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Scleroderma means hard skin. It exists in two clinical variants. The localized form is commonly referred to as morphea. The systemic form is usually referred to as systemic scleroderma. Morphea is a disease of skin the underlying connective tissue. Several variants have been described, as discussed below. Systemic scleroderma may affect multiple organ systems and is usually classified under autoimmune diseases. Occasionally, morphea and scleroderma may occur in the same patient. In these cases, morphea arises first followed by a milder and nonprogressive form of systemic scleroderma.


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Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
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Differential Diagnosis  
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A variant of acrokeratoelastoidosis in systemic scleroderma: Report of 7 cases.

Tajima S, Tanaka N, Ishibashi A, Suzuki K.

Departments of Dermatology, and First Internal Medicine, National Defense Medical College.

J Am Acad Dermatol 2002 May;46(5 Pt 1):767-70 Abstract quote

We describe acrokeratoelastoidosis-like lesions on the palms of the patients with systemic scleroderma.

Histology showed a focal hyperkeratosis with or without epidermal concavity, regular acanthosis, and hyalinization of collagen fibers and, in some cases, fragmentation and diminution of elastic fibers in the deep dermis. A slight degree of fibrotic change of collagen in the uninvolved neighboring skin was found in one case. The lesions were found in 7 of 26 patients with systemic scleroderma who were analyzed here, and were not found in the unrelated connective tissue disorders (n = 32) and normal controls (n = 27).

The cause of the unique skin lesions may be related to the altered connective tissue metabolism similar to that of systemic scleroderma.


Scleroderma in association with the use of docetaxel (taxotere) for breast cancer.

Hassett G, Harnett P, Manolios N.

Department of Rheumatology, Westmead Hospital, Australia.

Clin Exp Rheumatol 2001 Mar-Apr;19(2):197-200 Abstract quote

The taxanes, paclitaxel (Taxol) and docetaxal (Taxotere), are a new class of anti-microtubule agents which have shown cytotoxic activity in a number of solid tumours.

Phase I and II trials confirm that docetaxal is highly active in the treatment of metastatic breast cancer. Reported toxicities of docetaxel include, dose limiting neutropenia, alopecia, skin reactions and fluid retention.

Here we report the first case of rapid onset, diffuse scleroderma-like illness, which occurred in a 59-year-old female receiving treatment with docetaxel for locally invasive and advanced metastatic breast cancer.


Scleroderma "en coup de sabre": pathological evidence of intracerebral inflammation.

Stone J, Franks AJ, Guthrie JA, Johnson MH. Department of Clinical Neurosciences, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, UK.

J Neurol Neurosurg Psychiatry 2001 Mar;70(3):382-5 Abstract quote

Linear scleroderma "en coup de sabre" (LScs) is associated with neurological complications, the pathogenesis of which is uncertain.

A 27 year old woman is reported on who developed epilepsy and focal neurological signs in association with LScs. Brain MRI demonstrated predominantly ipsilateral relapsing and remitting grey and white matter lesions.

Analysis of CSF and pathology obtained at brain biopsy provides evidence of an inflammatory process which may be amenable to immunosuppressive treatment.

En coup de sabre morphea and Parry-Romberg syndrome: a retrospective review of 54 patients.

Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.

J Am Acad Dermatol. 2007 Feb;56(2):257-63. Abstract quote

BACKGROUND: The relationship between en coup de sabre morphea and Parry-Romberg syndrome is unclear, and not much is known regarding their demographic and clinical characteristics or the efficacy of the treatments that are used.

OBJECTIVE: The purpose of this study was to describe demographic data, clinical features, and medications used in a large cohort of patients with en coup de sabre morphea and Parry-Romberg syndrome.

METHODS: A retrospective review of patients diagnosed with en coup de sabre morphea or Parry-Romberg syndrome at the Mayo Clinic from 1984 to 2004 was conducted. Demographic data, examination findings, and treatments were noted.

RESULTS: We identified 54 patients who met criteria for inclusion in the study. Twenty-six patients (48%) had en coup de sabre morphea, 13 (24%) had Parry-Romberg syndrome, and 15 (28%) had both. Disease was present bilaterally in 7.4% of patients. Thirteen percent of all patients in the study group had seizures. Of patients who received treatment, most were treated with antimalarial agents (57.1%) or methotrexate (28.6%).

LIMITATIONS: The study design was that of a retrospective review at a tertiary care center with referral bias. There were also limitations present because of the inherent nature of the diseases studied.

CONCLUSION: En coup de sabre morphea and Parry-Romberg syndrome frequently coexist and are likely both variants of morphea. Bilateral disease is more common than previously reported. The efficacy of antimalarials and methotrexate in the treatment of these diseases remains unclear.

Necrotizing vasculitis in a patient with generalized morphea

Akimichi Morita, MD, PhD
Takuo Tsuji, MD

Nagoya, Japan

J Am Acad Dermatol 2001;45:S215-7 Abstract quote

Generalized morphea is rarely associated with systemic overlap. We report an unusual case with generalized morphea involving cutaneous large vessel vasculitis, mononeuritis multiplex, and lupus anticoagulant without any evidence of the coexistent systemic lupus erythematosus.


The Assessment of Anti–Endothelial Cell Antibodies in Scleroderma-Associated Pulmonary Fibrosis A Study of Indirect Immunofluorescent and Western Blot Analysis in 49 Patients With Scleroderma

Raghav Wusirika, MD, Clodoveo Ferri, MD, Mary Marin, Deborah A. Knight, MS, W. James Waldman, PhD, Patrick Ross, Jr, MD, PhD, and Cynthia M. Magro, MD
Am J Clin Pathol 2003;120:596-606 Abstract quote

We recently reported on the use of an indirect immunofluorescent method designated the rodent lung assay; this test assesses for the presence of circulating antibodies directed at components of the microvasculature. Serum samples from 49 patients with scleroderma were incubated with rodent lung tissue sections and visualized with fluoresceinated human anti-IgG. The assay also was performed on samples from a control group.

Western blot analysis was performed with endothelial cell protein extracts using serum samples from patients with scleroderma and from healthy control subjects. The control subjects had a negative indirect immunofluorescent assay result. In the patients with scleroderma, there was a significant positive correlation between intensity of indirect immunofluorescent staining and pulmonary fibrosis ( r = 0.316; P = .0347) and hypertension ( r = 0.310; P = .0408).

Western blot analysis revealed antibody binding to proteins in extracts of human endothelial cells in all patients in whom there was evidence of pulmonary disease. The indirect immunofluorescent rodent lung assay and Western blot data support a potential role of anti–endothelial cell antibodies in the propagation of scleroderma-associated pulmonary disease.
Alterations of basement membrane zone and cutaneous microvasculature in morphea and extragenital lichen sclerosus.

Kowalewski C, Kozlowska A, Gorska M, Wozniak K, Krajewski M, Blaszczyk M, Jablonska S.

From the Department of Dermatology, University of Medicine, Warsaw, Poland.

Am J Dermatopathol. 2005 Dec;27(6):489-96. Abstract quote  

The aim of this study was to compare alterations of the basement membrane zone (BMZ) and to visualize changes within the skin vascular network in morphea and extragenital lichen sclerosus with the use of laser scanning confocal microscopy.

This work was performed in eight plaques of morphea (three active and five inactive) and eight of lichen sclerosus (three of short duration and five long-lasting). Biopsy specimens from six healthy individuals served as controls. The biopsies were cut into 40-mum-thick sections, labeled with antibodies against beta4-intergin (a lamina lucida marker), collagen IV, and the N-terminal end of collagen VII (lamina densa markers) and C-terminal end of collagen VII (a sublamina densa marker) and studied using laser scanning confocal microscopy. Three-dimensional reconstruction of various regions of the BMZ showed a decreased number and size of the dermal papillae both in morphea and lichen sclerosus compared with normal skin. In morphea, the continuity of the BMZ at the level of lamina lucida, lamina densa, and sublamina densa was preserved whereas in LS numerous invaginations and holes were present in the BMZ at the level of the lamina lucida and lamina densa. Thus the alterations of the BMZ in morphea differ from those in lichen sclerosus.

Three-dimensional reconstruction of the skin vascular network showed increased angiogenesis only in the early inflammatory stage of morphea, whereas in inactive morphea and lichen sclerosus various numbers of enlarged vessels were visible. The changes in the vascular network in morphea appear to be related to the activity of the disease.

Development of histologic features of scleroderma in congenital lesions.

Harford R, Smith KJ, Skelton H.

Department of Dermatology and Pathology, National Naval Medical Center, Bethesda, MD, USA, and Department of Dermatology and Pathology, University of Alabama, Birmingham, AL, USA.


J Cutan Pathol 2002 Apr;29(4):249-54 Abstract quote

BACKGROUND: Localized scleroderma has been reported after radiation therapy, but has never been reported to occur at the site of a congenital lesion.

CASE REPORT:: We present two patients, both with family histories of autoimmune disease, who reported unilateral hypopigmented areas on the trunk since birth. The areas remained asymptomatic and grew with the patients until adulthood when the areas became indurated then firm and showed hyperpigmentation.

HISTOLOGY:: Histologically, both lesions showed features of localized scleroderma with diffuse sclerosis of collagen and loss of periadnexal fat. There was a perivascular lymphoplasmocytic infiltrate with occasional eosinophils extending into the subcutaneous fat predominantly along fat septae, and diffuse loss of CD34+ stromal cell populations within the lesions.

CONCLUSION:: We propose that somatic mutations affecting vessels may predispose to increased endothelial cell apoptosis. This could lead to the development of an autoimmune response in some individuals, and the areas of localized scleroderma may be markers of susceptibility to autoimmune disease.

"Borrelia-associated early-onset morphea": a particular type of scleroderma in childhood and adolescence with high titer antinuclear antibodies? Results of a cohort analysis and presentation of three cases.

Department of Dermatology, University of Munich, Munich, Germany.

J Am Acad Dermatol. 2009 Feb;60(2):248-55. Abstract quote

BACKGROUND: Morphea is an inflammatory autoimmune skin sclerosis of unknown etiology. A causative role of Borrelia burgdorferi infection has been controversially discussed, but no conclusive solution has yet been achieved.

OBJECTIVE: Intrigued by 3 young patients with severe Borrelia-associated morphea and high-titer antinuclear antibodies, we retrospectively examined the relationship between Borrelia exposure, serologic autoimmune phenomena and age at disease onset in morphea patients.

METHODS: In 90 morphea patients the presence of Borrelia-specific serum antibodies was correlated to the age at disease onset and the presence and titers of antinuclear antibodies. Patients with active Borrelia infection or high-titer antinuclear antibodies due to systemic sclerosis or lupus erythematosus served as controls.

RESULTS: We observed a statistically highly significant association between morphea, serologic evidence of Borrelia infection, and high-titer antinuclear antibodies when disease onset was in childhood or adolescence.

LIMITATIONS: Because pathogenic Borrelia species may vary in different geographic regions the relevance of Borrelia infection in morphea induction may show regional variations.

CONCLUSION: B burgdorferi infection may be relevant for the induction of a distinct autoimmune type of scleroderma; it may be called "Borrelia-associated early onset morphea" and is characterized by the combination of disease onset at younger age, infection with B burgdorferi, and evident autoimmune phenomena as reflected by high-titer antinuclear antibodies. As exemplified by the case reports, it may take a particularly severe course and require treatment of both infection and skin inflammation.
Link to Lyme disease-Borrelia burgdorferi

Br J Dermatol 2000;143:780-785

54 morphea patients from southern Germany with a high incidence of borreliosis, compared to two control groups

Second group of 25 patients with acrodermatitis chronica atrophicans, late stage of Lyme disease

Serology and PCR performed upon the skin biopsies

Only 4 patients with morphea had positive serology and PCR was negative within the biopsies

Hyperplasia of dermal microvascular pericytes in scleroderma.

Helmbold P, Fiedler E, Fischer M, Marsch WCh.

Universitatsklinik und Poliklinik fur Dermatologie und Venerologie der Martin-Luther-Universitat Halle - Wittenberg, Halle (Saale), Germany
J Cutan Pathol. 2004 Jul;31(6):431-40. Abstract quote  

BACKGROUND: Pericytes (PCs) are smooth muscle-like mural cells of capillaries and venules, which can synthesize matrix components and fibroblast-activating cytokines, and are thus potential mediators of pathological changes in scleroderma. In this study, alterations in microvessels were quantitatively imaged, taking PC into account for the first time.

METHODS: Skin biopsies from systemic (12) and localized (14) scleroderma forms as well as age-, sex-, and body location-matched controls were examined with respect to capillary and venular densities as well as endothelial cell (EC) and PC counts using a newly developed (in respect of PC and EC) indirect collagen IV immunostaining-based method.

RESULTS: Hyperplasia of the PC that doubled the microvascular PC density was the most conspicuous characteristic. In the capillaries of the upper dermal plexus of the periphery of the sclerotic zones, median ratios of PC : EC were 0.23 (controls 0.10) or 0.18 (controls 0.11) in systemic or localized scleroderma, respectively. Furthermore, an increase in capillary density in the upper dermal plexus could be demonstrated in the marginal zones of both types of disease.

CONCLUSIONS: The observed PC increase in the peripheral zones of active disease supports the hypothesis of a vascular pathogenesis of scleroderma and directs the focus to microvascular PC.

Identification of Clonal T Cells in the Blood of Patients With Systemic Sclerosis Positive Correlation With Response to Photopheresis

Lars E. French, MD; Stuart R. Lessin, MD; Kathakali Addya, PhD; Barbara Denardo, RN; David J. Margolis, MD, MSCE; Debra G. B. Leonard, MD, PhD; Alain H. Rook, MD

Arch Dermatol. 2001;137:1309-1313 Abstract quote

To search for circulating clonal T-cell populations in patients with systemic sclerosis (SSc), and to determine whether T-cell clonality in the blood predicts therapeutic response to photopheresis.

Analysis of clonal T-cell receptor gene rearrangements before photopheresis treatment and blinded clinical evaluation of cutaneous response to photopheresis in a case series. Setting University hospital setting.

Thirteen consecutive patients with SSc.

Photopheresis in 11 patients.

Main Outcome Measures
Clonality of T cells in the blood before photopheresis and clinical response to photopheresis.

Screening of blood samples from 13 SSc patients for clonal T-cell receptor gene rearrangements revealed a monoclonal T cell population in 6 (46%) of 13 SSc patients. Clinical response to photopheresis in 11 patients was evaluated in a blinded manner using skin severity scores. Clonality of T cells appeared to be associated with a higher chance of response to photopheresis therapy, as 4 (67%) of 6 patients in the clone-positive group vs 1 (20%) of 5 in the clone-negative group experienced a clinically significant response to treatment.

A high proportion of patients with SSc have detectable expanded clonal T-cell populations in the peripheral blood, and such patients appear more likely to respond to photopheresis.



Surfactant protein D (SP-D) and systemic scleroderma (SSc).

Maeda M, Ichiki Y, Aoyama Y, Kitajima Y.

Departament of Dermatology, Gifu Prefectural Hospital, Japan.

J Dermatol 2001 Sep;28(9):467-74 Abtract quote

We measured serum levels of SP-D in collagen diseases (110 cases) such as systemic scleroderma (SSc), scleroderma spectrum disorders (SSD), systemic lupus erythematodes (SLE), Sjogren syndrome (Sjs), dermatomyositis (DM), rheumatoid arthritis (RA), and dermatitis (DE) (109 cases) as a control. Additionally, we performad a correlation analysis to determine how these levels were related to pulmonary fibrosis and function test (vital capacity, %DLco).

The serum levels of SP-D increased in SSc patients with Barnett type III more than in SSc patients with Barnett type I or II, while they increased slightly in SSD (incomplete type of SSc) patients. The differences in these figures were statistically significant between the SSc (SSc & SSD) and non-SSc (SLE, DM, Sjs & RA) groups (p<0.005). The serum levels of SP-D in SSc patients with anti-topoisomerase I antibodies were statistically higher than those in SSc patients with other types of anti-nuclear antibodies. There was a statistically significant correlation between the severity of pulmonary fibrosis and the serum levels of SP-D, and a statistically negative correlation between SP-D levels and vital capacity or %DLco, but there was no proportional correlation with the forced expiatory volume (FEV1.0%). There was no statistical relationship between pre- and post-therapy with photopheresis; however, there was a statistical correlation between the serum levels of SPD and KL-6.

In the group of collagen diseases, plasma levels of SP-D were higher than serum levels of SP-D. Patients with SSc possess higher levels of SP-D than do those with other collagen diseases and dermatitis, which may correspond to the severity of pulmonary fibrosis.


Atrophoderma of Pasini and Pierini
Atrophoderma of Pasini and Pierini: a clinical and histopathological study.

Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon.


J Cutan Pathol. 2008 Dec;35(12):1108-14. Abstract quote

BACKGROUND: Idiopathic atrophoderma of Pasini and Pierini (IAPP) usually manifests as one or multiple depressed and hyperpigmented patches, with a predilection to the trunk. No diagnostic changes are usually seen on histology. Elastic stains often reveal no abnormalities.

OBJECTIVE: To review our cases of IAPP, describe their clinical and histological findings and compare them with the literature.

METHODS: Retrospective review of IAPP cases who presented to our institution between 1994 and 2006.

RESULTS: From a total of 16 patients, only 19% displayed hyperpigmented lesions, while 81% had either hypopigmented (9/16) or skin-colored (4/16) lesions. The sites predominantly affected were the lower extremities (62.5%), followed by the upper extremities and trunk. Only in one patient was IAPP co-existent with morphea. Histology revealed no diagnostic abnormalities; however, elastic stains showed a spectrum of changes ranging from normal to severe diminution and fragmentation of elastic fiber network.

CONCLUSIONS: Our study shows several new aspects of IAPP. Clinically, the lesions were most commonly hypopigmented and involved predominantly the extremities. Histologically, IAPP exhibited a spectrum of alterations in elastic fibers. The most prevalent form of IAPP in our country seems to be unassociated with morphea.
Usually with plaque type lesions
Small and superficial
Most common variant
Round or oval
Smooth surface with ivory color
Enlarging lesions may show violaceous border (lilac ring)

Usually extremities and anterior scalp
May have induration of skin and atrophy of underlying tissues with joint contractures and ankyloses of the joints

On scalp, called coup de sabre

Usually on one side of the face resulting in hemiatrophy
(Morphea profunda)
Thickened skin bound to underlying fascia and muscle
Involved plaques are ill defined
Skin is smooth and shiny
(Disabling pansclerotic morphea)
Usually in children but may occur in adults
Bullous lesions may rarely occur
Coexisting morphea with lichen sclerosis et atrophicus

Suggested that in Europe, some cases may be caused by Borrelia burgdorferi, agent of Lyme disease

No convincing evidence in the United States

Diffuse systemic scleroderma
CREST syndrome

Calcinosis cutis
Raynaud's phenomenon
Esophagus with dysphagia

Death from visceral involvement is unusual occurring in about 11% of cases
Polyarthritis is rarer-15%



Morphea and scleroderma cannot be distinguished by skin biopsy alone

Early lesions have thickened collagen bundles within the reticular dermis with a moderately severe inflammatory cell infiltrate, predominately lymphoplasmacytic between collagen bundles and around blood vessels

Infiltrate may extend into subcutaneous fat and project around eccrine glands

Late lesions may show sclerosis with a paucity of inflammatory cells
Collagen is closely packed and eccrine glands appear atrophic or absent
Collagen may replace fat cells in the subcutaneous tissue

BULLOUS MORPHEA Usually subcutaneous morphea
Subepidermal bullae suaully secondary to lymphatic obstruction causing subepidermal edema

Keloid-like Scleroderma.

Barzilai A, Lyakhovitsky A, Horowitz A, Trau H.


Am J Dermatopathol. 2003 Aug;25(4):327-30 Abstract quote

A 62-year-old female who developed concomitantly acrosclerosis and keloid-like lesions is described. Biopsy specimens from these linear lesions showed a fibrous proliferation in the dermis composed mostly of normal-appearing, horizontally oriented collagen bundles and myofibroblasts, thus resembling a scar.

Keloidal scleroderma is a rare variant of scleroderma. The diagnosis is considered for patients with scleroderma who develop lesions clinically and histologically indistinguishable from keloids. This case demonstrates for the first time that the histopathologic findings can mimic those of a scar, rather than a keloid, and hence is appropriately designated as keloid-like scleroderma.

Clinical pathological correlation is mandatory for the correct diagnosis.


Nailfold biopsy in scleroderma and related disorders. Correlation of histologic, capillaroscopic, and clinical data.

Thompson RP, Harper FE, Maize JC, Ainsworth SK, LeRoy EC, Maricq HR.

Arthritis Rheum 1984 Jan;27(1):97-103 Abstract quote

Although nailfold capillary abnormalities associated with connective tissue disease (CTD) have been studied by direct in vivo microscopy, little is known of the underlying histology and morphology of this tissue.

This report summarizes light microscopic study of glycolmethacrylate embedded nailfold biopsies from 13 CTD patients (9 scleroderma, 2 CREST, 2 undifferentiated CTD), 2 subjects with Raynaud's phenomenon alone, and 9 normal volunteers of similar age and sex distribution.

The most striking and consistent finding was the presence of globular, eosinophilic, PAS-positive deposits in the cuticles of 14 of 15 patients and none of the controls. This material, identified by immunofluorescent staining as serum protein exudates, was associated with pronounced parakeratosis and elevated epithelial mitotic activity. Capillary ectasia with thinning of the basement membrane was often present in CTD biopsies. Occasional signs of endothelial swelling and proliferation were encountered in both populations. Inflammatory changes were rarely seen.

In quantitative comparison with control tissues, the superficial dermis from CTD patients contained significantly fewer capillaries, cutaneous nerve bundles, and interstitial fibroblasts per unit area and fewer papillary capillaries per unit of epidermal length. Measures of capillary density in sectioned tissue correlated well with the results of in vivo microscopic examination.

Intimal thickening of arterioles may precede interstitial fibrosis
Adventitial fibrosis around the interlobar, arcuate, and interlobular arteries
May lead to cortical infarcts
Submucosal fibrosis



Elastic fiber pattern in scleroderma/morphea.

Dermatopathology Section, Department of Dermatology, New York University Medical Center, New York, NY 10016, USA.


J Cutan Pathol 2009;36:952-957 Abstract quote

BACKGROUND: Scleroderma/morphea is characterized by expansion of the dermis with thickened collagen bundles and loss of CD34(+) dermal dendrocytes. Variable elastic fiber changes have been described, but to our knowledge, no systematic study of the elastic fiber pattern correlated with CD34 expression has been reported.

METHODS: To better define the typical elastic fiber morphology, we examined seven cases of normal skin and 28 cases of scleroderma/morphea ranging from inflammatory to sclerosing stages. All but four biopsies were submitted with a clinical impression of either scleroderma or morphea. CD34 immunohistochemistry was performed on 26 biopsies with available tissue.

RESULTS: Elastic van Gieson stain showed preservation of elastic fibers in all cases. In addition, straightening with parallel orientation and compression between thickened collagen bundles was frequently present and was graded as limited in 46% and diffuse in 54% of cases. The extent of elastic fiber alteration correlated with the degree of sclerosis. A variable loss of CD34(+) dermal dendritic cells was seen in all cases.

CONCLUSION: This study confirms the preservation and frequent presence of parallel, straightened and compressed elastic fibers in scleroderma/morphea and suggests that the elastic fiber pattern, in addition to CD34 immunohistochemistry, may serve as a useful diagnostic adjunct.

Direct immunofluorescence (DIF)  
Indirect immunofluorescence (IIF)  
ANA pattern

Most common pattern is speckled then nucleolar

Systemic scleroderma has ANA in 80% of acrosclerosis to 94% in diffuse scleroderma

Characteristic of CREST syndrome
Presence associated with poor prognosis
Usually in patients with diffuse scleroderma or transitional forms from acrosclerosis to diffuse
Electron microscopy (EM)  



Ann Intern Med 1971;75:369-376

In systemic scleroderma, renal failure and cardiac complications are the most common causes of death

7 year survival rate in one series was 35% and another series of 267 patients, 10 year survival was 47%

Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients.

Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, Bullo A, Cazzato M, Tirri E, Storino F, Giuggioli D, Cuomo G, Rosada M, Bombardieri S, Todesco S, Tirri G; Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc).

Rheumatology Unit, Department of Internal Medicine, University of Pisa, Italy.

Medicine (Baltimore) 2002 Mar;81(2):139-53

Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival.

Scussel-Lonzetti L, Joyal F, Raynauld JP, Roussin A, Rich E, Goulet JR, Raymond Y, Senecal JL.

Hopital Notre-Dame, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada.

Medicine (Baltimore) 2002 Mar;81(2):154-67

Double-blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma.

Hulshof MM, Bouwes Bavinck JN, Bergman W, Masclee AA, Heickendorff L, Breedveld FC, Dijkmans BA.

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

J Am Acad Dermatol 2000 Dec;43(6):1017-23 Abstract quote

BACKGROUND: Various treatments including corticosteroids, nonsteroidal anti-inflammatory drugs, D-penicillamine, interferon gamma, cyclosporine, and cytostatic drugs have been used with limited success in both morphea and systemic sclerosis (SSc).

OBJECTIVE: We investigated the effect of treatment with oral calcitriol in patients with localized or systemic scleroderma.

METHODS: A randomized, double-blind, placebo-controlled study of 9 months' duration with a 6-month follow-up was performed at the Department of Dermatology. A total of 27 patients (7 patients with SSc and 20 with morphea) were selected on a minimal skin score of 3 for patients with morphea and 12 for those with SSc. Each patient received calcitriol (0.75 microg/day for 6 months plus 1.25 microg/day for 3 months) or placebo for 9 months. Efficacy parameters included skin score, measurement of serum markers of collagen synthesis and degradation and, additional for the patients with SSc, oral aperture measurements, lung function studies, and esophagus motility.

RESULTS: The skin score in patients with morphea after 9 months' treatment showed no significant difference between the placebo and calcitriol groups (mean percentage reduction [SD] in skin score in the placebo group was -29.3 [57.9]; in the calcitriol group it was -19.4 [46.6]). The small group of patients with SSc was inadequate to allow us to draw any conclusions regarding efficacy. No significant change was found in the serum markers of collagen metabolism.

CONCLUSION: In this study calcitriol was not more effective than placebo in patients with morphea. Because of the small group of patients with SSc treated, no conclusions regarding efficacy in SSc can be drawn.

Pulsed High-Dose Corticosteroids Combined With Low-Dose Methotrexate in Severe Localized Scleroderma

Alexander Kreuter, MD; Thilo Gambichler, MD; Frank Breuckmann, MD; Sebastian Rotterdam, MD; Marcus Freitag, MD; Markus Stuecker, MD; Klaus Hoffmann, MD; Peter Altmeyer, MD

Arch Dermatol. 2005;141:847-852. Abstract quote

Objective  To evaluate the efficacy of pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy in patients with severe localized scleroderma (LS).

Design  A prospective, nonrandomized, open pilot study.

Setting  Dermatology department at a university hospital in Bochum, Germany.

Patients  Fifteen patients with histologically confirmed severe LS.

Interventions  Oral methotrexate (15 mg/wk) combined with pulsed intravenous methylprednisolone (1000 mg for 3 days monthly) for at least 6 months.

Main Outcome Measures  Treatment outcome was evaluated by means of a clinical score, 20-MHz ultrasonography, and histopathologic analysis. Safety assessment included the monitoring of adverse effects and clinical laboratory parameters.

Results  One patient discontinued therapy. In most of the remaining 14 patients, significant elimination of all signs of active disease (inflammation) and remarkable softening of formerly affected sclerotic skin that resulted in a decrease of the mean ± SD clinical score from 10.9 ± 5.3 at the beginning to 5.5 ± 2.5 at the end of therapy was observed (P<.001). Clinical improvement was confirmed by histologic and ultrasonographic assessments. No serious adverse effects were noted.

Conclusions  These data suggest that pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy is beneficial and safe in the treatment of patients with LS. This treatment regimen should especially be considered for severe forms of LS in which conventional treatments have failed.

A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis.

Knobler RM, French LE, Kim Y, Bisaccia E, Graninger W, Nahavandi H, Strobl FJ, Keystone E, Mehlmauer M, Rook AH, Braverman I; Systemic Sclerosis Study Group.

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

J Am Acad Dermatol. 2006 May;54(5):793-9. Abstract quote  

BACKGROUND: Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggressive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed.
OBJECTIVE: Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma).
METHODS: This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis.
RESULTS: A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline.
LIMITATIONS: The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms.
CONCLUSION: Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.

PUVA-cream photochemotherapy for the treatment of localized scleroderma.

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.

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

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.


Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34-positive dendritic cells

Nydia R. Camacho, MD
Julio E. Sánchez, MD
Rafael F. Martin, MD, etal

San Juan, Puerto Rico

J Am Acad Dermatol 2001;45:697-9. Abstract quote

Background: UVA1 radiation seems to be effective in morphea. CD34+ dendritic cells are significantly decreased in lesional skin of morphea patients.

Objective: We evaluated the therapeutic effectiveness of medium-dose UVA1 phototherapy in localized scleroderma and its effect in the number of dermal CD34+ dendritic cells in skin biopsy specimens of these patients.

Method: Patients were irradiated with UVA1 (30 J/cm2) 30 times. Dermal CD34+ dendritic cells were counted before and after therapy.

Results: There was clinical improvement after UVA1 irradiation. Dermal CD3 4+ dendritic cells significantly increased after UVA1 irradiation.

Conclusion: Medium-dose UVA1 therapy is effective in the treatment of localized morphea. Effectiveness is associated with an increase in the number of CD34+ dendritic cells in the dermis. ()

Moderate dose UVA1 for systemic sclerosis

J Am Acad Dermatol 2000;43:670-674

UVA1 induces T-helper cell apoptosis and fibroblast collagenase production and reduces collagen synthesis

4 patients with disease for average of 4 years

Forearms and hands treated with UVA1 (60 J/cm2) for 20 minutes/day with mean of 20 treatments

Significant improvement in passive joint movement and cutaneous elasticity

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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