Eosinophilic fasciitis

Introduction

Nephrogenic fibrosing dermopathy (NFD) is a newly-reported illness associated with renal disease; more specifically, with dialysis. Papules, subcutaneous nodules, and joint contractures are present in the skin. Pathologically, it is very similar to scleromyxedema. Increased dermal fibroblasts, thickened collagen bundles with clefting, and increased mucin are seen in the dermis and subcutis. We report a case of a 53-year-old female with nephrogenic fibrosing dermopathy after 5 days of hemodialysis. The patient experienced progressive bound-down, indurated erythematous plaques on her extremities with limited range of motion and pain shortly after hemodialysis. Biopsy showed increased dermal fibroblasts, thickened collagen bundles with clefting, and increased mucin in the dermis and subcutis. No paraproteinemia was found. She did not improve when her renal function improved, nor did prednisone improve her condition. This report and others are vital to help elucidate the etiological factors, course, and best treatment options for this disease process.

Case Report

A 53-year-old woman with an 8-week history of syncope, fatigue, anorexia, and nausea was admitted to an outside hospital with mild congestive heart failure and acute renal insufficiency (creatinine of 2.8 mg/dL). Her past medical history was significant for hypertension, peripheral vascular disease, hepatitis C, polysubstance dependence, and bipolar disease. Her medications included amlodipine, citalopram, valproic acid, labetalol, olanzapine, and aspirin. Imaging revealed bilateral renal artery stenosis and angioplasty and stenting was performed. The procedure was complicated by damage to the right renal artery and the patient underwent emergent bilateral renal artery bypass. She developed acute renal failure (ARF) secondary to acute tubular necrosis, and required daily hemodialysis for 5 days. Ten days after discharge, she was admitted to the same facility with severe edema and dyspnea which improved with diuretics. Two weeks later, she presented to our hospital's emergency department with increasing pain, swelling, tightness, and erythema of her upper and lower extremities. She had extensive warm, red, slightly-erythematous papules, plaques, and nodules with woody induration on her bilateral upper and lower extremities (Figure 1). Upper extremity lesions were yellow-brown in color and some aspects displayed a "peau d' orange" texture (Figure 2). She displayed mild to moderate lower extremity pitting edema. The differential included NFD, scleromyxedema, and eosinophilic fasciitis. Serum protein electrophoresis and liver function enzymes were within normal limits. Abnormal studies included a creatinine of 1.8 mg/dL, mild leukocytosis with minimal left shift, thrombocytosis, and an elevated sedimentation rate that was three times normal. Scanning power microscopic examination of a 6 mm punch biopsy displayed a squared-off specimen with a thickened dermis containing increased dermal spindle cells and thickened collagen bundles (Figure 3). The subcutis showed thickened septa. Higher magnification revealed clefted collagen bundles with invested fibroblast-like cells and little or no inflammation (Figure 4). A colloidal iron stain demonstrated increased mucin (Figure 5).

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The patient was started on prednisone 40 mg daily without benefit over 3 months. She was admitted at another facility one month later for surgical management of a small bowel obstruction. No surgical specimen was available to examine if the fibrosis was involving her viscera. Two months later, she was admitted for congestive heart failure (felt to be diastolic dysfunction) and a lobar pneumonia. She was given supplemental oxygen for home use because of an overall pulmonary decline of unclear etiology. Psoralen and long-wave ultraviolet radiation (PUVA) therapy was discussed, but the patient was unable to commute to a site to receive the treatment. Higher doses of prednisone, cytotoxic agents, and immunosuppressants have been discussed, but the patient has not kept several appointments to implement such therapies.

Discussion

The first reported case of NFD occurred in 1997, and Cowper et al. reported the clinicopathological features in 14 patients in 2000 (1). Over fifty cases have since been reported. Although it most often manifests as a scleromyxedema-like illness associated with hemodialysis or renal transplant, the cause is unknown (2). NFD is characterized by thickening and hardening of the skin with brawny hyperpigmenta tion3. The extremities are most commonly affected, and the face is usually spared (3). Patients may report pruritus or burning pain and the lesions are often warm (4). Initial cases were in renal transplant patients who were undergoing hemodialysis (1). However, cases of NFD in patients on peritoneal dialysis, those with chronic renal insufficiency, and even those who have yet to be dialyzed have been reported (3). The clinical course is yet unknown.

Clinically, the differential diagnosis includes scleromyxedema, systemic sclerosis, scleroderma or its localized variant morphea, eosinophilic fasciitis, eosinophilic myalgia syndrome (from L-tryptophan), toxic oil syndrome (from cooking oil), porphyria cutanea tarda (PCT), beta 2-microglobulin amyloidosis, calciphylaxis, and cellulitis (3). Certain characteristics distinguish these entities (2). Unlike NFD, scleromyxedema often involves the face, and is associated with a monoclonal paraproteinemia (4). Systemic sclerosis differs from NFD in that it often involves the face, features calcification, and has systemic involvement. Morphea usually involved ivorycolored plaques with a violaceous border (3). Eosinophilic fasciitis and the eosinophilic myalgia syndrome also display systemic involvement, and the latter often features eosinophilia (3). PCT includes bullae, milia, scarring and hypertrichosis. Beta 2-microglobulin amyloidosis displays papules and/or nodules and hyperpigmentation (3). Calciphylaxis often displays a livedo pattern with subsequent necrosis. Cellulitis is very erythematous, localized, and demarcated.

Histologically, NPF displays an increase in subcutaneous spindle cells, and collagen bundles are thickened and clefted. Increased mucin is seen, but only a paucity of inflammatory cells (4). Calcification is not usually a feature. The histological features of NFD closely resemble scleromyxedema, which also displays increased collagen and mucin deposition. The most prominent difference is the heavier inflammatory infiltrate in scleromyxedema composed primarily of plasma cells. NFD may also display fragmented elastic fibers (3). Systemic sclerosis and morphea contain a normal or decreased number of fibroblasts, atrophy of adnexae, and a mixed inflammatory infiltrate. Eosinophilic fasciitis and the eosinophilicmyalgia syndrome show a predominantly eosinophilic infiltrate. PCT is characterized by a cell-poor subepidermal vesicular dermatitis with preserved dermal papillae on sun-damaged dermis. Amyloidosis shows hyaline deposits in the dermis via staining with Congo red and crystal violet, among others. Calcium deposits staining with von Kossa stain distinguish calciphylaxis. Cellulitis displays variable edema and a sparse, primarily neutrophilic infiltrate.

Hemodialysis and renal transplant remain the major clinical context of NFD (2). Currently, the etiology of kidney disease does not seem relevant. The recent description of this disease makes one hypothesize that a recent alteration in the dialysis milieu may have led to its development (2). Mackay et al. comment that anti-phospholipid antibodies (APA) are more prevalent in end-stage renal disease patients (2). They propose an interaction between APA and a substance involved in the dialysis process (2). Furthermore, severe edema, as described in previous patients and ours, may trigger a fibrotic and mucinous reaction. It is also possible that NFD represents a variant of traditional scleromyxedema with out the paraproteinemia (2).

Infectious agents have been hypothesized. Cowper et al. tested for the Epstein-Barr virus in three sampies from their series, but all were negative (4). McNeill and Barr report a similar case and discuss the possible role of liver disease in this new disorder, and specifically hepatitis C and renal disease (5). They suggest the concomitant increase in transforming growth factor-beta 1 (TGF-beta 1) in patients with hepatitis C as an etiological possibility. TGF-beta 1 is a mediator of hepatic fibrogenesis in patients with hepatitis C. Studies have shown an interaction between TGF-beta 1 and basic fibroblastic growth factor (bFGF) in the stimulation of skin fibroblasts and irreversible skin fibrosis. TGF-beta 1 increases in patients receiving peritoneal dialysis and bFGF increases in peritonitis in such patients (5). Our patient had hepatitis C and underwent dialysis.

In a small case-controlled study of 24 renal transplant patients, cases with worse renal function and more medications were associated with severe disease (6). Some patients improve if the renal disease abates. The fact that our patient has pulmonary. cardiac, and gastrointestinal disease that is at least temporarily associated with her cutaneous disease makes us question if she has concomitant fibrosis of lung, heart, and intestinal tissue. Of course, internal involvement would be more common in scleromyxedema and systemic sclerosis, but understanding of NFD is still lacking. Her case could also be traditional scleromyxedema without paraproteinemia.

No effective treatment exists, and options are similar to treatments for scleromyxedema outlined by Godby et al (7). These include melphalan, systemic steroids, PUVA, radiation therapy, plasmapheresis, retinoids, and numerous cytotoxic and immunosuppressive medications.

In summary, nephrogenic fibrosing dermopathy appears to be a new entity in which patients display indurated plaques on the trunk and extremities in the setting of' renal disease, most specifically those receiving dialysis. The etiology, incidence, prevalence, and natural course of this disease are yet unknown.

This case was presented at the 2003 International Society of Dermatopathology as part of a resident symposium.

References

(1.) Cowper SE, et al. Scleroderma-like cutaneous disease in renal dialysis patients. The Lancet 2000; 16:1000 1.

(2.) Mackay-Wiggan JM. et al. Nephrogeriic fibrosing deropathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003; 48:55-60.

(3.) Streams BN. et al, Clinical and patlhologic features of nephrogenic fibrosing dermopathy: A report of two cases. J Am Acad Dermatol 2003; 48:42-7.

(4.) Cowper SE, et al. Nephrogenic fibrosing dermopathy Amer J Dermatopathol 2001; 23:383-93.

(5.) McNeill AM, Bart RJ. Scleromyxedema-like libromucinosis in a patient undergoing hemodialysis Int J Derm 2002; 41:364-7.

(6.) Fibrosing skin condition among patients with renal disease United States and Europe 19972002. MMWR/Morb Mortal Wkly Rep 2002; 51:25-6.

(7.) Godby A,et al Fatal scleromyxedema: Report of a case and review of the literature.J Am Acad Dermatol 1998; 38:289-94.

JOHN G HANCOX MD (1), YEBABE M MENGESHA MD (1), OMAR P SANGUENZA (1),

GIL YOSIPOVITCH MD (1)

DEPARTMENTS OF DERMATOLOGY (1) AND PATHOLOGY (2)

WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE.

WINSTON-SALEM, NORTH CAROLINA

ADDRESS FOR CORRESPONDENCE:

Gil Yosipovitch MD, Associate Professor

Wake Forest University School of Medicine

Department of Dermatology

Winston-Salem, NC 27157

T: 336-716-2901

F: 336-716-7732

E: gyosipov@wfubrnc.edu

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