Dermatology

Eosinophilic Fasciitis (Shulman Disease, Diffuse Fasciitis with Eosinophilia)

Eosinophilic Fasciitis (Shulman Disease, Diffuse Fasciitis with Eosinophilia)

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Patients with eosinophilic fasciitis (EF) typically give a history of progressive, symmetric skin thickening of the extremities. Some patients complain of rapidly progressive muscle weakness, with associated pain and stiffness of the extremities. The muscle complaints may predate any cutaneous changes. Constitutional symptoms such as fever, decline of general health, and weight loss may accompany the cutaneous and muscular symptoms.

  • Characteristic findings on physical examination

On physical examination, there is an initial symmetric swelling and cutaneous thickening of the extremities. These findings progress to peau d’orange with hyperpigmentation, to woody induration and skin tightening. A groove sign, or linear depressions following veins within the affected skin, may be present as well (Figure 1). Some authors describe skin in the later stages of EF as having a "hidebound" consistency.

Figure 1.

Physical examination reveals an indurated, erythematous plaque extending along the proximal medial left thigh.(Courtesy of Victoria Werth, MD)

EF classically spares the neck, face and digits. Extracutaneous manifestations include joint contractures, carpal tunnel syndrome, and inflammatory arthritis. Rare cases may demonstrate unilateral cutaneous thickening, which makes EF more difficult to distinguish from scleroderma variants.

  • Expected results of diagnostic studies

Full-thickness skin biopsy extending to muscle demonstrates inflammation and fibrosis of the collagen bundles in the superficial muscle fascia with infiltration by lymphocytes and plasma cells. The fascia can thicken up to 10 to 20 times that of normal. In contrast to scleroderma, the dermis is rarely affected. Eosinophils can be seen on biopsy (up to 50% of cases), but are not necessary to make the diagnosis (Figure 2, Figure 3, Figure 4). If the disease has been partially treated, or a peripheral eosinophilia is not present, it will be less likely to see eosinophils on skin biopsy. If the disease is biopsied early in its course, the biopsy is more likely to demonstrate eosinophils.

Figure 2.

Punch biopsy revealing deep dermal sclerosis and an inflammatory infiltrate composed of mononuclear cells and eosinophils.

Figure 3.

High-power view of the deeper collagen bundles of the muscular fascia showing scattered eosinophils.

Figure 4.

High-power view of the skeletal muscle below the subcutaneous fat revealing scattered eosinophils.

Abnormal blood laboratory results include an elevated erythrocyte sedimentation rate (ESR) (29-80%), hypergammaglobulinemia (35-72%), and perpiheral eosinophilia (63-86%).

If a full-thickness skin biopsy cannot be obtained, magnetic resonance imaging (MRI) may be used to assist with the diagnosis. Reported in only 20 patients in the literature, MRI shows high signal intensity on T2 weighted sequences of the muscle fascia, and fascial thickening with enhancement after gadolinium injection on T1 weighted sequences. The muscle pattern is typically normal.

The sensitivity and specificity of MRI for diagnosing or monitoring EF has not been determined. If the above changes are noted, then an MRI guided biopsy of the muscle and overlying fascia can be obtained. There has been one report of a positron emission tomography (PET) scan being used in conjunction with a deep tissue biopsy to determine the extent of one patient’s disease.

  • Diagnosis confirmation

The differential diagnosis for eosinophilic fasciitis includes: scleroderma, polymyositis, mixed connective tissue disease, hypereosinophilic syndrome, and eosinophilia-myalgia associated with L-tryptophan intake, nephrogenic systemic fibrosis (NSF), scleromyxedema, and Churg-Strauss. The classic findings of scleroderma such as Raynaud’s phenomenon, sclerodactyly, abnormal nail fold capillaries, and a positive antinuclear antibody are typically not seen in EF.

To differentiate EF from NSF, a careful history should be taken regarding exposure to gadolinium particularly in the setting of renal failure. Scleromyxedema is differentiated based on the presence of a monoclonal gammopathy, normal thyroid function, and histologically increased mucin deposition, fibroblast proliferation and fibrosis. Churg-Strauss will likely be accompanied by asthma, and would also have a positive p-ANCA. The diagnosis of eosinophilic fasciitis is classically confirmed with a full-thickness skin to muscle biopsy.

Patients may have been seen by many other physicians when they present to the clinic. There are reports of patients being misdiagnosed as having tendonitis, Lyme disease, fibromyalgia, intertrigo, or skin manifestations of pregnancy.

Who is at Risk for Developing this Disease?

The exact epidemiology of EF has not been described. It has been reported in greater than 300 patients, affecting all age groups. It was previously thought that EF mostly affected patients between the second and sixth decade of life. Two case series state the mean age of onset as approximately 50 years old, with most cases falling between 40 and 60 years old. EF has been reported in approximately 30 children, with the youngest case described in a 1-year old.

To date, there has been no reported or estimated incidence of EF. The male-to-female ratio appears to be equal in EF. Most reported cases are in the Caucasian population; however, there have been some cases in African-Americans, Africans and Asians.

What is the Cause of the Disease?

  • Etiology

The etiology of EF is unclear at this time. It has been associated with trauma, physical exertion, Lyme disease, arthropod bites, ingestion of L-tryptophan, and statins. EF or EF-like conditions have also been reported in association with treatments for multiple sclerosis, such as dimethyl fumarate.

  • Pathophysiology

The pathophysiology of EF is unknown. It has been hypothesized that EF is an aberrant immune response to various stimuli resulting in a unique cutaneous reaction pattern. Extracellular matrix proteins, such as metalloproteinase 1 (TIMP-1), have been implicated, as well as upregulated cytokines such as transforming growth factor beta (TGF-beta), IL-4, IL-5, IL-13, and connective tissue growth factor.

Systemic Implications and Complications

The most common complication of EF is joint contracture, which has been reported in up to 55-66% of cases. These contractures may be painless, especially in the pediatric population. Carpal tunnel syndrome has been reported in 20% of patients with EF. Finally, inflammatory arthritis has been reported in 44% of patients with EF.

Systemic involvement with EF is rare. There have been reports of involvement of the lungs (restrictive ventilatory disorder), esophagus (dystonia and GERD), liver (hepatomegaly), myocardium, kidney (IgA nephropathy), colon and nervous system (polyneuropathy).

EF has been associated with thyroid abnormalities in the form of Hashiimoto’s disease and Graves disease. Hematologic derangements and malignancies have been associated in up to 10% of reported cases. These cases are associated with a poorer prognosis. The associated diseases include aplastic anemia, immune thrombocytopenia, peripheral T-cell lymphoma, pure red cell aplasia, acquired thrombocytopenic purpura, Hodgkin and non-Hodgkin lymphoma. EF has also been associated with breast and prostate cancers.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for eosophilic fasciitis
Medical Therapies Physical Modalities Surgical Procedures
Oral prednisone 0.5 to 1mg/kg/day tapered over 6-24 months
Hydroxychloroquine
Hydroxyzine
Histamine 2 antagonists, cimetidine
NSAIDS (ibuprofen)
Cyclosporine Physical therapy Fasciectomy for joint contracture relief (reported in only five cases)
Azathioprine
Methotrexate
Infliximab
Cyclophosphamide
Allogenic bone marrow transplant (in setting of aplastic anemia)
Topical tacrolimus (reported in one case without any improvement) Photochemotherapy with either psoralen + UVA or extracorporeal photophoresis

Optimal Therapeutic Approach for this Disease

There has been no controlled trial for the treatment of EF. Systemic corticosteroids are the mainstay of therapy for EF, based on case reports and case series. High-dose oral prednisone (range of 0.5 to 1 mg/kg/day), with a slow taper as the disease responds, is the most consistent recommendation. The majority of cases will respond rapidly to corticosteroid therapy, in contrast to cases of scleroderma.

EF patients (59-88%) typically show a full or nearly full remission with 1-5 months of oral prednisone therapy. Therapy is typically complete anywhere between 6-24 months. Prognosis for remission is more favorable if treated at an earlier stage of the disease.

While treating medically with systemic steroids, all patients should be referred to and followed carefully by a physical therapist to prevent joint contractures. In one recent cohort study, only 37% of patients diagnosed with EF were referred to physical therapy. Patients should have their blood pressure, blood glucose, and bone density assessed while on systemic steroid therapy. Calcium and vitamin D supplementation is also recommended. Current recommendations from the Institute of Medicine specify that adults between 19-70 years old should have a daily intake of 1000 mg/day of calcium and 600 IU/day of Vitamin D.

Bisphosphonate therapy can be used as well in the appropriate age groups. One acceptable bisphosphonate regimen is alendronate 70 mg by mouth each week for those with osteoporosis, or 35 mg by mouth per week to help prevent osteoporosis in those at risk.

If prednisone fails, or if the patient only has partial remission with systemic steroids, treatment can be altered. Any of the following agents may be used alone or in combination with the systemic steroids: hydroxychloroquine 200 mg twice daily, hydroxyzine 25-100 mg every 8 hours, cimetidine 400 mg by mouth twice daily, ibuprofen 800 mg three to four times daily by mouth (max 3200 mg/day), azathioprine 1-2.5 mg/kg/day by mouth, cyclosporine 2.5-4 mg/kg/day by mouth divided into twice daily dosing, methotrexate10-25 mg by mouth weekly, infliximab 5 mg/kg intravenous every 8 weeks or cyclophosphamide 1.5-3 mg/kg by mouth daily. Pulse high-dose methotrexate (4 mg/kg monthly for 5 months) has been studied in a small case series with improvement. Tocilizumab has also been used in a single case. Sirolimus has also been used with some success. Topical tacrolimus has been used in conjunction with hydroxychloroquine and prednisone in one patient and provided no benefit.

A surgical fasciectomy was performed shortly after diagnosis in four cases of joint contractures of the upper extremities in the setting of EF, followed by treatment with oral prednisone. In those cases, surgical intervention may have expedited recovery, giving greater range of motion within a few weeks than with corticosteroids alone. Another report revealed that fasciectomy was beneficial for the relief of joint contractures when other medical management had failed. Thus, surgical intervention may play a role in the therapy of joint contractures in EF, however, there is no trial to compare medical, surgical or combined therapies at this time.

Patient Management

Patients with suspected EF should have the following tests performed:

- Full-thickness excisional skin biopsy to muscular fascia

- Complete blood count with differential (CBC d/p)

- Complete metabolic panel (electrolytes, renal panel, liver function tests)

- Erythrocyte sedimentation rate (ESR)

- Urinalysis

- Aldolase

- Gammaglobulins

- Serum and urine protein electrophoresis, as well as immunofixation

- Lyme titre

- Thyroid stimulating hormone (TSH) and free T4

- Antinucleur antibody (ANA)

- Anitneutrophilic cytoplasmic antibodies (c-ANCA and p-ANCA)

- Creatine kinase

- Consider MRI or PET scan to evaluate involved limb(s).

The T2 weighted images should reveal fasical signal hyperintensity while T1 weighted images should show fascial thickening, especially in chronic disease. MRI may be used to assist in guiding the full thickness excisional biopsy. A PET scan has only been used once to assist in biopsy, not as a singular diagnostic tool.

Patients have often been seen by multiple physicians (mean of 2.4 physicians, range of 1-7) by the time they present for diagnosis. The mean time from onset of symptoms to diagnosis is approximately 11 months. They may be understandably frustrated with their care. Reassurance should be provided that most cases are steroid responsive, and that the disease is typically self limited, even when treatment is not administered.

If review of systems or physical examination is concerning, age-appropriate screening for internal malignancy is appropriate. A full physical examination by their primary care physician should be performed also. At follow-up every 3-6 months, EF patients should be monitored with regular CBC to monitor any change in peripheral eosinophilia, and for any evolving hematologic malignancy. TSH should also be evaluated for any evolving thyroid disease.

Oral prednisone therapy may be used as a monotherapy for 3-6 months. At that time point, if the patient has had minimal or no response it is reasonable to add other agents, as discussed above.

Without any medical therapy, the disease typically takes 3-5 years for remission. However, treatment with systemic steroids is necessary to minimize the risk of joint contractures. Regular physical therapy is essential for minimizing joint contractures. Referral to a physical therapist is prudent.

Unusual Clinical Scenarios to Consider in Patient Management

Rarely, EF occurs unilaterally and will require an extensive work-up to distinguish it from scleroderma and scleroderma variants. Patients may also present solely with myositis as their first symptom, with skin findings following a few weeks to months later, which may make it initially difficult to distinguish from polymyositis.

EF can recur in certain patients, even after a complete remission. Patients with EF who are in remission should be made aware of this possibility.

If the patient complains of SOB on review of systems, a plain film of the chest and PFTs is reasonable to rule out a restrictive process. If the patient complains of reflux symptoms on review of systems, a referral to gastroenterology for possible upper endoscopy is reasonable.

What is the Evidence?

Antic, M, Lautenschlager, S, Itin, PH. "Eosinophilic fasciits 30 years after - What do we really know". Dermatology. vol. 213. 2006. pp. 93-101.

(The authors present 11 patients with EF and carefully review the literature. They present a variety of patients, including the youngest case reported, in a 1 year old female. They present treatment modalities, and review the need for an extensive work up to distinguish EF from other diseases. They recognize that in the 30 years since EF was described by Shulman, our understanding of the disease has not advanced, and that further in vitro and in vivo investigations are needed.)

Bischoff, L, Derk, CT. "Eosinophilic Fasciitis: demographics, disease pattern, and response to treatment: report of 12 cases and review of the literature". Int J of Dermatol. vol. 47. 2008. pp. 29-35.

(This most recent review of the EF literature also presents the findings of 12 patients in a scleroderma center at a university-based rheumatology practice. They highlight the common characteristics of the disease, and report the high frequency with which patients with EF are misdiagnosed, leading to delays in therapy. Delays in therapy for EF have been associated with poorer outcomes.)

Cheriet, S, Chastan, M, Levesque, H, Marie, I. "Positron emission tomography in the diagnosis of eosinophilic fasciitis". Q J Med. 2010.

(This article demonstrates the use of PET scans to examine the overall burden of one patient’s disease. The authors propose that further studies of patients with EF undergo PET scans to further evaluate the use of this modality, especially in patients in whom a biopsy cannot be performed.)

Daniel, RS, Lavery, S, Maize, JC, Brown, AN, Bolster, MB. "Unilateral eosinophilic fasciitis: An under-recognized subtype". J Clin Rheumatol. vol. 15. 2009. pp. 247-9.

(A brief report of a patient with an unusual variant of EF with unilateral involvement. The authors stress the importance of review of a full-thickness skin biopsy by a dermatopathologist, as well as the ability to distinguish EF from a scleroderma variant based on a rapid response to steroids. They raise concern that EF may be often misdiagnosed as a scleroderma variant, and therefore EF may be more common than previously recognized.)

Desvignes-Englelbert, A, Sauliere, N, Loeuille, D, Blum, A, Chary-Valckenaere, I. "From diagnosis to remission: place of MRI in eosinophilic fasciitis". Clin Rheumatol. vol. 29. 2010. pp. 1461-4.

(This article reviews the use of MRI in diagnosing and following the response to treatment in EF. The authors describe a patient who underwent a MRI guided biopsy of his muscle and muscular fascia to confirm his diagnosis, who also demonstrated "MRI remission" after several months of corticosteroids. They briefly review EF and the evolving use of MRI in diagnosis of the disease.)

Ortega-Loayza, AG, Merritt, BG, Groben, PA, Morrell, DS. "Eosinophilic fasciitis in a female child". J Am Acad Dermatol. vol. 58. 2008. pp. S72-4.

(This case report illustrates a case of EF in a young 12-year-old female patient, who was managed successfully with systemic steroids, methotrexate and physical therapy. The authors state that her case may highlight that the existence of an EF phenotype more common in children, with the majority of pediatric cases occurring in females, and most cases being steroid responsive.)

Suzuki, G, Itoh, Y, Horiuchi, Y. "Surgical management of eosinophilic fasciitis of the upper extremity". J Hand Surg Brit. vol. 22. 1997. pp. 405-7.

(A case series of four patients who underwent surgical intervention for joint contractures of the upper extremities in the setting of eosinophilic fasciitis, followed by treatment with oral prednisone.)

Neumiester, NW, Robertson, GA. "Therapeutic fasciectomy for eosinophilic fasciitis". Ann Plast Surg. vol. 41. 1998. pp. 208-10.

(A case report of a patient who had failed medical therapy for EF with resulting joint contractures, who experienced relief of symptoms and increased range of motion after a forearm fasciectomy.)

Mertens, JS, Zweers, MC, Kievit, W, Knaapen, HK, Gerritsen, M, Radstake, TR, van den Hoogen, FH, Creemers, MC7, de Jong, EM. "High-Dose Intravenous Pulse Methotrexate in Patients With Eosinophilic Fasciitis". JAMA Dermatol. vol. 152. 2016 Nov 1. pp. 1262-1265.

(A small study of 12 patients who were treated with high dose pulse methotrexate [4 mg/kg monthly] with an improvement in their condition as measured by the modified skin score, as well as secondary outcome measures such as joint mobility, visual analog scales, and subjective health questionnaires.)

Das, J1, Chinoy, H, Dick, J, Matthews, R, Roberts, M. "A literature review of eosinophilic fasciitis with an illustrated case". Curr Rheumatol Rev. 2016 Oct 7.

(A current, comprehensive review of the condition and currently favored treatment options.)

Wright, NA, Mazori, DR, Patel, M, Merola, JF, Femia, AN, Vleugels, RA. "Epidemiology and Treatment of Eosinophilic Fasciitis: An Analysis of 63 Patients From 3 Tertiary Care Centers". JAMA Dermatol. vol. 152. 2016 Jan. pp. 97-9.

(Largest cohort study of eosinophilic fasciitis in the literature with considerations regarding delay in diagnosis, misdiagnosis, diagnostic mimickers, treatment with corticosteroids and steroid sparing agents, as well as expected outcomes.)

Sheu, J, Kattapuram, SV, Stankiewicz, JM, Merola, JF. "Eosinophilic fasciitis-like disorder developing in the setting of multiple sclerosis therapy". J Drugs Dermatol. vol. 13. 2014 Sep. pp. 1144-7.

(A case report describing an eosinophilic fasciitis-like syndrome occurring with treatment for MS with dimethyl fumarate, which was FDA approved to treat MS.)

Espinoza, F, Jorgensen, C, Pers, YM. "Efficacy of Tocilizumab in the treatment of Eosinophilic fasciitis: Report of one case". Joint Bone Spine. vol. 82. 2015 Dec. pp. 460-1.

(A case report of a patient who had failed treatment with systemic corticosteroids and methotrexate treated with biologic anti-IL-6 treatment with immediate and durable response.)

Vikash, S Oza, Rabina, Walsh, Jeffrey, North, Timothy, GBerger, Jenny, E Murase. "Treatment of Eosinophilic Fasciitis With Sirolimus". JAMA Dermatology. vol. Vol.152. 2016. pp. 488-490.

(A case report of a single patient who was failed systemic corticosteroids and methotrexate, with improvement after the addition of sirolimus to systemic corticosteroids.)
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