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Eosinophilic Fasciitis

Shulman syndrome

Eosinophilic fasciitis, a disease also referred to as Shulman syndrome, is characterized by chronic inflammation of fasciae. Eosinophilia is present in most patients, but the precise etiology of this disorder is unknown.


Presentation

Patients who present with early stages of EF may show dermatological symptoms like erythema and edema that mainly affect trunk and proximal limbs. Acute symptom onset may be related to recent vigorous exercise or trauma [7]. Fasciitis doesn't occur until later stages of the disease and typically manifests in progressive thickening and induration of the skin, subsequent joint contracture and decreased mobility. Of note, "later" refers to a few days or weeks after symptom onset. While erythema and edema don't usually affect hands and feet, joint stiffness frequently affects articulations of distal limbs. In this context, carpal tunnel syndrome is sometimes observed. The latter is caused by compression of nerves by fibrotic tissues and provokes numbness and paresthesias in the affected hands. Pain, particularly myalgia and arthralgia, is often reported.

Despite their acute onset, symptoms progress slowly. Disease progress can best be evaluated after observation of skin changes. Initially, thickening and hardening of the skin may be accompanied by formation of grooves along the veins. Ultimately, large areas of skin may become very wrinkled, take on the appearance of orange peel or even resemble tree bark.

In general, symptoms manifest symmetrically, although cases of unilateral eosinophilic fasciitis have been reported [11].

Weight Loss
  • Other signs and symptoms that may be present include: Malaise , weakness, fever and weight loss Joint contractures of the elbows, wrists, ankles, knees and shoulders Carpal tunnel syndrome Inflammatory arthritis How is eosinophilic fasciitis diagnosed[dermnetnz.org]
  • Fatigue and weight loss are common. Rarely, aplastic anemia, thrombocytopenia, and lymphoproliferative processes develop. Diagnosis EF should be suspected in patients with typical symptoms.[msdmanuals.com]
  • Loss and Lung Nodules 411 Case 65 A Woman with Difficulty Walking and Ataxia 415 Case 66 A Man with Progressive Neuropathy and Congestive Heart Failure 422 Case 67 An Elderly Woman with a Progressive Neuropathy 429 Case 68 A Young Woman with Difficulty[books.google.com]
  • Patient 1 presented at 14 years of age with a 3-month history of upper limb joint stiffness and swelling after prolonged physical exertion with associated general malaise and weight loss.[jrheum.org]
  • Other than general lethargy and weight loss my main symptom was bad stomach pain when drinking even a small amount of booze - Was told I'd grow out of by one doc and prescribed antacids by another. All the best with your treatment.[muscletalk.co.uk]
Fatigue
  • Higher levels of psychological distress were significantly related to greater severity of skin disease; more pain and fatigue; impact of disease on daily life; more perceived stigmatization; illness cognitions of greater helplessness; and less acceptance[ncbi.nlm.nih.gov]
  • Fatigue and weight loss are common. Rarely, aplastic anemia, thrombocytopenia, and lymphoproliferative processes develop. Diagnosis EF should be suspected in patients with typical symptoms.[msdmanuals.com]
  • Half reported fatigue and nonspecific arthralgias in the morning but no constitutional symptoms. All had cutaneous involvement, and 14 reported induration of the skin.[medpagetoday.com]
  • The phases share many common symptoms including muscle pain and fatigue. The acute phase comes first and may last anywhere between three and six months.[verywell.com]
  • Kathleen S: Eosinophilic Fasciitis I noticed that winter during gym, that when we did push-ups, I had to do knuckle push-ups because I could not straighten my fingers… Karen H: Eosinophilic Fasciitis I am experiencing extreme fatigue and muscle pain on[sclero.org]
Malaise
  • A 57-year-old woman presented with malaise and heaviness in her extremities. At first there were no clues of an inflammatory disease, but the patient developed slowly progressive oedema of her arms and legs with induration of the skin.[ncbi.nlm.nih.gov]
  • Other signs and symptoms that may be present include: Malaise , weakness, fever and weight loss Joint contractures of the elbows, wrists, ankles, knees and shoulders Carpal tunnel syndrome Inflammatory arthritis How is eosinophilic fasciitis diagnosed[dermnetnz.org]
  • Patient 1 presented at 14 years of age with a 3-month history of upper limb joint stiffness and swelling after prolonged physical exertion with associated general malaise and weight loss.[jrheum.org]
  • Introduction Aetiology History Eosinophilic fasciitis predominantly occurs in Caucasians , with females and males equally affected It may occur at any age, although most cases arise between the ages of 30 and 60 years It has an acute, painful onset Malaise[pcds.org.uk]
  • There is systemic upset with fever, arthralgia, malaise and weight loss. It can resemble scleroderma with Raynaud's phenomenon and dysphagia.[patient.info]
Hand Pain
  • Symptoms Bone pain or tenderness Carpal tunnel syndrome Numbness or tingling in one or both hands Pain in one or both hands Weakness in one or both hands Muscle weakness Tenderness and swelling of the arms and legs (occasionally including joints) Thickened[g2crforum.net]
  • The latter is caused by compression of nerves by fibrotic tissues and provokes numbness and paresthesias in the affected hands. Pain, particularly myalgia and arthralgia, is often reported. Despite their acute onset, symptoms progress slowly.[symptoma.com]
Hodgkin's Disease
  • Only a few cases of EF have been previously described preceding or concomitant to the Hodgkin disease, peripheral T-cell lymphoma, B-cell lymphoma, and mycosis fungoides.[ncbi.nlm.nih.gov]
Arthritis
  • Radiology 120 : 269 – 275 , 1976 9 Zvaifler NJ : Chronic postrheumatic-fever (Jaccoud's) arthritis .[onlinelibrary.wiley.com]
  • Arthritis & Rheumatism . 24 (5): 677–683. doi : 10.1002/art.1780240508 . ISSN 0004-3591 . Moulton SJ, Kransdorf MJ, Ginsburg WW, Abril A, Persellin S (March 2005). "Eosinophilic fasciitis: spectrum of MRI findings" . AJR.[en.wikipedia.org]
  • Chronic GVHD simulating eosinophilic fasciitis (EF) is relatively rare, frequently presenting with skin induration, a typical "peau d'orange" appearance, peripheral blood eosinophilia, myalgia, arthralgia, and arthritis leading to joint contractures in[ncbi.nlm.nih.gov]
  • Extracutaneous presentations, such as arthritis and carpal tunnel syndrome can precede cutaneous changes.[ncbi.nlm.nih.gov]
  • Arthritis is a rare complication of EF. 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.[medlineplus.gov]
Myalgia
  • Eosinophilic fasciitis is a rare disease, but it must be considered in patients with adult myalgia.[ncbi.nlm.nih.gov]
  • It is characterized by painful swelling of the extremities, accompanied by rapid weight gain, fever and myalgia.[ncbi.nlm.nih.gov]
  • The fibrosing disorders represent a diverse group of uncommon chronic diseases that include systemic sclerosis, eosinophilic fasciitis, eosinophilia-myalgia syndrome, toxic oil syndrome, and localized forms of fibrosis.[ncbi.nlm.nih.gov]
  • The differential diagnosis includes systemic sclerosis and other scleroderma subsets such as morphea, and epidemic fasciitis syndromes caused by toxic agents such as the myalgia-eosinophilia syndrome and toxic oil syndrome.[ncbi.nlm.nih.gov]
  • 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[ncbi.nlm.nih.gov]
Flexion Contracture
  • CS alone in patients with severe eosinophilic fasciitis, defined as clinically apparent cutaneous fibrotic involvement affecting more than 15% body surface area (BSA) or more than 10% BSA with joint flexion contractures.[ncbi.nlm.nih.gov]
  • Flexion contractures occur in up to 56% of EF cases 3 but painless contractures have rarely been reported 4,5 . A scleroderma-like illness is more typical with skin induration being a feature in all patients in one case series 1 .[imj.ie]
  • Although spontaneous remission of EF has been reported, treatment can help prevent the progression of flexion contractures and limited mobility.[clinicalgate.com]

Workup

Despite of acute symptom onset, several months may pass until EF is diagnosed. Due to unspecific symptoms and little awareness of this rare connective tissue disorders, many EF patients are misdiagnosed with systemic scleroderma, deep vein thrombosis and other diseases [7]. After physical examination, additional diagnostic measures like laboratory analyses of blood samples may be carried out - and should support a tentative diagnosis of EF - but only visualization of fasciae involvement by means of imaging techniques and histopathological examination of tissue samples are considered diagnostic.

With regards to the former, hemogram and blood biochemistry may reveal the following:

  • Eosinophilia. Although elevated numbers of eosinophil granulocytes are measured in up to 90% of all EF patients, eosinophilia is not an exclusion criterion for this disease. Patients who present with typical clinical and histopathological alterations may be diagnosed with EF despite of an unaltered hemogram.
  • Increase of proinflammatory parameters, prolonged erythrocyte sedimentation rate and hypergammaglobulinemia.
  • Additional alterations of cell counts may be associated with underlying hematological disorders and require a specific workup.

Magnetic resonance imaging and computed tomography scans are most frequently applied to assess the condition of subcutaneous tissues and muscles. Both techniques allow for visualization of fascial thickening and their results should be considered before deciding on a biopsy site. Tissue samples typically show fascial thickening, infiltration with lymphocytes, macrophages and eosinophils, and fibrosis. As fibrosis augments, inflammation subsides.

Non-invasive follow-ups based on diagnostic imaging will also permit to evaluate the patient's response to treatment.

Elevated Sedimentation Rate
  • […] e·o·sin·o·phil·ic fas·ci·i·tis [MIM*226350] induration and edema of the connective tissues of the extremities, usually appearing following exertion; associated with elevated sedimentation rate, elevated IgG, and eosinophilia. eosinophilic fasciitis inflammation[medical-dictionary.thefreedictionary.com]

Treatment

The standard treatment for EF consists in prolonged application of corticosteroids, e.g., prednisone, prednisolone or derivatives. Follow-ups should reveal softening of the skin as early as one month of therapy, although complete resolution may not occur until several months later. Blood counts often normalize within two months, but inflammatory parameters like erythrocyte sedimentation rate and globulin levels may not lower until various months after initiation of treatment. Although a variety of other drugs, mainly immunosuppressive compounds, has been administered to accelerate recovery or to treat persistent cases of fasciitis, there is no scientific evidence regarding their efficacy.

Physiotherapy should accompany drug treatment and aim at improving joint mobility and rebuilding muscle strength.

Surgery is generally not indicated, but may constitute an alternative treatment option in intractable cases of EF.

Prognosis

With regards to mortality, possibly underlying hematological disorders or malignancies largely determine the likelihood of a fatal outcome. And while EF is not considered a lethal disease, permanent restriction of joint mobility may constitute a considerable reduction of life quality. In a retrospective study analyzing the outcome of 88 EF cases, the following findings have been identified as unfavorable prognostic factors, i.e., as factors associated with higher risks of residual fibrosis:

  • Morphea-like skin lesions
  • Young age at onset
  • Trunk involvement
  • Histopathological evidence for dermal sclerosis

The relative importance of factors listed above seems to decrease top down [10].

Many patients may expect complete resolution of symptoms, although recovery may take months. Spontaneous resolution has been described.

Etiology

The etiology of EF is largely unknown. However, retrospective analysis of EF cases revealed prevalence rates of certain comorbidities that exceed those calculated for the general population. Due to the limited number of cases reported to date, coincidence cannot be excluded for all such findings. The following list of possible etiological factors contributing to EF should be interpreted keeping that limitation in mind.

  • Hematological disorders associated with decreased or elevated cell counts of erythrocytes, granulocytes, lymphocytes and platelets have repeatedly been related with EF. Hemolytic anemia, thrombocytopenia, lymphoma and leukemia shall be mentioned as examples. See, for instance, references [4] [5].
  • Because EF has not only been diagnosed in patients suffering from hematological malignancies but also in individuals with solid neoplasms, it has also been proposed to develop as paraneoplastic syndrome [5].
  • EF has repeatedly been related with Borrelia burgdorferi infection. However, only a very small share of borreliosis patients develops EF and it is not clear which additional factors trigger the onset of fasciitis in patients infected with these spirochetes.
  • Administration of distinct drugs has been reported to induce EF. In this context, L-tryptophan should be highlighted. This amino acid or traces of other compounds found in L-tryptophan formulations have been shown to induce eosinophilia myalgia syndrome, a disease characterized by progressive thickening and hardening of the skin and eosinophilia, amongst other symptoms [6]. The resemblance of clinical presentation of both disorders had researchers speculate that their etiology may be similar, too.

Epidemiology

EF is a rare disease and less than 300 cases have been reported to date [3]. Recently, a retrospective study has been published that includes case data of 63 EF patients [7]. According to this study, the vast majority of EF patients are Caucasians. However, this study has been conducted in the United States and may not be representative for other countries with larger populations of Blacks and Asians. The male-to-female ratio seems to approximate 1:2. Although precise values differ slightly, a female predominance had been reported before.

EF may manifest at any age.

While EF may be associated with significant morbidity, it is not a lethal disease. However, EF patients may suffer from additional pathologies like hematological disorders and solid neoplasms that considerably reduce their life expectancy.

Sex distribution
Age distribution

Pathophysiology

EF results from an inflammatory process mainly involving fasciae. As has been described above, its triggers are not yet known. More light could be shed on the pathophysiological events following fascia infiltration with inflammatory cells.

Histopathological analysis revealed that lymphocytes and macrophages predominate in biopsy samples obtained from EF patients. Eosinophil granulocytes only account for minor shares of inflammatory infiltrates. With regards to macrophages, it has been shown that their precursors, peripheral blood mononuclear cells, release abnormally high amounts of proinflammatory cytokines interleukin-2 and interferon-γ as well as increased quantities of antiinflammatory cytokines interleukin-5 and interleukin-10 [8].

Although elevated levels of antiinflammatory cytokines may not explain fasciitis, interleukin-5 has been shown to activate eosinophil granulocytes, induces growth, maturation and differentiation of these cells. It also exerts chemotactic effects, which may explain infiltration of eosinophils into inflamed fasciae.

Additionally, elevated concentrations of transforming growth factor-β have been measured in serum samples of EF patients [9]. This cytokine causes fibroblast proliferation and production of extracellular matrix. Although it is probable that other factors contribute, transforming growth factor-β may partially account for progressive fibrosis of affected fasciae.

Prevention

No specific measures can be recommended to prevent EF.

Summary

Eosinophilic fasciitis (EF) is a rare, chronic inflammatory disease of unknown etiology. The same disease may also be referred to as diffuse eosinophilic fasciitis or Shulman syndrome, whereby the latter name was chosen in honor of Lawrence E. Shulman. This US-American physician first described the disease in 1975 [1].

The main characteristics of EF are erythema and edema of large parts of the skin, eosinophilia, and structural remodeling, thickening and funcio laesa of fasciae. Unspecific dermatological symptoms often precede fasciitis, but if blood samples are analyzed during early stages of the disease, elevated cell counts of eosinophil granulocytes are already detectable in most cases. Of note, eosinophilia is not an exclusion criterion for EF.

Fascia involvement manifests in progressive induration of the skin and soft tissues [2], symptoms that are easily confounded with cutaneous scleroderma. In fact, EF is sometimes also classified as a scleroderma-like disease. However, scleroderma patients commonly present with digital lesions while erythema and edema due to EF are usually limited to trunk and proximal limbs. Also, Raynaud's phenomenon is typical for scleroderma but not for EF. Even though these clinical differences may imply that a patient is suffering from EF rather than from scleroderma, a tentative diagnosis of this connective tissue disorder needs to be confirmed by application of diagnostic imaging and/or histopathological analysis of biopsy samples in order to demonstrate involvement of fasciae instead of the dermis. Fasciae infiltration of inflammatory cells, mainly lymphocytes and macrophages, can only be shown histopathologically. Magnetic resonance imaging and computed tomography scans are the methods of choice to assess a possible involvement of internal organs, a finding often noted in systemic scleroderma but not in EF.

EF patients usually respond to corticosteroid treatment. If comorbidities are diagnosed that possibly contribute to the onset and progress of fasciitis, they should be treated accordingly. Non-curable underlying diseases often diminish the efficacy of immunosuppressive therapy and worsen the prognosis significantly. Several of such intractable cases have been reported and a variety of drugs has been administered to relieve EF-associated symptoms in these patients, but general recommendations cannot be given to this end.

Low incidence and prevalence rates - less than 300 cases have been reported to date [3] - complicate research regarding EF etiology, pathogenesis and causative treatment. To date, case reports are the main source of data and several hypotheses presented in this article or elsewhere require further validation.

Patient Information

Eosinophilic fasciitis (EF) is a rare connective tissue disorder characterized by reddening and swelling of large parts of the skin, elevated cell counts of eosinophil granulocytes, and structural remodeling, thickening and loss of function of fasciae.

Less than 300 cases have been reported to date, which is why knowledge regarding the disease' causes, progress and therapy is still rather limited.

Causes

Little is known about the causes of EF. Some EF patients also present hematological disorders, e.g., anemia, reduced amounts of platelets, increased numbers of lymphocytes and other white blood cells. Also, EF may be related with cancer, tick-borne borreliosis or ingestion of L-tryptophan. Few of these causal relations are supported by scientific evidence; they merely base on observations made in this little group of patients that have been diagnosed with EF.

Symptoms

Dermatological symptoms, e.g., reddening and swelling of the skin, often precede fasciitis. These symptoms are usually limited to trunk and proximal limbs, while hands and feet are generally spared. As the diseases progresses, the skin becomes increasingly thick and hard. This condition may even limit joint mobility.

If blood samples are analyzed, they typically reveal eosinophilia and imply inflammation.

Diagnosis

Clinical symptoms may easily be confounded with those of cutaneous scleroderma or other diseases. Thus, fasciae have to be visualized by means of magnetic resonance imaging or computed tomography scans and histopathological examination of tissue samples. Only if thickened, inflamed fasciae can be seen both from the outside and under the microscope, a patient may be diagnosed with EF.

Treatment

Most patients respond well to corticosteroid application. Symptoms may start to subside after about a month, but complete resolution may not be achieved until several months later.

Physiotherapy is helpful to regain joint mobility.

References

Article

  1. Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome?. Trans Assoc Am Physicians. 1975; 88:70-86.
  2. Sène D. [Eosinophilic fasciitis (Shulman's disease): Diagnostic and therapeutic review]. Rev Med Interne. 2015; 36(11):738-745.
  3. Samona J. Orthopedic considerations with eosinophilic fasciitis: a case report and literature review. Case Rep Orthop. 2012; 2012:865360.
  4. Bachmeyer C, Monge M, Dhote R, Sanguina M, Aractingi S, Mougeot-Martin M. Eosinophilic fasciitis following idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia and Hashimoto's disease. Dermatology. 1999; 199(3):282.
  5. Haddad H, Sundaram S, Magro C, Gergis U. Eosinophilic fasciitis as a paraneoplastic syndrome, a case report and review of the literature. Hematol Oncol Stem Cell Ther. 2014; 7(2):90-92.
  6. Dourmishev LA, Dourmishev AL. Activity of certain drugs in inducing of inflammatory myopathies with cutaneous manifestations. Expert Opin Drug Saf. 2008; 7(4):421-433.
  7. 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. 2016; 152(1):97-99.
  8. Viallard JF, Taupin JL, Ranchin V, Leng B, Pellegrin JL, Moreau JF. Analysis of leukemia inhibitory factor, type 1 and type 2 cytokine production in patients with eosinophilic fasciitis. J Rheumatol. 2001; 28(1):75-80.
  9. Dziadzio L, Kelly EA, Panzer SE, Jarjour N, Huttenlocher A. Cytokine abnormalities in a patient with eosinophilic fasciitis. Ann Allergy Asthma Immunol. 2003; 90(4):452-455.
  10. Endo Y, Tamura A, Matsushima Y, et al. Eosinophilic fasciitis: report of two cases and a systematic review of the literature dealing with clinical variables that predict outcome. Clin Rheumatol. 2007; 26(9):1445-1451.
  11. Danis R, Akbulut S, Altintas A, Ozmen S, Ozmen CA. Unusual presentation of eosinophilic fasciitis: two case reports and a review of the literature. J Med Case Rep. 2010; 4:46.

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Last updated: 2018-06-22 00:48