Immunohistological studies, with anti-connective tissue and anti-immunoglobulin antisera, of the skin in lupus erythematosus and scleroderma

Skin lesions from six patients with systemic lupus erythematosus, five patients with discoid lupus erythematosus, twelve patients with systemic sclerosis, five patients with localized morphoea and twenty controls were examined by immunohistological techniques using fluorescein-labelled antihuman IgG, anti-human C3 and anti-human renal glomerulus antisera. The major immunohistological changes in systemic sclerosis and in localized morphoea consisted of foci of intercollagenous staining for connective tissue antigens in the reticular layer of the dermis. It is suggested that these findings indicate collagen neogenesis. In lupus erythematosus the major changes occur in the dermo-epidermal junction and consist of deposits of IgG and C3 and thickening and disruption of the membrane as demonstrated by the use of heterologous sera containing antibasement membrane antibodies. Immunohistological techniques are useful in the diagnostic differentiation between scleroderma and lupus erythematosus.     

Autoantibodies to the heat-shock protein hsp73 in localized scleroderma

We determined the presence of antibodies to the heat-shock protein hsp73 (anti-hsp73) in 57 serum samples from patients with localized scleroderma using an enzyme-linked immunosorbent assay (ELISA). In addition, 30 samples from healthy individuals, 30 from patients systemic lupus erythematosus (SLE) and 32 from patients with systemic sclerosis were assessed. IgG and/or IgM anti-hsp73 antibodies were detected in 33% (19/57) of the patients with localized scleroderma. Among the three subtypes of localized scleroderma, generalized morphoea showed the highest incidence of anti-hsp73 antibodies (40%, 6/15). IgG and/or IgM anti-hsp73 antibodies were also detected in 9/30 samples (30%) from patients with SLE and in 13/32 samples (41%) from patients with systemic sclerosis, while the samples from the healthy controls were all negative for anti-hsp73. By immunoblotting, specific binding of antibodies to hsp73 was confirmed with representative serum samples that were positive for anti-hsp73 in the ELISA. Our findings indicate that the presence of anti-hsp73 is an additional immunological abnormality in localized scleroderma.     

Clinical appearance of skin lesions and disturbances of pigmentation in localized scleroderma

Skin manifestations of localized scleroderma were assessed clinically in 58 patients presenting 214 circumscribed scleroderma lesions (23 patients with localized morphoea plaques, 15 with generalized morphoea, 11 with linear scleroderma of trunk and extremities, 9 with scleroderma en coup de sabre). Characteristic differences between different types of localized scleroderma with respect to age at debut, regional distribution, symmetry and linearity, degree of sclerosis of the lesions, and the presence of inflammatory change of colour, pigmentation and visible atrophy of underlying subcutaneous tissue were found. Separate brown-pigmented spots resembling atrophoderma. Pasini-Pierini were observed in 49% of the patients. A regional distribution chart of linearity in localized scleroderma was elaborated. The frequent finding of disturbances of pigmentation, the character of the linear distribution-pattern, and affections of underlying anatomical structures is discussed to indicate a predisposing defect in the migration of crest cells during embryonal life.     

Collagen specific amino acids in skin in localized scleroderma

Hydroxyproline, hydroxylysine and proline were determined on skin from 18 patients with localized scleroderma (10 with localized morphoea plaque and 8 with generalized morphoea). Three skin biopsies (4mm punch) were obtained from each patient: One from the center of a sclerotic plaque, one from the perilesional area, and one (control) from unaffected skin of the same region. Clinically, the sclerosis was more pronounced (p less than 0.01) in localized morphoea plaque as compared to generalized morphoea. Patients with localized morphoea plaque had an increased concentration of hydroxylysine (p less than 0.01) and an increased ratio of hydroxylysine to hydroxyproline (p less than 0.01) in the plaques. Hydroxylysine concentration was not changed in patients with generalized morphoea. In the entire material, increased hydroxylysine concentration were related to shorter age of the plaques (p less than 0.05) and to advanced degree of sclerosis (p less than 0.05). The hydroxylysine and hydroxyproline content per mm2 skin surface, and the weight of the dried defatted biopsy cores were increased in sclerotic plaques (p less than 0.01) in localized as well as generalized morphoea. There were no changes in the hydroxyproline and proline concentrations in any of the groups. Specimens from perilesional area showed intermediate changes. The results were compared with selected cases of lichen sclerosis et atrophicus and atrophic skin diseases. The increase in hydroxylysine concentration and ratio to hydroxyproline indicate that patients with localized morphoea plaque contain an increased proportion of newly synthesized collagen in the fibrotic plaque.     

Eosinophilic fasciitis (Shulman syndrome) in association with morphoea and systemic sclerosis

A case of Shulman syndrome or diffuse fasciitis with eosinophilia is reported. Both superficial scleroderma (morphoea) and systemic sclerosis accompanied the subcutaneous changes.     

Linear scleroderma in children (apropos of 27 cases)

Twenty-seven cases of linear morphoea are reported and compared with 218 cases collected from the literature. The various parameters studied, including clinical features and laboratory results, were identical in both series. The aetiology of linear morphoea is unknown, even though injuries or fever have been noted as triggering factors in 20 p. 100 of the cases. Linear morphoea is a childhood disease: it begins at the age of 7 or 8 and predominates in females (63 p. 100 of the cases). Its onset is marked by the abrupt occurrence of sclerosis in most cases, although a solitary morphoea or a trophic plaque may precede the disease proper. In our series, muscular or articular involvement appeared from the start in 40 p. 100 of the patients at the same time as the initial cutaneous lesions. The active stage lasts 3 years and sometimes longer. It is characterized by extension (37 p. 100) or both extension and multiplication (63 p. 100) of the initial lesions. Regional complications aggravate linear morphoea and are more frequent in patients whose lesions extend and multiply. Their incidence was lower among the published cases than in our series. Depending on the author, retractile myositis is present in 37 to 59 p. 100 of the cases, joint stiffness in 18 to 40 p. 100 and shortening of a limb in 10 to 22 p. 100. These complications often regress incompletely, leaving sequelae which persist in the steady state in 75 p. 100 of the patients. Antinuclear antibodies, present in 37 p. 100 of the cases, are either of the homogeneous or of the speckled type. Jablonska has met them more frequently (50 p. 100), and they were often of the speckled type. The significance of these antibodies in linear morphoea is unclear since they appear inconstantly and later than clinical signs. The skin lesions associated with linear morphoea show that the other forms of scleroderma--i.e. plaque morphoea, erythematous atrophic or dyschromic plaques and guttate scleroderma--belong to the same family. The same associations are found in frontoparietal "coup de sabre" scleroderma. The treatment of linear morphoea is not yet standardized. At the moment, the best and most regular results are obtained with systemic corticosteroids and local physiotherapy.     

Localized and systemic scleroderma

Scleroderma is a broad term encompassing both localized and systemic sclerosis. Localized scleroderma is a cutaneous limited fibrosis that manifests as plaque morphea, generalized morphea, linear scleroderma, and deep morphea. Systemic scleroderma (sclerosis) can manifest as either limited or diffuse disease. Limited systemic sclerosis is typically preceded by Raynaud's phenomenon, involves cutaneous sclerosis distal to the elbows, with gastrointestinal and pulmonary fibrosis, and anticentromere antibody positivity. Diffuse systemic scleroderma is characterized by simultaneous Raynaud's phenomenon, cutaneous skin involvement proximal to the elbow with gastrointestinal, pulmonary, renal and cardiac fibrosis, and positive serology for antitopoisomerase and anti-RNAP III antibodies. This article discusses the classification, epidemiology, pathogenesis, clinical manifestations, treatment, and prognosis of the scleroderma.     

Genital lichen sclerosus associated with morphoea or systemic sclerosis: clinical and HLA characteristics

Although patients with both morphoea and lichen sclerosus have been reported previously, in the majority of these reports the lichen sclerosus has been extragenital. We report nine patients in whom genital lichen sclerosus coexisted with scleroderma spectrum disorders including seven with morphoea, one with morphoea and lichen planus, and one with systemic sclerosis. The clinical features, associated autoimmune disease, autoantibodies and HLA type are reported. Antibodies to Borrelia burgdorferi were not detected in any of the patients. The coexistence of these diseases raises a number of intriguing questions about the relationship between them.     

Salazopyrin in the treatment of scleroderma

Following reports of successful treatment of various forms of scleroderma with salazopyrin, 13 selected patients were treated, 8 with acrosclerosis, one with sclerodermatomyositis and four with generalized morphoea. No effect was observed except in two cases of generalized morphoea which were in the acute stage of spreading to involve most of body surface. These two were more or less cured. This observation seems to warrant further trials with salazopyrin in this rare but serious form of scleroderma.     

Expression of HLA class II antigens on skin fibroblasts in scleroderma

Skin biopsies were taken from 11 patients with morphoea, nine with acrosclerosis and 10 with diffuse systemic sclerosis and processed for immunohistochemical studies using a panel of monoclonal antibodies including antibodies to MHC class II antigens. A significantly higher percentage of HLA-DR positive dermal cells were observed in the reticular dermis in biopsies from patients with morphoea (44.1 +/- 16.2%), acrosclerosis (15.9 +/- 5.4%) and systemic sclerosis (39.5 +/- 2.3%) when compared with the controls (6.6 +/- 2%). A smaller percentage of dermal cells also expressed HLA-DP and -DQ. The degree of monocnuclear cell infiltrate in the biopsies, however, did not correlate with the percentage of HLA class II positive fibroblasts. In organ culture, the expression of the HLA class II antigens was almost totally lost after 3 days and was no longer detected on fibroblasts after 3 weeks of culture.     

The treatment of linear morphoea with D-penicillamine

Localized morphoea (localized scleroderma) generally has a good prognosis and only rarely evolves into systemic sclerosis. The linear form, however, can cause considerable disfigurement and disability due to the involvement of skin, subcutaneous tissue, muscle, bone, and synovium. When it occurs in childhood, growth arrest, limb shortening, and joint contractures may result in severe local deformity and rarely even loss of a limb.¹ A lowered ratio of soluble to insoluble collagen in skin biopsies from patients with scleroderma has been demonstrated², and the discovery that D-penicillamine could normalize this ratio led Moynahan³ to treat 14 children with linear morphoea with low-dose D-penicillamine. He reported uniformly good results in all patients. Kesler and colleagues⁴, however, found no benefit when comparing two children with linear morphoea, one of whom was treated with D-penicillamine. We report two patients with linear morphoea who showed striking improvement following treatment with 250 mg D-penicillamine daily.     

Presence of eosinophilia in progressive systemic sclerosis and localized scleroderma

Summary Recent studies on eosinophilic fasciitis have lead to this investigation of eosinophilia in progressive systemic sclerosis and localized scleroderma.Eosinophilia (eosinophilic count >300/cmm) was found in ten of 63 progressive systemic sclerosis patients (15.8%) and in two of nine localized scleroderma cases (22.2%). In patients with progressive systemic sclerosis eosinophilia was found occasionally in six cases; it was transitory, but frequent in three cases; it was constant and very high in one case. In patients with localized scleroderma eosinophilia was found occasionally in one case and frequent, but not constant, in the other one.The possible influence of drugs could be excluded in five cases: three progressive systemic sclerosis cases and two affected with localized scleroderma.Therefore, it is possible to confirm that eosinophilia is not a distinctive sign of eosinophilic fasciitis in patients suffering from scleroderma-like syndromes.While eosinophilia is related to inflammation in eosinophilic fasciitis, eosinophilia and disease activity could not be correlated in our patients with PSS.Recently, it has been suggested that eosinophilia might be an unfavorable prognostic criterion in progressive systemic sclerosis. Our data does not allow confirmation of this assumption.     

Treatment of scleroderma.

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.     

Localized scleroderma (morphoea): thickness of sclerotic plaques as measured by 15 MHz pulsed ultrasound

The thickness of morphoea plaques was measured by A-mode ultrasound and compared to regional control measurements in the same individuals. The thickness of morphoea plaques was increased by 18-310% in 17 patients with one or a few morphoea plaques (p less than 0.01), and by 13-145% in 6 patients with generalized morphoea (p less than 0.05). The increase in thickness of morphoea plaques was local confined to the plaques. Ipsilateral and contralateral control measurements were not different, and measurements in a standard region (forearm) were not different from those in a group of healthy controls matched for sex and age. Plaques of clinically 'advanced' scleroderma were more thickened (p less than 0.01) than plaques of 'slight' scleroderma. The relative increase in thickness was larger (p less than 0.01) in skin with a habitual thickness of 0.8-1.1 mm. The habitual skin thickness on the extremities (mean 1.0 mm) was less (p less than 0.01) than on the trunk (mean 1.5 mm), and, consistently, plaques with 'advanced' scleroderma were more frequent (p less than 0.05) on the extremities. Ultrasound measurement of skin thickness was accurate with SD form 0.05-0.09 mm and coefficients of variation from 3-7% in reproducibility studies of typical morphoea plaques as well as normal appearing skin.     

VCAM-1 expression on endothelium in lesions from cutaneous lupus erythematosus is increased compared with systemic and localized scleroderma

Summary The cutaneous lesions in systemic sclerosis (SSc) and lupus erythematosus (LE) are pathologically distinct and may display separate cell adhesion receptors. We have scored lesional skin for the presence of cell adhesion molecules that may influence inflammatory and fibrotic processes in five patients with LE, six patients with diffuse scleroderma and four patients with morphoea. The immunohistological distribution, and the number and intensity of cells staining, were recorded for VCAM-1, ICAM-1, E-selectin, α2 to α6 and β2 integrins and HLA-DR, VCAM-1 staining intensity was increased on endothelium from lesions in LE compared with SSc (P=0.05). Low-level VCAM-1 and E-selectin expression was present on endothelium from uninvolved skin including that from patients with morphoea. HLA-DR expression was increased on infiltrating mononuclear cells (P < 0.05) and keratinocytes in LE (P < 0.05) and the number of fibroblasts staining for ICAM-1 was increased in lesions from patients with SSc, although this did not reach statistical significance. Overall, with respect to endothelial adhesion events, our findings support an important role for VCAM-1 in sustaining chronic inflammation in cutaneous LE.     

Capillary abnormalities, Raynaud's phenomenon, and systemic sclerosis in patients with localized scleroderma.

OBJECTIVES AND DESIGN--In vivo capillaroscopic examination was performed on patients with localized scleroderma to determine whether nailfold capillary abnormalities seen in systemic scleroderma (systemic sclerosis) were also present in the localized form. Twenty-seven patients (24 women, three men) were examined by this technique. RESULTS--Only two patients exhibited scleroderma-type nailfold capillary abnormalities similar to those seen in systemic sclerosis. Both patients also suffered from Raynaud's phenomenon and showed evidence of coexisting systemic sclerosis, one on first examination, the other 1.5 years later. Our results are compared with earlier studies reporting such rare coexistence of the two forms of scleroderma. Earlier capillaroscopic work in this disorder is also reviewed. CONCLUSIONS--These results suggest that the presence, in a patient with localized scleroderma, of nailfold capillary abnormalities similar to those seen in systemic sclerosis should alert the physician to a possible association with systemic sclerosis.     

Localized scleroderma: clinical spectrum and therapeutic update

Scleroderma is a rare connective tissue disease that is manifested by cutaneous sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement, and localized scleroderma or morphea which classically presents benign and self-limited evolution and is confined to the skin and/or underlying tissues. Localized scleroderma is a rare disease of unknown etiology. Recent studies show that the localized form may affect internal organs and have variable morbidity. Treatment should be started very early, before complications occur due to the high morbidity of localized scleroderma. In this review, we report the most important aspects and particularities in the treatment of patients diagnosed with localized scleroderma.     

硬皮病的超微结构观察

本文对4例临床症状典型并经病理证实的硬皮病进行了电子显微镜观察,其中进行性系统性硬化症2例,限局性硬皮病2例,观察了它们的胶原纤维、真皮中的细胞成份和血管的变化.见到2种胶原微纤维.一种比较年轻,纤维细,电子密度高,没有周期横纹.另一种为成熟的胶原微纤维.纤维粗.电子密度低,有特征性的周期横纹.这两种纤维在其横切面上也有所不同.硬皮病患者的真皮内胶原纤维不但数量增多,其宽度为1000~1200Å,也比正常人为粗(正常人为400~700Å),这可能是硬皮病结缔组织病变的一个特点.成纤维细胞有二类:一类在其胞质中细胞器十分丰富.有很多内质网,高尔基复合体和线粒体,它可能是一种具有活力的细胞,胶原纤维的产生主要是这一部份细胞完成的.另一类细胞体积小,细胞器少而发育差,这一类细胞,可能处于“静止状态”,本组病例中以前一类占优势.电镜下.血管数量不多,但小血管内皮细胞增生,血管内膜层增厚,内膜中还可见到一些嗜饿性颗粒物质,性质尚不明.     

Eosinophilic fasciitis: an early variant of scleroderma

Eosinophilic fasciitis, originally reported as a syndrome distinct from scleroderma, appears now to be an early inflammatory variant of scleroderma. No less than one half of the cases reported as eosinophilic fasciitis have convincing features of scleroderma, including Raynaud's phenomenon, esophageal dysmotility, restrictive lung disease, diffuse hyperpigmentation, synovitis, flexion contractures, dermal sclerosis, colonic diverticula, scleroderma kidney, positive latex fixation test, and the presence of serum antinuclear antibodies (ANA). Clinical presentations of scleroderma range from isolated acrosclerosis to rapidly progressive systemic sclerosis. As clinical experience and long-term follow-up data on eosinophilic fasciitis accumulate, it appears that the syndrome may well represent another variant in the scleroderma spectrum. Reported here is a case which presented clinically and histologically as eosinophilic fasciitis, but which progressed over 3 years to diffuse, histologically confirmed scleroderma.     

A case of nodular scleroderma

Nodular scleroderma is a rare complication of systemic sclerosis; the pathogenetic implications are still unknown, although many factors are supposed to play a role in lesion development. We report the case of a young woman suffering from systemic sclerosis, who developed nodular lesions during therapeutic management with D-penicillamine and plasmapheresis. In order to better understand the essence of this disease, we examined all the possible pathogenetic mechanisms that could be implicated in nodular lesion development.