Clinical and Pathologic Features and Therapeutic Management of Eosinophilic Fasciitis

Eosinophilic fasciitis (EF) is a rare scleroderma-like syndrome characterized by diffuse fasciitis and eosinophilia. The etiology of EF remains unknown, and it affects both sexes almost equally. The mean age of onset is typically between 40 and 50 years. The disease presents with a range of clinical manifestations, including sclerotic lesions, cutaneous induration, and fascial thickening with inflammatory infiltration. Skin lesions may progress from edema of the extremities to peau d’orange with hyperpigmentation, the “groove” sign, and woody induration with skin tightness. Extracutaneous manifestations, such as synovitis, contractures, and arthritic, pulmonary, hematologic, and neoplastic manifestations, may also occur. Magnetic resonance imaging (MRI) has recently been utilized for the diagnosis of EF. Laboratory findings often include an elevated erythrocyte sedimentation rate, peripheral eosinophilia, and hypergammaglobulinemia. The therapeutic management of EF is challenging, with steroids being the mainstay of treatment, effective in just over 60% of patients. In some cases, immunosuppressive drugs, anti-tumor necrosis factor alpha inhibitors, and photochemotherapy are also employed.

Demographics and Clinical Presentation

In a retrospective study of 78 Chinese patients with EF, 47 (60%) were females and 31 (40%) were males. The mean age at onset was 31.88 ± 17.04 years. The average time from the first symptoms to diagnosis was 4.84 ± 6.20 years. For patients with failed treatment, the median time was 8 years, compared to 2 years for those who experienced remission. The disease was diagnosed sooner in men (average 3.33 years) than in women (average 6.82 years). The duration of the disease before the initial biopsy ranged from 2 months to 26 years, with only ten cases diagnosed within one year of onset. Five patients (6.4%) had a fever lasting from days to weeks, and six patients experienced fatigue. Six patients had a history of surgery or trauma preceding the onset of EF, and one female patient was breastfeeding.

The majority of patients presented with swelling and induration of the forearms and legs, followed by hyperpigmentation. Over time, patients developed severe induration of the skin and subcutaneous tissues, with marked motor limitations of the hands and feet. Upper extremity involvement was identified in 44 patients, and 57 patients had lower extremity involvement. Thirty patients (38%) exhibited the groove sign on the limbs, 39 patients (50%) had morphea-like lesions, and nine patients (12%) had a peau d’orange appearance. The type of disease was associated with the duration of disease, with the groove sign and morphea lasting longer than the peau d’orange appearance. In 59 cases, the induration of skin and subcutis was limited to the extremities, while in 19 patients, it extended variably to the trunk.

Extracutaneous Manifestations and Laboratory Findings

Joint contractures were the most common extracutaneous manifestations, affecting 19 patients. The lesions involved the hand (2/78), wrist (3/78), elbow (7/78), knee (11/78), ankle (3/78), and shoulder (1/78). Ten patients (13%) had arthralgia, one patient (1.3%) had chronic hepatitis, and one patient (1.3%) had frequent diarrhea. Two patients (2.6%) had a significant family history. Five patients with disease duration less than 10 years and flexion contractures complained of short stature, and the affected limb appeared different from the other extremity. High C-reactive protein was found in six out of 20 patients, and hypereosinophilia was found in 14 patients. The mean initial peripheral eosinophil count was 9.42 ± 4.59% (range: 0.2–17.9%). Hypereosinophilia in patients diagnosed within 12 months after initial symptoms was 8.07%, compared to 9.79% in patients diagnosed more than 12 months after their initial symptoms. The total eosinophil count was >1 × 10^9 cells/L in six patients. Twenty patients (20/51, 39%) tested positive for anti-nuclear antibodies. Six patients (6/44, 13.6%) had positive ds-DNA, and three patients (3/44, 6.8%) had positive extractable nuclear antigens. Patients with high anti-nuclear antibody titers were usually younger with more diffuse lesions.

Pathologic Features

Thirty patients underwent full-thickness skin to fascia biopsy. The epidermis was normal in five cases, showed mild atrophy in 16 cases, moderate atrophy in nine cases, with no cases of severe atrophy. Increased melanin deposits were present in the basal layer of the epidermis in all 30 patients. The dermis was normal in two cases, while 25 patients exhibited sclerosis: seven severe cases, seven moderate cases, and 11 cases of mild disease. There was infiltration of lymphocytes, plasma cells, histiocytes, and occasionally eosinophils, in patchy periappendageal and circumvascular locations in 19 cases (18 mild, one moderate) and the interstitium in four cases. The interlobular fibrous septums of the subcutis, particularly in the lower limbs, were markedly sclerotic in three biopsies, moderately sclerotic in nine biopsies, and mildly sclerotic in seven biopsies. An infiltrate of lymphocytes, plasma cells, histiocytes, and eosinophils occupied the fibrous septums (marked infiltration in one biopsy, moderate infiltration in one biopsy, and mild infiltration in seven biopsies) or the periphery of the fat lobules (marked infiltrate in one biopsy, moderate infiltration in four biopsies, and mild infiltration in five biopsies), or both (three biopsies). As the disease progressed, the thick sclerotic septums often fused with the fascia and occasionally the reticular dermis. Severe fascial thickening and sclerosis were observed in ten patients, moderate in 13 patients, and mild in seven patients. The components of the inflammatory infiltrate were the same as subcutis (marked infiltrate in two biopsies, moderate infiltrate in four biopsies, and mild infiltrate in 14 biopsies). Tissue eosinophils were quantitated according to the scale described by Barnes et al: three biopsies showed grade 1+ eosinophilia, one biopsy showed grade 2+ eosinophilia, and there were no cases of grade 3+ eosinophilia. Only one of the 30 cases had grade 2+ or higher eosinophilia, and these cells were very focal in distribution. They were more often found in the fibrous septums and fascia.

Therapeutic Management and Outcomes

Treatment regimens were evaluated in 78 patients; however, only 35 patients had been followed up at the time of writing. Only 16 patients received corticosteroids (with an initial dose of 30 mg/d prednisone equivalent), while all the patients received Chinese herbs called fusong or fusu tablets. The patients were followed up for an average period of 20 months (range: 3–60 months). Patients with rapid progression of the disease were prescribed oral corticosteroids, while those with relatively stable disease were treated with Chinese herbal medicine. After treatment, eosinophil counts were reduced in all patients. Remission with disability occurred in 31 patients (89%), and treatment failure occurred in four patients (11%). Remission was achieved in all four patients who received steroids and Chinese herbs and in 31 of the 35 patients who received Chinese herbs. Patients with treatment failure tended to have a longer diagnosis time delay (8 years vs. 15 years) and symptoms located in distal limbs. One case in a child quickly progressed to atrophy and joint contractures within 4 months. The effect of Chinese herbs was shown by the remission of induration, hyperpigmentation, and activity of the limbs.

Discussion

Few similar studies have been performed in Asian patients. In this study, biopsy results of only one of the 30 patients showed grade 2+ or higher eosinophilia. Hypereosinophilia of leukocyte differential was found in 14 patients, which was lower than in previous reports. A potential explanation is that eosinophilia may be transient; the duration of study for our patients was generally longer than in other studies, and tissue collections of these cells were quite focal. Eosinophilia may disappear more quickly than blood eosinophilia. Some biases, including a retrospective design and the lack of standardized criteria for the evaluation of treatment response, may have impacted the results of the present study. Nevertheless, this study offers valuable information on the clinical practice relating to EF with regard to the clinical, biologic, and histologic features and disease management.

doi.org/10.1097/CM9.0000000000001078

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