relationship between onychomadesis and HFMD has been noted, there are few reports in the literature.^1-9 We present 2 cases of onychomadesis following HFMD in Taiwanese siblings.

A 3-year-old girl presented with proximal nail plate detachment from the proximal nail fold on the bilateral great toenails (Figure 1) and a transverse whole-thickness sulcus on the bilateral thumbnails (Figure 2) of several weeks’ duration. Her 6-year-old sister had similar nail changes. Hand-foot-and-mouth disease was diagnosed about 4 weeks prior to nail changes. The mother reported that only the younger sister experienced fever. There was no history of notable medication intake, nail trauma, periungual erythema, vesicular lesion, or dermatitis. In both patients, the nail changes were temporary with spontaneous normal nail plate regrowth several months later. A diagnosis of onychomadesis was made.

The etiology of onychomadesis includes drug ingestion, especially chemotherapy; severe systemic diseases; high fever; infection, including viral illnesses such as influenza, measles, and HFMD; and idiopathic onychomadesis.^1,2,5,10 In 2000, Clementz and Mancini¹ reported 5 children with nail matrix arrest following HFMD and suggested an epidemic caused by the same virus strain. Bernier et al² reported another 4 cases and suggested more than one viral strain may have been implicated in the nail matrix arrest. Although these authors list HFMD as one of the causes of onychomadesis,^1,2 the number of cases reported was small; however, studies with a larger number of cases and even outbreak have been reported more recently.^3-8 Salazar et al³ reported an onychomadesis outbreak associated with HFMD in Valencia, Spain, in 2008 (N=298). This outbreak primarily was caused by coxsackievirus (CV) A10 (49% of cases).⁵ Another onychomadesis outbreak occurred in Saragossa, Spain, in 2008, and CV B1, B2, and unidentified nonpoliovirus enterovirus were isolated.⁶ Outbreaks also occurred in Finland in 2008, and the causative agents were identified as CV A6 and A10.^7,8 The latency period for onychomadesis following HFMD was 1 to 2 months (mean, 40 days), and the majority of cases occurred in patients younger than 6 years.^1-5 Not all of the nails were involved; in one report, each patient shed only 4 nails on average.⁶

Although there is a definite relationship between HFMD and onychomadesis, the mechanism is still unclear. Some authors claim that nail matrix arrest is caused by high fever¹⁰; however, we found that 40% (2/5)¹ to 63% (10/16)⁴ of reported cases did not have a fever. Additionally, only 1 of our patients had fever. Therefore high fever–induced nail matrix arrest is not a reasonable explanation. Davia et al⁵ observed no relationship between onychomadesis and the severity of HFMD. In addition, no serious complications of HFMD were mentioned in prior reports.

We propose that HFMD-related onychomadesis is caused by the viral infection itself, rather than by severe systemic disease.^1-5,7 Certain viral strains associated with HFMD can induce arrest of nail matrix activity. Osterback et al⁷ detected CV A6 in shed nail fragments and suggested that virus replication damaged the nail matrix and resulted in temporary nail dystrophy. This hypothesis can explain that only some nails, not all, were involved. In our cases, we noted an incomplete and slanted cleft on the thumbnail (Figure 2). We also found that incomplete onychomadesis appeared in the clinical photograph from a prior report.⁵ The slanted cleft in our case may be caused by secondary external force after original incomplete onychomadesis or a different rate of nail regrowth because of different intensity of nail matrix damage. The phenomenon of incomplete onychomadesis in the same nail further suggests the mechanism of onychomadesis following HFMD is localized nail matrix damage.

In conclusion, we report 2 cases of onychomadesis associated with HFMD. Our report highlights that there is no racial difference in post-HFMD onychomadesis. These cases highlight that HFMD is an important cause of onychomadesis, especially in children. We suggest that certain viral strains associated with HFMD may specifically arrest nail matrix growth activity, regardless of fever or disease severity.

To the Editor:

Onychomadesis is characterized by separation of the nail plate from the matrix due to a temporary arrest in nail matrix activity. Hand-foot-and-mouth disease (HFMD) is a relatively common viral infection, especially in children. Although the relationship between onychomadesis and HFMD has been noted, there are few reports in the literature.^1-9 We present 2 cases of onychomadesis following HFMD in Taiwanese siblings.

A 3-year-old girl presented with proximal nail plate detachment from the proximal nail fold on the bilateral great toenails (Figure 1) and a transverse whole-thickness sulcus on the bilateral thumbnails (Figure 2) of several weeks’ duration. Her 6-year-old sister had similar nail changes. Hand-foot-and-mouth disease was diagnosed about 4 weeks prior to nail changes. The mother reported that only the younger sister experienced fever. There was no history of notable medication intake, nail trauma, periungual erythema, vesicular lesion, or dermatitis. In both patients, the nail changes were temporary with spontaneous normal nail plate regrowth several months later. A diagnosis of onychomadesis was made.

The etiology of onychomadesis includes drug ingestion, especially chemotherapy; severe systemic diseases; high fever; infection, including viral illnesses such as influenza, measles, and HFMD; and idiopathic onychomadesis.^1,2,5,10 In 2000, Clementz and Mancini¹ reported 5 children with nail matrix arrest following HFMD and suggested an epidemic caused by the same virus strain. Bernier et al² reported another 4 cases and suggested more than one viral strain may have been implicated in the nail matrix arrest. Although these authors list HFMD as one of the causes of onychomadesis,^1,2 the number of cases reported was small; however, studies with a larger number of cases and even outbreak have been reported more recently.^3-8 Salazar et al³ reported an onychomadesis outbreak associated with HFMD in Valencia, Spain, in 2008 (N=298). This outbreak primarily was caused by coxsackievirus (CV) A10 (49% of cases).⁵ Another onychomadesis outbreak occurred in Saragossa, Spain, in 2008, and CV B1, B2, and unidentified nonpoliovirus enterovirus were isolated.⁶ Outbreaks also occurred in Finland in 2008, and the causative agents were identified as CV A6 and A10.^7,8 The latency period for onychomadesis following HFMD was 1 to 2 months (mean, 40 days), and the majority of cases occurred in patients younger than 6 years.^1-5 Not all of the nails were involved; in one report, each patient shed only 4 nails on average.⁶

Although there is a definite relationship between HFMD and onychomadesis, the mechanism is still unclear. Some authors claim that nail matrix arrest is caused by high fever¹⁰; however, we found that 40% (2/5)¹ to 63% (10/16)⁴ of reported cases did not have a fever. Additionally, only 1 of our patients had fever. Therefore high fever–induced nail matrix arrest is not a reasonable explanation. Davia et al⁵ observed no relationship between onychomadesis and the severity of HFMD. In addition, no serious complications of HFMD were mentioned in prior reports.

We propose that HFMD-related onychomadesis is caused by the viral infection itself, rather than by severe systemic disease.^1-5,7 Certain viral strains associated with HFMD can induce arrest of nail matrix activity. Osterback et al⁷ detected CV A6 in shed nail fragments and suggested that virus replication damaged the nail matrix and resulted in temporary nail dystrophy. This hypothesis can explain that only some nails, not all, were involved. In our cases, we noted an incomplete and slanted cleft on the thumbnail (Figure 2). We also found that incomplete onychomadesis appeared in the clinical photograph from a prior report.⁵ The slanted cleft in our case may be caused by secondary external force after original incomplete onychomadesis or a different rate of nail regrowth because of different intensity of nail matrix damage. The phenomenon of incomplete onychomadesis in the same nail further suggests the mechanism of onychomadesis following HFMD is localized nail matrix damage.

In conclusion, we report 2 cases of onychomadesis associated with HFMD. Our report highlights that there is no racial difference in post-HFMD onychomadesis. These cases highlight that HFMD is an important cause of onychomadesis, especially in children. We suggest that certain viral strains associated with HFMD may specifically arrest nail matrix growth activity, regardless of fever or disease severity.

Treatment with opioids is not cost effective in osteoarthritis patients without comorbidities, according to Savannah R. Smith and her associates.

When a 10% reduction in total knee arthroplasty (TKA) effectiveness from opioid-based therapies was assumed, tramadol therapy delayed TKA by 7 years and tramadol plus oxycodone therapy delayed TKA by 9 years. Opioid-based therapy reduced primary TKA utilization by 4% for tramadol and by 10% for tramadol plus oxycodone, and reduced revision TKA use by 23% and 39%, respectively.

©decade3d/Thinkstock

While both opioid-based therapies reduced dependence on TKA, treatment was more expensive and it reduced quality of life, compared with an opioid-sparing therapy. For a 60-year-old OA patient for whom TKA was not an option, the incremental cost-effectiveness ratio for tramadol was $39,600 per quality-adjusted life-year, compared with a therapy without opioids, and the incremental cost-effectiveness ratio for tramadol plus oxycodone was $116,800 per quality-adjusted life-year.

“Given the risk of diversion and its associated cost for potent opioids, policy makers may consider limiting the use of potent opioids in knee OA patients. From a cost-effectiveness standpoint, both opioid-based strategies led to higher costs without providing additional benefits, unless patients were unwilling or unable to undergo TKA later,” the investigators noted.

Find the full study in Arthritis Care and Research (doi: 10.1002/acr.22916).

[email protected]

Treatment with opioids is not cost effective in osteoarthritis patients without comorbidities, according to Savannah R. Smith and her associates.

When a 10% reduction in total knee arthroplasty (TKA) effectiveness from opioid-based therapies was assumed, tramadol therapy delayed TKA by 7 years and tramadol plus oxycodone therapy delayed TKA by 9 years. Opioid-based therapy reduced primary TKA utilization by 4% for tramadol and by 10% for tramadol plus oxycodone, and reduced revision TKA use by 23% and 39%, respectively.

©decade3d/Thinkstock

While both opioid-based therapies reduced dependence on TKA, treatment was more expensive and it reduced quality of life, compared with an opioid-sparing therapy. For a 60-year-old OA patient for whom TKA was not an option, the incremental cost-effectiveness ratio for tramadol was $39,600 per quality-adjusted life-year, compared with a therapy without opioids, and the incremental cost-effectiveness ratio for tramadol plus oxycodone was $116,800 per quality-adjusted life-year.

“Given the risk of diversion and its associated cost for potent opioids, policy makers may consider limiting the use of potent opioids in knee OA patients. From a cost-effectiveness standpoint, both opioid-based strategies led to higher costs without providing additional benefits, unless patients were unwilling or unable to undergo TKA later,” the investigators noted.

Find the full study in Arthritis Care and Research (doi: 10.1002/acr.22916).

[email protected]

Treatment with opioids is not cost effective in osteoarthritis patients without comorbidities, according to Savannah R. Smith and her associates.

When a 10% reduction in total knee arthroplasty (TKA) effectiveness from opioid-based therapies was assumed, tramadol therapy delayed TKA by 7 years and tramadol plus oxycodone therapy delayed TKA by 9 years. Opioid-based therapy reduced primary TKA utilization by 4% for tramadol and by 10% for tramadol plus oxycodone, and reduced revision TKA use by 23% and 39%, respectively.

©decade3d/Thinkstock

While both opioid-based therapies reduced dependence on TKA, treatment was more expensive and it reduced quality of life, compared with an opioid-sparing therapy. For a 60-year-old OA patient for whom TKA was not an option, the incremental cost-effectiveness ratio for tramadol was $39,600 per quality-adjusted life-year, compared with a therapy without opioids, and the incremental cost-effectiveness ratio for tramadol plus oxycodone was $116,800 per quality-adjusted life-year.

“Given the risk of diversion and its associated cost for potent opioids, policy makers may consider limiting the use of potent opioids in knee OA patients. From a cost-effectiveness standpoint, both opioid-based strategies led to higher costs without providing additional benefits, unless patients were unwilling or unable to undergo TKA later,” the investigators noted.

Find the full study in Arthritis Care and Research (doi: 10.1002/acr.22916).

[email protected]

Lab mouse

Researchers say they have developed an animal model that allows them to better understand the mechanisms leading to multiple myeloma (MM) and other plasma cell neoplasms.

The group described this model in Scientific Reports.

“So far, there have not been animal models of malignant plasma cell diseases that allow us to study their stepwise progression and fully understand the complex cellular mechanisms,” said study author Stephen D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Now that we have a proper model of the disease, we’ll be able to more effectively study multiple myeloma as well as potential treatments.”

To create this model, the researchers crossed 2 genetically modified mice: mice lacking the Mef gene and mice with a Rad50 gene mutation (Rad50s).

Mef, also called Elf4, is a transcription factor known to both promote and suppress cancer formation. Rad50 is a component of a sensor of DNA damage induced by various stresses, and it regulates the DNA damage response pathways in cells.

The researchers found that Mef^−/−Rad50^s/s mice initially had abnormal plasma cell proliferation and monoclonal protein production.

Then, they developed anemia and a decreased bone mineral density. And 70% of these mice died from MM or other plasma cell neoplasms.

“We also found that the phenotype of these mice is not linked to activation of a specific oncogene or inactivation of a specific tumor suppressor, other than Mef,” said study author Takashi Asai, MD, PhD, also of the Sylvester Comprehensive Cancer Center.

Considering their findings together, the researchers said this model recapitulates the systemic manifestations of human MM and other plasma cell neoplasms. And their work suggests the Rad50s and Mef/Elf4 pathways cooperate to initiate myelomagenic mutations that promote plasma cell transformation.

“Although outcomes for multiple myeloma patients have greatly improved, it remains an incurable disease, despite the availability of newer treatments,” Dr Nimer noted.

“Several animal models of multiple myeloma have been reported, including models of human myeloma cells. However, these models imperfectly mimic the human disease. Developing more reliable and accurate animal models that help us better understand myeloma and test new treatments will take us to the next level on the long and challenging road to a cure.”

Lab mouse

Researchers say they have developed an animal model that allows them to better understand the mechanisms leading to multiple myeloma (MM) and other plasma cell neoplasms.

The group described this model in Scientific Reports.

“So far, there have not been animal models of malignant plasma cell diseases that allow us to study their stepwise progression and fully understand the complex cellular mechanisms,” said study author Stephen D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Now that we have a proper model of the disease, we’ll be able to more effectively study multiple myeloma as well as potential treatments.”

To create this model, the researchers crossed 2 genetically modified mice: mice lacking the Mef gene and mice with a Rad50 gene mutation (Rad50s).

Mef, also called Elf4, is a transcription factor known to both promote and suppress cancer formation. Rad50 is a component of a sensor of DNA damage induced by various stresses, and it regulates the DNA damage response pathways in cells.

The researchers found that Mef^−/−Rad50^s/s mice initially had abnormal plasma cell proliferation and monoclonal protein production.

Then, they developed anemia and a decreased bone mineral density. And 70% of these mice died from MM or other plasma cell neoplasms.

“We also found that the phenotype of these mice is not linked to activation of a specific oncogene or inactivation of a specific tumor suppressor, other than Mef,” said study author Takashi Asai, MD, PhD, also of the Sylvester Comprehensive Cancer Center.

Considering their findings together, the researchers said this model recapitulates the systemic manifestations of human MM and other plasma cell neoplasms. And their work suggests the Rad50s and Mef/Elf4 pathways cooperate to initiate myelomagenic mutations that promote plasma cell transformation.

“Although outcomes for multiple myeloma patients have greatly improved, it remains an incurable disease, despite the availability of newer treatments,” Dr Nimer noted.

“Several animal models of multiple myeloma have been reported, including models of human myeloma cells. However, these models imperfectly mimic the human disease. Developing more reliable and accurate animal models that help us better understand myeloma and test new treatments will take us to the next level on the long and challenging road to a cure.”

Lab mouse

Researchers say they have developed an animal model that allows them to better understand the mechanisms leading to multiple myeloma (MM) and other plasma cell neoplasms.

The group described this model in Scientific Reports.

“So far, there have not been animal models of malignant plasma cell diseases that allow us to study their stepwise progression and fully understand the complex cellular mechanisms,” said study author Stephen D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Now that we have a proper model of the disease, we’ll be able to more effectively study multiple myeloma as well as potential treatments.”

To create this model, the researchers crossed 2 genetically modified mice: mice lacking the Mef gene and mice with a Rad50 gene mutation (Rad50s).

Mef, also called Elf4, is a transcription factor known to both promote and suppress cancer formation. Rad50 is a component of a sensor of DNA damage induced by various stresses, and it regulates the DNA damage response pathways in cells.

The researchers found that Mef^−/−Rad50^s/s mice initially had abnormal plasma cell proliferation and monoclonal protein production.

Then, they developed anemia and a decreased bone mineral density. And 70% of these mice died from MM or other plasma cell neoplasms.

“We also found that the phenotype of these mice is not linked to activation of a specific oncogene or inactivation of a specific tumor suppressor, other than Mef,” said study author Takashi Asai, MD, PhD, also of the Sylvester Comprehensive Cancer Center.

Considering their findings together, the researchers said this model recapitulates the systemic manifestations of human MM and other plasma cell neoplasms. And their work suggests the Rad50s and Mef/Elf4 pathways cooperate to initiate myelomagenic mutations that promote plasma cell transformation.

“Although outcomes for multiple myeloma patients have greatly improved, it remains an incurable disease, despite the availability of newer treatments,” Dr Nimer noted.

“Several animal models of multiple myeloma have been reported, including models of human myeloma cells. However, these models imperfectly mimic the human disease. Developing more reliable and accurate animal models that help us better understand myeloma and test new treatments will take us to the next level on the long and challenging road to a cure.”

Clinical question: What is the relationship between crowding in the ED and the number of interventions adopted by the ED to address this?

Background: ED crowding results in long waits, prolonged lengths of stay, and delays in providing treatments, which can result in adverse events. Numerous interventions, including bedside registration, ED observation units, fast track, bed czar, surgical schedule smoothing, and pooled nursing, have been implemented to reduce crowding.

Study design: Retrospective, cross-sectional analysis.

Setting: U.S. hospitals in the National Hospital Ambulatory Medical Care Survey (NHAMCS).

Synopsis: From 2007 to 2010, an average of 341 hospitals per year were analyzed from the NHAMCS, representing 139,502 patient encounters. This study evaluated the adoption of nine crowding interventions at the emergency department level (bedside registration, electronic dashboard, RFID tracking, etc.) and eight crowding interventions at the hospital level (bed czar, pooled nursing, full-capacity protocol, board patients in inpatient hallways, etc.).

Bedside registration, electronic dashboard, RFID tracking, bed census, pooled nursing, full-capacity protocol, and boarding patients in the hallway had the highest statistically significant increases in adoption over the study period.

The average number of interventions adopted increased to 6.6 from 5.2, and more-crowded EDs adopted a greater number of interventions than less-crowded EDs. However, in the most-crowded quartile of EDs, 19% did not use bedside registration, and 94% did not use surgical schedule smoothing.

Given that this study is a retrospective, cross-sectional study, it is difficult to determine causality.

Bottom line: More interventions are being adopted by EDs and hospitals to decrease ED crowding, but several of the busiest EDs and hospitals have room for improvement.

Citation: Warner LS, Pines JM, Chambers JG, Schuur JD. The most crowded US hospital emergency departments did not adopt effective interventions to improve flow, 2007–10. Health Aff. 2015;34(12):2151-2159.

Clinical question: What is the relationship between crowding in the ED and the number of interventions adopted by the ED to address this?

Background: ED crowding results in long waits, prolonged lengths of stay, and delays in providing treatments, which can result in adverse events. Numerous interventions, including bedside registration, ED observation units, fast track, bed czar, surgical schedule smoothing, and pooled nursing, have been implemented to reduce crowding.

Study design: Retrospective, cross-sectional analysis.

Setting: U.S. hospitals in the National Hospital Ambulatory Medical Care Survey (NHAMCS).

Synopsis: From 2007 to 2010, an average of 341 hospitals per year were analyzed from the NHAMCS, representing 139,502 patient encounters. This study evaluated the adoption of nine crowding interventions at the emergency department level (bedside registration, electronic dashboard, RFID tracking, etc.) and eight crowding interventions at the hospital level (bed czar, pooled nursing, full-capacity protocol, board patients in inpatient hallways, etc.).

Bedside registration, electronic dashboard, RFID tracking, bed census, pooled nursing, full-capacity protocol, and boarding patients in the hallway had the highest statistically significant increases in adoption over the study period.

The average number of interventions adopted increased to 6.6 from 5.2, and more-crowded EDs adopted a greater number of interventions than less-crowded EDs. However, in the most-crowded quartile of EDs, 19% did not use bedside registration, and 94% did not use surgical schedule smoothing.

Given that this study is a retrospective, cross-sectional study, it is difficult to determine causality.

Bottom line: More interventions are being adopted by EDs and hospitals to decrease ED crowding, but several of the busiest EDs and hospitals have room for improvement.

Citation: Warner LS, Pines JM, Chambers JG, Schuur JD. The most crowded US hospital emergency departments did not adopt effective interventions to improve flow, 2007–10. Health Aff. 2015;34(12):2151-2159.

Clinical question: What is the relationship between crowding in the ED and the number of interventions adopted by the ED to address this?

Background: ED crowding results in long waits, prolonged lengths of stay, and delays in providing treatments, which can result in adverse events. Numerous interventions, including bedside registration, ED observation units, fast track, bed czar, surgical schedule smoothing, and pooled nursing, have been implemented to reduce crowding.

Study design: Retrospective, cross-sectional analysis.

Setting: U.S. hospitals in the National Hospital Ambulatory Medical Care Survey (NHAMCS).

Synopsis: From 2007 to 2010, an average of 341 hospitals per year were analyzed from the NHAMCS, representing 139,502 patient encounters. This study evaluated the adoption of nine crowding interventions at the emergency department level (bedside registration, electronic dashboard, RFID tracking, etc.) and eight crowding interventions at the hospital level (bed czar, pooled nursing, full-capacity protocol, board patients in inpatient hallways, etc.).

Bedside registration, electronic dashboard, RFID tracking, bed census, pooled nursing, full-capacity protocol, and boarding patients in the hallway had the highest statistically significant increases in adoption over the study period.

The average number of interventions adopted increased to 6.6 from 5.2, and more-crowded EDs adopted a greater number of interventions than less-crowded EDs. However, in the most-crowded quartile of EDs, 19% did not use bedside registration, and 94% did not use surgical schedule smoothing.

Given that this study is a retrospective, cross-sectional study, it is difficult to determine causality.

Bottom line: More interventions are being adopted by EDs and hospitals to decrease ED crowding, but several of the busiest EDs and hospitals have room for improvement.

Citation: Warner LS, Pines JM, Chambers JG, Schuur JD. The most crowded US hospital emergency departments did not adopt effective interventions to improve flow, 2007–10. Health Aff. 2015;34(12):2151-2159.

Clinical question: What is the appropriate frequency of INR monitoring in the hospital and its relationship to the risk of over-anticoagulation and warfarin-related adverse events?

Background: Warfarin use is a common cause of adverse drug events in hospitalized patients due to narrow therapeutic windows, drug interactions, and variability of metabolism. Current guidelines, including those by the American College of Chest Physicians, do not provide recommendations on how often to monitor INR or adjust warfarin dosing in the hospital.

Study design: Retrospective cohort.

Setting: Hospitalized patients included in the Medicare Patient Safety Monitoring System.

Synopsis: The study included 14,217 adult patients ≥18 years of age from the Medicare Patient Safety Monitoring System admitted from 2009 to 2013 with pneumonia, acute cardiac disease (myocardial infarction or congestive heart failure), or surgery and taking warfarin. Of those, 1,055 (7.4%) developed a warfarin-associated adverse event (bleeding, drop in hematocrit ≥3, hematoma, death, intracranial bleeding, or cardiac arrest). Patients admitted for acute cardiac disease (acute myocardial infarction or heart failure) or surgery on warfarin for ≥3 days but not monitored for ≥2 days had more warfarin-associated adverse events (OR 1.48; 95% CI, 1.02–2.17), but this association was not true in pneumonia patients. Cardiac and pneumonia patients with ≥1 day without INR being measured had higher rates of INR ≥6.0 (OR 1.61; 95% CI, 1.07–2.41, and OR 1.92, 95% CI, 1.36–2.71, respectively). A single-day rise in INR ≥0.9 had a likelihood ratio of 4.2 in predicting subsequent INR ≥6.0.

Bottom line: Frequent monitoring of INR may decrease warfarin-associated adverse events in hospitalized patients.

Citation: Metersky ML, Eldridge N, Wang Y, et al. Predictors of warfarin-associated adverse events in hospitalized patients: opportunities to prevent harm. J Hosp Med. 2016;11(4):276-282.

Short Take

CDC Guidelines on Prescribing Opioids

New CDC guidelines for chronic pain management stress the importance of non-pharmacologic (physical therapy, etc.) and non-opioid therapy (NSAIDs, etc.), using opioid therapy only if the expected benefits outweigh the risks.

Citation: CDC. CDC guideline for prescribing opioids for chronic pain. Available at: http://www.cdc.gov/drugoverdose/prescribing/guideline.html. Published March 16, 2016. Accessed April 8, 2016.

Clinical question: What is the appropriate frequency of INR monitoring in the hospital and its relationship to the risk of over-anticoagulation and warfarin-related adverse events?

Background: Warfarin use is a common cause of adverse drug events in hospitalized patients due to narrow therapeutic windows, drug interactions, and variability of metabolism. Current guidelines, including those by the American College of Chest Physicians, do not provide recommendations on how often to monitor INR or adjust warfarin dosing in the hospital.

Study design: Retrospective cohort.

Setting: Hospitalized patients included in the Medicare Patient Safety Monitoring System.

Synopsis: The study included 14,217 adult patients ≥18 years of age from the Medicare Patient Safety Monitoring System admitted from 2009 to 2013 with pneumonia, acute cardiac disease (myocardial infarction or congestive heart failure), or surgery and taking warfarin. Of those, 1,055 (7.4%) developed a warfarin-associated adverse event (bleeding, drop in hematocrit ≥3, hematoma, death, intracranial bleeding, or cardiac arrest). Patients admitted for acute cardiac disease (acute myocardial infarction or heart failure) or surgery on warfarin for ≥3 days but not monitored for ≥2 days had more warfarin-associated adverse events (OR 1.48; 95% CI, 1.02–2.17), but this association was not true in pneumonia patients. Cardiac and pneumonia patients with ≥1 day without INR being measured had higher rates of INR ≥6.0 (OR 1.61; 95% CI, 1.07–2.41, and OR 1.92, 95% CI, 1.36–2.71, respectively). A single-day rise in INR ≥0.9 had a likelihood ratio of 4.2 in predicting subsequent INR ≥6.0.

Bottom line: Frequent monitoring of INR may decrease warfarin-associated adverse events in hospitalized patients.

Citation: Metersky ML, Eldridge N, Wang Y, et al. Predictors of warfarin-associated adverse events in hospitalized patients: opportunities to prevent harm. J Hosp Med. 2016;11(4):276-282.

Short Take

CDC Guidelines on Prescribing Opioids

New CDC guidelines for chronic pain management stress the importance of non-pharmacologic (physical therapy, etc.) and non-opioid therapy (NSAIDs, etc.), using opioid therapy only if the expected benefits outweigh the risks.

Citation: CDC. CDC guideline for prescribing opioids for chronic pain. Available at: http://www.cdc.gov/drugoverdose/prescribing/guideline.html. Published March 16, 2016. Accessed April 8, 2016.

Clinical question: What is the appropriate frequency of INR monitoring in the hospital and its relationship to the risk of over-anticoagulation and warfarin-related adverse events?

Background: Warfarin use is a common cause of adverse drug events in hospitalized patients due to narrow therapeutic windows, drug interactions, and variability of metabolism. Current guidelines, including those by the American College of Chest Physicians, do not provide recommendations on how often to monitor INR or adjust warfarin dosing in the hospital.

Study design: Retrospective cohort.

Setting: Hospitalized patients included in the Medicare Patient Safety Monitoring System.

Synopsis: The study included 14,217 adult patients ≥18 years of age from the Medicare Patient Safety Monitoring System admitted from 2009 to 2013 with pneumonia, acute cardiac disease (myocardial infarction or congestive heart failure), or surgery and taking warfarin. Of those, 1,055 (7.4%) developed a warfarin-associated adverse event (bleeding, drop in hematocrit ≥3, hematoma, death, intracranial bleeding, or cardiac arrest). Patients admitted for acute cardiac disease (acute myocardial infarction or heart failure) or surgery on warfarin for ≥3 days but not monitored for ≥2 days had more warfarin-associated adverse events (OR 1.48; 95% CI, 1.02–2.17), but this association was not true in pneumonia patients. Cardiac and pneumonia patients with ≥1 day without INR being measured had higher rates of INR ≥6.0 (OR 1.61; 95% CI, 1.07–2.41, and OR 1.92, 95% CI, 1.36–2.71, respectively). A single-day rise in INR ≥0.9 had a likelihood ratio of 4.2 in predicting subsequent INR ≥6.0.

Bottom line: Frequent monitoring of INR may decrease warfarin-associated adverse events in hospitalized patients.

Citation: Metersky ML, Eldridge N, Wang Y, et al. Predictors of warfarin-associated adverse events in hospitalized patients: opportunities to prevent harm. J Hosp Med. 2016;11(4):276-282.

Short Take

CDC Guidelines on Prescribing Opioids

New CDC guidelines for chronic pain management stress the importance of non-pharmacologic (physical therapy, etc.) and non-opioid therapy (NSAIDs, etc.), using opioid therapy only if the expected benefits outweigh the risks.

Citation: CDC. CDC guideline for prescribing opioids for chronic pain. Available at: http://www.cdc.gov/drugoverdose/prescribing/guideline.html. Published March 16, 2016. Accessed April 8, 2016.

NEW YORK (Reuters Health) - Certain metal-on-metal (MoM) hip replacement devices implanted after 2006 have an "unacceptably high" revision rate, due mainly to manufacturing problems, according to a new study.

"Although the use of MoM hip devices has declined dramatically in the past five years, hundreds of thousands remain in situ, with the long-term future uncertain," Dr. David Langton, of University Hospital of North Tees in Stockton, UK, and colleagues wrote in an article online April 29 in BMJ Open.

To determine risk factors for revision in patients implanted with the commonly used DePuy Pinnacle MoM hip prostheses, the researchers identified all patients at the Stockton-based hospital who were implanted with a 36 mm MoM Pinnacle hip in conjunction with an S-ROM or Corail uncemented stem. They then identified only patients with components that had been implanted by either of the two senior authors of the study, Dr. Raj Logishetty or Dr. Antoni Viral Francis Nargol.

Implantations were performed from 2003-2009 and patients were monitored yearly. From 2007-2011, as awareness of the risk of adverse reactions to metal debris (ARMD) from MoMs increased, the hospital offered patients who developed symptoms blood metal ion testing and as-needed ultrasound scanning. From 2011 onward, given the widespread problems reported with MoMs, the hospital recalled all Pinnacle MoM patients for examination.

A total of 489 MoM Pinnacle hips had been implanted into 243 women and 191 men. Of these, 352 patients attended the MoM recall clinics and 64 died during the study period (mean

followup, about 7.5 years). For the purposes of survival analyses, those who did not attend the recall clinics were assumed to have well-functioning prostheses.

A total of 71 hips were revised -- an "unacceptably high" rate, according to the authors. All but one were carried out for ARMD, with one revision for a loose cup. Prosthetic survival rate for the cohort as a whole was 83.6% at nine years.

In 53 revisions (75%), "copious amounts" of fluid were found, and in 32 (45%), it was noted to be under pressure or had fistulated through the capsule. No abnormal fluid was identified at revision in only one case.

The researchers noted obvious damage to the abductor musculature in 38 cases. They documented a moderate-to-severe aseptic lymphocyte-dominated vasculitis-associated lesion on examination of retrieved tissues in 36 cases (51%). In 13 cases (19%), they found metallosis with no identified lymphocytic infiltration.

The majority of explanted devices showed signs of taper junction failure. A significant number of devices were found to be manufactured out of their specifications -- a finding that was confirmed by an analysis of a wider data set from the Northern Retrieval Registry.

Risk factors for revision were bilateral MoM prostheses, smaller Pinnacle liners, and implantation in 2006 or later. Women were found to be at greater risk of early device failure. However, shell sizes and bearing diameters confounded the analyses, and liner size and/or earlier year of liner manufacture were determined to be greater threats to prosthetic survival than gender. The authors suggest that this analysis be repeated with input from an additional registry.

Dr. Langton, who is involved in litigation related to the Pinnacle device, told Reuters Health by email, "We have essentially shown that one of the major health care/orthopedic product manufacturers sold a product to surgeons and health care systems on the basis (that it was a) technologically advanced precision-engineered device, and it wasn't precision-engineered."

He added, "the product was produced in the same factories as (DePuy's) other failed product, the ASR, which was . . . marketed on the same premise."

Mindy Tinsley, senior director, Communications and Public Affairs at DePuy Synthes Franchise, refuted the study findings. "We stand behind the strong record of safety and effectiveness of the (Pinnacle) ULTAMET Metal-on-Metal," she told Reuters Health by email.

She added that "there are no manufacturing problems" with the device and noted that DePuy "questions the validity of the . . . paper given significant flaws in how it was conducted." According to Tinsley, "measurements taken following an accepted international standard at the DePuy UK manufacturing facility" showed the device liners "were manufactured within specification."

Dr. Mark W. Hungerford, director of Joint Replacement and Reconstruction at Mercy Medical Center in Baltimore, told Reuters Health by phone, "One study does not make or break anything in science. There have been issues in the field about MoM and early failure rates or not. That's a serious issue being looked at by a lot of people. This is one more study showing a problem, but it's not a definitive one."

With respect to patients, "the obligation is no different than for any orthopedic device," said Dr. Hungerford, who has not used the Pinnacle device. "All can fail, all need to be monitored for failure on a regular basis, and if problems arise, they need to be dealt with."

The authors reported no funding. Dr. Langton, Dr. Nargol, and coauthors Dr. Thomas Joyce and Dr. Nick Cooke are retained experts for plaintiffs in ongoing MoM litigation. Dr. Langton and Dr. Nargol have worked with the U.S. Department of Justice in litigation involving DePuy.

NEW YORK (Reuters Health) - Certain metal-on-metal (MoM) hip replacement devices implanted after 2006 have an "unacceptably high" revision rate, due mainly to manufacturing problems, according to a new study.

"Although the use of MoM hip devices has declined dramatically in the past five years, hundreds of thousands remain in situ, with the long-term future uncertain," Dr. David Langton, of University Hospital of North Tees in Stockton, UK, and colleagues wrote in an article online April 29 in BMJ Open.

To determine risk factors for revision in patients implanted with the commonly used DePuy Pinnacle MoM hip prostheses, the researchers identified all patients at the Stockton-based hospital who were implanted with a 36 mm MoM Pinnacle hip in conjunction with an S-ROM or Corail uncemented stem. They then identified only patients with components that had been implanted by either of the two senior authors of the study, Dr. Raj Logishetty or Dr. Antoni Viral Francis Nargol.

Implantations were performed from 2003-2009 and patients were monitored yearly. From 2007-2011, as awareness of the risk of adverse reactions to metal debris (ARMD) from MoMs increased, the hospital offered patients who developed symptoms blood metal ion testing and as-needed ultrasound scanning. From 2011 onward, given the widespread problems reported with MoMs, the hospital recalled all Pinnacle MoM patients for examination.

A total of 489 MoM Pinnacle hips had been implanted into 243 women and 191 men. Of these, 352 patients attended the MoM recall clinics and 64 died during the study period (mean

followup, about 7.5 years). For the purposes of survival analyses, those who did not attend the recall clinics were assumed to have well-functioning prostheses.

A total of 71 hips were revised -- an "unacceptably high" rate, according to the authors. All but one were carried out for ARMD, with one revision for a loose cup. Prosthetic survival rate for the cohort as a whole was 83.6% at nine years.

In 53 revisions (75%), "copious amounts" of fluid were found, and in 32 (45%), it was noted to be under pressure or had fistulated through the capsule. No abnormal fluid was identified at revision in only one case.

The researchers noted obvious damage to the abductor musculature in 38 cases. They documented a moderate-to-severe aseptic lymphocyte-dominated vasculitis-associated lesion on examination of retrieved tissues in 36 cases (51%). In 13 cases (19%), they found metallosis with no identified lymphocytic infiltration.

The majority of explanted devices showed signs of taper junction failure. A significant number of devices were found to be manufactured out of their specifications -- a finding that was confirmed by an analysis of a wider data set from the Northern Retrieval Registry.

Risk factors for revision were bilateral MoM prostheses, smaller Pinnacle liners, and implantation in 2006 or later. Women were found to be at greater risk of early device failure. However, shell sizes and bearing diameters confounded the analyses, and liner size and/or earlier year of liner manufacture were determined to be greater threats to prosthetic survival than gender. The authors suggest that this analysis be repeated with input from an additional registry.

Dr. Langton, who is involved in litigation related to the Pinnacle device, told Reuters Health by email, "We have essentially shown that one of the major health care/orthopedic product manufacturers sold a product to surgeons and health care systems on the basis (that it was a) technologically advanced precision-engineered device, and it wasn't precision-engineered."

He added, "the product was produced in the same factories as (DePuy's) other failed product, the ASR, which was . . . marketed on the same premise."

Mindy Tinsley, senior director, Communications and Public Affairs at DePuy Synthes Franchise, refuted the study findings. "We stand behind the strong record of safety and effectiveness of the (Pinnacle) ULTAMET Metal-on-Metal," she told Reuters Health by email.

She added that "there are no manufacturing problems" with the device and noted that DePuy "questions the validity of the . . . paper given significant flaws in how it was conducted." According to Tinsley, "measurements taken following an accepted international standard at the DePuy UK manufacturing facility" showed the device liners "were manufactured within specification."

Dr. Mark W. Hungerford, director of Joint Replacement and Reconstruction at Mercy Medical Center in Baltimore, told Reuters Health by phone, "One study does not make or break anything in science. There have been issues in the field about MoM and early failure rates or not. That's a serious issue being looked at by a lot of people. This is one more study showing a problem, but it's not a definitive one."

With respect to patients, "the obligation is no different than for any orthopedic device," said Dr. Hungerford, who has not used the Pinnacle device. "All can fail, all need to be monitored for failure on a regular basis, and if problems arise, they need to be dealt with."

The authors reported no funding. Dr. Langton, Dr. Nargol, and coauthors Dr. Thomas Joyce and Dr. Nick Cooke are retained experts for plaintiffs in ongoing MoM litigation. Dr. Langton and Dr. Nargol have worked with the U.S. Department of Justice in litigation involving DePuy.

NEW YORK (Reuters Health) - Certain metal-on-metal (MoM) hip replacement devices implanted after 2006 have an "unacceptably high" revision rate, due mainly to manufacturing problems, according to a new study.

"Although the use of MoM hip devices has declined dramatically in the past five years, hundreds of thousands remain in situ, with the long-term future uncertain," Dr. David Langton, of University Hospital of North Tees in Stockton, UK, and colleagues wrote in an article online April 29 in BMJ Open.

To determine risk factors for revision in patients implanted with the commonly used DePuy Pinnacle MoM hip prostheses, the researchers identified all patients at the Stockton-based hospital who were implanted with a 36 mm MoM Pinnacle hip in conjunction with an S-ROM or Corail uncemented stem. They then identified only patients with components that had been implanted by either of the two senior authors of the study, Dr. Raj Logishetty or Dr. Antoni Viral Francis Nargol.

Implantations were performed from 2003-2009 and patients were monitored yearly. From 2007-2011, as awareness of the risk of adverse reactions to metal debris (ARMD) from MoMs increased, the hospital offered patients who developed symptoms blood metal ion testing and as-needed ultrasound scanning. From 2011 onward, given the widespread problems reported with MoMs, the hospital recalled all Pinnacle MoM patients for examination.

A total of 489 MoM Pinnacle hips had been implanted into 243 women and 191 men. Of these, 352 patients attended the MoM recall clinics and 64 died during the study period (mean

followup, about 7.5 years). For the purposes of survival analyses, those who did not attend the recall clinics were assumed to have well-functioning prostheses.

A total of 71 hips were revised -- an "unacceptably high" rate, according to the authors. All but one were carried out for ARMD, with one revision for a loose cup. Prosthetic survival rate for the cohort as a whole was 83.6% at nine years.

In 53 revisions (75%), "copious amounts" of fluid were found, and in 32 (45%), it was noted to be under pressure or had fistulated through the capsule. No abnormal fluid was identified at revision in only one case.

The researchers noted obvious damage to the abductor musculature in 38 cases. They documented a moderate-to-severe aseptic lymphocyte-dominated vasculitis-associated lesion on examination of retrieved tissues in 36 cases (51%). In 13 cases (19%), they found metallosis with no identified lymphocytic infiltration.

The majority of explanted devices showed signs of taper junction failure. A significant number of devices were found to be manufactured out of their specifications -- a finding that was confirmed by an analysis of a wider data set from the Northern Retrieval Registry.

Risk factors for revision were bilateral MoM prostheses, smaller Pinnacle liners, and implantation in 2006 or later. Women were found to be at greater risk of early device failure. However, shell sizes and bearing diameters confounded the analyses, and liner size and/or earlier year of liner manufacture were determined to be greater threats to prosthetic survival than gender. The authors suggest that this analysis be repeated with input from an additional registry.

Dr. Langton, who is involved in litigation related to the Pinnacle device, told Reuters Health by email, "We have essentially shown that one of the major health care/orthopedic product manufacturers sold a product to surgeons and health care systems on the basis (that it was a) technologically advanced precision-engineered device, and it wasn't precision-engineered."

He added, "the product was produced in the same factories as (DePuy's) other failed product, the ASR, which was . . . marketed on the same premise."

Mindy Tinsley, senior director, Communications and Public Affairs at DePuy Synthes Franchise, refuted the study findings. "We stand behind the strong record of safety and effectiveness of the (Pinnacle) ULTAMET Metal-on-Metal," she told Reuters Health by email.

She added that "there are no manufacturing problems" with the device and noted that DePuy "questions the validity of the . . . paper given significant flaws in how it was conducted." According to Tinsley, "measurements taken following an accepted international standard at the DePuy UK manufacturing facility" showed the device liners "were manufactured within specification."

Dr. Mark W. Hungerford, director of Joint Replacement and Reconstruction at Mercy Medical Center in Baltimore, told Reuters Health by phone, "One study does not make or break anything in science. There have been issues in the field about MoM and early failure rates or not. That's a serious issue being looked at by a lot of people. This is one more study showing a problem, but it's not a definitive one."

With respect to patients, "the obligation is no different than for any orthopedic device," said Dr. Hungerford, who has not used the Pinnacle device. "All can fail, all need to be monitored for failure on a regular basis, and if problems arise, they need to be dealt with."

The authors reported no funding. Dr. Langton, Dr. Nargol, and coauthors Dr. Thomas Joyce and Dr. Nick Cooke are retained experts for plaintiffs in ongoing MoM litigation. Dr. Langton and Dr. Nargol have worked with the U.S. Department of Justice in litigation involving DePuy.

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”