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Eosinophilic fasciitis

 Eosinophilic fasciitis is a rare idiopathic fibrotic disease characterized histologically by fibrosis of the fascia and clinically by acute, painful thickening of the skin limbs and / or body, which progresses to disabling cutaneous fibrosis, which affects considerably the quality of life. it is considered a variety of morphea, while according to others, is a special disease entity. Clinically, it has great similarities to systemic scleroderma, from which it is separated by the absence of Raynaud's phenomenon and visceral organ involvement and mainly on the basis of the characteristic histological picture. Although it is known for about 30 years, its etiology and pathophysiology have not been determined and there is no consensus on treatment.

EPIDEMIOLOGY

Frequency: In the U.S., eosinophilic fasciitis is very rare. In other countries, it is unusual.

Race: Eosinophilic fasciitis mainly affects people of the white race

Sex: In adults, eosinophilic fasciitis is significantly more common in men than women. The ratio of male / female ratio is 2:7.

Age: Eosinophilic fasciitis occurs in people aged 2-88 years, but usually during the third to sixth decade of life. In childhood ιs rare.

ETIOLOGY

The etiology of eosinophilic fasciitis is unknown, although several factors have been implicated (genetic, immunological, environmental, etc.).

Genetic factors

Eosinophilic fasciitis may have genetic susceptibility, since it has been reported in twins (Thomson GT et al, 1989), in 2 sisters, who later developed breast cancer (Watts RA and Merry P, 1994), and in a man and his son (Rosenfeld K and Stodell MA, 1994).

Infections

Eosinophilic fasciitis may be associated with infections such as B Burgdorferi, since antibodies against borrelias have been found in the serum (Mosconi S et al, 2002) and part of the gene of B Burgdorferi in the skin (Hashimoto Y et al, 1996) of patients with eosinophilic fasciitis.

Immunological factors

Eosinophilic fasciitis is associated with hypergammaglobulinemia, positive ANA and deposition of immunoglobulins and/or the complement in the skin.

A patient with eosinophilic fasciitis had simultaneously eosinophilic cellulitis, abnormal T-cell clones in the circulation and increased production of IL-5. These manifestations may be responsible for peripheral eosinophilia and eosinophilic tissue damage occurring in eosinophilic fasciitis (French LE et al, 2003).

The inflammatory infiltrates are predominated by macrophages and CD8 + T lymphocytes, some of which contain Granzyme B, indicating that eosinophilic fasciitis is due to cytotoxic immune response induced by infectious or environmental factors (Toquet C et al, 2003).

Fibroblasts derived from tissue lesions of patients with eosinophilic fasciitis produce increased amounts of collagen in vitro and exhibit elevated levels of TGF-b and type 1 collagen mRNA when examined by in situ hybridism with special Cdna. According to these findings, eosinophilic fasciitis seems to be the result of simultaneous increase in gene expression of TGF-b and proteins of the extracellular matrix in fibroblasts of affected tissues.

Environmental factors

Eosinophilic fasciitis can occur after exposure to toxic substances, drugs (see below) or environmental factors.

A patient with renal failure presented with eosinophilic fasciitis 4 weeks after initiation of hemodialysis (Florell SR et al, 2001).

TABLE 1

MEDICATIONS ASSOCIATED WITH EOSINOPHILIC FASCIITIS

  • Phenytoin
  • Tryptophan
  • Heparin
  • Lansoprazole
  • Trichloroethylene

TABLE 2

COEXISTENCE OF EOSINOPHILIC FASCIITIS WITH OTHER DISEASES

Blood Diseases

  • True polycythemia
  • Aplastic anemia
  •  Autoimmune hemolytic anemia
  •  Pernicious anemia
  • Idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia and Hashimoto’s thyroiditis
  • Thrombocytopenia (common variable immunodeficiency)
  • Megaloblastic aplasia
  •  Myelodysplasia
  • Multiple myeloma

Rheumatic - skin diseases

  • Algodystrophy
  • Vasculitis
  • Systemic lupus erythematosus and/or retroperitoneal fibrosis
  • Linear scleroderma
  • Morphea in association with linear scleroderma or systemic sclerosis
  • Rheumatoid arthritis
  • Ichthyosis
  • Malignant diseases
  • Hodgkin or non-Hodgkin Lymphoma
  • T-cell lymphoma
  • Sarcoidosis

CLINICAL PICTURE

Eosinophilic fasciitis is characterized by peripheral eosinophilia, hypergammaglobulinemia and scleroderma-like inflammation of the skin and fascia.

In some cases, the initial manifestations of the disease may be:

  • Fever and night sweats (Lewis D et al, 1990)
  • Psoriatic arthritis (Wright GD et al, 1992)
  • Inflammatory polyarthritis (Olson NY et al, 1986; Pressly TA et al, 1989; Ching DW and Petrie JP, 1991)
  • Multiple painless joint contractures without skin or joint involvement (Huppke P et al, 2002)
  • Stiffness, joint pain, joint contracture, thickening of the skin of the hands, forearms and thighs, ie similar picture similar to JIA with dry synovitis (Patrone NA and Kredich DW, 1984).

Both in adults and children, eosinophilic fasciitis can coexist with/or evolve into local (linear scleroderma morphea) or systemic (systemic scleroderma) fibrotic diseases (Fraya RA et al, 1985; Williams HJ et al, 1986 ; Valentini G et al, 1988; Balat A et al, 1999).

The internal organs are rarely affected in eosinophilic fasciitis, in contrast with SSc.

Cutaneous lesions

They are characterized by edema and progressive thickening of the skin, along with prickly pain of the limbs and sometimes morning stiffness. In descending order of frequency, the forearms, arms, laver limbs, thighs and trunk are affected.

The skin lesions may be divided into 3 stages:

1st Stage: Symmetrical, diffuse, erythematous sensitivity of limbs

2nd stage: Edematous phase, in which the affected area shows dimpling similar to "cobblestone" or "orange peel» («peau d 'orange») appearance.

3d Stage: Is characterized by hypopigmentation, shrinkage, thickening and dilatation of the skin. In areas of severe involvement the skin adheres to subcutaneous tissues and underlying muscles, acquiring a woody texture.

The skin lesions develop over the course of weeks, but may also have acute or subacute onset. In 50% of cases, they occur 2 days to several weeks after intense exercise or physical activity.

In 55-75% of patients they rapidly lead to severe contracture and limitation of joint mobility, especially of the hands, shoulders, elbows, wrists, ankles and knees without the typical manifestations of arthritis.

With elevation of the affected limb grooves may be observed along the path of superficial veins (groove sign).

Other skin lesions :

  • Recurrent localized lesions of morphea (25%)
  • Erythema
  • Urticaria
  • Bullae
  • Alopecia
  • Atrophic and lichen sclerosus
  • Vitiligo
  • Hyperpigmentation
  • Raynaud’s phenomenon (rare)

Musculoskeletal manifestations

  • Inflammatory arthritis (40%), which mainly affects the hands and wrists, and sometimes is erosive and destructive (Kennedy C and Leak A, 1982; Pressly TA et al, 1989)
  • Clawhand
  • Tenosynovitis of the wrist flexors, which can lead to carpal tunnel syndrome (20% of cases)
  • Subclinical myositis (in a small percentage of patients)

Systemic manifestations

  • Malaise
  • Weakness
  • Fever

Neurological disorders

  • Convulsions
  • Peripheral neuropathy

Other manifestations

  • Dyskinesia of esophagus
  • Restrictive respiratory disease (in cases of fasciitis of the chest)
  • Pericarditis
  • Colitis
  • Sjögren's syndrome
  • Pulmonary and pleuritic involvement
  • Renal involvement, interstitial - tubular nephritis and IgA nephropathy (Takeda S et al, 1995; Miret C et al, 2003)
  • Reactive hepatitis and splenomegaly

LABORATORY FINDINGS

  • Hemolytic anemia
  • Aplastic anemia. It's rare, but the most common serious blood complication of eosinophilic fasciitis
  • Immune complexes
  • IgA deficiency
  • Increased ESR (50-70%)
  • Increased serum muscle enzymes, particularly aldolase (sometimes)
  • Eosinophilia (10-40%) in 80-90% of patients, in the blood, bone marrow and sometimes fascia
  • Positive ANA (in titres> 1:160) (in 36% of patients)
  • Positive rheumatoid factor (some times)
  • Thrombocytopenia
  • Pernicious anemia
  • Leukemia (rare)
  • Pancytopenia
  • Hypergammaglobulinemia (75%), usually due to polyclonal increase in IgG
  • Large increase in histamine levels in serum
  • Increase in GSF-b1 (Dziadzio L et al, 2003)

BIOPSY

It is essential for the diagnosis. The biopsied sample should include the skin, dermis, subcutaneous fat, fascia and superficial muscles (full thickness).

HISTOLOGICAL FINDINGS

The histologic hallmark of eosinophilic fasciitis is inflammation, swelling, thickening and hardening of the fascia.

In the early stages, the deep fascia and the lower subcutaneous layers show edema and infiltration of lymphocytes, plasma cells, histiocytes and eosinophils.

The iiltration involves the lower layer of the dermis, fibrous septum and periphery of lipoid lopules, fascia and muscles (epimysium, perimysium and endomysium), but sparing the epidermis, papillary dermis and adnexal structures of the skin. Often perivascular infiltration of lymphocytes and plasma cells is observed.

Eosinophilic infiltration may be focal or diffuse and usually occurs in the fascia and/or the lower subcutaneous layers. The presence of eosinophils in the fascia is not necessary for the diagnosis. The term "eosinophilic fasciitis" refers to the peripheral, rather than tissue, eosinophilia. Tissue eosinophilia is closely correlated with peripheral blood eosinophilia.

In advanced cases, dense sclerosing and hyalinized collagen bands runs parallel to the fascia, trapping small foci of fat cells.

Other histological findings

  • Lesions  of chronic synovitis and tenosynovitis, which is often associated with carpal tunnel syndrome
  • IgM deposition in the dermo-epidermal junction (in direct immunofluorescence) and IgG and C3 around blood vessels in the lower layer of the dermis, fascia and skeletal muscle.
  • Inflammatory neutrophilic vasculitis (Magaro M et al, 1990)
  • Ischemic collapse of glomerular capillaries, cortical tubular atrophy, and cortical hyperplasia of epithelioid cells of renin factors in the juxtaglomerular apparatus (Kirschstein M et al, 1999).

ENHANCED CONTRAST RADIOGRAPHS

In one (a) case, they showed decreased peristalsis of the upper GI track without symptoms of esophageal dysfunction

MAGNETIC RESONANCE IMAGING

Can show high signal intensity in the fascia.

ELECTROMYOGRAPHY

It can dynamically show slow motor unit potentials of short duration and low amplitude findings consistent with myositis.

DIFFERENTIAL DIAGNOSIS

  • Linear scleroderma
  • Facial elastosis
  • Eosinophilia
  • Morphea
  • Juvenile idiopathic arthritis
  • Systemic scleroderma
  • Eosinophilia - myalgia syndrome
  • Toxic oil syndrome (TOS)

Systemic scleroderma

Clinically, eosinophilic fasciitis has many similarities with SSc, but with the following differences:

  • Responds dramatically to corticosteroids
  • It is related to previous physical strain
  • it is not accompanied by Raynaud’s phenomenon
  • It does not affect the epidermis and its adnexal structures and especially the phalanges of the hands
  • The skin is not shiny, hard and atrophic and has no telangiectasias perionychial vascular abnormalities and color changes
  • it does not usually affect the internal organs, although it sometimes affects internal organs and is accompanied by arthritis similar to JIA
  • It develops rapidly, while diffuse systemic scleroderma progressively and at a slower rate
  • MRI and biopsy reveal marked thickening of the fascia
  • It has characteristic laboratory findings, i.e. an increase in ESR and IgG and often striking eosinophilia in the peripheral blood and muscle fascia.

Toxic oil syndrome (TOS) - eosinophilia myalgia syndrome (EMS)

Is characterized by thickening of the skin, which has striking clinical and histopathological similarities with eosinophilic fasciitis, but sparing the face, hands and feet.

Eosinophilic fasciitis clinically and histologically is detected in the fascia, while EMS and TOS may be accompanied by fasciitis, but have other manifestations (especially cardiopulmonary and neuromuscular), which are absent in eosinophilic fasciitis:

  • Mucocutaneous lesions (urticaria, dermographism, maculopapular rash, mucinosis, alopecia)
  • Neuromuscular complications (myalgia/myopathy, severe cramps, peripheral sensorineural neuropathy, mononeuritis multiplex, recognition disorders)
  • Cardiopulmonary complications (pneumonitis, respiratory muscle dysfunction, pulmonary hypertension)
  • Gastrointestinal disorders
  • Severe fatigue
  • Sicca complex
  • Increased aldolase, LDH and liver enzymes in serum
  • Corticosteroids improve skin involvement in 88% of patients with eosinophilic fasciitis, but are only partially effective in EMS.
  • Deaths occur only in patients with EMS.

Juvenile idiopathic arthritis

Eosinophilic fasciitis can have as a first manifestation stiffness, pain and contracture of the small joints of hands and skin thickening (Patrone NA and Kredich DW, 1984), symmetric polyarthritis (Olson NY et al, 1986) and seronegative inflammatory polyarthritis (Ching DW et al, 1991). These manifestations can be attributed to NIA. The absence of clinical signs and symptoms of true arthritis and the characteristic picture of skin thickening direct towards the correct diagnosis.

Diseases associated with joint contracture

Eosinophilic fasciitis can have as a first manifestation multiple joint contractures without skin lesions and/or arthritis (Nishiyama K et al, 1991; Huppke P et al, 2002), and hence it must enter the DD of diseases associated with contracture in childhood.

TREATMENT

Physiotherapy(active and passive exercises to increase range of motion of the affected limbs) for the prevention and treatment of joint contracture.

Corticosteroidsare the treatment of choice for eosinophilic fasciitis. They cause improvement in 88%, and remission in 25% of patients, although the disease can remit spontaneously and immediate depression of peripheral eosinophilia can occur.

The response is considered satisfactory if edema, skin thickening and joint contracture are improved and carpal tunnel syndrome resolves. Skin thickening usually improves after 4-8 weeks of treatment. Complete remission of the disease may require 1-3 years.

DOSE REGIMEN: 0.5-1 mg/kg/24h PO/IV/IM, until improvement occurs. Then gradual reduction of the dose to 5-10 mg/24 h. Treatment may be needed to continue at low-dose steroids for 2-5 years.

Alternatively hydroxychloroquine 200 -400 mg per day can be used. 

Other treatments and drugs that have been used mainly in adults refractory to corticosteroids

  • Azathioprine with/or without penicillamine
  • Antimalarials (chloroquine, hydroxychloroquine) (Allen SC, 1984)
  • Griseofalvin
  • Infliximab
  • Ketotiphen
  • Colchicine
  • Cyclosporine (Hayashi N et al, 2000) + antithymic globulin (for aplastic anemia) (Bonnote B et al, 1998)
  • Cyclophosphamide
  • Methotrexate
  • NSAIDs in combination with intensive physiotherapy (Gaffney K et al, 1993)
  • Penicillamine
  • Cimetidine
  • Sulfasalazine (for arthritis) (Jones AC and Doherty M, 1993)
  • Hydroxyzine (2 mg/kg/24h)
  • Methylprednisolone pulses + antihistamines (Farrell AM et al, 1999)
  • Psoralen combined with ultraviolet light A baths (Schiener R et al, 2000)
  • Extracorporeal photochemotherapy (Romano C et al, 2003).

Surgery

  • Surgical decompression of carpal tunnel syndrome   

OUTCOME

Eosinophilic fasciitis can remit spontaneously or remain for many years if left untreated. In 2/3 of children residual cutaneous fibrosis may remain, while in 1/3 (of them) lesions subside completely. Despite corticotherapy, skin thickening and joint contracture sometimes persist. In some cases, cutaneous lesions of eosinophilic fasciitis evolve into progressive SSc (Frayha RA et al, 1985) or linear scleroderma (Williams HJ et al, 1986; Balat A et al, 1999). In 10% of cases, eosinophilic fasciitis complicates with aplastic anemia, which has a rather poor prognosis.

 

LAST UPDATED 23/7/12



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