The eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by symmetrical and painful swelling with a progressive induration and thickening of the skin and soft tissues. The diagnosis of EF is often based on the association of characteristic skin or subcutaneous abnormalities and a thickened fascia with an inflammatory infiltration, mostly composed of lymphocytes and eosinophils. A peripheral eosinophilia is frequently present, but is not mandatory for the EF diagnosis. The diagnosis might be helped by a muscle magnetic resonance imaging which typically may evidence an increased signal intensity within the fascia and marked fascia enhancement after gadolinium administration at the acute phase of the disease.
Differential diagnoses should be ruled out, including eosinophilia-myalgia syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes (HES), systemic sclerosis, Churg-Strauss syndrome, and/or peripheral T cell lymphomas with cutaneous involvement.
Due to the scarcity of the EF disease, there is no consensual therapeutic strategy. However, oral corticosteroids remain the mainstay treatment and may be associated to an immunosuppressive drug such as methotrexate in patients with morphea-like lesions or an unsatisfactory response to corticosteroids alone.
Introduction
Eosinophilic fasciitis (EF) is a rare connective-tissue disease characterised by symmetrical and painful swelling with a progressive induration and thickening of the skin and soft tissues . In 1974, Shulman described the first cases of EF and reported them as a new syndrome defined by scleroderma-like skin changes associated with peripheral eosinophilia, hypergammaglobulinaemia and elevated erythrocyte sedimentation rate (ESR) . There are no international diagnostic criteria and the diagnosis of EF is often based on the association of characteristic skin or subcutaneous abnormalities and a thickened fascia with an inflammatory infiltration, mostly composed of lymphocytes and eosinophils . After the first publication of Shulman, more than 300 cases have been reported but the largest retrospective study comprised 52 patients and was published in 1988 . The therapeutic management of EF is now one of the most significant challenges, as the clinical–biological and pathological features are yet well defined. Its evaluation is hampered by the lack of standardised criteria for the treatment modalities and responses . Recently, we have reported our experience of 34 patients with a biopsy-proven EF with a detailed analysis of clinical, biological, pathological and morphological features and a specific focus on the therapeutic management .
The main goals of this review will be first to report the clinical, biological, pathological and morphological features that may lead to the diagnosis of EF and second to define a therapeutic strategy.
Clinical manifestations of EF
The onset of the disease may be featured by weight loss (26%), asthenia (38%) and spontaneous or provoked myalgia (67%) . The anamnesis may also evidence a recent preceding history of intense physical exertion or trauma in 30–46% of patients .
Cutaneous manifestations of EF
At diagnosis, a cutaneous involvement is reported in up to 90% of patients including pitting oedema, induration and ‘ peau d’orange ’ aspect with hyperpigmentation . Initially, swelling and stiffness might affect distal extremities before evolving to induration . Noteworthily a depressed vein aspect, also called the ‘groove sign’, can be present in up to half of patients and seems to be highly suggestive of a deep fibrosis or a fasciitis involvement ( Fig. 1 ). The upper extremities are quite almost involved (88%) and the lower limbs are involved in up to 70% of patients . Other localisations are possible even less frequent, including the neck (6–18%) and the trunk (17–32%) .
Morphea (localised scleroderma) is present in about one-third of patients . A Raynaud phenomenon is rare and capillaroscopy is usually normal . Although EF is mainly symmetrical, unilateral disease is possible . Virtually, any part of the body might be involved but distality is more frequently concerned, mainly on the lower extremities . Other parts of the body are less frequently involved: abdomen 12/52 (23%), chest 9/52 (17%), back 3/52 (6%), face or neck 3/52 (6%) of patients .
Muscular and articular manifestations of EF
Myalgias, spontaneous or provoked, are present at the onset of the disease in up to 67% of patients and up to 86% of patients at diagnosis.
An articular involvement is frequently reported including joint contracture and inflammatory arthralgia in up to 40% of patients . Distal synovitis is reported in 3–11.5% of patients. Morning stiffness may also be present in about 23% of patients. Carpal tunnel syndrome is present in about 23% of patients . Tendon retraction and joint contracture might be assessed by the prayer sign, the inability to close fist or restricted joint movement but mostly occurs at a late stage of the disease, reflecting the severity of the fascia fibrosis .
Visceral involvement of EF
In the main retrospective series, none of the patients exhibited renal, pulmonary or heart involvement . Nevertheless, few case reports described the following visceral involvement:
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Pulmonary and bilateral pleural involvement. This patient exhibited eosinophilia with cutaneous lesions and histologic findings consistent with EF . Pleural effusion punction revealed inflammatory cells, mostly eosinophils. High-resolution computed tomography (CT) of the chest showed nodular interstitial thickening but no distortion. Pulmonary and cutaneous lesions improved after prednisolone treatment.
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Pericarditis associated with pleural effusion .
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Renal involvement in a 17-year-old boy with EF. Proteinuria led to a renal biopsy, which revealed ischaemic collapse of glomerular capillaries and atrophy of tubules of the cortex . Another patient exhibited EF-associated with a focal segmental glomerulosclerosis . Immunofluorescence was negative.
In summary, a visceral involvement is not expected with a typical EF, and should lead us to exclude other systemic diseases such as hypereosinophilic syndrome and Churg–Strauss vasculitis.
Associated malignancies
Haematological disorders might be associated with EF in less than 10% of patients , including thrombocytopaenia, myelomonocytic leukaemia, chronic lymphocytic leukaemia and myeloproliferative disorder. Severe aplastic anaemia (SAA) has been described with EF with a good response to cyclosporine A and antithymocyte globulin or allogeneic haematopoietic stem cell transplantation (HSCT) . Other reports of EF-associated haematological diseases are anecdotic including multiple myeloma , B-cell lymphoma ,Hodgkin’s disease and peripheral T-cell lymphoma .
Nevertheless, it is difficult to assess the precise link between EF and haematological disorder. Whether EF is considered as a paraneoplastic syndrome associated with the haematological disorder or as the direct trigger of an initial haematological event is unknown. In the rare cases of EF-associated T cell lymphoma, the potential role of interleukin (IL)-5 producing T lymphocytes might be hypothesised as IL-5 is known to induce eosinophil proliferation.
Solid malignant tumours are scarcely reported with EF including a breast cancer with a complete resolution of EF after mastectomy , a choroidal melanoma with bone metastases , a prostatic cancer and a bronchopulmonar cancer . In view of the scarcity of these cases, there is no need to investigate an underlying malignancy in patients with EF, unless a suggestive manifestation is evidenced.
Clinical manifestations of EF
The onset of the disease may be featured by weight loss (26%), asthenia (38%) and spontaneous or provoked myalgia (67%) . The anamnesis may also evidence a recent preceding history of intense physical exertion or trauma in 30–46% of patients .
Cutaneous manifestations of EF
At diagnosis, a cutaneous involvement is reported in up to 90% of patients including pitting oedema, induration and ‘ peau d’orange ’ aspect with hyperpigmentation . Initially, swelling and stiffness might affect distal extremities before evolving to induration . Noteworthily a depressed vein aspect, also called the ‘groove sign’, can be present in up to half of patients and seems to be highly suggestive of a deep fibrosis or a fasciitis involvement ( Fig. 1 ). The upper extremities are quite almost involved (88%) and the lower limbs are involved in up to 70% of patients . Other localisations are possible even less frequent, including the neck (6–18%) and the trunk (17–32%) .
Morphea (localised scleroderma) is present in about one-third of patients . A Raynaud phenomenon is rare and capillaroscopy is usually normal . Although EF is mainly symmetrical, unilateral disease is possible . Virtually, any part of the body might be involved but distality is more frequently concerned, mainly on the lower extremities . Other parts of the body are less frequently involved: abdomen 12/52 (23%), chest 9/52 (17%), back 3/52 (6%), face or neck 3/52 (6%) of patients .
Muscular and articular manifestations of EF
Myalgias, spontaneous or provoked, are present at the onset of the disease in up to 67% of patients and up to 86% of patients at diagnosis.
An articular involvement is frequently reported including joint contracture and inflammatory arthralgia in up to 40% of patients . Distal synovitis is reported in 3–11.5% of patients. Morning stiffness may also be present in about 23% of patients. Carpal tunnel syndrome is present in about 23% of patients . Tendon retraction and joint contracture might be assessed by the prayer sign, the inability to close fist or restricted joint movement but mostly occurs at a late stage of the disease, reflecting the severity of the fascia fibrosis .
Visceral involvement of EF
In the main retrospective series, none of the patients exhibited renal, pulmonary or heart involvement . Nevertheless, few case reports described the following visceral involvement:
- •
Pulmonary and bilateral pleural involvement. This patient exhibited eosinophilia with cutaneous lesions and histologic findings consistent with EF . Pleural effusion punction revealed inflammatory cells, mostly eosinophils. High-resolution computed tomography (CT) of the chest showed nodular interstitial thickening but no distortion. Pulmonary and cutaneous lesions improved after prednisolone treatment.
- •
Pericarditis associated with pleural effusion .
- •
Renal involvement in a 17-year-old boy with EF. Proteinuria led to a renal biopsy, which revealed ischaemic collapse of glomerular capillaries and atrophy of tubules of the cortex . Another patient exhibited EF-associated with a focal segmental glomerulosclerosis . Immunofluorescence was negative.
In summary, a visceral involvement is not expected with a typical EF, and should lead us to exclude other systemic diseases such as hypereosinophilic syndrome and Churg–Strauss vasculitis.
Associated malignancies
Haematological disorders might be associated with EF in less than 10% of patients , including thrombocytopaenia, myelomonocytic leukaemia, chronic lymphocytic leukaemia and myeloproliferative disorder. Severe aplastic anaemia (SAA) has been described with EF with a good response to cyclosporine A and antithymocyte globulin or allogeneic haematopoietic stem cell transplantation (HSCT) . Other reports of EF-associated haematological diseases are anecdotic including multiple myeloma , B-cell lymphoma ,Hodgkin’s disease and peripheral T-cell lymphoma .
Nevertheless, it is difficult to assess the precise link between EF and haematological disorder. Whether EF is considered as a paraneoplastic syndrome associated with the haematological disorder or as the direct trigger of an initial haematological event is unknown. In the rare cases of EF-associated T cell lymphoma, the potential role of interleukin (IL)-5 producing T lymphocytes might be hypothesised as IL-5 is known to induce eosinophil proliferation.
Solid malignant tumours are scarcely reported with EF including a breast cancer with a complete resolution of EF after mastectomy , a choroidal melanoma with bone metastases , a prostatic cancer and a bronchopulmonar cancer . In view of the scarcity of these cases, there is no need to investigate an underlying malignancy in patients with EF, unless a suggestive manifestation is evidenced.
Biological features of EF
A peripheral eosinophilia is present in 63–93% of patients, but is not mandatory for the EF diagnosis . Furthermore, the level of the eosinophilia does not correlate with disease severity and some patients may experience progressive skin induration despite normal laboratory data . An inflammatory syndrome is frequent with raised C-reactive protein in 55% of patients, elevated ESR in 29–63% of patients and a hypergammaglobulinaemia in more than one-half of patients. Antinuclear antibodies may be detected in 15–20% of patients, but anti-DNA and anti-extractable nuclear antigen (ENA) antibodies are expected negative . To avoid a Churg–Strauss vasculitis misdiagnosis, antineutrophil cytoplasmatic antibodies should be negative. Serum creatinine kinase is rarely elevated (4–6%) and might reflect a moderate muscle involvement . No human leucocyte antigen (HLA) status was found to be associated with this disease .
Pathological features of EF
A pathological confirmation is mandatory for EF diagnosis and a full skin-to-muscle biopsy should be realised whenever possible. Typically, the diagnosis can be assessed by the evidence of a fasciitis with a thickened fascia and inflammatory infiltrates composed of lymphocytes and/or eosinophils ( Fig. 2 ). Perivascular infiltrates of lymphocytes are quite almost present (>95%) and are mainly composed of CD8+ lymphocytes (CD4/CD8 ratio <1) . Eosinophil infiltrates are present in 69–75% of patients but not mandatory for EF diagnosis . They can be absent at a chronic stage of the disease or after corticosteroid treatment . Other cells such as macrophages and plasma cells are frequently present in less than half of patients and polymorphonuclear cells in less than 10% of patients . An interstitial myositis can be evidenced in 8–68% of patients but a muscle necrosis is rarely reported. The epidermis is normal or slightly atrophic and the dermis shows mild accumulation of cells (mainly lymphocytes). Dermal collagen may be mildly sclerotic but is often normal unless in cases of associated morphea, which can be highlighted in up to 37% of patients .
Morphological investigations in EF
Muscle magnetic resonance imaging
The muscle MRI is now considered the best morphological procedure for EF diagnosis . Typically, the muscle MRI evidenced a markedly increased signal intensity within the fascia on fluid-sensitive sequences and marked fascia enhancement after gadolinium administration at the acute phase of the disease in up to 80% of patients ( Fig. 3 ). It might also be useful in indicating the optimal location for muscle biopsy and in the therapeutic re-evaluation of patients after treatment by evidencing a rapid relief of MRI abnormalities after corticosteroid treatment . 5.2 Ultrasounds.
Preliminary studies reported a possible correlation between ultrasonography and MRI findings in EF . Another report described correlation between ultrasonography and clinical improvement with treatment of EF, suggesting the use of this method for patients follow-up under treatment .
Differential diagnosis of EF
The diagnosis of EF might be delayed because of initial aspecific signs such as muscular or joint pain. Furthermore, several differential diagnoses might be difficult with the following conditions:
A: An eosinophilia–myalgia syndrome (EMS) after L-tryprophane ingestion . The Centres for Disease Control definition includes peripheral blood eosinophils count greater than 1000 mm −3 , generalised myalgia (severe enough to affect patient’s ability to pursue daily activities) and the absence of infection or neoplasm to account for the first two criteria. The acute phase of EMS starts with generalised myalgia, dyspnoea, cough, fever, cutaneous hyperaesthesia, rash, pruritus and swelling of the extremities . The chronic phase associates scleroderma-like cutaneous changes and progresses to multi-organ system involvement.
B: The hypereosinophilic syndromes (HES). They are characterised by a peripheral eosiniphilia, a systemic organ involvement (cardiac, pulmonary and neurological) and include a myeloproliferative and a lymphocytic variant with different clinical, histologic, cytogenetic or molecular patterns .
C: Systemic sclerosis (SS) as EF and SS may be both responsible for an extensive cutaneous fibrosis. However, SS is associated with neither a peripheral eosinophilia, nor satisfying response to corticosteroids and more frequently leads to a visceral involvement (pulmonary or oesophageal). The capillaroscopy is usually normal in EF contrary to SS.
D: A Churg–Strauss syndrome should be excluded in any case of EF-associated visceral involvement. An actual fasciitis is rare in Churg–Strauss syndrome and inversely, typical features of Churg–Strauss syndrome, which include a steroid-dependent asthma with sinusal and/or neurologic, cardiac, dermatologic and renal involvement , are absent in EF. Moreover, antineutrophilic cytoplasmic antibodies, which are present in 38–48% of cases of Churg–Strauss syndrome , are absent in EF patients.
E: Peripheral T-cell lymphomas may have a cutaneous and sometimes a fascia involvement, but are easily excluded by the muscle biopsy pathological examination.
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