Eosinophilic fasciitis

Eosinophilic fasciitis

Eosinophilic fasciitis also known as Shulman syndrome, is a very rare condition in which muscle tissue underneath the skin, called fascia, becomes swollen and thick 1). Rapid swelling can occur in the hands, arms, legs, and feet. People with eosinophilic fasciitis have a buildup of eosinophils, a type of white blood cell, in the affected fascia and muscles. The exact cause of eosinophilic fasciitis is unknown. Corticosteroids and other immune-suppressing medications are used to relieve the symptoms. Eosinophilic fasciitis is similar in appearance to scleroderma but is not related 2). Eosinophilic fasciitis is more common in people ages 30 to 60.

About 10-20% of people with eosinophilic fasciitis recover spontaneously without treatment. For those who do not, glucocorticoids (0.5–1 mg/kg/day), such as prednisone, are the mainstay therapy. Even with treatment, improvement in symptoms can take weeks or months. Glucocorticoids are successful in treating eosionophilic fasciitis in over 70% of cases 3). If glucocorticoids are unsuccessful, methotrexate at low doses (15–25 mg once weekly) is probably the most favored second-line treatment, especially in people with reddish to purpleish (morphea-like) skin lesions 4). Other treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, chloroquine, cimetidine, azathioprine, cyclosporin A, infliximab, UVA-1, and bath PUVA  5). Physical therapy may help improve joint mobility and decrease contractures. Surgical release has been used in some severe cases to manage significant joint contractures 6).

Figure 1. Eosinophilic fasciitis

Eosinophilic fasciitis

Footnote: Classical symptoms of eosinophilic fasciitis with venous furrowing on the arms of the patient.

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Eosinophilic fasciitis causes

The cause of eosinophilic fasciitis is unknown. In people with eosinophilic fasciitis, white blood cells, called eosinophils, build up in the muscles and tissues. Eosinophils are linked to allergic reactions. Classified as an autoimmune disorder, eosinophilic fasciitis was first described in 1974 by Shulman 8) and is also known to be complicated by other autoimmune diseases, such as scleroderma, polymyositis, hypereosinophilic syndrome, and Churg-Strauss vasculitis 9).

Several possible triggers have been reported with some consistency. A preceding history of vigorous exercise or trauma has been reported in 30%-50% of patients 10). Multiple drugs have also been implicated, including simvastatin, atorvastatin, and phenytoin 11). Rare cases have occurred after taking L-tryptophan supplements 12). Despite this, there is no consistent association between L-tryptophan or other dietary exposure and eosinophilic fasciitis. As evidence, L-tryptophan use was significantly associated with dyspnea, an uncommon finding in eosinophilic fasciitis cases. In another instance, a patient with eosinophilic fasciitis had used l-tryptophan for several years but had started a formal exercise program 2 weeks prior to disease onset.

Eosinophilic fasciitis has been associated with several diseases 13). Hematologic diseases have been consistently reported and are supported by large case series and case reports 14). The spectrum of associated hematologic disease is broad and includes aplastic and hemolytic anemia, thrombocytopenia, myeloproliferative disorders, myelodysplastic disorders, lymphoma, leukemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma 15).

An association with thyroid disease has been reported in several cases 16). Eosinophilic fasciitis has rarely been linked to solid-organ tumors and primary biliary cirrhosis, in addition to several other diseases. These disease associations may suggest a shared pathophysiology of cellular dysregulation and/or autoimmunity.

In general, the pathophysiology underlying eosinophilic fasciitis is postulated to involve an inflammatory response resulting in an activated inflammatory cell infiltrate of affected tissues and subsequent dysregulation of extracellular matrix production by lesional fibroblasts.

Viallard et al 17) demonstrated that, when stimulated, peripheral blood mononuclear cells of eosinophilic fasciitis patients produce significantly higher amounts of five cytokines, including interleukin (IL)–5 and interferon (IFN)–gamma. IL-5 is known to activate mature eosinophils and to stimulate eosinophil chemotaxis, growth, and differentiation. IFN-gamma activates tissue macrophages and T cells. The findings of Dziadzio et al 18) support increased levels of IL-5 in eosinophilic fasciitis, in addition to increased levels of transforming growth factor (TGF)–beta, another fibrogenic cytokine.

Toquet et al 19) investigated the phenotype of the lesional inflammatory cell infiltrate in patients with eosinophilic fasciitis and demonstrated a predominance of macrophages, CD8+ lymphocytes, and few eosinophils. Pathologic specimens from patients with eosinophilic fasciitis demonstrate increased numbers of eosinophils, especially early in the disease course.

Taken together, the findings of these studies suggest a mechanistic framework marked by a proinflammatory and fibrogenic cytokine response with resultant tissue inflammatory cell infiltration.

In the tissues, the end effector cell of fibrosis is the fibroblast. Fibroblasts from lesional tissue of patients with eosinophilic fasciitis produce excess collagen in vitro and display elevated TGF-beta and type 1 collagen mRNA levels when examined via in situ hybridization with specific cDNA 20). Therefore, the pathogenesis appears to involve the concomitant increase in the expression of genes for TGF-beta and extracellular matrix proteins in fibroblasts in the affected tissues.

Mori et al 21) suggested that an autocrine stimulatory loop involving major basic protein, a product of eosinophil degranulation, IL-6, which enhances collagen production and is induced my major basic protein, and TGF-beta could account for the progressive fibrosis seen in several eosinophil prominent disorders.

Other studies showed elevated levels of serum manganese superoxide dismutase and tissue metalloproteinase 1 (TIMP-1) in eosinophilic fasciitis, suggesting a role in pathogenesis and providing a possible marker of disease activity 22).

Eosinophilic fasciitis symptoms

Eosinophilic fasciitis symptoms may include:

  • Tenderness and swelling of the skin on the arms, legs, or sometimes the joints (most often on both sides of the body)
  • Arthritis
  • Carpal tunnel syndrome
  • Muscle pain
  • Thickened skin that looks puckered

Classically, patients with eosinophilic fasciitis present with symmetric swelling of the skin associated with an aching of the affected extremities, which may develop acutely over a period of days to weeks. Eosinophilic fasciitis may also manifest subacutely. In addition, if patients present later in their disease course, they are more likely to have symptoms of induration or fibrosis of the affected areas.

The onset of illness is not accompanied by fever or other systemic symptoms. In up to half of all patients, disease onset follows an episode of strenuous physical exercise or activity 23).

Neither Raynaud phenomenon nor symptoms of respiratory, gastrointestinal, or cardiac involvement are typically present.

Inflammatory arthritis has been reported and manifests as joint pain, swelling, and morning stiffness 24).

With progressive fibrosis, patients may experience limited range of motion due to joint contractures and paresthesias in a distribution pattern consistent with carpal tunnel syndrome.

Cutaneous manifestations include the following 25):

  • The cutaneous manifestations of eosinophilic fasciitis evolve as the disease progresses. In the acute inflammatory stage, cutaneous changes include erythematous swelling and nonpitting edema. These findings are later replaced by skin induration, and, eventually, fibrosis predominates. The affected skin is taut and firmly adherent to underlying tissues. Dimpling, peau d’orange, and venous furrowing, or the “groove sign,” can be seen.
  • Other cutaneous changes reported include urticaria, bullae, alopecia, lichen sclerosus et atrophicus, vitiligo, and hyperpigmentation.
  • Cutaneous manifestations are generally bilateral and symmetric. The upper extremity, proximal and distal to the elbow, and the lower extremity, proximal and distal to the knee, are most commonly involved. The trunk and neck can also be involved. Face and hand involvement are rare.
  • A concurrent localized lesion of morphea may be seen in 25% of patients.

Extracutaneous manifestations include the following:

  • Joint contractures represent the most common extracutaneous manifestation of eosinophilic fasciitis, occurring in 50%-75% of patients, and can affect elbows, wrists, ankles, knees, and shoulders 26). Extensive truncal fibrosis may limit chest expansion. A clawlike deformity of the hand has been described.
  • Inflammatory arthritis was reported in roughly 40% of patients in two series 27). The knees, wrists, hands, and feet appear to be most commonly involved.
  • Carpal tunnel syndrome is seen in 16%-23% of patients 28).
  • Clinically significant visceral involvement is rare, limited to case reports. If present, significant visceral involvement should prompt investigation of an alternative diagnosis. When pursued, specific testing with pulmonary function testing, esophagogastroduodenoscopy and electromyelography (EMG) may demonstrate subtle or nonspecific abnormalities 29).

Eosinophilic fasciitis possible complications

Arthritis is a rare complication of eosinophilic fasciitis. Some people may develop very serious blood disorders or blood-related cancers, such as aplastic anemia or leukemia. The outlook is much worse if blood diseases occur.

Eosinophilic fasciitis diagnosis

Tests that may be done include:

  • Complete blood count (CBC) with differential
  • Gamma globulins (a type of immune system protein)
  • Erythrocyte sedimentation rate (ESR)
  • MRI
  • Muscle biopsy
  • Skin biopsy (the biopsy needs to include the deep tissue of the fascia)

Definitive diagnosis relies on a full-thickness incisional skin biopsy. The specimen should include the skin, fat, fascia, and superficial muscle in continuity. Biopsy is especially important in an atypical presentation 30).

Characteristic laboratory findings of eosinophilic fasciitis include the following:

  • Peripheral blood eosinophilia is present in 61%-83% of patients. The degree of eosinophilia is variable over time, even in the absence of specific therapy 31).
  • Hypergammaglobulinemia is characteristic, although this finding varies widely by case series, occurring in 18%-67% of patients. It is most often due to a polyclonal increase in immunoglobulin G 32).
  • An increase in the erythrocyte sedimentation rate (ESR) is found in 29%-70% of cases 33).

Additional laboratory findings of eosinophilic fasciitis include the following 34):

  • Serum creatine kinase and aldolase levels are generally normal.
  • Rheumatoid factor and antinuclear antibodies are occasionally positive.
  • Hematologic abnormalities and disease are associated with eosinophilic fasciitis. Aplastic anemia, although rare, is the most frequent common associated hematological complication, but cases have been described with thrombocytopenia, hemolytic anemia, pernicious anemia, lymphoma, and leukemia 35)
  • Borrelia serology or polymerase chain reaction (PCR) findings are occasionally positive and may suggest a treatable etiology. However, as discussed above, the exact correlation between eosinophilic fasciitis and Borrelia remains unclear 36)
  • Metalloproteinase 1 (TIMP-1) may be a new serological marker of disease activity 37)

Imaging studies

Magnetic resonance imaging (MRI) is the imaging modality of choice. MRI of the involved areas shows characteristic findings of fascial thickening, abnormal signal intensity, and contrast enhancement. Additionally, MRI aids in making the diagnosis, locating the biopsy site, and monitoring the response to treatment 38).

Although it has not been used frequently or studied extensively in eosinophilic fasciitis, one case report has shown that ultrasonography can aid in early diagnosis 39). According to a study by Kissin et al 40) that included 12 patients with eosinophilic fasciitis, a 12-MHz, B-mode ultrasound may be used to measure subcutaneous compressibility and thereby serve as an adjunctive tool to distinguish eosinophilic fasciitis from diffuse systemic sclerosis, especially when tissue sampling is less feasible or when the result of tissue sampling is equivocal.

Eosinophilic fasciitis treatment

First-line therapy for eosinophilic fasciitis is with systemic corticosteroids 41). Although patients may require prolonged therapy, it should be noted that up to one third of eosinophilic fasciitis cases may spontaneously resolve 42).

Case reports describe the use of a number of agents for second-line therapy. No consensus exists on which agent is best for that purpose.

Physical therapy should be initiated to improve joint mobility and to decrease contractures.Surgical release has been used in some cases to manage significant joint contractures 43).

Dermatologists, rheumatologists, and surgeons (for the skin-muscle biopsy) are consulted most often for management of these cases.

Eosinophilic fasciitis prognosis

In most cases, eosinophilic fasciitis goes away within 1 to 3 years. However, symptoms may last longer or come back.

A retrospective review found that clinical factors associated with persistent fibrosis included presence of morphealike skin lesions, younger age at onset, truncal involvement, and presence of dermal fibrosclerosis on histopathologic specimen 44).

Loss of edema is usually the first clinical sign of improvement and can occur within 4 weeks of commencing treatment. Concurrently, the skin becomes softer, but 3-6 months may elapse before maximal reduction in induration and contractures is achieved 45).

While total resolution of the clinical signs can occur, some degree of induration remaining even after many months of corticosteroid therapy is not unusual.

A direct correlation does not always exist between clinical disease activity and laboratory findings. The eosinophilia and ESR usually return to reference ranges within 6-8 weeks, although the ESR and hypergammaglobulinemia may remain abnormal for up to 12 months 46).

Eventually, corticosteroid therapy can be withdrawn in many of the patients, without relapse occurring.

The development of aplastic anemia is a rare but grave complication 47). One study reported on 4 patients with eosinophilic fasciitis and severe aplastic anemia. In 3 cases, the aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. However, in 1 patient, rituximab displayed significant efficacy for both the skin and hematologic symptoms. In an additional 19 cases of eosinophilic fasciitis and aplastic anemia, corticosteroid regimens improved skin symptoms in 5 of 12 cases but were ineffective in the treatment of aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases and was the cause of death in 8 cases. Only 5 patients achieved long-term remission 48).

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