To the Editor: Papuloerythroderma of Ofuji (PEO) is a rare disorder characterized by pruritic erythematous papules, which progress to fold-sparing erythroderma.1,2 Currently, there is no standardized therapeutic approach for PEO. The aim of this systematic review is to summarize treatments and outcomes for patients with PEO.
This systematic review was registered on PROSPERO (CRD42020222951) and followed PRISMA guidelines. EMBASE and MEDLINE in OVID were searched on October 22, 2020. A total of 82 studies were included. These studies described 212 treatments for 135 patients (mean age: 72.0 years) with PEO. The mean duration of the disease course was 2.6 years, with a predilection for males (83%, n = 112/135) and Japanese ethnicity (11.9%, n = 16/135) (Table I). Of all reported PEO cases, 47.4% were of primary or idiopathic etiology (n = 64/135) and 52.6% were secondary (n = 71/135), most commonly due to cutaneous T-cell lymphoma (n = 35/71) or HIV (n = 5/71).
Table I.
Summary of demographic information in patients with PEO
| Demographics | Pooled total | Primary PEO | Secondary PEO |
|---|---|---|---|
| Sex (n, %) | |||
| Female | 22 (16.3%) | 11 (17.2%) | 11 (15.5%) |
| Male | 112 (83.0%) | 52 (81.3%) | 60 (84.5%) |
| NR | 1 (0.7%) | 1 (1.6%) | 0 (0.0%) |
| Total (n) | 135 | 64 | 71 |
| Age (years) | |||
| Mean age | 72.0 | 72.4 | 71.7 |
| Age range | 30-97 | 36-97 | 30-89 |
| NR | 0 | 0 | 0 |
| Ethnicity | |||
| African Canadian | 1 (0.7%) | 0 (0.0%) | 1 (1.4%) |
| Asian | 4 (3.0%) | 2 (3.1%) | 2 (2.8%) |
| Caucasian | 9 (6.7%) | 5 (7.8%) | 4 (5.6%) |
| Hispanic | 1 (0.7%) | 0 (0.0%) | 1 (1.4%) |
| Indian | 1 (0.7%) | 0 (0.0%) | 1 (1.4%) |
| Jamaican | 1 (0.7%) | 1 (1.6%) | 0 (0.0%) |
| Japanese | 16 (11.9%) | 4 (6.3%) | 12 (16.9%) |
| Korean | 2 (1.5%) | 1 (1.6%) | 1 (1.4%) |
| Pakistani | 1 (0.7%) | 1 (1.6%) | 0 (0.0%) |
| NR | 99 (73.3%) | 50 (78.1%) | 49 (69.0%) |
| PEO duration (months) | |||
| Mean number of months | 31.0 | 39.5 | 25.5 |
| Months Range | 0.5-300 | 0.5-300 | 0.5-132 |
| NR | 34 | 24 | 10 |
| Comorbidities associated with PEO onset | |||
| Cutaneous T-cell lymphoma | 35 (25.9%) | 0 | 35 (49.3%) |
| HIV | 5 (3.7%) | 0 | 5 (7.0%) |
| Furosemide drug reaction | 2 (1.5%) | 0 | 2 (2.8%) |
| Peripheral T-cell lymphoma | 2 (1.5%) | 0 | 2 (2.8%) |
| Hepatocellular carcinoma | 2 (1.5%) | 0 | 2 (2.8%) |
| Gastric cancer | 2 (1.5%) | 0 | 2 (2.8%) |
| Esophageal cancer | 2 (1.5%) | 0 | 2 (2.8%) |
| Myelodysplastic syndrome | 2 (1.5%) | 0 | 2 (2.8%) |
| Hepatitis C Virus | 1 (0.7%) | 0 | 1 (1.4%) |
| Dermatitis herpetiformis | 1 (0.7%) | 0 | 1 (1.4%) |
| Acute myeloid leukemia | 1 (0.7%) | 0 | 1 (1.4%) |
| Bullous pemphigoid | 1 (0.7%) | 0 | 1 (1.4%) |
| Hodgkin's lymphoma | 1 (0.7%) | 0 | 1 (1.4%) |
| Malignant lymphocytic lymphoma | 1 (0.7%) | 0 | 1 (1.4%) |
| T-cell prolymphocytic leukemia | 1 (0.7%) | 0 | 1 (1.4%) |
| Capillary leak syndrome | 1 (0.7%) | 0 | 1 (1.4%) |
| Chronic lymphatic leukemia | 1 (0.7%) | 0 | 1 (1.4%) |
| Colon cancer | 1 (0.7%) | 0 | 1 (1.4%) |
| Bladder cancer | 1 (0.7%) | 0 | 1 (1.4%) |
| Pancreatic cancer | 1 (0.7%) | 0 | 1 (1.4%) |
| Lung cancer | 1 (0.7%) | 0 | 1 (1.4%) |
| Scabies | 1 (0.7%) | 0 | 1 (1.4%) |
| Eczematide-like purpura | 1 (0.7%) | 0 | 1 (1.4%) |
| Follicular mucinosis | 1 (0.7%) | 0 | 1 (1.4%) |
| Monoclonal gammopathy of undetermined significance | 1 (0.7%) | 0 | 1 (1.4%) |
| Strongyloidiasis | 1 (0.7%) | 0 | 1 (1.4%) |
| Choledocholithiasis | 1 (0.7%) | 0 | 1 (1.4%) |
NR, Not reported; PEO, papuloerythroderma of Ofuji.
The reported treatments for primary and secondary PEO were the same aside from treatment differences addressing the underlying disease. Oral corticosteroids (13.7%, n = 29/212), psoralen and ultraviolet A (PUVA) (9.9%, n = 21/212), oral retinoids (3.8%, n = 8/212), and combination therapy were the most frequently reported treatments with favorable patient outcomes (Table II). Of the 29 treatments utilizing oral corticosteroids, 31.0% resulted in complete resolution (n = 9) within 24.0 days, 55.2% in partial resolution (n = 16) within 38.0 days, 10.3% in no resolution (n = 3), and 3.4% in worsening (n = 1). PUVA treatments resulted in complete resolution in 61.9% (n = 13/21) of cases within 105.0 days, partial resolution in 33.3% (n = 7/21) of cases within 106.5 days, and worsening in 4.8% (n = 1/21) of cases. Oral retinoid treatment led to complete resolution in 87.5% (n = 7/8) of cases within 25.0 days and partial resolution in 12.5% (n = 1/8).
Table II.
Summary of treatment outcomes in patients with primary and secondary PEO
| PEO treatment | Number of patients treated (n) | Complete resolution | Time to complete resolution (days) | Partial resolution | Time to partial resolution (days) | No resolution | Worsening | Mean follow-up period post treatment (months) |
|---|---|---|---|---|---|---|---|---|
| Monotherapy | ||||||||
| Corticosteroid (oral) | 29 | 9 (31.0%) | 24.0 (n = 2) | 16 (55.2%) | 38.0 (n = 3) | 3 (10.3%) | 1 (3.4%) | 70.7 (n = 14) |
| PUVA | 21 | 13 (61.9%) | 105.0 (n = 10) | 7 (33.3%) | 106.5 (n = 4) | 0 (0.0%) | 1 (4.8%) | 72.9 (n = 14) |
| Corticosteroid (topical) | 9 | 1 (11.1%) | 14.0 (n = 1) | 5 (55.6%) | NR | 3 (33.3%) | 0 (0.0%) | 3.0 (n = 1) |
| UVB | 8 | 3 (37.5%) | NR | 1 (12.5%) | NR | 4 (50.0%) | 0 (0.0%) | 108.0 (n = 1) |
| Retinoid (oral) | 8 | 7 (87.5%) | 25.0 (n = 7) | 1 (12.5%) | NR | 0 (0.0%) | 0 (0.0%) | 24.0 (n = 1) |
| Treating underlying condition | 7 | 2 (28.6%) | 2.0 (n = 1) | 5 (71.4%) | 14.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | 13.0 (n = 2) |
| Immunosuppressant | 6 | 3 (50%) | 120.0 (n = 1) | 2 (33.3%) | NR | 1 (16.7%) | 0 (0.0%) | 10.5 (n = 2) |
| IL-4 inhibitor | 3 | 1 (33.3%) | 98.0 (n = 1) | 2 (66.7%) | 90.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | 8.3 (n = 3) |
| Antihistamine | 2 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (50.0%) | 1 (50.0%) | 108.0 (n = 1) |
| Antibiotic | 2 | 1 (50.0%) | 90.0 (n = 1) | 1 (50.0%) | NR | 0 (0.0%) | 0 (0.0%) | NR |
| Interferon-α | 1 | 1 (100.0%) | 28.0 (n = 1) | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | NR |
| Antifungal | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | NR |
| Androgen deprivation | 1 | 0 (0.0%) | N/A | 1 (100.0%) | 28.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | NR |
| No treatment | 1 | 1 (100.0%) | NR | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | NR |
| Combination therapy | ||||||||
| Corticosteroid (topical), antihistamine | 33 | 3 (9.1%) | 21.0 (n = 1) | 8 (24.2%) | 226.3 (n = 3) | 16 (48.5%) | 6 (18.2%) | 58.4 (n = 3) |
| Corticosteroid (topical), corticosteroid (oral) | 9 | 0 (0.0%) | N/A | 3 (33.3%) | NR | 6 (66.7%) | 0 (0.0%) | 16.8 (n = 6) |
| Corticosteroid (topical), PUVA | 9 | 4 (44.4%) | NR | 3 (33.3%) | 7.0 (n = 1) | 1 (11.1%) | 1 (11.1%) | 108.0 (n = 6) |
| Corticosteroid (topical), UVB | 7 | 2 (28.6%) | NR | 5 (71.4%) | NR | 0 (0.0%) | 0 (0.0%) | 87.6 (n = 5) |
| Corticosteroid (topical), corticosteroid (oral), antihistamine | 5 | 3 (60.0%) | 10.0 (n = 3) | 2 (40.0%) | NR | 0 (0.0%) | 0 (0.0%) | 20.0 (n = 3) |
| Corticosteroid (topical), antihistamine, immunosuppressant∗,† | 2 | 0 (0.0%) | N/A | 1 (50.0%) | NR | 1 (50.0%) | 0 (0.0%) | 7.0 (n = 1) |
| Corticosteroid (topical), antihistamine, PUVA | 2 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (50.0%) | 1 (50.0%) | 8.0 (n = 2) |
| Corticosteroid (topical), corticosteroid (oral), antihistamine, antibiotic‡ | 2 | 0 (0.0%) | N/A | 1 (50.0%) | NR | 1 (50.0%) | 0 (0.0%) | 7.5 (n = 2) |
| Corticosteroid (topical), antibiotic§ | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | 20.0 (n = 1) |
| Corticosteroid (topical), antihistamine, UVB | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | 12.0 (n = 1) |
| Corticosteroid (topical), corticosteroid (oral), immunosuppressant‖ | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Corticosteroid (topical), corticosteroid (oral), antihistamine, UVB | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | 12.0 (n = 1) |
| Corticosteroid (topical), corticosteroid (oral), antihistamine, retinoid (oral), immunosuppressant∗ | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | 12.0 (n = 1) |
| Corticosteroid (topical), PUVA, interferon-α | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | NR |
| Corticosteroid (topical), retinoid (oral), interferon-α | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Corticosteroid (topical), retinoid (oral), PUVA | 1 | 1 (100.0%) | 90.0 (n = 1) | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | 48.0 (n = 1) |
| Corticosteroid (topical), retinoid (oral), UVB | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Corticosteroid (topical), UVB, interferon-α | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Corticosteroid (topical), antihistamine, antifungal | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | 24.0 (n = 1) |
| Corticosteroid (topical), antihistamine, immunosuppressant∗, PUVA | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | 10.0 (n = 1) |
| Corticosteroid (topical), antihistamine, immunosuppressant∗, UVB | 1 | 0 (0.0%) | N/A | 1 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | NR |
| Corticosteroid (oral), PUVA | 5 | 1 (20.0%) | NR | 4 (80.0%) | 28.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | 108.0 (n = 3) |
| Corticosteroid (oral), immunosuppressant∗ | 5 | 1 (20.0%) | 150.0 (n = 1) | 2 (40.0%) | 90.0 (n = 1) | 2 (40.0%) | 0 (0.0%) | 10.0 (n = 4) |
| Corticosteroid (oral), antihistamine | 4 | 0 (0.0%) | N/A | 2 (50.0%) | 30.0 (n = 1) | 2 (50.0%) | 0 (0.0%) | 2.0 (n = 1) |
| Corticosteroid (oral), UVB | 2 | 0 (0.0%) | N/A | 1 (50.0%) | N/A | 1 (50.0%) | 0 (0.0%) | NR |
| Corticosteroid (oral), antihistamine, PUVA | 2 | 0 (0.0%) | N/A | 2 (100.0%) | NR | 0 (0.0%) | 0 (0.0%) | NR |
| Corticosteroid (oral), antihistamine, UVB | 1 | 0 (0.0%) | N/A | 1 (100.0%) | 90.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | NR |
| Corticosteroid (oral), PUVA, interferon-α | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Retinoid (oral), PUVA | 5 | 3 (60.0%) | 180.0 (n = 3) | 2 (40.0%) | 28.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | 30.3 (n = 3) |
| Retinoid (oral), UVB | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Retinoid (oral), PUVA, interferon-α | 1 | 1 (100.0%) | 365.0 (n = 1) | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | 36.0 (n = 1) |
| Retinoid (oral), antibiotic‡, interferon-α | 1 | 0 (0.0%) | N/A | 0 (0.0%) | N/A | 1 (100.0%) | 0 (0.0%) | NR |
| Immunosuppressant, folic acid | 2 | 1 (50.0%) | 90.0 (n = 1) | 1 (50.0%) | 60.0 (n = 1) | 0 (0.0%) | 0 (0.0%) | 19.5 (n = 2) |
| PUVA, antibiotic‡ | 1 | 1 (100.0%) | NR | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | NR |
n, number of eruptions, denominator for percentages; %, percentage.
N/A, Not applicable; NR, not reported; PEO, papuloerythroderma of Ofuji; PUVA, psoralen and ultraviolet A; UVB, ultraviolet B.
Cyclosporine.
Tacrolimus.
Unreported type.
Amoxycillin and clavulanic acid.
Methotrexate.
The most commonly used combination treatment was topical corticosteroids with oral antihistamines; however, it resulted in no resolution in 48.5% (n = 16/33) of cases, worsening in 18.2% (n = 6/33) of cases, partial resolution in 24.2% (n = 8/33) of cases, and complete resolution in 9.1% (n = 3/33) of cases. Of all combination therapies reported, the use of PUVA with either topical corticosteroids or oral retinoids resulted in the most number of complete resolution outcomes (44.4%, n = 4/9 and 60.0%, n = 3/5, respectively) and partial resolution outcomes (33.3%, n = 3/9 and 40.0%, n = 2/5, respectively).
Our findings suggest that only a portion of patients with PEO respond well to treatment with oral corticosteroids, PUVA, oral retinoids, or a combination of PUVA with either topical corticosteroids or oral retinoids. One of the main challenges of treatment stems from the unknown pathogenesis of PEO, which is thought to be mediated by Th2 and Th22 cytokines.1 Th2 cytokines are important mediators of IgE production and eosinophil survival,3 which are both elevated in patients with PEO.2 Additionally, the percentage of IL-4, IL-13, and IL-22 producing CD4+ and CD8+ T cells were found to be increased in the circulatory systems of patients with PEO and decreased with disease remission.1 Accordingly, the inhibition of IL-4 and IL-13 through the use of dupilumab was recently reported as a successful treatment for 2 patients with PEO.4
The limitations of our review include its small sample size and the observational nature of studies (9 case series and 73 case reports). Additionally, there were limited data available for treatment combinations, doses, timelines of resolution outcomes, and adverse events. Investigations are warranted to further explore other therapeutic modalities and to develop effective treatment guidelines for patients with PEO.
Conflicts of interest
Dr. Jensen Yeung has been a speaker, consultant, and investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, Leo, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant, and Xenon. Dr. Mufti, Dr. Lytvyn, Mr. Abduelmula Mr. Kim, and Ms. Sachdeva have nothing to declare.
Footnotes
Funding Sources: None.
IRB approval status: Not applicable.
References
- 1.Teraki Y., Inoue Y. Skin-homing Th2/Th22 cells in papuloerythroderma of Ofuji. Dermatology. 2014;228(4):326–331. doi: 10.1159/000358588. [DOI] [PubMed] [Google Scholar]
- 2.Torchia D., Miteva M., Hu S., Cohen C., Romanelli P. Papuloerythroderma 2009: two new cases and systematic review of the worldwide literature 25 years after its identification by Ofuji et al. Dermatology. 2010;220(4):311–320. doi: 10.1159/000301915. [DOI] [PubMed] [Google Scholar]
- 3.Brandt E.B., Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011;2(3):110. doi: 10.4172/2155-9899.1000110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Teraki Y., Taguchi R., Takamura S., Fukuda T. Use of dupilumab in the treatment of papuloerythroderma of Ofuji. JAMA Dermatol. 2019 doi: 10.1001/jamadermatol.2019.0946. [DOI] [PubMed] [Google Scholar]