Refractory Skin Disease Research Articles

Efficacy of combined lymphoplasma exchange for the treatment of severe refractory immune-related skin diseases: a clinical observation

Objective To evaluate the clinical efficacy of lymphoplasma exchange (LPE) for the treatment of severe refractory immune-related skin diseases. Methods From May 2013 to October 2015, 8 patients with toxic epidermal necrolysis, drug-induced hypersensitivity syndrome (DIHS) , pemphigus vulgaris, pemphigoid or paraneoplastic pemphigus were enrolled from Department of Dermatology, Xiangya Hospital, Central South University, who showed no response to conventional therapy or presented with multiple organ dysfunction. After the treatment with LPE, the efficacy was evaluated, and adverse reactions were observed. Results After one session of LPE therapy, 6 patients received marked improvement, and were cured at last. In 1 patient with pemphigus vulgaris who was resistant to the treatment with high doses of glucocorticoids and immunosuppressive agents, the rashes regressed during the treatment with LPE, but recurred after the end of treatment. One patient with bullous pemphigoid presented with eruptive blisters on the next day after the treatment with LPE, which were considered as allergic reactions to allogeneic plasma. There were no obvious differences in white blood cell count, lymphocyte count, neutrophil count and blood platelet count in the peripheral blood of 8 patients before and after the treatment with LPE. During the follow-up of 3-5 years, all of the patients were recovered without recurrence, except 1 patient with bullous pemphigoid who died of disseminated tuberculosis after 1 year. Conclusion LPE is effective for the treatment of severe immune-related skin diseases, but attention should be paid to potential transfusion reaction and allergic reactions. Key words: Plasma exchange; Epidermal necrolysis, toxic; Pemphigus; Pemphigoid, bullous; Drug reaction with eosinophilia and systemic symptoms; Paraneoplastic pemphigus

Intravenous immunoglobulin is an effective treatment for refractory cutaneous dermatomyositis.

Cutaneous dermatomyositis (DM) is often refractory to multiple systemic medications, suggesting a need for effective alternative treatments. To investigate the effects of intravenous immunoglobulin (IVIG) on patients with refractory cutaneous DM. This was a retrospective review of 42 patients treated with IVIG for refractory cutaneous DM at our institution with clinical data available at DM diagnosis. IVIG was initiated for refractory cutaneous DM alone (n = 15) or refractory cutaneous and muscle/lung disease (n = 27) in patients with various DM subtypes. Overall, 83% of patients had cutaneous DM improvement, including 87% treated for refractory skin disease alone and 81% treated for refractory skin/muscle/lung disease. Cutaneous DM improvement occurred regardless of DM subtype, and was observed after a mean of 1.82 ± 1.38 IVIG cycles. No statistically significant clinical predictors of IVIG response or lack of response were detected. IVIG use resulted in decreased systemic glucocorticoid exposure with or without a decrease in steroid-sparing immunosuppressive medications in 80% of patients. This study is limited by its retrospective nature and lack of objective cutaneous DM activity assessment. Use of IVIG resulted in improvement of refractory cutaneous DM in the vast majority of patients relatively soon after initiation and regardless of DM subtype or clinical manifestations. Additionally, IVIG allowed decrease or discontinuation of immunosuppressive medications in 80% of patients. These findings suggest that IVIG can be a clinically efficacious and cost-effective treatment for refractory cutaneous DM and warrants prospective study.

Combined mepacrine-hydroxychloroquine treatment in patients with systemic lupus erythematosus and refractory cutaneous and articular activity.

Aim The aim of this study was to evaluate the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with systemic lupus erythematosus and refractory joint and/or skin disease. Methods Mepacrine was added to 46 systemic lupus erythematosus patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs ( n = 24), hydroxychloroquine + prednisone ( n = 16), hydroxychloroquine + prednisone + retinoids ( n = 2), hydroxychloroquine alone ( n = 1), hydroxychloroquine + one immunosuppressive drug ( n = 1), hydroxychloroquine + prednisone + one immunosuppressive drug + belimumab ( n = 1) or hydroxychloroquine + prednisone + belimumab ( n = 1). The outcome variable was the clinical response, either complete or partial, based on clinical judgement. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score were additionally used. Results A total of 91% patients showed complete/partial response, with similar rates among those with joint or skin disease. In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen. There also was a statistically significant decrease in the SLEDAI. The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/d ( p = 0.001). Prednisone could be discontinued in 20% of patients. No serious adverse events were seen. Smoking was the only predictor of complete response. Conclusion In the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses. The fact that smokers responded better opens the door to further studying the combination of mepacrine-hydroxychloroquine as a first-line therapy in such patients.

014 Combining secukinumab and apremilast to successfully treat refractory psoriatic skin and joint disease: a novel approach

014 Combining secukinumab and apremilast to successfully treat refractory psoriatic skin and joint disease: a novel approach

Current developments in phototherapy for psoriasis.

Phototherapy utilizes the beneficial effects of ultraviolet (UV) wavelengths to affect immunoregulatory functions. UV light phototherapy using narrowband UV-B (NB-UVB) and bath-psoralen UV-A (bath-PUVA) therapy are well-established treatments for psoriasis. Dual-action mechanisms of UV phototherapy have been identified: apoptosis and immune suppression. NB-UVB depletes pathogenic T cells by inducing apoptosis and regulatory T cells. Other wavelengths are also utilized for phototherapy, namely 308-nm excimer light and 312-nm flat-typed NB-UVB. Excimer light (308-nm) therapy effectively targets the affected skin without unduly exposing other areas and increases the levels of regulatory T cells. Phototherapy improves impaired resting regulatory T cells and increases activated regulatory T cells in patients with psoriasis. Intensive studies of phototherapy effects have led to several improvements in the design, protocols, and light sources, such as UV light-emitting diodes, thereby providing several options for patients with refractory skin disease, such as psoriasis.

The use of biodegradable microneedle patches to increase penetration of topical steroid for prurigo nodularis.

The stratum corneum is an almost impermeable barrier. Recently, microneedles have been used to increase drug delivery passing the stratum corneum by incorporating the drug within the microneedle or by coating the surface of the microneedle with the drug. This study was performed to investigate whether applying a biodegradable microneedle patch after topical steroid application increases penetration of the steroid in vitro, as well as treatment efficacy in patients with prurigo nodularis. In vitro penetration of topical steroids after biodegradable microneedle patch application was measured using a 3D skin model. To evaluate the treatment efficacy of the combination of biodegradable microneedle and topical steroids, a split-body clinical study was performed. Penetration of topical steroid in the in vitro skin model was significantly greater in the microneedle-applied skin. In a split-body clinical study with prurigo nodularis patients, the area and height of skin lesions decreased after four weeks of treatment on both sides, however, the microneedle patch side exhibited a significantly greater decrease in both area and height, compared to the control side. The pruritus visual analogue scale was also significantly lower on the microneedle side. We suggest that simply applying a microneedle patch after topical steroid application could be a useful strategy for treating refractory skin diseases such as prurigo nodularis.

Effect of BTXA on Inhibiting Hypertrophic Scar Formation in a Rabbit Ear Model.

Hypertrophic scar (HS) is a refractory skin disease caused by major physical damage or other inflammation. Some reports found that botulinum toxin type A (BTXA) could be an alternative treatment of the HS. Therefore, the authors studied the effects of BTXA on the treatment of HS and the dose response of BTXA. Hypertrophic scars were harvested from the ears of 18 young adult New Zealand big-eared rabbits and treated with BTXA or triamcinolone acetonide (TAC) in vivo experiment. The hypertrophic index (HI) was measured by histological examination. Collagen fibrils were checked by sirius red straining, and the cell nucleuses of fibroblasts were checked by Ki67. The HI of hypertrophic scars with BTXA treatment was lower than that with phosphate-buffered saline treatment (P<0.05). Compared with the TAC treatment group, the efficacy of treatment with the middle dose of BTXA (1.0, 1.5IU) had no significant difference, as shown by sirius red staining and immunohistochemistry Ki67. These results demonstrated that BTXA effectively improved the appearance of hypertrophic scars and inhibited the formation of collagen fibrils and fibroblasts in vivo. Treatment with the middle dose of BTXA achieved similar efficacy as TAC treatment, indicating that BTXA might be useful for inhibiting hypertrophic scars and worth investigating further. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Altered balance of epidermis-related chemokines in epidermolysis bullosa

BackgroundEpidermolysis bullosa (EB) is a congenital, refractory skin disease and there are no fundamental treatments. Recently, allogenic cell therapies are beginning to be applied as potential treatments, that are based on the concept that the allogenic cells can migrate into the skin and reconstitute the skin components. Although the mechanisms of cell migration into skin are not fully understood, chemokines are regarded as key factors in recruiting bone marrow-derived cells. ObjectivesOur study aims to elucidate the expression of chemokines in the EB patients. MethodsWe determined the expression of wound-healing related chemokines in the sera, keratinocytes, and skin tissues of EB patients and compared them to those of healthy volunteers by enzyme-linked immunosorbent assays, quantitative reverse transcription PCR, and immunofluorescence staining. ResultsThe serum levels of CXCL12 and HMGB1 were found to be significantly elevated in the EB patients. Conversely, the serum levels of CCL21 were found to be lower in the EB patients than in healthy controls. In addition, the serum levels of CXCL12 tended to increase and the serum levels of CCL27 tended to decrease with an increase in the affected body surface areas. To detect the origin of the circulating chemokines, we performed immunofluorescence staining. CCL21, CCL27, HMGB1 and CXCL12 were stained more broadly in the EB patient tissues than those in the control tissues. ConclusionsThese results suggest that fluctuations in chemokine levels may contribute in a coordinated way to the wound-healing process and lend clues toward efficient cell therapies for EB.

Risk factors and treatment responses in patients with vitiligo in Japan—A retrospective large-scale study

Vitiligo is a refractory skin disease. To investigate the risk factors and treatment responses of patients with vitiligo in Japan, we recorded and analyzed the details of 713 vitiligo patients (comorbidity, treatment responses, family history, age, and sex) who visited the dermatology clinic of the Nagoya City University Hospital, Nagoya, Japan between January 2004 and August 2010 (mean age, 35.2 years; 302 men, 411 women) using logistic regression analysis. The results are expressed as odds ratios (OR) with 95% confidence interval (CI). Patients were diagnosed with vitiligo [n = 644; 338 generalized type (47.4%), 170 segmental type (23.8%), and 136 localized type (19.1%)], nevus depigmentosus (n = 53, 7.4%), halo nevus (n = 14, 2.0%), and hypomelanosis of Ito (n = 2, 0.3%). For generalized and localized types, none of the analyzed factors were statistically significant. For the segmental type, antinuclear antibody (OR = 1.005; 95% CI, 1.00–1.01; p < 0.05) and onset age < 14 years were the significant factors in patients between 15 years and 29 years (OR = 0.246; 95% CI, 0.113–0.538; p < 0.001), 30–54 years (OR = 0.0419; 95% CI, 0.0133–0.132; p < 0.001), and >55 years (OR = 0.0171; 95% CI, 0.00333–0.0879; p < 0.001). The treatment response rates for narrow-band UV-B, topical vitamin D3, and punch graft (1 mm minigraft) were, respectively, as follows: (1) generalized type: 46.3%, 21.1%, and 38.9%; (2) segmental type: 20.3%, 29.0%, and 77.3%; and (3) localized type: 29.2%, 54.8%, and 73.3%. We report the comorbidities and efficacy rates of these treatments. The response data for these treatments, in particular, would be of assistance to the previous explanations, because there were only a few reports on the response data for these treatments. The appropriate treatment should be selected depending on the type of vitiligo.

Two-Stage Surgery for Hidradenitis Suppurativa: Staged Artificial Dermis and Skin Grafting

Hidradenitis suppurativa is a chronic and often refractory skin disease that can require radical excision of the full layer of fatty tissue under the lesion. Closure using a split-thickness skin graft often results in depression deformity and lack of tissue flexibility. We have developed a two-stage procedure to preserve fatty tissue during radical excision and apply an artificial dermis graft, and we have performed this procedure in 18 patients (33 lesions). To describe our two-stage procedure and report results of the procedure in our patient series. In the first step, all diseased skin including the superficial subcutaneous fatty tissue is excised; normal deep subcutaneous fatty tissue is preserved. Artificial dermis is then grafted to the preserved fatty tissue. Two weeks later, split-thickness skin grafts are applied to the skin defects. We evaluated graft success, any recurrence, and postoperative appearance in our patients, who were followed up for 8 to 36months. All 32 skin grafts were successful. There was only one recurrence, which was treated using reoperation, and postoperative appearances were good. Our new procedure incorporating artificial dermis appears to be a good treatment option for advanced hidradenitis suppurativa.

Granulocyte and Monocyte Adsorption Apheresis for Refractory Skin Diseases due to Activated Neutrophils, Psoriasis, and Associated Arthropathy

Granulocyte and monocyte adsorption apheresis (GMA), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is designed to remove activated granulocytes and monocytes. We previously demonstrated that GMA was useful for treating neutrophilic dermatoses and associated arthropathy as it adsorbs Mac-1 (CD11b/CD18)-expressing neutrophils to the CA beads by the binding of complement component (iC3b) and CD11b expressed on activated neutrophils. The objective of this study is to further assess the clinical effectiveness of GMA in the treatment of neutrophilic dermatoses and associated arthropathy. The effect of GMA for skin lesions and joint lesions was assessed in 44 and 23 patients, respectively. Mac-1 expression on peripheral neutrophils was measured by flow cytometry. Skin lesions and arthropathy improved in 39 of 44 patients (88.6%) and 22 of 23 (95.6%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, 27.1 ± 6.66 MFI (mean fluorescence intensity) before treatment, was reduced to 17.9 ± 3.02 MFI by GMA (P < 0.05). Clinical effectiveness of GMA for the treatment of intractable neutrophilic dermatoses and associated arthropathy was further confirmed.

Intranasally Administered Antigen 85B Gene Vaccine in Non-Replicating Human Parainfluenza Type 2 Virus Vector Ameliorates Mouse Atopic Dermatitis

Atopic dermatitis (AD) is a refractory and recurrent inflammatory skin disease. Various factors including heredity, environmental agent, innate and acquired immunity, and skin barrier function participate in the pathogenesis of AD. T -helper (Th) 2-dominant immunological milieu has been suggested in the acute phase of AD. Antigen 85B (Ag85B) is a 30-kDa secretory protein well conserved in Mycobacterium species. Ag85B has strong Th1-type cytokine inducing activity, and is expected to ameliorate Th2 condition in allergic disease. To perform Ag85B function in vivo, effective and less invasive vaccination method is required. Recently, we have established a novel functional virus vector; recombinant human parainfluenza type 2 virus vector (rhPIV2): highly expressive, replication-deficient, and very low-pathogenic vector. In this study, we investigated the efficacy of rhPIV2 engineered to express Ag85B (rhPIV2/Ag85B) in a mouse AD model induced by repeated oxazolone (OX) challenge. Ear swelling, dermal cell infiltrations and serum IgE level were significantly suppressed in the rhPIV2/Ag85B treated mouse group accompanied with elevated IFN-γ and IL-10 mRNA expressions, and suppressed IL-4, TNF-α and MIP-2 mRNA expressions. The treated mice showed no clinical symptom of croup or systemic adverse reactions. The respiratory tract epithelium captured rhPIV2 effectively without remarkable cytotoxic effects. These results suggested that rhPIV2/Ag85B might be a potent therapeutic tool to control allergic disorders.

Successful management of refractory cases of canine demodicosis with homeopathy medicine Graphitis.

Canine demodicosis is a refractory skin disease caused by excessive proliferation of mite Demodex canis. Despite availability of several treatment options, the disease poses a great challenge to clinicians for its long term management as some drugs may be ineffective or toxic. Present report describes successful treatment of two refractory cases of canine demodicosis using homeopathy medicine. After oral administration of Graphitis 200 C two drops once daily for 2months, complete cure from the disease was observed. No adverse health effects of the medication were recorded during the treatment. Thus, it may be concluded that homeopathy medicine may be used safely for long-term management of canine demodicosis.

Development of PAC-14028, a novel transient receptor potential vanilloid type 1 (TRPV1) channel antagonist as a new drug for refractory skin diseases

The transient receptor potential vanilloid 1 (TRPV1) is a member of nonselective cation channels and has been implicated in the progression of neurogenic inflammation and nociception. Through the synthesis of over 2,000 new compounds, a novel non-vanilloid TRPV1 antagonist PAC-14028 was discovered. As well as ideal physicochemical and pharmacokinetic properties, PAC-14028 showed meaningful efficacies against diverse disease models that include visceral pain, inflammatory bowel disease, and inflammatory pain. Of note, PAC-14028 effectively attenuates atopic dermatitis and pruritus without significant adverse effects, which is a substantial benefit over conventional pharmacotherapy. This report introduces the potential of a novel TRPV1 antagonist PAC-14028 as a new drug for atopic dermatitis and pruritus.

Efficacy of 1-mm minigrafts in treating vitiligo depends on patient age, disease site and vitiligo subtype

Vitiligo vulgaris is a refractory skin disease. Treatment modalities include topical steroids, phototherapy, suction blister roof grafts and cellular grafting techniques. Adverse effects may occur, however, and some cases remain unresponsive to treatment. To evaluate the efficacy of small (1-mm) punch minigraft therapy in relation to patient age, disease site, disease duration and vitiligo subtype. We used a recently developed disposable 1.0-mm punch apparatus to perform minigraft therapy in 20 patients with either generalized (n = 4), segmental (n = 9) or limited (n = 7) vitiligo, and evaluated the area and rate of repigmentation in relation to patient age, disease site, disease duration and vitiligo subtype. The area of repigmentation was significantly greater in patients with segmental vitiligo (n = 9) than in those with generalized vitiligo (n = 4). Repigmentation covered a broader area and occurred more quickly in patients under 15 years of age than in those over 20 years of age (n = 9). Disease duration did not affect the repigmentation rate. The results of the present study suggest that 1-mm minigrafts are effective for treating patients with vitiligo. Better results occurred in patients under 15 years of age, patients with facial grafts, and patients with segmental and limited subtypes.

Successful treatment of psoriasis vulgaris with targeted narrow‐band ultraviolet B therapy using a new flat‐type fluorescent lamp

Narrow-band ultraviolet B (NB-UVB) therapy is widely used for refractory skin diseases. Targeted phototherapy is now being used to reduce the number of sessions and to avoid exposing normal skin. We developed a targeted NB-UVB therapy using a flat-type lamp emitting a wavelength similar to that of the TL-01 fluorescent lamp. Six Japanese patients with psoriasis were recruited and treated with the flat-type NB-UVB device with an initial dose of 70% of the minimal erythema dose, with a 20% increase at each subsequent session. The plaque severity score was determined. All lesions of the tested patients were responsive to NB-UVB therapy using the flat-type lamp. The mean percent reduction of the lesion was 58.3 ± 17.7%. The mean cumulative dose was 20.8 ± 10.8 J/cm². No side effects were observed during treatment. The flat-type targeted NB-UVB device is compact and convenient, and highly effective for the treatment of limited psoriasis lesions.

Ultraviolet rays in cutaneous photobiology

Currently. cutaneOU8 photobiology is extensively investigated in the field of dermatology.Ultraviolet rays can not only induce skin injury, photoaging, and even skin tumors, but also be utilized to treat numerous refractory skin diseases; hence. they act as a double-edged sword. Experimental and clinical work focusing on ultraviolet photobiology will unveil their mystery, help avoid the harmful and use the favorable effects of ultraviolet rays. Key words: Photobiology; Ultraviolet rays; Cell aging

Feasibility and accuracy of a newly developed hand‐held device with a flat‐type fluorescent lamp for measuring the minimal erythema dose for narrow‐band UVB therapy

Narrow-band ultraviolet B (NB-UVB) for the treatment of refractory skin diseases, such as psoriasis and atopic dermatitis, requires an adequate irradiation protocol based on the minimal erythema dose (MED) to establish an optimal dosage schedule. Although MED can be measured using a systemic-type irradiation unit, there are difficulties associated with this device. There is no standardized device available to determine the MED for NB-UVB. Here, we compared a conventional device with a newly developed device for measuring MED. MED was measured in 16 psoriasis patients using both a conventional measuring device and the newly developed device, which comprised a hand-held NB-UVB (311-313 nm) flat-type fluorescent lamp with neutral density filters having different transmittances ranging from 10% to 90%. This device was designed to be stably maintained on the skin surface and to provide a highly accurate measurement with only one UV irradiation exposure while also preventing UV radiation from leaking to nonirradiated areas. The MED values obtained from each patient were the same using both devices. One-time irradiation using the new hand-held device with the NB-UVB flat-type fluorescent lamp is feasible and accurate for determining the MED to use in calculating the UV irradiation treatment dose.

Rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report

Pulmonary hypertension is a common but underdiagnosed complication of systemic lupus erythematosus, which can be associated with significant morbidity and early mortality. Although often associated with anti-phospholipid antibodies, the etiology remains poorly understood. In case reports and small open trials, the anti-CD20, B-cell targeted therapeutic antibody, rituximab, has been reported to provide benefits for systemic lupus erythematosus patients with glomerulonephritis, anti-phospholipid antibody syndrome, vasculitis, arthritis, and refractory skin disease. However, the outcome of rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus has not been described. We, therefore, present a case of a young systemic lupus erythematosus patient with early onset of pulmonary arterial hypertension during the disease course, refractory to multiple treatment modalities, who had significant improvement with rituximab therapy.

Advances in the treatment of benign familial pemphigus

家族性良性天疱疮是一种少见的常染色体显性遗传性疾病,由ATP2C1基因突变所致.临床上病情反复,治疗困难,目前主要有药物治疗、外科治疗和激光治疗.药物治疗包括糖皮质激素、抗生素、维A酸类、维生素D3类似物、他克莫司和肉毒毒素等.为防止复发和延长缓解时间,可选用外科治疗和激光治疗.抗白介素-6抗体等生物学疗效有望治疗本病。