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Objective: To study the prevalence and antigen specificity of antihistone antibodies (AHA) in localized scleroderma., Methods: Forty-nine serum samples from patients with localized scleroderma were examined by an enzyme-linked immunosorbent assay (ELISA) and by immunoblotting., Results: By ELISA, AHA were demonstrated in 47% (23 of 49) of patients with localized scleroderma and in 87% (13 of 15) of patients with generalized morphea. Immunoblotting revealed that the predominant antigens were histones H1 and H3. The presence of AHA correlated with that of anti-single-stranded DNA antibody., Conclusion: Some of the major antigens for antinuclear antibodies in patients with localized scleroderma are histones.

Background and Design: Interleukin 8 (IL-8), a chemotactic cytokine produced by various cell types, displays structural homology to the connective tissue-activating peptide III. Little is known of the possible role of IL-8 in connective tissue disorders. We therefore determined serum concentrations of IL-8 and autoantibodies to IL-8 in 134 patients with systemic sclerosis (SSc) and related connective tissue disorders, as well as in pooled serum from 28 healthy control subjects by a sensitive enzyme-linked immunosorbent assay., Results: Interleukin 8 was undetectable in the pooled serum from 28 healthy controls, but detectable in serum samples from 24 of the 134 patients described above. It was detected in 13 of 60 patients with limited SSc and in eight of 48 patients with diffuse SSc. It was also detectable in one of three patients with eosinophilic fasciitis and in two of 10 patients with Raynaud's syndrome without skin involvement. In contrast, none of the three patients with morphea or the 10 patients with eosinophilia-myalgia syndrome had detectable IL-8 levels. We further determined the concentration of autoantibodies to IL-8 in the same serum samples. The values in healthy controls were 6.7 +/- 0.2 ng/mL (mean +/- SEM). Significantly elevated autoantibody levels were detected in patients with limited SSc (21.5 +/- 1.7), diffuse SSc (23.4 +/- 2.2), and Raynaud's syndrome (20.5 +/- 3.7). Elevated levels were also detected in patients with eosinophilic fasciitis (43.7 +/- 8.6) and morphea (14.7 +/- 3.2). Normal levels (7.5 +/- 2.0) were found in patients with eosinophilia-myalgia syndrome. Analysis of variance between the levels of autoantibodies to IL-8 and duration of the disease, extent of skin involvement, drug therapy, or serologic findings failed to show a significant correlation., Conclusions: These results suggest that increased production of IL-8 may relate to activation of mononuclear phagocytes, fibroblasts, or endothelial cells, among other cell types, in patients with SSc, but not in those with eosinophilia-myalgia syndrome. This activation could be related to the production of autoantibodies to IL-8.

Recently, a causative association has been made between the ingestion of levotryptophan (L-tryptophan) and the eosinophilia-myalgia syndrome (EMS), a new entity manifested by peripheral blood eosinophilia, myalgias, constitutional symptoms, and cutaneous edema with fibrosis. Contaminated levotryptophan preparations produced at a single manufacturing company between October 1988 and June 1989 have been implicated in all EMS cases. In this study, we analyzed retrospectively 49 patients with cutaneous fibrosis for a history of levotryptophan use. Levotryptophan ingestion prior to the onset of their disease was reported by 11 (65%) of 17 patients with eosinophilic fascilitis (EF), two (20%) of 10 patients with localized scleroderma, and none of 22 patients with systemic sclerosis. The onset of levotryptophan-associated cutaneous disease preceded the availability of contaminated levotryptophan preparations in seven (54%) of 13 patients. One patient with levotryptophan-associated generalized morphea also had lichen sclerosus et atrophicus and acanthosis nigricans, findings not previously reported in patients with EMS. In addition, we compared the clinical and laboratory features of levotryptophan-associated EF and idiopathic EF. Myalgias, muscle weakness, paresthesias, morpheaform plaques, cutaneous ulcers, and livedo reticularis were more common in patients with levotryptophan-associated EF. We conclude that levotryptophan-associated EF and localized scleroderma were present before the presumed date of contaminated levotryptophan availability. The clinical spectrum of cutaneous fibrosis associated with the ingestion of levotryptophan includes generalized morphea and EF, which are similar though not identical to their idiopathic counterparts.

We examined whether immunological disturbances could influence the development of scleroderma-like skin lesions in patients affected by the Spanish toxic oil syndrome (TOS). To this end, peripheral blood mononuclear cells (PBMC) were collected from 13 chronic patients and 8 control subjects. All patients had suffered a toxic-induced severe neuromyopathy, and 6, in addition, had developed sclerodermoid skin manifestations. The phenotypic profile and the concentrations of interleukin-2 (IL-2) and of molecules with B cell differentiation factor IgG activity (BCDF-IgG) in supernatants of phytohemagglutinin-stimulated lymphocytes were analyzed both in patients and in normal controls. Molecules with BCDF-IgG activity were found increased in supernatants of mitogen-stimulated lymphocytes from TOS patients. Concentrations of IgG secreted by staphylococcus aureus-SAC-B blasts in the presence of TOS PBMC supernatant was 88 +/- 32.62 ng/ml (mean +/- 1 SD) versus 53 +/- 5.34 ng/ml in the presence of control supernatant (p less than 0.01). Levels of BCDF-IgG activity in TOS PBMC supernatants positively correlated with IgG serum levels (r = 0.69, p less than 0.01). The phenotypic profile of lymphocyte populations and the production of IL-2 were not altered in TOS subjects. No statistically significant differences were observed in the lymphocyte distribution nor in the IL-2 and BCDF-IgG production when comparing patients with or without scleroderma-like skin lesions. The results indicate that there was a dysfunction of the immune response in TOS subjects, which, however, was not sufficient for the development of the sclerodermoid lesions.

Fiftyone patients with a diagnosis of erythema chronicum migrans (ECM), lymphadenosis cutis benigna (LABC), systemic progressive sclerosis, localized scleroderma and lichen sclerosus et atrophicans were investigated in order to obtain serological evaluation of Borrelia burgdorferi circulating antibodies. In addition sera from 9 patients with pellagroid erythema, prurigo and panniculitis were performed: in these dermatoses there was no evidence of a possible borrelia relationship. Indirect immunofluorescence assay was used for serologic testing. Elevated IgG antibody titers were detected in one female patient with localized scleroderma (1:128) and in one male patient with LABC (1:64). Serologic testing was not positive in the other 58 patients. The very small number of patients with positive antibodies in our study would indicate that Borrelia burgdorferi infection is sporadic in Lazio.

A total of 104 patients with scleroderma were examined. Anticardiolipin antibodies were detected in 37.5 per cent of the patients with systemic scleroderma and in 3 per cent of healthy individuals; they were more often detected in 46.8 per cent of the patients with diffuse affections of the skin, atherosclerosis, Raynaud's syndrome accompanied by ulcero-necrotic affections of the skin as compared to patients with restricted affections of the skin (sclerodactylia and focal scleroderma)--29.8 per cent. No significant changes in the frequency of detecting a rheumatic factor, antibodies to Scl-70 were revealed in subgroups of patients with scleroderma, positive and negative anticardiolipin antibodies. Of the greatest interest is a significant difference in levels of C-reactive protein which were high in half of the patients with anticardiolipin antibodies. Anticentromere antibodies were detected twice as more often in patients without anticardiolipin antibodies that corresponded to systemic sclerodermia with minimum involvement of the skin into the pathological process. It is suggested that ulcero-necrotic affection of the skin in systemic sclerodermia is associated with C-reactive protein but it is not of an immunocomplex nature.

Several cutaneous entities described in Europe as Chronic Migrans Erythema (CME), Mild Cutis Lymphadenosis (MCL) and Chronic Atrophyc Acrodermatitis (CAA) constitute clinical manifestations of a Borrellia Burgdorferi. The presence of clinical and hystologic lesions similar to those of liquen esclerosus and atrophyc (LEA) and localized esclerodermia (morphea) in patients with CAA has driven to several authors to demonstrate the aethiologic participation of B. Burgdorferi in patients carrying those cutaneous lesions with contradictory results. A serologic study with indirect immunofluorescence (IIF) and FIAX test was performed in 16 patients (9 with morphea, 6 with LEA and 1 with CME) in order to evaluate the role of this microorganism in our environment. Five reactive sera were obtained of which only one presented IgG antibodies titrated at 1/256. The IgM antibodies by IIF and IgG by FIAX test turned out to be negative. A specific relationship between B. Burgdorferi and the studied entities could not be established.

Systemic sclerosis is characterized by excessive deposition of collagen and other matrix proteins in the skin and internal organs. One hypothesis supports fibroblast stimulation for production of excess amounts of collagen by factors present in the blood or released by cells composing inflammatory tissue infiltrates. Increased numbers of mast cells are present in the involved skin of patients with systemic sclerosis, and histamine has been thought to be a possible mediator of fibrosis in this and other fibrotic conditions. We therefore measured plasma histamine levels in 32 patients with systemic sclerosis and found elevated levels in 18 patients (56%). Elevated plasma histamine levels were more common in patients with diffuse disease (74%), in contrast to limited disease (31%). The degree of clinical activity and the duration of disease could not be correlated with histamine levels.

Examinations of the hemostasis system parameters in patients with scleroderma, psoriatic arthritis, malignant lymphoma of the skin have revealed a significant elevation of fibrinogen concentration, acceleration of blood clotting time, increased prothrombin consumption in all the patients. Elevation of the prothrombin index was detected in the patients with scleroderma and psoriatic arthritis. A direct relationship between the disease severity, size of the involvement of the skin integument, inflammation activity in the joints, and severity of hemostasis impairment has been revealed.

Studies of the function of cyclic nucleotide system in the lymphocytes of patients with focal scleroderma have revealed that this condition is characterized by growth of the intracellular cAMP/cGMP ratio, correlating with the process duration, severity, and dissemination. A correlation between lymphocyte regulatory function defect and the presence of immunodeficiency syndrome was demonstrated. Sensitivity of lymphocytic cyclic nucleotides in focal scleroderma patients to thymoptin, a thymic agent, was examined. Manifest clinical effect of this drug is based on stabilization of the function of lymphocytic cyclic nucleotides system and, consequently, on normalization of the immunologic parameters. Potentialities and prospects of thymic factors immunotherapy of focal scleroderma patients are discussed.

Blood fibrinolytic activity was measured in 20 patients with primary lymphedema, ten without and ten with skin changes usually attributed to "chronic cellulitis". The patients with abnormal skin showed reduced fibrinolytic activity, a finding previously described in patients with chronic venous disease and lipodermatosclerosis . It is postulated that changes of "chronic cellulitis" are identical to lipodermatosclerosis and are produced by a similar mechanism, namely reduced fibrinolysis.

Various dermal fibrotic conditions, such as progressive systemic sclerosis, localized morphea and familial cutaneous collagenoma, are characterized by excessive deposition of collagen in the skin. In the present study, we examined the possibility that a circulating serum factor(s) is responsible for increased collagen production in these diseases. The effects of human serum on the synthesis of procollagen were examined by incubating normal human dermal fibroblasts with [3H]proline and varying concentrations of dialyzed heat-inactivated serum. The synthesis of procollagen was measured as formation of nondialyzable [3H]hydroxyproline and collagenase-digestible 3H]polypeptides. In the absence of serum little procollagen was formed but the synthesis was markedly stimulated by the addition of normal serum in a concentration-dependent manner. THe ratio of genetically distinct 3H-procollagens of type I and type III, assayed by DEAE-cellulose chromatography and SDS-polyacrylamide gel electrophoresis after limited pepsin proteolysis, was unaffected by the addition of serum. Thus, normal human serum contains a nondialyzable factor(s) which stimulates the synthesis of procollagens type I and type III equally. Sera from 5 patients with progressive systemic sclerosis, 3 with localized scleroderma, and 2 with familial cutaneous collagenoma were also tested. Sera from these patients failed to stimulate 3H-procollagen production more than sera from healthy age-matched controls. Therefore, no increased quantities or qualitatively aberrant factors were shown to be present in the sera of these patients.

The effects on cell proliferation and on collagen and protein synthesis of prolonged exposure of control and scleroderma skin fibroblasts to control and scleroderma serum were studied. The previously described mitogenic effect originally noted at 3 days was observed to a lesser degree at 21 days, at which time a doubling of protein synthesis and a 3-fold increase in collagen synthesis were noted. Since earlier studies of shorter exposure times did not show effects on protein or collagen synthesis, the prolonged exposure of heterogeneous mass cultures of dermal fibroblasts to the mitogenic effects of scleroderma serum may result in the emergence of high collagen producing cells.

The incidence rates of combinations of A and B loci histocompatibility antigens in loci and haplotypes and of ceruloplasmin phenotypes have been examined in 137 patients with lupus erythematosus (LE) and scleroderma circumscriptum (SC). The studies have revealed that LE and SC are associated with certain haplotypes and HLA antigens combinations, this indicating the contribution of these phenotypes to the realization of the genetic predisposition to these diseases. In A1B8 haplotype carriers the disease is characterized by a benign course and manifests by integument forms of LE and scleroderma. IN A2B8 haplotype carriers the disease is more grave and presents as the systemic variant of LE. The third type of ceruloplasmin not detectable in normal subjects is usually associated with A9B18, A25B18, A3B27 haplotypes and with HLA A3A9 antigenic combination mostly in LE patients.

The clinical presentation of scleroderma in childhood is even more varied than in adult life. This study of 19 children shows that antinuclear antibodies (ANA) detected on the HEp2 cell substrate are just as common as in the adult disorders. All seven children with diffuse scleroderma or acrosclerosis were ANA positive, as were eight of the 12 with more localised disease. Antinucleolar antibodies were particularly frequent (58% overall), but anticentromere antibody was not observed. Enzyme-linked immunosorbent assays (ELISAs) for antibodies to collagen types I-V, in contrast to adult scleroderma, gave normal results in all childhood cases.

Eosinophilic fasciitis is an additional clinical entity to many others manifested by sclerodermic changes in the skin. A case with this process is reported. It presents vast cutaneous sclerodermic changes associated with eosinophilia, signs of muscular exertion, and a massive inflammatory infiltrate involving the lower part of the dermis, subcutaneous tissue and the muscle fascia. Prednisone therapy was followed by rapid and marked improvement.

We describe a patient with a scleroderma-like illness which involved the arms and legs but not the face and hands. Clinical, laboratory and histological features were those of the recently described syndrome, eosinophilic fasciitis. This rare condition is worthy of note because it appears to have a much better prognosis than conventional scleroderma, and because it responds very well to corticosteroid therapy.

Recent studies on eosinophilic fasciitis have lead to this investigation of eosinophilia in progressive systemic sclerosis and localized scleroderma. Eosinophilia (eosinophilic count greater than 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 faciitis, 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.

Presents thromboelastography data on the blood coagulation system in focal scleroderma patients over the course of electroacupuncture.

Fibrinolytic activity is notoriously related to the maintenance of an adequate microcirculatory blood flow and its impairment is related to thrombosis. In this report cutaneous fibrinolytic activity has been evaluated with an autohistographic method in ten subjects with morphea and in five subjects with systemic sclerosis before and after injection of histamine into the skin. Cutaneous fibrinolytic activity (CFA) appeared normal (3/5 cases) or increased (2/5) in uninvolved and involved skin in systemic scleroderma and always increased after histamine injection. In circumscribed scleroderma the CFA appeared reduced in 2/10 cases, normal in 4/10 cases and increased in 4/10 cases. These data show that an endothelial pool of plasminogen activator is available in the skin of scleroderma patients and that fibrinolytic agents can rationally be employed only in certain stages of the disease.

The course of scleroderma is compared in patients with and without diabetes mellitus. In combined pathology, bullous foci of injury and trophic abnormalities occur more frequently. All the patients were diagnosed to have abnormalities on the part of connective tissue metabolism.

Studies of serum copper and caeruloplasmin were performed in patients with ankylosing spondylitis, systemic sclerosis, and morphea. Mean levels of both were raised significantly in ankylosing spondylitis, with the greatest increases in the worst cases. In patients with systemic sclerosis there was a significant increase in the mean level of caeruloplasmin, but not of copper, although both were raised in the 2 patients with the most aggressive disease. No alterations were found in patients with morphea. The values in the patients overlapped considerably with the values in the control subjects. It is thought that the increase in serum copper is probably secondary to the increase in caeruloplasmin which occurs as a nonspecific response to inflammation.

Sera from 31 patients with progressive systemic sclerosis (PSS), 5 patients with widespread localized scleroderma (LS), and 3 patients with lichen sclerosus et atrophicus were analyzed for aminoterminal propeptide of type III procollagen (PIIINP) using a radioimmunoassay based on human propeptide. Thirty-eight per cent of the patients with PSS had levels above normal range, including all of the 3 patients with diffuse scleroderma. The same applies to 4 of 5 patients with widespread localized LS, while PIIINP in all 3 patients with lichen sclerosus et atrophicus were within normal levels. In patients with acrosclerosis, elevated PIIINP seems to be correlated to rapid progression and extension of lesions. A significant increase in PIIINP was found in a patient following discontinuation of prednisone and cyclophosphamide, while the present investigation did not allow judgement of effects of treatment with either penicillamine or cyclosporin A.

Sixteen patients had biopsy-proved inflammatory sclerosis of the panniculus or fascia, which usually was seen in a generalized distribution. Although the sclerosis involved the digits of five patients, it was the result of centrifugal spread of the sclerosis and was not accompanied by ulcers, calcinosis, distal phalangeal resorption or telangiectasia. Four patients may have had digital vasopasm in the extremities involved in the sclerotic process. Five patients also had cutaneous lesions of dermal morphoea or lichen sclerosus et atrophicus. Four patients had a reduced carbon monoxide diffusing capacity, and one of these had roentgenographic evidence of pulmonary fibrosis. In three patients, oesophageal motility or barium swallow studies showed evidence of sclerodermatous changes. The sclerotic process was a contributory cause of the death of one patient. Five patients had peripheral eosinophilia. Six patients seemed to have responded to anti-inflammatory agents. We believe that subcutaneous morphoea is generally more inflammatory than generalized morphoea of the dermal type and may be more likely to progress to mild systemic sclerosis. We suggest that response of subcutaneous morphoea to anti-inflammatory agents is simply a reflection of the degree of inflammation present.

The case of a 20-year-old girl who had morphea with bullous lesions is reported. Two bullae appeared on an indurated patch of morphea on the right side of the trunk. A half-moon-shaped lesion was localized along the superior border of the patch and the other followed the anterior border and extended into the patch. Both contained a hemorrhagic fluid. The bullae spontaneously regressed in a few months without therapy. We emphasize the very rare occurrence of hemorrhagic bullous lesions as a complication of morphea.

Blood eosinophilia is a common feature of eosinophilic fasciitis and is variably reported in systemic sclerosis and localized scleroderma. Since these diseases share cutaneous fibrosis as the final outcome and have other clinical and pathologic features that are difficult to differentiate, the presence of blood eosinophilia may be a further source of confusion. In this study, we examined the frequency and level of blood eosinophilia in 715 patients with systemic sclerosis, 72 patients with localized scleroderma, and 22 patients with clinically active eosinophilic fasciitis. When defined as greater than 400 cells/mm3, eosinophilia was present in 7% of patients with systemic sclerosis, 31% of patients with localized scleroderma, and 83% of patients with eosinophilic fasciitis. Greater than 1000 eosinophils/mm3 were present less frequently in systemic sclerosis (1%) and localized scleroderma (8%) than in eosinophilic fasciitis (61%). No difference in the frequency of eosinophilia was present in patients with the limited cutaneous CREST syndrome or the diffuse cutaneous variety of systemic sclerosis, and in these patients the presence of eosinophilia did not correlate with the extent of cutaneous or internal organ involvement or with other laboratory abnormalities. Among patients with localized scleroderma, eosinophilia was more common in those with linear scleroderma and generalized morphea than in those with morphea, and both the frequency and level of eosinophilia were greater in individuals with clinically active disease (p less than 0.02). Eosinophilia was a persistent feature in untreated patients with active eosinophilic fasciitis, even up to 30 months of disease duration.