Eosinophilic fasciitis

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Eosinophilic fasciitis

Shaheen H. Ensanyat, Amir A. Larian, Brian S. Fuchs and Marsha L. Gordon

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Eosinophilic fasciitis (EF), also known as Shulman syndrome, is a rare fibrosing disorder characterized by the rapid onset of symmetric induration of the extremities. The trunk and neck can be affected, with typical sparing of the hands, feet, and face. Clinically, the progression of EF is marked by edema and erythema followed by dimpling of the skin and a peau d’orange appearance evolving into woody induration and stiffness of the limbs. Laboratory investigations often reveal hypergammaglobulinemia, an elevated erythrocyte sedimentation rate, and peripheral blood eosinophilia, but are not essential in securing a diagnosis, given their transient levels. Histologically, EF presents with severe fascial thickening associated with an inflammatory infiltrate composed of plasma cells, eosinophils, histiocytes, and lymphocytes that can ultimately lead to dermal sclerosis. While the etiology remains unknown, vigorous physical activity has been reported before the onset of EF in many cases, presumably triggering an aberrant immune response.

Management strategy

Whether a distinct entity or variant of scleroderma, EF is differentiated by the relative absence of sclerodactyly, Raynaud phenomenon, and serologic markers. Unlike scleroderma, patients with EF typically demonstrate a more rapid onset with normal nail fold capillaries, infrequent visceral involvement, and response to corticosteroid therapy. EF must also be distinguished from the eosinophilia–myalgia syndrome, which is characterized by diffuse muscle pain and weakness, polyneuropathy, respiratory and pulmonary problems, and most notably a history of contaminated L-tryptophan ingestion.

EF has been reported in association with hematological disorders, including aplastic anemia, hemolytic anemia, thrombocytopenia, leukemias, and lymphomas. In addition, EF has to a lesser extent been linked to administration of simvastatin or exposure to trichloroethylene; these should be checked for in the patient history.

While clinical and laboratory findings help identify EF, diagnosis can only be confirmed with histopathological examination from a full-thickness skin-to-muscle biopsy, which characteristically reveals deep dermal fibrosis and fascial thickening with inflammatory infiltration of lymphocytes, plasma cells, and eosinophils. Magnetic resonance imaging (MRI) has also proven to be a useful non-invasive tool for establishing the diagnosis, choosing the optimal biopsy site, and monitoring the effectiveness of treatment. Findings typically show high signal intensity of the deep and superficial fasciae on T1, T2, and STIR imaging with enhancement after intravenous contrast administration.

Although spontaneous remission of EF has been reported, treatment can help prevent the progression of flexion contractures and limited mobility. Clinical response is usually defined as marked improvement in skin thickening, as fibrosed tissue becomes softer and looser, allowing for increased range of motion. Serum aldolase levels have been proposed as a useful indicator of disease activity.

There is substantial agreement among published reports that moderate- to high-dose corticosteroids serve as the first-line treatment for EF with prednisone as the standard agent, initially at 40–60 mg daily. A clinical response usually is noted within the first few weeks, and the dosage is then tapered slowly over several months to an alternate day regimen. In steroid-refractory patients, the addition of hydroxychloroquine at 200–400 mg daily has also been effective both in combination and as monotherapy.

In patients with partial or no response to corticosteroids, immunosuppressive drugs are frequently introduced as a second-line treatment. Cyclosporine at 3.7 mg/kg daily tapered to 2.5 mg/kg daily has been successful within 1 month at improving clinical symptoms with no relapse after a year. Methotrexate at 15–20 mg/week in conjunction with prednisone has also been commonly used with a favorable response.

Cimetidine at 400 mg every 6 to 12 hours has shown reported success in some cases. Pulsed methylprednisolone 1 g daily for 5 days combined with cyclosporine 150 mg twice daily is another regimen that has led to remission for patients in need of more aggressive therapy. Infliximab, D-penicillamine, ketotifen, chloroquine, psoralen and UVA (PUVA), azathioprine, griseofulvin, dapsone and sulfasalazine have all been reported to have beneficial effects.

Specific investigations

First-line therapies

imageSystemic corticosteroids B
imagePulsed methylprednisolone D

Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases.

Lakhanpal S, Ginsburg WW, Michet CJ, Doyle JA, Moore SB. Semin Arthritis Rheum 1988; 17: 221–31.

Of the 52 patients, 34 were treated with prednisone dosages ranging from 40 to 60 mg daily. The remaining 18 were treated with either hydroxychloroquine, colchicine, D-penicillamine, or no medication. Twenty of the 34 patients treated with prednisone had a partial response (>25% improvement) and five had complete resolution, detected after 3 to 6 months. Eight of the nine patients who had a poor response were treated with the addition of hydroxychloroquine at a dose of 200–400 mg daily. Two responded completely, two had an improvement of over 50%, and three were lost to follow-up. Eight patients also responded to treatment with hydroxychloroquine alone: two had complete resolution, four had a partial response, and the others were lost to follow-up. Relapses occurred in some patients, and responses were not predictive of future recovery with the same therapy.

Eosinophilic fasciitis (Shulman disease): new insights into the therapeutic management from a series of 34 patients.

Lebeaux D, Francès C, Barete S, Wechsler B, Dubourg O, Renoux J, Maisonobe T, et al. Rheumatology (Oxford) 2012; 51: 557–61.

Prednisone served as a first-line therapy for all patients at a mean daily dose of 52.7 mg (range, 10–90 mg). Before treatment initiation, 15 patients received methylprednisolone pulses (MPPs), 500–1000 mg daily for 3 consecutive days, which reduced the need for an immunosuppressive drug and increased the probability of complete remission. After treatment initiation, 12 patients received methotrexate as a second-line therapy for a mean duration of 24.7 months (range, 5–93 months). A poor outcome was present in 10 patients and was associated with a diagnosis time delay of more than 6 months and a lack of MPPs at treatment initiation. Overall, complete remission was achieved in 69% of patients.

Second-line therapies

imageHydroxychloroquine C
imageCyclosporine E
imageMethotrexate E
imageCimetidine C

Third-line therapies

imagePUVA E
imageExtracorporeal photochemotherapy E
imageD-Penicillamine E
imageAzathioprine E
imageChloroquine E
imageSulfasalazine E
imageSurgery E
imageInfliximab E
imageHydroxyzine E
imageRituximab E
imageDapsone E
imageCombination UVA1–retinoid–corticosteroid E
imageMycophenolate mofetil E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Eosinophilic fasciitis

Shaheen H. Ensanyat, Amir A. Larian, Brian S. Fuchs and Marsha L. Gordon

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Eosinophilic fasciitis (EF), also known as Shulman syndrome, is a rare fibrosing disorder characterized by the rapid onset of symmetric induration of the extremities. The trunk and neck can be affected, with typical sparing of the hands, feet, and face. Clinically, the progression of EF is marked by edema and erythema followed by dimpling of the skin and a peau d’orange appearance evolving into woody induration and stiffness of the limbs. Laboratory investigations often reveal hypergammaglobulinemia, an elevated erythrocyte sedimentation rate, and peripheral blood eosinophilia, but are not essential in securing a diagnosis, given their transient levels. Histologically, EF presents with severe fascial thickening associated with an inflammatory infiltrate composed of plasma cells, eosinophils, histiocytes, and lymphocytes that can ultimately lead to dermal sclerosis. While the etiology remains unknown, vigorous physical activity has been reported before the onset of EF in many cases, presumably triggering an aberrant immune response.

Management strategy

Whether a distinct entity or variant of scleroderma, EF is differentiated by the relative absence of sclerodactyly, Raynaud phenomenon, and serologic markers. Unlike scleroderma, patients with EF typically demonstrate a more rapid onset with normal nail fold capillaries, infrequent visceral involvement, and response to corticosteroid therapy. EF must also be distinguished from the eosinophilia–myalgia syndrome, which is characterized by diffuse muscle pain and weakness, polyneuropathy, respiratory and pulmonary problems, and most notably a history of contaminated L-tryptophan ingestion.

EF has been reported in association with hematological disorders, including aplastic anemia, hemolytic anemia, thrombocytopenia, leukemias, and lymphomas. In addition, EF has to a lesser extent been linked to administration of simvastatin or exposure to trichloroethylene; these should be checked for in the patient history.

While clinical and laboratory findings help identify EF, diagnosis can only be confirmed with histopathological examination from a full-thickness skin-to-muscle biopsy, which characteristically reveals deep dermal fibrosis and fascial thickening with inflammatory infiltration of lymphocytes, plasma cells, and eosinophils. Magnetic resonance imaging (MRI) has also proven to be a useful non-invasive tool for establishing the diagnosis, choosing the optimal biopsy site, and monitoring the effectiveness of treatment. Findings typically show high signal intensity of the deep and superficial fasciae on T1, T2, and STIR imaging with enhancement after intravenous contrast administration.

Although spontaneous remission of EF has been reported, treatment can help prevent the progression of flexion contractures and limited mobility. Clinical response is usually defined as marked improvement in skin thickening, as fibrosed tissue becomes softer and looser, allowing for increased range of motion. Serum aldolase levels have been proposed as a useful indicator of disease activity.

There is substantial agreement among published reports that moderate- to high-dose corticosteroids serve as the first-line treatment for EF with prednisone as the standard agent, initially at 40–60 mg daily. A clinical response usually is noted within the first few weeks, and the dosage is then tapered slowly over several months to an alternate day regimen. In steroid-refractory patients, the addition of hydroxychloroquine at 200–400 mg daily has also been effective both in combination and as monotherapy.

In patients with partial or no response to corticosteroids, immunosuppressive drugs are frequently introduced as a second-line treatment. Cyclosporine at 3.7 mg/kg daily tapered to 2.5 mg/kg daily has been successful within 1 month at improving clinical symptoms with no relapse after a year. Methotrexate at 15–20 mg/week in conjunction with prednisone has also been commonly used with a favorable response.

Cimetidine at 400 mg every 6 to 12 hours has shown reported success in some cases. Pulsed methylprednisolone 1 g daily for 5 days combined with cyclosporine 150 mg twice daily is another regimen that has led to remission for patients in need of more aggressive therapy. Infliximab, D-penicillamine, ketotifen, chloroquine, psoralen and UVA (PUVA), azathioprine, griseofulvin, dapsone and sulfasalazine have all been reported to have beneficial effects.

Specific investigations

Eosinophilic fasciitis. A pathologic study of twenty cases.

Barnes L, Rodnan GP, Medsger TA, Short D. Am J Pathol 1979; 96: 493–517.

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