Biological effects of a new ultraviolet A1 prototype based on light-emitting diodes on the treatment of localized scleroderma.

Ultraviolet A1 (UVA1 ) phototherapy (spectral range 340-400 nm) is a well-established treatment option for various skin diseases such as localized scleroderma. Recent improvements of conventional UVA1 light sources (metal-halide or fluorescent lamps) have brought attention to a new light-emitting diode (LED) technology with remarkable advantages in handling and clinical routine. This study provides a preclinical histological and molecular evaluation of an LED-based UVA1 prototype with a narrower spectral range (360-400 nm) for treating localized scleroderma. Scleroderma mouse models and fibroblasts in vitro were exposed to LED-based UVA1 phototherapy or to irradiation with a commercially available metal-halide lamp emitting low-dose (20, 40 J/cm2 ), medium-dose (60 J/cm2 ) and high-dose (80, 100 J/cm2 ) UVA1 light. Both UVA1 light sources affected inflammatory genes (IL-1α and IL-6) and growth factors (TGFß-1 and TGFß-2). Increased collagen type 1 was reduced after UVA1 phototherapy. Matrix metalloproteinase-1 was more enhanced after a medium dose of LED-based UVA1 phototherapy than after conventional treatment. In vivo, dermal thickness and the amount of collagen were reduced after both treatment methods. Remarkably, myofibroblasts were more effectively reduced by a medium dose of LED-based UVA1 phototherapy. The study indicates that LED-based UVA1 phototherapy yields similar or even better results than conventional treatment. In terms of biosafety and patient comfort, LED-based UVA1 phototherapy offers clear advantages over conventional treatment because of the use of a narrower and less harmful UVA1 spectrum, less heat generation and shorter treatment times at the same irradiation intensity. Clinical studies are required to confirm these results in patients with localized scleroderma.

The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice.

PURPOSE: To define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. MATERIALS AND METHODS: 42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365±5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. RESULTS: Skin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9±113.2µm and 394±125.9µm, respectively) in comparison to the dermal thickness of non-treated animals (599±55.7µm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11±1.7 and 13±2.2, respectively, as compared to that in non-treated mice (23±3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. CONCLUSIONS: The results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment.

The impact of high-dose narrowband ultraviolet A1 on dermal thickness, collagen and matrix-metalloproteinases in animal model of scleroderma.

OBJECTIVE: The main purpose of the present study was to define the impact of high-dose of 365±5nm ultraviolet A1 (UVA1) on dermal fibrosis in the pre-established, bleomycin-induced mouse model of scleroderma. METHODS: DBA/2 strain mice with the pre-established, bleomycin-induced scleroderma were irradiated with cumulative UVA1 dose of 1200J/cm2 and in parallel were challenged with prolonged administration of bleomycin. Non-treated groups served as the control. Light source emitting a narrow band UVA1 light of 365±5nm and 21mW/cm2 power density was used in the study. Histological analysis was performed for the evaluation of dermal thickness. The expressions of matrix-metalloproteinase-1 (MMP-1), matrix-metalloproteinase-3 (MMP-3), collagen types I and III were evaluated by immunohistochemical analyses. The Mann - Whitney U test was used for statistical analysis. RESULTS: Dermal thickness in mice injected with bleomycin during all the experiment (8weeks) and irradiated with UVA1 for the last 5weeks was significantly lower than that in mice challenged only with bleomycin for 8weeks (253.96±31.83µm and 497.43±57.83µm, respectively; P=0.002). The dermal thickness after phototherapy was lower as compared with the pre-existing fibrotic changes observed after 3weeks of bleomycin injections (253.96±31.83µm and 443.87±41.76µm, respectively; P=0.002). High-dose of UVA1 induced the 5.8- and 5.2-fold increase in MMP-1 and MMP-3 expressions, respectively, and the 1.2- and 1.4-fold decrease in collagen type I and collagen type III expressions in the pre-established, bleomycin-induced scleroderma model as compared to that in the control non-irradiated mice (P=0.002). CONCLUSIONS: Our study has demonstrated that a cumulative 365±5nm UVA1 radiation dosage of 1200J/cm2 not only prevents the progression of dermal fibrosis, but also induces a regression of pre-existing fibrotic changes.

[Pemetrexed-induced scleroderma-like changes in the lower legs]. / Sclérose cutanée des deux membres inférieurs sous pemetrexed.

BACKGROUND: Pemetrexed (Alimta(®)) is a new-generation antifolate used to treat malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). We report two cases of a new toxicity induced by pemetrexed: scleroderma-like induration of the lower extremities. PATIENTS AND METHODS: The first case concerned a 66-year-old man diagnosed with pulmonary adenocarcinoma metastatic from the outset and in whom maintenance treatment comprised pemetrexed after first-line therapy comprising six courses of cisplatin-pemetrexed. After the fourth cycle of pemetrexed, he presented an erythematous oedema of the left leg, which was subsequently bilateral. Clinically, there was painful cellulitis associated with areas of bruising. The lesions had an appearance of erysipeloid-like infection, and there was no fever. The second case concerned a 70-year-old woman diagnosed with metastatic NSCLC. From the first course of pemetrexed, given as maintenance therapy, she presented erythematous oedema of both legs, without fever. After the second course, we observed the recurrence of the lesions consisting of erythemato-violaceous plaques on both legs, with severe bilateral indurated and painful oedema, associated with major functional disability. A diagnosis of bilateral erysipelas was made, and antibiotic treatment with cloxacillin was given. In both cases, pemetrexed was discontinued and the local outcome was very slowly favourable, with persistence of scleroderma. DISCUSSION: This cutaneous adverse effect is unrecognized, resulting in delayed diagnosis. It is often initially confused with bilateral erysipelas, despite absence of fever. According to some studies, the severity of the cutaneous toxicity may be connected with patients' folate status. Thus folate and vitamin B12 supplementation combined with dexamethasone could decrease the incidence of this side effect. There was no recurrence and no worsening with taxanes, chemotherapy agents known to induce scleroderma. We feel that this cutaneous toxicity must be recognised on account of its potential severity.

New side effect of TNF-alpha inhibitors: morphea.

An otherwise healthy 45-year-old man with a 3-year history of poorly controlled psoriasis (no arthritis) was treated with etanercept 50-mg subcutaneous injections twice weekly for 3 months and then once weekly. Alternative treatment options were either unavailable (long commute for phototherapy) or contraindicated (history of alcohol abuse). The patient initially tolerated etanercept well with significant clinical improvement and had an uneventful course; however, approximately 18 months after initiating therapy, he abruptly developed dusky, indurated, and tender plaques on his abdomen and thighs at the sites of etanercept injections (Figure 1). There was also diffuse woody induration involving his flanks and back where injections had not been performed. His only recent prior exposure to an injectable medication was rabies vaccination in his arm 1 year earlier. The patient denied any systemic symptoms. Upon noting these findings, etanercept was immediately discontinued. Biopsy of an indurated plaque on his right lower abdomen revealed a superficial and deep perivascular lymphoplasmacytic inflammatory infiltrate in a background of thickened and hyalinized collagen fibers with notable loss of perieccrine fat (Figure 2). These features were most consistent with the inflammatory stage of morphea. Further work-up revealed a negative antinuclear antibody, anti-double-stranded DNA, anti-Scl-70, and anti-centromere. Borrelia titers were not obtained. The differential diagnosis included scleredema and scleromyxedema; serum and urine protein electrophoresis were within normal limits. The sites were treated with intralesional corticosteroids. During the next 3 months, there was minimal progression of disease although the plaques of morphea had not yet resolved.

[Effect of Bufei Qingyu Granule in mollifying skin of mouse scleroderma model].

OBJECTIVE: To investigate the effect and mechanism of Bufei Qingyu Granule (BQG) in mollifying the skin of scleroderma model mice. METHODS: Scleroderma model induced with bleomycin in BALB/C mice 8-weeks old were administered with different dose of BQG for 26 days. The pathological changes of the mice skin were observed. RESULTS: Treatment with low, medium and high dose of BQG showed a tendency to ameliorate the thickened dermis in scleroderma mice but without statistical significance. Medium and high dose of BQG reduced the perivasculitis of dermis and alleviated the reduction or deletion of accessory structure, such as hair follicle and sweat gland. And the spleen index was lower markedly in mice treated with BQG of any dose than that in the untreated model mice (P < 0.05). CONCLUSION: BQG could ameliorate the sclerosed skin in model mice and prevent the occurrence of splenomegaly.

Post-mammoplasty human adjuvant disease.

Morphoea and keratoconjunctivitis sicca developed in a woman with seronegative rheumatoid arthritis six years after augmentation mammoplasty. Previous reports of post-mammoplasty connective tissue disease have followed the use of silicone gel, whereas the more 'biologically inert' saline-filled silastic implants were used in this case.