1.) Use of Imiquimod Cream 5% in the Treatment of Localized Morphea.

 2.) Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study.

3.) PUVA-cream photochemotherapy for the treatment of localized scleroderma.

4.) Topical calcipotriol ointment in the treatment of morphea.

5.) Combined treatment with calcipotriol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea.

6.) Treatment of scleroderma.

7.) Classification of morphea (localized scleroderma).

8.) Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma.

9.) Morphea and Toxoplasma Gondii [In Process Citation].

10.) Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma.

11.) Topical tacrolimus in the treatment of localized scleroderma.

12.) Does solitary morphoea profunda progress?.

13.) Oral calcitriol as a new therapeutic modality for generalized morphea.

14.) Morphea-like reaction to D-penicillamine therapy.

15.) Treatment of generalized morphea with oral 1,25-dihydroxyvitamin D3.

 

 

1.)  Use of Imiquimod Cream 5% in the Treatment of Localized Morphea.

J Cutan Med Surg. 2004 May 3 [Epub ahead of print]

Man J, Dytoc MT.

Division of Dermatology, University of Alberta, T6G 2G3, Edmonton, Alberta, Canada.

Fibrosis is characterized by the increased deposition of collagen and other matrix components by fibroblasts. This process occurs as a reaction to inflammation and is mediated by numerous cytokines including transforming growth factor beta (TGF-beta). Localized cutaneous scleroderma or morphea is characterized by fibrosis. Current treatment for morphea includes topical, intralesional, or systemic corticosteroids, vitamin D analog (calcitriol and calcipotriol), photochemotherapy, laser therapy, antimalarials, phenytoin, D-penicillamine, and colchicine, all with varying degrees of success. In this case report, imiquimod cream 5% (Aldara(R)), which induces interferon and in turn inhibits TGF-beta, was employed to treat morphea.

2.) Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study.

Photodermatol Photoimmunol Photomed. 2004 Apr;20(2):93-100.

El-Mofty M, Mostafa W, Esmat S, Youssef R, Bousseila M, Nagi N, Shaker O, Abouzeid A.

Department of Dermatology, Phototherapy Unit, Faculty of Medicine, Cairo University, Egypt.

BACKGROUND: Ultraviolet A (UVA) phototherapy proved to be an efficient line of treatment of scleroderma. The mechanism through which it acts is still not clear. OBJECTIVES: To detect the mechanism of action of UVA phototherapy in morphea through measuring its effect on the levels of different parameters related to collagen metabolism. METHODS: Twenty-one cases of morphea were treated with low-dose broad-band UVA for 20 sessions. Twelve cases received 20 J/cm(2)/session with a cumulative dose of 400 J/cm(2) and nine cases received 10 J/cm(2)/session with a cumulative dose of 200 J/cm(2). The response was assessed clinically every week. Two skin biopsies were taken from the lesional skin of each patient before starting and after the end of therapy. Paraffin sections were examined for quantitative polymerase chain reaction measurement of collagen I, collagen III, collagenase, transforming growth factor-beta (TGF-beta) and interferon gamma (IFNgamma). RESULTS: Eighteen patients reported remarkable softening of the skin lesions, with variable degrees ranging from moderate in 57.1% of them good in 19% to very good response in 9.5%. After treatment, all the studied parameters revealed statistically significant changes. There was a significant decrease in collagen I, collagen III and TGF-beta and a significant increase in collagenase (MMP-1) and IFNgamma. The relative change was found to be greatest in collagenase, followed by IFNgamma then TGF-beta and finally collagen I. The changes in collagen I, collagenase, IFNgamma and TGF-beta were found to increase gradually with the degree of clinical response. In all the parameters studied the relative change was significantly higher in cases treated with 20 J/cm(2)/session in contrast to those treated with 10 J/cm(2)/session although no statistically significant difference could be detected in the clinical response to those doses. CONCLUSIONS: The efficacy of low-dose UVA phototherapy in the treatment of localized scleroderma is mainly obtained by the increased production of MMP-1 and IFNgamma, and to a lesser extent by decreasing TGF-beta and collagen production. Concerning the use of 10 or 20 J/cm(2)/session those effects are dose dependent, but the clinical response does not significantly differ.

 

3.) PUVA-cream photochemotherapy for the treatment of localized scleroderma.

J Am Acad Dermatol. 2000 Oct;43(4):675-8

Grundmann-Kollmann M, Ochsendorf F, Zollner TM, Spieth K, Sachsenberg-Studer E, Kaufmann R, Podda M.

Department of Dermatology, Johann Wolfgang Goethe University, Frankfurt, Germany.

BACKGROUND: The efforts to treat localized scleroderma, including therapies with potentially hazardous side effects, are often unsatisfactory. Recently, PUVA-bath photochemotherapy has been proven highly effective in the treatment of localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen (8-MOP) containing cream or gel preparations, has been proven to be as effective as PUVA-bath therapy for palmoplantar dermatoses. OBJECTIVE: We sought to assess the efficacy of PUVA-cream photochemotherapy in patients with localized scleroderma. METHODS: Four patients with localized scleroderma were included in the study. Diagnosis was confirmed by 20 MHz ultrasound assessment as well as pretreatment skin biopsy specimens from lesional skin. PUVA-cream therapy was performed 4 times a week; all patients received 30 treatments. RESULTS: PUVA-cream photochemotherapy induced significant clinical improvement or clearance of localized scleroderma in all patients. Clearance was documented by clinical features as well as by 20 MHz ultrasound and histopathologic analysis. CONCLUSION: PUVA-cream phototherapy can be highly effective in patients with localized scleroderma even if previous therapy was unsuccessful.

 

4.)  Topical calcipotriol ointment in the treatment of morphea.

J Dermatolog Treat. 2003 Dec;14(4):219-21.

Tay YK.

National Skin Centre, and Changi General Hospital, 2 Simei Street 3, Singapore 529889. yong_kwang_tay@cgh.com.sg

A 5-year-old girl presented with a 2-month history of an indurated hypopigmented, atrophic plaque of biopsy-documented morphea over the right hip area. Previous treatment with 0,1% betamethasone valerate cream twice a day for 3 months failed to improve the lesion. She was treated with calcipotriol ointment twice daily, with nightly occlusion to the plaque for 9 months, and this resulted in resolution. No side effects were noted.

 

5.) Combined treatment with calcipotriol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea.

Pediatr Dermatol. 2001 May-Jun;18(3):241-5.

Kreuter A, Gambichler T, Avermaete A, Jansen T, Hoffmann M, Hoffmann K, Altmeyer P, von Kobyletzki G, Bacharach-Buhles M.

Department of Dermatology, Ruhr-University Bochum, Bochum, Germany. a.kreuter@derma.de

Various therapies for morphea have been used with limited success, including ones with potentially hazardous side effects. When morphea occurs in childhood it may lead to progressive and long-lasting induration of the skin and subcutaneous tissue, growth retardation, and muscle atrophy. We report an open prospective study in which the efficacy of a combined treatment with calcipotriol ointment and low-dose ultraviolet A1 (UVA1) phototherapy in childhood morphea was investigated. Nineteen children (mean age 8.5 years, range 3-13 years) with morphea were exposed to UVA1 (340-400 nm) phototherapy at a dose of 20 J/cm(2) four times a week for 10 weeks. Forty phototherapy sessions resulted in a cumulative dose of 800 J/cm(2) UVA1. In addition, calcipotriol ointment (0.005%) was applied twice a day. After 10 weeks, palpation and inspection showed a remarkable softening and repigmentation of formerly affected skin resulting in a highly significant (p < 0.001) decrease of the mean clinical score from 7.3 +/- 0.9 at the beginning to 2.4 +/- 0.9 (relative reduction 67.1%) at the end of combined therapy. Our results indicate that a combined therapy with calcipotriol ointment and low-dose UVA1 phototherapy is highly effective in childhood morphea. Further controlled studies are necessary to investigate whether this combined therapy is superior to UVA1 phototherapy alone.

 

6.) Treatment of scleroderma.

Arch Dermatol. 2002 Jan;138(1):99-105.

Sapadin AN, Fleischmajer R.

Department of Dermatology, Mount Sinai School of Medicine, 1425 Madison Ave, PO Box 1047, New York, NY 10029, USA.

The treatment of systemic sclerosis (scleroderma) is difficult and remains a great challenge to the clinician. Because the cause is unknown, therapies are directed to improve peripheral blood circulation with vasodilators and antiplatelet aggregation drugs, to prevent the synthesis and release of harmful cytokines with immunosuppressant drugs, and to inhibit or reduce fibrosis with agents that reduce collagen synthesis or enhance collagenase production. The purpose of this review is to critically analyze conventional and new treatments of systemic sclerosis and localized scleroderma. The therapeutic options discussed for the treatment of systemic sclerosis include the use of (1) vasodilators (calcium channel blockers [nifedipine], angiotensin-converting enzyme inhibitors [captopril, losartan potassium], and prostaglandins [iloprost, epoprostenol]), (2) immunosuppressant drugs (methotrexate, cyclosporine, cyclophosphamide, and extracorporeal photopheresis), and (3) antifibrotic agents (D-penicillamine, colchicine, interferon gamma, and relaxin). The treatment options reviewed for localized scleroderma include the use of corticosteroids, vitamin D analogues (calcitriol, calcipotriene), UV-A, and methotrexate. Preliminary reports on new therapies for systemic sclerosis are also considered. These include the use of minocycline, psoralen-UV-A, lung transplantation, autologous stem cell transplantation, etanercept, and thalidomide.

 

 7.) Classification of morphea (localized scleroderma).
 

Mayo Clin Proc. 1995 Nov;70(11):1068-76.

Comment in:
Mayo Clin Proc. 1996 Mar;71(3):318.

Peterson LS, Nelson AM, Su WP.

Division of Rheumatology and Internal Medicine, Mayo Clinic Rochester, MN 55905, USA.

OBJECTIVE: To classify and describe morphea (localized scleroderma). DESIGN: A review of morphea and its subtypes is presented. RESULTS: The current classification of morphea is incomplete and confusing. As knowledge of the spectrum of disease continues to evolve, the controversy and confusing nature of its multiple subtypes present a challenge for the physician who encounters a patient with this condition. Thus, we propose that morphea be classified into the following five groups: plaque, generalized, bullous, linear, and deep. This classification, based on clinical morphologic findings, will simplify the diagnostic and therapeutic approach. CONCLUSION: Morphea represents a wide variety of clinical entities that seen to be on the opposite end of the scleroderma spectrum from systemic sclerosis. The cutaneous lesions eventually evolve from a sclerotic stage to a nonindurated stage, and residual hypopigmentation or hyperpigmentation follows. The histologic pattern in patients with morphea is similar to that in patients with progressive systemic sclerosis. Although treatment is nonstandardized, hydroxychloroquine sulfate may be beneficial.

 

8.) Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma.

J Invest Dermatol. 2004 Mar;122(3):594-601.

Nagai M, Hasegawa M, Takehara K, Sato S.

Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Abnormal production of reactive oxygen species (ROS) induces tissue damage and superoxide dismutase (SOD) that converts superoxide radicals to hydrogen peroxide functions as defense against ROS. Cu/Zn SOD administration has been shown to be effective for various fibrotic conditions by inhibiting the fibrogenic effects of ROS. We hypothesized that autoimmune background in localized scleroderma induced anti-Cu/Zn SOD autoantibodies that inhibited SOD activity and thereby contributed to fibrosis by increasing ROS. ELISA using human purified Cu/Zn SOD revealed that IgG or IgM anti-Cu/Zn SOD Ab was detected in the serum of 89% of localized scleroderma patients, especially 100% of patients with generalized morphea, the severest form of localized scleroderma, but was positive only in the serum of less than 15% of patients with other autoimmune disorders, including systemic sclerosis, systemic lupus erythematosus, dermatomyositis, and autoimmune bullous disorders. The immunoblotting analysis confirmed the presence of IgG anti-Cu/Zn SOD Ab in sera from localized scleroderma patients. Remarkably, anti-Cu/Zn SOD autoantibody could inhibit Cu/Zn SOD enzymatic activity. Collectively, these results indicate that anti-Cu/Zn SOD Ab is a novel, major autoantibody in localized scleroderma, and also suggest that the autoantibody may play a role in the development of fibrosis by directly inhibiting SOD activity.

 

9.) Morphea and Toxoplasma Gondii [In Process Citation]

Rev Med Chir Soc Med Nat Iasi. 2003 Jul-Sep;107(3):646-9.
[Article in Romanian]

Solovastru L, Amalinei C.

Disciplina de Dermatologie, Facultatea de Medicina, Universitatea de Medicina si Farmacie Gr.T. Popa Iasi.

Circumscribed scleroderma or morphea is a rare disease that involves limited areas of skin and usually is not associated with visceral lesions. Its etiology is still debated, but its appearance signifies a particular immunological status. We present a case of a male patient, which developed morphea lesions during the infection with Toxoplasma gondii. Clinical manifestation was characteristic for the classic plaque-type of morphea. Diagnosis was confirmed by the histopathologic examine of the cutaneous lesions. The evolution of lesions was correlated with antibodies titre for Toxoplasma gondii, and local administration of corticosteroids accelerated the evolution to cutaneous lesions stabilization.

 

10.) Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma.

.

Arthritis Rheum. 2004 Jan;50(1):227-32.

Hayakawa I, Hasegawa M, Takehara K, Sato S.

Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

OBJECTIVE: To determine the prevalence and clinical correlation of anti-DNA topoisomerase IIalpha (anti-topo IIalpha) antibody in patients with localized scleroderma. METHODS: Anti-topo IIalpha antibodies or anti-DNA topoisomerase I (topo I) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Inhibition of topo IIalpha enzymatic activity by the antibodies was evaluated by decatenation assays using kinetoplast DNA as a substrate. RESULTS: IgG or IgM anti-topo IIalpha antibody was detected in 76% (35 of 46) of patients with localized scleroderma, and in 85% (11 of 13) of patients with generalized morphea, the severest form of localized scleroderma. This prevalence of the antibody in patients with localized scleroderma was much higher than that found in patients with systemic sclerosis (SSc) (5 of 37 [14%]), systemic lupus erythematosus (2 of 26 [8%]), dermatomyositis (2 of 20 [10%]), and in healthy controls (3 of 42 [7%]). Immunoblotting confirmed the presence of IgG anti-topo IIalpha antibody in sera from patients with localized scleroderma and showed no cross-reactivity of anti-topo IIalpha antibody with topo I. Anti-topo I antibody was not detected by ELISA in any sera from patients with localized scleroderma. In addition, anti-topo I antibody from SSc patients did not cross-react with topo IIalpha. The presence of anti-topo IIalpha antibody was associated with a greater total number of sclerotic lesions and number of plaque lesions in patients with localized scleroderma. Furthermore, anti-topo IIalpha antibody was able to inhibit topo IIalpha enzymatic activity. CONCLUSION: The results of the present study indicate that anti-topo IIalpha is a major autoantibody in localized scleroderma, and is distinct from anti-topo I antibody in SSc.



 

 

11.)  Topical tacrolimus in the treatment of localized scleroderma.

Eur J Dermatol. 2003 Nov-Dec;13(6):590-2.

Mancuso G, Berdondini RM.

Department of Dermatology, Municipal Hospital of Lugo, via Pescantini 33, 48022 Lugo (RA), Italy.

Although the cause of localized scleroderma is unknown, an autoimmune mechanism is suspected. We describe two patients with localized scleroderma treated with topical tacrolimus, an immunosuppressive macrolide antibiotic. Topical tacrolimus 0.1% ointment applied twice daily under occlusion led to a significant clinical improvement of late sclerotic lesions and complete clearance of early inflammatory skin lesions in 3 months. These were the first cases of successful topical tacrolimus therapy in localized scleroderma and should be regarded as a promising treatment option for LS, especially on account of its high tolerability that permits prolonged use without side-effects.

 

12.)  Does solitary morphoea profunda progress?.

Clin Exp Dermatol. 2004 Jan;29(1):25-7.

Azad J, Dawn G, Shaffrali FC, Holmes SC, Barnetson RJ, Forsyth A.

Department of Dermatology, Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, Scotland, UK. gmitali@eggconnect.net

Solitary morphoea profunda (SMP) is an unusual form of scleroderma and is rarely mentioned in the literature. The back of the trunk is described as the commonest site of involvement by SMP. This disease has been recognized as a nonprogressive condition. We report three cases of SMP seen at our department within a 1-year period. Interestingly, all three patients were females and the lesions were situated on the right upper buttock. In one patient the lesion extended despite using topical tacrolimus but subsequently the lesion was kept under control with topical clobetasol propionate.
Eur J Dermatol. 2003 Nov-Dec;13(6):590-2.

 

13.)  Oral calcitriol as a new therapeutic modality for generalized morphea.

Arch Dermatol. 1994 Oct;130(10):1290-3.

Comment in:
Arch Dermatol. 1995 Jul;131(7):850-1.

Hulshof MM, Pavel S, Breedveld FC, Dijkmans BA, Vermeer BJ.

Department of Dermatology, University Hospital Leiden, The Netherlands.

BACKGROUND: None of the commonly used drugs for the treatment of scleroderma appears to significantly influence the fibrotic stage of this disorder. Recently, a beneficial effect of the treatment with oral calcitriol (1,25 dihydroxyvitamin D3) in 10 patients with systemic sclerosis and four patients with morphea was described. This fact could be ascribed to the immunoregulatory effects of calcitriol observed in vitro and to inhibition of fibroblast growth. We treated three patients with extensive morphea with remarkable results. OBSERVATION: Three patients with generalized morphea were treated with calcitriol in an oral daily dose of 0.50 to 0.75 microgram. After 3 to 7 months of treatment, the mobility of the joints improved and the skin extensibility increased. No adverse effects were observed. The improvement persisted after discontinuation of therapy during a follow-up period of 1 to 2 years. CONCLUSION: Calcitriol showed a beneficial effect in generalized morphea during an open study. Double-blind, placebo-controlled trials are needed to assess its therapeutic value.

 

14.)  Morphea-like reaction to D-penicillamine therapy.

Morphea-like reaction to D-penicillamine therapy.
Ann Rheum Dis. 1981 Feb;40(1):42-4.

Bernstein RM, Hall MA, Gostelow BE.

We report the case of a 48-year-old woman who developed morphea-like plaques after 1 year of treatment with D-penicillamine at 250 mg daily for a seronegative erosive arthritis of rheumatoid type. The rash began as several red itchy patches on the trunk; these became thickened and shiny over about 3 months. The histological appearance was of increased dermal fibrosis with an inflammatory infiltrate round dermal capillaries. However, epidermal changes were not typical of morphea. New lesions ceased to appear within a few months of stopping penicillamine, and by 1 year all the plaques were pale and symptomless.

 

15.)  Treatment of generalized morphea with oral 1,25-dihydroxyvitamin D3.

Adv Exp Med Biol. 1999;455:299-304.

Caca-Biljanovska NG, Vlckova-Laskoska MT, Dervendi DV, Pesic NP, Laskoski DS.

Department of Dermatology, University Hospital Skopje, Republic of Macedonia.

Scleroderma is a chronic connective tissue disease characterized by excessive collagen synthesis and its deposition in the skin and various internal organs. Immune system abnormalities and disturbances of connective tissue metabolism have been suggested to play a central role in the pathogenesis of scleroderma. 1.25-Dihydroxyvitamin D3 (1.25(OH)2 D3 causes inhibition of fibroblast growth, has a role in controlling collagen synthesis and deposition and has numerous immunoregulatory activities. We assessed the effects of oral 1.25 (OH)2 D3 in the treatment of patients with generalized morphea. Three patients with generalized morphea, entered an open prospective study. They were treated with oral calcitriol (1.25 dyhidroxyvitamin D3) in an oral daily dose of 0.50-0.75 microgram. After the treatment period of 4-6 months, a significant clinical improvement was observed. The mobility of the joints improved, the skin extensibility increased and a substantial improvement of the skin induration. No serious side effects were observed. The improvement persisted after discontinuation of therapy during a follow-up period of one year. The evolution of the patients' condition during the 6 months therapy with calcitriol, suggests that it can be used as a beneficial agent in the treatment of generalized morphea. Double-blind, placebo-controlled trials are needed to assess its therapeutic value and a larger number of patients is desirable.

 

 

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