Papuloerythroderma of Ofuji

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Continuing Education Activity

Papuloerythroderma of Ofuji is a rare skin disorder predominantly found in Japan. Characterized by polygonal, flat-topped erythematous-brown papules that coalesce into sheets that often cover the entire skin surface but spare the skin folds, this disorder poses diagnostic challenges. This activity explores the foundational diagnostic criteria established through meta-analysis, initially proposed by Torchia et al, comprising major and minor criteria pivotal in defining the condition and delineating its subtypes. With its discovery in 1984 by Ofuji, Furukawa, Miyachi, and Ohno, Papuloerythroderma of Ofuji commonly presents with pruritus, peripheral eosinophilia, and elevated immunoglobulin E (IgE) levels, necessitating a nuanced approach to diagnosis and management.

This course discussion underscores the interdisciplinary collaboration essential for effectively managing patients afflicted with Papuloerythroderma of Ofuji. Given the condition's rarity and potential resemblance to other dermatological and lymphoproliferative disorders, healthcare professionals will benefit from an in-depth understanding of the diagnostic criteria and differential diagnoses. By highlighting the role of an interprofessional team, this CME activity aims to enhance healthcare practitioners' proficiency in accurately diagnosing and managing Papuloerythroderma of Ofuji, thereby improving patient outcomes and ensuring appropriate therapeutic interventions.


  • Identify the epidemiology of Papuloerythroderma of Ofuji.

  • Screen patients for Papuloerythroderma of Ofuji.

  • Compare the treatment and management options available for Papuloerythroderma of Ofuji.

  • Collaborate with the interprofessional team to optimize care coordination and communication to advance the management of Papuloerythroderma of Ofuji and improve outcomes.


Papuloerythroderma of Ofuji is a rare skin disorder most commonly found in Japan. It is characterized by polygonal, flat-topped erythematous-brown papules coalescing into sheets that often cover the entire skin surface but spare the skin folds.[1] Papuloerythroderma of Ofuji was first discovered in Japan in 1984 by Ofuji, Furukawa, Miyachi, and Ohno.[2] It is commonly accompanied by pruritus, peripheral eosinophilia, and elevated immunoglobulin E (IgE).[3]

The basis of the disease and initial diagnosis stems from an initial meta-analysis comprised of 170 patients via Torchia et al, who proposed a preliminary set of 5 major and 5 minor criteria that define Papuloerythroderma of Ofuji. These criteria help determine etiology and allow for categorization into 4 subtypes, which include primary, secondary, and a nonpapular form of Papuloerythroderma of Ofuji.[4] There is also a consideration for patients that appear clinically, like Papuloerythroderma of Ofuji, but have a diagnosis more consistent with lymphoma.[5]


Although the underlying etiology of Papuloerythroderma of Ofuji has not been elucidated, a clear connection between underlying malignancy, infectious processes, and pharmacological agents preceding the presentation of Papuloerythroderma of Ofuji has been a consistent theme.[6] The range of oncologic disorders found in association with Papuloerythroderma of Ofuji includes gastric carcinomas, hepatocellular carcinoma, adenocarcinoma of the colon, cutaneous T-cell lymphoma, prostate cancer, and chronic lymphocytic leukemia; however, gastric adenocarcinoma has been noted to be the most common form of malignancy in a meta-analysis of cases of Papuloerythroderma of Ofuji.[1][7][8][9][10] This finding leads to the possibility of Papuloerythroderma of Ofuji being a paraneoplastic syndrome, with screening for underlying malignancy being a crucial component in the work-up of patients with Papuloerythroderma of Ofuji.[11]

In addition to oncologic processes, the hepatitis C virus has also been found to cause Papuloerythroderma of Ofuji, with complete resolution of all lesions after the levels of hepatitis C viral antigen become undetectable.[12] Drug-induced Papuloerythroderma of Ofuji is a distinct T-helper cell type 2 (Th2)-mediated drug hypersensitivity, and the role of Th2 has been implicated in other associated with atopic disease.[3][13] Pharmacological agents associated with this phenomenon include nicardipine, aspirin, isoniazid, furosemide, etretinate, ranitidine, leuprorelin, and diltiazem; interestingly, some of these medications, like etretinate, have been associated with the onset of Papuloerythroderma of Ofuji.[13]


The incidence of Papuloerythroderma of Ofuji has been reported to be 1.5 cases per million; however, this is considered an underestimate since the condition is likely underdiagnosed.[14] The most common subset of the population affected by Papuloerythroderma of Ofuji consists of those 55 years or older and of Asian or Caucasian descent. There is a predilection for males to females with a ratio of 4 to 1.[1]

Epidemiologic factors, including age and gender, comprise 2 of the 5 minor criteria for diagnosing Papuloerythroderma of Ofuji.[4] The condition is also commonly found in individuals with underlying cutaneous T-cell lymphoma (CTCL).[5][15] This close correlation between the 2 diseases is a common theme and plays a significant role in evaluating Papuloerythroderma of Ofuji.[16]


The pathophysiology of Papuloerythroderma of Ofuji remains unclear; however, multiple studies have shown it to be associated with malignancy, medications, infections, and atopic disease, with the resolution of the association generally linked with the cessation of Papuloerythroderma of Ofuji symptoms.[1] For malignancy, there is debate about whether it is a paraneoplastic syndrome since it has been associated with malignancy in between 22% and 55% of cases.[4][9] Because of its association with a strong Th2 response, it has been postulated to arise in relation to atopic disease, allergies, or drug reactions.[17][18][19] Infection has also been postulated as a preceding factor that causes an overactive immune system leading to this condition, but this cause has only been found in 4% of patients.[4][20] Most importantly, because Papuloerythroderma of Ofuji can be conflated with cutaneous lymphoma, particularly CTCL and mycosis fungoides, it has been proposed that its development has to do with an early stage of lymphoma.[5][21]


Histopathological examination of the tissue reveals focal hyperkeratosis and an acanthotic epidermis with some spongiosis.[1] An inflammatory infiltrate is present in a perivascular distribution with a nonspecific collection of plasma cells, eosinophils, macrophages, Langerhans cells, and lymphocytes with rare neutrophils; importantly, lymphocytes can demonstrate exocytosis but do not reveal epidermotropism, which would be more diagnostic for cutaneous lymphoma.[1] These findings are not pathognomonic; however, they aid in diagnosing and evaluating Papuloerythroderma of Ofuji.[10][22]

History and Physical

Included in the history and physical of a patient with suspected Papuloerythroderma of Ofuji, the provider should elucidate the presence of pruritus, establish the status of atopy, and exclude all external triggering factors, including atopy, infectious processes, malignancy (including CTCL), and drug-induced lesions, per the major criteria for diagnosing Papuloerythroderma of Ofuji.[1] 

The minor criteria for diagnosing Papuloerythroderma of Ofuji include age over 55, male sex, peripheral eosinophilia, elevated serum IgE, and reduced lymphocyte count.[1][4] A full-body skin examination will likely reveal erythematous lesions comprised of flat, confluent, reddish-brown papules with distribution on the trunk, extremities, and extensor surfaces. In addition to these lesions, a positive deck-chair sign should be present, defined by the exclusion of inframammary folds, axillary folds, inguinal creases, and popliteal fossae.[23] Other findings may include palmoplantar keratoderma and lymphadenopathy, which may raise suspicion of malignancy.[1] Dermoscopy of Papuloerythroderma of Ofuji reveals multiple erythematous pinpoint papules with surrounding whitish halos on an erythematous-pinkish background.[16]


Laboratory, histopathological, and clinical features are the hallmarks of the evaluation of Papuloerythroderma of Ofuji through the major and minor criteria. However, the disease is a diagnosis of exclusion after excluding other causes of erythroderma (eg, atopic dermatitis, psoriasis, malignancy, cutaneous T-cell lymphoma, etc).[1] Laboratory tests, including complete blood count, comprehensive metabolic panel, serum IgE, and titers for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, and HIV should be performed; testing for syphilis, including rapid plasma reagin and venereal diseases reference laboratory tests should be performed.[1] 

The presence of lymphopenia, elevated serum IgE, and peripheral eosinophilia are consistent with the diagnosis of Papuloerythroderma of Ofuji.[1] Histological evaluation of a punch biopsy should be performed in patients. Due to the similarity in the clinical presentation of CTCL and that of Papuloerythroderma of Ofuji, patients should undergo flow cytometry and T-cell receptor clonality studies to rule out the possibility of misdiagnosis and to prevent further delay of treatment in patients with CTCL.[5] Further studies have indicated that testing for thymus and activation-regulated chemokine (TARC) may be a diagnostic marker that could help tailor treatment.[1][3] One study suggested obtaining PET scans to rule out malignancy.[1][24][25]

Treatment / Management

Treatment of Papuloerythroderma of Ofuji initially consists of finding the underlying etiology and treating the secondary disease. This step may include the treatment of infectious processes or the removal of pharmacological agents.[1][20] For cases of idiopathic disease, there is no gold standard of therapy; however,  cases have been treated with photochemotherapy (psoralen plus ultraviolet A [PUVA]-psoralen and ultraviolet A), topical corticosteroids, methotrexate, azathioprine, interferon alfa, etretinate, and cyclosporine.[1][26][27][28][29][30][31]

Wet wraps and oral antihistamines have been shown as treatments in 2 cases.[32] Additionally, A 9-month course of cyclosporine at 3 mg/kg was noted to lead to complete resolution of skin lesions with some residual postinflammatory change.[13][22] Because of a suggested Th2-based etiology of Papuloerythroderma of Ofuji, newer studies have suggested treatment with dupilumab; however, this may need to be used cautiously after a complete workup for malignancy.[19][33][34][35]

Differential Diagnosis

The differential diagnosis of Papuloerythroderma of Ofuji should include CTCL, secondary syphilis, and drug reaction with eosinophilia and systemic symptoms (DRESS).[1][21][25] CTCL and Papuloerythroderma of Ofuji can be differentiated through flow cytometry and evaluation of clonal T-cell samples; secondary syphilis may be ruled out via VDRL and RPR testing; and DRESS can be differentiated via its acute presentation versus the more gradual, chronic, and indolent course of Papuloerythroderma of Ofuji.[13] There is a wide differential of diseases associated with the deck-chair sign since this is not specific to Papuloerythroderma of Ofuji; the differential can include psoriasis, atopic or contact dermatitis, lymphoma, acanthosis nigricans, and drug eruptions.[1]


The course of Papuloerythroderma of Ofuji is generally indolent, with remission occurring many years after the initial onset in idiopathic cases.[23] Those with secondary etiology leading to Papuloerythroderma of Ofuji may experience rapid clearance of lesions upon removing the offending agents or treating the underlying causes.[1][36] Without secondary bacterial superinfection, the overall disease progression is nonacute and consists of resolving pruritus, which generally leads to complete resolution.[37] It has been noted that the course of Papuloerythroderma of Ofuji is approximately 7 months, but it is expected to be a chronic and indolent skin disease.[1] The association of Papuloerythroderma of Ofuji with atopic disease and malignancy is notable, with one study reporting atopic disease in 20% of patients and reporting malignancy in 22%-55% of patients.[1] 


A significant complication of Papuloerythroderma of Ofuji is secondary bacterial superinfection of the polygonal papular lesions, likely due to excoriation.[1][4] These secondary infections may lead to erysipelas or cellulitis, significantly impacting patients' overall well-being. These complications are manageable with brief oral courses of clindamycin or cefuroxime.[22] In addition to bacterial superinfection, a delay in diagnosis of CTCL can also occur if there is a diagnosis of Papuloerythroderma of Ofuji without proper evaluation to rule out CTCL.[5] It is unclear if lymphoma is an eventual outcome of Papuloerythroderma of Ofuji or if it is a similar diagnosis; for conservative measures, it may be most appropriate to monitor the patient for the development of signs of lymphoma as some have proposed that Papuloerythroderma of Ofuji is a precursor to mycosis fungoides.[1][21][38]

Deterrence and Patient Education

Patients suffering from Papuloerythroderma of Ofuji should receive proper education on the correlations between Papuloerythroderma of Ofuji and multiple internal malignancies, as well as its similarity and possible association with CTCL. Proper screening and evaluation to rule out these internal malignancies are crucial components in the management of Papuloerythroderma of Ofuji, and informing patients regarding the types of screening they should undergo will aid in the adequate evaluation of possible underlying disease processes.

Enhancing Healthcare Team Outcomes

The management of Papuloerythroderma of Ofuji requires the participation of an interprofessional healthcare team approach. Aside from the primary care provider, nurse practitioner, and internist, the involvement of specialists in multiple fields to aid in diagnosing underlying malignancy should have participation at an early stage in the disease process. Pharmacists can be integral in helping determine when the condition is drug-induced, as well as providing recommendations for pharmaceutical therapy. Nursing is often the primary point of contact for patients and families, providing education.

Patients with Papuloerythroderma of Ofuji should undergo evaluation via a gastroenterologist to perform upper endoscopy and colonoscopy to rule out gastric carcinoma and adenocarcinoma of the colon. In addition to proper gastroenterological work-up, patients should be evaluated for any hematological abnormalities and referred to hematology and oncology specialists if any cell line abnormalities, flow cytometry abnormalities, or clinical features of malignancy are present.[7][8][9][10]

(Click Image to Enlarge)
Papuloerythroderma of Ofuji, rash, skin folds
Papuloerythroderma of Ofuji, rash, skin folds
StatPearls Publishing Illustration


12/1/2023 12:48:16 PM



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