S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin.

Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S. epidermidis to examine its effects on the skin. The results showed that in S. epidermidis-conditioned ACD, the ear thickness of S1pr2fl/flK14-Cre mice was lower than that of S1pr2fl/fl mice, and mRNA expressions of Il-1ß and Cxcl2 of S1pr2fl/flK14-Cre mice were lower than that of S1pr2fl/fl mice in ACD with S. epidermidis. Furthermore, the gene expression of Claudin-1 and Occludin in S1pr2fl/flK14-Cre mice was higher than that of S1pr2fl/fl mice in ACD with S. epidermidis. The study concludes that S. epidermidis colonization improves the skin barrier and prevents ACD even when S1P signaling malfunctions.

Use of Contact Immunotherapy in the Treatment of Skin Diseases Other than Alopecia Areata.

For decades, contact immunotherapy with dinitrochlorobenzene, diphencyprone, and squaric acid dibutylester has played an important role in both clinical practice and scientific research. It is listed as the first-line treatment for extensive alopecia areata and was more recently approved for melanoma treatment as an orphan drug in the USA. Moreover, owing to the relative low cost and safety, topical immunotherapy has also been used in many infectious, neoplastic, and inflammatory dermatological diseases. It is especially valuable in vulnerable groups, for cosmetic/pain sensitive areas, or for multiple lesions. In this review, we summarize the current evidence supporting the use of contact immunotherapy for treatment of skin diseases, from articles collected from PubMed database. Owing to space limitation and already numerous studies focusing on alopecia areata, we include only skin diseases other than alopecia areata. In addition to diseases that have been reported to be treated by contact immunotherapy, the hypothesized mechanism, prognosis prediction, efficacy, and safety of these topical agents are discussed.

Making a mouse out of a molehill: how precision modeling repurposes drugs for congenital giant nevi.

Patients with congenital giant nevi (CGN), which can compromise quality of life and progress to melanoma, have limited treatment options. Choi et al. have demonstrated that topical application of a proinflammatory hapten for alopecia treatment [squaric acid dibutylester (SADBE)] caused nevus regression and prevented melanoma in an Nras mouse CGN model. Their results demonstrate the promise of repurposing drugs through precision modeling.

Therapeutic approach with squaric acid dibutylester for steroid resistant-alopecia areata incognita: A pilot study of a single center.

Topical immunotherapy is widely used in the treatment of alopecia areata (AA). Alopecia areata incognita (AAI) is a relatively common disorder, predominantly affecting females, characterized by widespread hair thinning in the absence of typical alopecic patches. AAI can have a chronic relapsing course and in some cases can be resistant to current standard treatments. Topical immunotherapy has been used in the management of AA with encouraging results, but to date there are no literature studies reporting the efficacy of topical immunotherapy with squaric acid dibutylester (SADBE) in AAI. The aim of our study is to evaluate the efficacy and tolerance of topical immunotherapy with SADBE in AAI not responding to conventional steroid therapy. A total of 12 patients were enrolled in our Hair Disease Outpatient Service, with a proved histological diagnosis of AAI, and resistant to classical steroid therapy. Each patient underwent global photography, pull test, and trichoscopy at beginning and during the follow-ups. The efficacy of topical immunotherapy with SADBE was assessed by evaluating the changes of clinical and trichoscopic signs. Complete regrowth was achieved in 66.7% of cases (8/12), three patients remained unchanged on clinical evaluation but showed subclinical improvement on trichoscopy, whereas one patient progressed and worsened both on clinical and trichoscopic examination. All patients reported scalp diffuse mild erythema and itching the day after the application of SADBE, which were well tolerated. Three patients developed reactive cervical lymphoadenomegaly. No other side effects were observed. Topical immunotherapy with SADBE is widely used in the management of patchy AA and can be considered an effective alternative in resistant AAI, providing visible clinical and trichoscopic improvement in the majority of cases. Further studies are warranted to confirm and validate our findings.

Squaric acid dibutyl ester for the treatment of alopecia areata: A retrospective evaluation.

Squaric acid dibutyl ester (SADBE) as topical immunotherapy is a good alternative in patients with refractory alopecia areata. In this study, we aimed to evaluate the effectiveness of SADBE treatment in alopecia areata (AA) and alopecia totalis/alopecia universalis (AT/AU) patients and determine the prognostic factors affecting treatment response. Data obtained from 34 (AA/AT/AU) patients treated with SADBE were analyzed retrospectively. Of the 34 patients, 16 (47.1%) were female and 18 (52.9%) were male. Sufficient responses were obtained in 19 (55.9%) patients. About 9 of the 19 patients (47.4%) with sufficient response reached a cosmetically acceptable level. As the severity of disease subsided, response to treatment increased. A better response was obtained when the disease onset in the spring and winter. Patients with a disease duration between 1 and 5 years responded better to the SADBE treatment compared to those with a disease shorter than 1 year and longer than 5 years. Severity of the disease, onset season of the disease, number of flares, duration of disease, and low levels of vitamin D in adult patients were observed to affect the SADBE response negatively.

Topical immunotherapy in combination with anthralin in the treatment of refractory alopecia areata.

BACKGROUND: Treatment is often challenging in patients with alopecia areata. We often try topical immunotherapy to treat alopecia areata in Japan. Anthralin is sometimes used in other countries. OBJECTIVES: The aim of this study was to examine effectiveness of combination therapy with both topical immunotherapy with squaric acid dibutylester or diphenylcyclopropenone and anthralin in the treatment of refractory alopecia areata. METHODS: We treat four patients with refractory alopecia areata by topical immunotherapy and anthralin. Two patients had alopecia areata multilocularis and the other two patients had alopecia totalis. The entire scalp was treated with weekly application of squaric acid dibutylester or diphenylcyclopropenone and daily 0.5% anthralin ointment. Patients were followed up weekly, and adverse effects were recorded. RESULTS: One patient with multifocal patches of alopecia areata got complete hair regrowth at week 30, the other patient with multifocal patches of alopecia areata turned for the worse at week 30 and recovered at week 52. Hair regrowth was not seen in the other two patients with alopecia totalis. Localized pruritis and hyperpigmentation of the scalp were seen in two patients. CONCLUSIONS: To treat alopecia areata unresponsive to topical immunotherapy alone, topical immunotherapy in combination with anthralin is worth a try.

Modified immunotherapy for alopecia areata.

Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA.

SADBE (Squaric acid dibutylester) Immunotherapy in Alopecia Areata / 대한피부과학회지

BACKGROUND: To date, highly variable results for use of topical Squaric acid dibutylester (SADBE) in the treatment of alopecia areata have been reported. Furthermore, there are no reports on SADBE in Korean dermatologic literature yet. OBJECTIVE: The purpose of this study was to evaluate the efficacy and the tolerability of SADBE in the treatment of severe alopecia areata. METHOD: A total of 22 cases of severe alopecia areata were enrolled in this study. After sensitization of the patients with 2% SADBE in acetone, the subsequent on-going treatments were done with 0.00001% to 2% SADBE with an interval of 1 to 2 weeks. The sensitization rate, the therapeutic efficacy and side effects of SADBE during the treatment course were evaluated. The efficacy was evaluated by 5 rating scales and we continued to check the recurrence of the lesions in the patients who had shown complete regrowth. RESULTS: The mean sensitization rate was 1.55. The treatment frequency at the time of initial hair regrowth ranged from 5 to 21 (mean-10.2). In the 22 patients who were treated for 6 months, more than 90% regrowth in 10 patients (45.5%) was observed, good or fair results (50-89% regrowth) in 3 patients (13.6%), and less than 49% regrowth in 9 patients (40.9%). In this study, only the duration of disease and being recurrent or not, among many prognostic factors, were statistically significant (p<0.05, chi2 -test). In half of the patients, various side effects were observed. Most common side was severe eczema at the sensitization site. Side effects during the treatment course were as follows; severe contact dermatitis, remote dermatitis, generalized pruritus, lymphadenopathy, and dermographism. But the result of side effects was not enough to give up treatment. Of the 10 patients who showed more than 90% regrowth, 4 patients had a recurrence of the lesion in their follow-up period (mean-4.75 months). CONCLUSION: The SADBE immunotherapy is effective and well-tolerated in Korean patients with severe alopecia areata.