Serum levels of matrix metalloproteinase‐13 in patients with eosinophilic fasciitis

Matrix metalloproteinase‐13 (MMP‐13), a member of the collagenase family, has been implicated in the pathogenesis of connective tissue diseases characterized by extracellular matrix remodeling. Since serum MMP‐13 levels reflect disease severity of systemic sclerosis and localized scleroderma, we evaluated the clinical significance of serum MMP‐13 levels in eosinophilic fasciitis (EF). All the EF patients had serum MMP‐13 levels lower than the mean – 2SD of healthy controls. Serum MMP‐13 levels were also significantly decreased in EF patients compared with diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, and generalized morphea patients. Although serum MMP‐13 levels did not reflect any clinical and serological features of EF, these results indicate that MMP‐13 may be involved in the development of this disease.     

Evaluation of transforming growth factor beta and type I procollagen gene expression in fibrotic skin diseases by in situ hybridization

Full thickness biopsies of affected skin and fascia from one patient with diffuse fasciitis and eosinophilia (DF), two patients with generalized morphea (GM), and five patients with progressive systemic sclerosis (PSS) of recent onset were examined for the expression of transforming growth factor beta 1 (TGF beta 1) and type I procollagen genes by in situ hybridization with human sequence-specific cDNA. An increased number of fibroblasts showing clearly detectable expression of pro alpha 1(I)collagen gene was found in all fibrotic lesions when compared with unaffected skin from the patient with DF and skin from two normal individuals examined in parallel. Expression of the TGF beta 1 gene was noted in a fibroblast subpopulation of the affected tissues from the patients with DF and GM. In contrast, the TGF beta 1 gene was not expressed at a detectable level in affected skin from the five patients with PSS. The results suggest that TGF beta 1 may play a role in the development of skin fibrosis in cases of DF and GM. However, from these studies, we cannot implicate TGF beta 1 in the pathogenesis of skin fibrosis in PSS.     

Bullous morphea profunda

A deep sclerotic process developed on the shins of a 58-year-old man, and eosinophilic fasciitis or morphea profunda was suspected clinically. Bullae later arose on the plaques, and histologic examination of a skin biopsy specimen revealed sclerosis and inflammation of the deep dermis, panniculus, and fascia, with subepidermal edema causing formation of bullae. No lymphatic obstruction or vasculitis was seen. Two plaques of typical morphea on the penis were noticed 10 months later. The patient had no peripheral or tissue eosinophilia, hypergammaglobulinemia, hematologic abnormality, or history of exertion before the onset of the disease. The sclerotic process involved more than the fascia. In describing this deeper variant of morphea, the term "morphea profunda" appears to be more appropriate than "eosinophilic fasciitis."     

Immunoglobulin A Nephropathy in Association with Generalized Inflammatory Peeling Skin Syndrome

We describe an 8‐year‐old girl born to second‐degree consanguineous parents with complaints of recurrent episodes of hematuria for 6 months. She had generalized peeling of the skin since birth and recurrent purulent cutaneous infections. The clinical presentation and histopathology of the skin biopsy specimen were consistent with the inflammatory variant of peeling skin syndrome (PSS). She also had a single ventricle with pulmonary stenosis, for which a bidirectional Glenn shunt had been placed. The renal biopsy specimen showed immunoglobulin A (IgA) nephropathy. She responded well to enalapril and steroids, with a decrease in proteinuria. IgA nephropathy has not been previously reported in PSS. Complications such as IgA nephropathy in children with PSS would help to further delineate the diverse clinical presentations and the clinical course of this rare dermatosis. We discuss the mechanisms that could explain this hitherto unreported association.     

Childhood‐Onset Anti‐Ku Antibody‐Positive Generalized Morphea with Polymyositis: A Japanese Case Study

We report a 16‐year‐old Japanese girl with anti‐Ku antibody‐positive generalized morphea and polymyositis who, at the age of 7 years, developed multiple brownish plaques on her left forearm that gradually extended to her upper arm, back, and left thigh, which a skin biopsy revealed as morphea. Laboratory testing was positive for antinuclear antibody and a high serum creatine kinase level. Although there were no clinical signs of muscular involvement, magnetic resonance imaging revealed findings consistent with myositis. The patient is one of the youngest reported cases positive for anti‐Ku antibody. Anti‐Ku positivity concomitant with generalized morphea is rare.     

Eosinophilic fasciitis: Current concepts

Eosinophilic fasciitis (EF) is an uncommon connective tissue disease characterized by abrupt onset of edema, followed by progressive induration of primarily the distal extremities. Patients may exhibit inflammatory arthritis, joint contractures, decreased mobility, and nerve entrapment. Almost half of patients with EF may have coexisting morphea plaques. Classic laboratory studies display peripheral eosinophilia, hypergammaglobulinemia, and elevated inflammatory markers. EF is included in the spectrum of scleroderma like disorders and may be difficult to distinguish from other sclerosing skin disorders. Full-thickness biopsy containing muscle and fascia is considered the gold standard for diagnosis and reveals sclerosis of the middeep dermis, subcutaneous fat, and thickening of the fascia. Magnetic resonance imaging (MRI) has been increasingly utilized to augment diagnostic capabilities. Ultimately, the diagnosis of EF relies upon the combination of characteristic clinical, laboratory, imaging, and histologic findings. Although some patients experience spontaneous remission, systemic corticosteroids (SCS) are the mainstay of treatment. Patients who fail to improve with SCS alone require the addition of a second immunosuppressive drug. Additionally, although data are limited, there is evidence to suggest that initial combination therapy with SCS and methotrexate (MTX) may be most beneficial.     

Concurrent Drug-Induced Linear Immunoglobulin A Dermatosis and Immunoglobulin A Nephropathy

Diseases associated with immunoglobulin A (IgA) antibody include linear IgA dermatosis, IgA nephropathy, Celiac disease, Henoch-Schönlein purpura, etc. Although usually idiopathic, IgA antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes. So far, only a few cases of IgA bullous dermatosis coexisting with IgA nephropathy have been reported. A 64-year-old female receiving intravenous ceftriaxone and metronidazole for liver abscess had purpuric macules and papules on her extremities. One week later, she had generalized edema and skin rash with bullae and was diagnosed with concurrent linear IgA dermatosis and IgA nephropathy. After steroid treatment, the skin lesion subsided within two weeks, and kidney function slowly returned to normal. As both diseases occurred after a common possible cause, we predict their pathogeneses are associated.     

Idiopathic and L-tryptophan-associated eosinophilic fasciitis before and after L-tryptophan contamination

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.     

Eosinophilic fasciitis (Shulman syndrome) in association with morphea, immunological disturbance and profuse achromia

A case of localized eosinophilic fasciitis (EF) is reported. Profuse hypopigmentation, guttate morphea and immunological disturbances accompanied the subcutaneous changes. The case links Shulman's syndrome with classical localized cutaneous scleroderma.     

Morphoea‐like plaques revealing an eosinophilic (Shulman) fasciitis

Eosinophilic fasciitis (EF) is a connective‐tissue disease characterized by thickened fascia. Involvement of the dermis may occur during the progression of the disease, characterized clinically by morphoea‐like plaques (MLPs). This more superficial feature of EF carries a poor prognosis, suggestive of refractory EF that requires intensive therapy. We report a case in which morphoea‐like plaques occurred before the EF. This case and previous cases of MLPs show some differences between MLPs and classic morphoea. Clinically, MLPs present with ill‐defined brown plaques, with no lilac ring or ivory colour. Histologically, there is a more marked inflammatory infiltrate and an increase in the number of eosinophils. The discovery of MLPs at an early stage should prompt examination of the fascia with magnetic resonance imaging or surgical biopsy, and aggressive treatment.     

The skin in IgA nephropathies

Fifteen men (average age 54.6 +/- 14.6 years) with IgA-associated glomerulonephritis underwent concomitant skin and renal biopsies to clarify any potential diagnostic relationships. Both types of tissues were studied by standard light, immunofluorescent, and electron microscopic techniques. The glomeruli of all the patients studied showed renal mesangial IgA deposits. All corresponding skin biopsy specimens showed no IgA deposition in the cutaneous blood vessels. The negative association suggests that examination of the skin biopsy specimen alone is not reliable in establishing the diagnosis of primary IgA nephritis. In view of the known skin involvement in Henoch-Sch?nlein nephropathy, we propose that skin biopsy specimens be examined routinely when renal biopsy specimens demonstrate IgA deposits, to differentiate primary IgA nephropathy from a forme fruste of Henoch-Sch?nlein purpura.     

IgA antiendomysial antibodies in dermatitis herpetiformis

Sera from 24 patients with dermatitis herpetiformis and 80 control subjects (patients with other bullous diseases, nonbullous dermatoses, and noncutaneous diseases) were studied to determine the usefulness of assay for IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of dermatitis herpetiformis. The overall sensitivity of IgA-EMA for the diagnosis of dermatitis herpetiformis was 79% and the specificity was 96%. When the three patients with dermatitis herpetiformis who were faithfully following gluten-free diets were excluded, the sensitivity was 90% and the specificity was 96%. No patient in the bullous disease control group (including patients with linear IgA bullous dermatosis) had circulating IgA-EMA. One patient, who did not have direct immunofluorescence evidence for dermatitis herpetiformis but had IgA nephropathy, had a positive IgA-EMA result, an interesting association in light of the rare reports of dermatitis herpetiformis in patients with IgA nephropathy and IgA antigliadin antibodies associated with IgA nephropathy. Although direct immunofluorescence testing of skin biopsy specimens remains the most definitive diagnostic test for dermatitis herpetiformis, indirect immunofluorescence assay of serum for IgA-EMA is a minimally invasive study with a high sensitivity and specificity for dermatitis herpetiformis.     

Epithelial–mesenchymal transition of the eccrine glands is involved in skin fibrosis in morphea

Morphea is a type of localized scleroderma. It is a skin disease involving the development of fibrosis in the dermis and subcutaneous fat tissue beneath without a visceral lesion, and the cause is still unclear. An involvement of epithelial–mesenchymal transition (EMT) has been reported as a cause of tissue fibrosis, but this was mostly observed in pulmonary and hepatic fibrosis, and the involvement of EMT in a skin disease, morphea, has not been studied . Thus, we analyzed the involvement of EMT in skin fibrosis in morphea patients using pathological techniques. Skin lesions of six morphea patients were analyzed (five female and one male patient). As a control, non‐light‐exposed skin lesions of 11 healthy females were analyzed. Concretely, tissue samples were prepared from these subjects and subjected to immunostaining of transforming growth factor (TGF)‐β1, α‐smooth muscle actin (α‐SMA) and fibronectin, which have been reported to be associated with fibrosis, and Snail1 and E‐cadherin, which are considered to be involved in EMT, and expressions of these were analyzed. In morphea patients, dermal expression of TGF‐β1, α‐SMA and fibronectin, which are involved in fibrosis, was enhanced, and, at the same time, enhanced expression of Snail1 and reduced expression of E‐cadherin, which are involved in EMT, were observed in the dermal eccrine glands. These findings suggested the progression of EMT in the dermal eccrine glands in morphea.     

Linear scleroderma in an adolescent woman treated with methotrexate and excimer laser

A 17‐year‐old Caucasian woman presented for evaluation and treatment of a tender expanding linear plaque on her left flank. Biopsy findings were consistent with morphea. Treatment initially included intralesional steroid injections and topical calcipotriene ointment, followed by methotrexate and excimer laser. The lesion decreased in size considerably with relief of symptomatic discomfort by 7 months. An excisional biopsy of a persistent eroded papule on the superior aspect of the morphea plaque revealed dermal thickening and sclerosis with superimposed perforation of a calcified nodule. Localized scleroderma, or morphea, is an autoimmune disease of the skin and underlying subcutaneous tissue primarily affecting the pediatric population. The excimer laser has been reported to effectively treat a variety of dermatologic conditions, including morphea. Its mechanism of action may be via depletion of T cells, altering apoptosis‐mediating molecules and decreasing cytokine expression. Methotrexate is also useful for the acute and deep forms of morphea and has been shown to decrease levels of inter leukins‐2 and ‐6, tenascin, and mast cells. This patient had a good clinical response with a combination of these two modalities. The epidermal perforation with transepidermal elimination of calcified necrotic collagen is a unique complication that may have been secondary to this combination treatment modality.     

Amicrobial pustulosis associated with autoimmune disease in a patient with Sjögren syndrome and IgA nephropathy

Amicrobial pustulosis associated with autoimmune disease (APAD) is a rare clinical condition, characterized by relapsing pustular eruption, affecting mainly the skin folds. Almost all previously described cases were young women with varying underlying autoimmune diseases. We report a 36‐year‐old woman with the interesting triad of APAD, Sjögren syndrome and IgA nephropathy. Her rashes responded to oral prednisolone and cyclophosphamide.     

Extracorporeal photochemotherapy in the treatment of eosinophilic fasciitis

BACKGROUND: Eosinophilic fasciitis (EF) is a rare connective tissue disorder characterized clinically by symmetrical swelling, induration and thickening of the skin and histologically by thickening of the fascia with chronic inflammatory infiltrate containing eosinophils. The disease is classified in the spectrum morphea/systemic sclerosis and treated with systemic steroids and other immunosuppressant drugs. OBJECTIVE: The purpose of this study was to use extracorporeal photochemotherapy (ECP) in patients with EF to evaluate the effectiveness of this therapy. SUBJECTS AND METHODS: Three patients affected by EF were treated with ECP because they failed to respond or with contraindications to immunosuppressant treatment. The patients underwent ECP with a UVAR XTS apparatus. Subjects were treated on two consecutive days at 2-week intervals for the first 3 months and thereafter every 4 weeks on the basis of clinical response. The patients were assessed before therapy and then monthly by means of a clinical score. Changes in affected areas were evaluated at predetermined points by computerized skin elastometry (Cutometer SEM 474). RESULT: After 1 year of therapy we found considerable improvement of clinical parameters in two cases. There was less striking improvement in the other case. These clinical results were confirmed by the elastometry measurements. All patients reported improved quality of life, which enabled a reduction in the dose of immunosuppressants. CONCLUSION: ECP emerged as a safe and effective therapy in association with low doses of immunosuppressants in our three patients. A randomized comparative multicentre study between ECP as single therapy and ECP plus immunosuppressants and conventional therapies is required to firmly establish photopheresis as a possible basic treatment to combine with conventional therapies for EF.     

Letter: Methotrexate for localized morphea with severe pain: a case report

Morphea, also known as localized scleroderma, is characterized by idiopathic fibrosis of the skin and adjacent structures. Patients with morphea classically present with skin lesions without any associated symptoms and the lesions usually regress spontaneously over time. We describe a patient with morphea who presented with debilitating pain in her skin plaque. She failed topical therapy and required systemic methotrexate to control her disease. We titrated the methotrexate dose with the goal of pain relief. Although unusual, pain associated with morphea can be debilitating. Physicians should assess for pain in patients with morphea and prescribe treatments accordingly. We propose using pain, when present, in addition to physical examination as a guide for titrating morphea therapy.     

Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis

Linear immunoglobulin (Ig)A/G bullous dermatosis (LAGBD) is an autoimmune bullous disease characterized by formation of subepidermal blisters and linear deposition of IgA and IgG antibodies along the basement membrane zone (BMZ). The association between linear IgA bullous dermatosis and ulcerative colitis (UC) is well recognized, but reports of UC‐associated LAGBD are lacking. We have reported a 24‐year‐old man suffering from LAGBD associated with UC, which occurred before exacerbations of skin rash. A skin biopsy indicated a subepidermal blister with an infiltration of primarily neutrophils and eosinophils in the dermis. Direct immunofluorescence (IF) studies showed a linear deposition of IgA, IgG and C3c. Indirect IF of human skin revealed IgA and IgG anti‐BMZ autoantibodies. Indirect IF of 1 M NaCl‐split human skin demonstrated reactivity of IgA and IgG antibodies at the epidermal side. Immunoblotting showed that IgG antibodies reacted to the BP180 NC16a domain and 120‐kDa linear IgA dermatosis‐1, and enzyme‐linked immunoassay detected IgG anti‐BP230 antibodies. Administration of prednisolone and diaminodiphenyl sulfone (DDS) via the p.o. route improved skin lesions and bowel conditions. These results suggest that the bowel inflammation observed in UC may have a causative effect of initiation of the immune response to the skin and development of the bullous skin lesions in LAGBD. A combination of DDS and corticosteroid could be a recommended therapeutic option for patients with LAGBD with UC.     

Two Cases of Eosinophilic Fasciitis

Eosinophic fasciitis (EF) is an uncommon connective tissue disease characterized by scleroderma-like cutaneous changes, peripheral eosinophilia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate (ESR). Typical histopathologic findings include chronic inflammatory infiltration affecting the deep fascia with lymphocytes, histiocytes, and occasionally eosinophils. We report two cases of EF, the first of which is a 36-year-old man with a tender brownish induration on both forearms, for 2 months. Histopathologic examination showed fibrotic fascia with a mixed inflammatory cell infiltration. The second case is a 52-year-old woman with a symmetrical painful swelling and skin induration on both forearms, for 4 months. A deep biopsy demonstrated chronic inflammatory cell infiltration and hyaline degeneration in the fascia. Increased signal intensity in the fascia and tendon sheath was shown on magnetic resonance imaging. In laboratory examination, mild eosinophilia was found in both cases. Both patients had a history of physical activity (weight training and excessive housework, respectively) and showed marked improvement with high doses of oral prednisolone for several months.