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Peripheral and tissue eosinophilia can be a prominent feature of several unique rheumatologic and vascular diseases. These diseases span a wide range of clinical features, histologic findings, therapeutic approaches, and outcomes. Despite the rare nature of these entities--which makes large-scale studies challenging--knowledge has continued to grow regarding their epidemiology, pathophysiology, and management. This review compares and contrasts 5 rheumatologic and vascular conditions in which eosinophilia can be seen: eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin G4-related disease, diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, and eosinophilic myositis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Several distinct entities associated with dermal fibrosis can mimic scleroderma/systemic sclerosis. The list of scleroderma-like conditions or scleroderma variants includes eosinophilic fasciitis, localized forms of scleroderma, scleredema and scleromyxedema, keloids, and environmental exposure-associated conditions including eosinophilia-myalgia syndrome and pseudosclerodermas induced by various drugs. Although these conditions are relatively uncommon, their accurate recognition is essential to avoid misdiagnosis and inappropriate therapy. The pathogenesis of these scleroderma variants appears to share similarities with each other and with that of scleroderma. Better understanding of scleroderma-like disorders is emerging through epidemiologic investigations, and in vivo and in vitro experimental research. Activation of eosinophils and disordered regulation of fibroblast collagen synthesis, apoptosis, and proliferation are recurrent findings in these disorders. The etiologic role of infection with Borrelia species or other microorganisms remains controversial. Cytokines such as transforming growth factor-beta, interleukin-4, interleukin-13, and connective tissue growth factor contribute to fibrosis in these disorders by inducing an accentuated and persistent fibrogenic response to tissue injury. The role of genetic factors in susceptibility and clinical expression of scleroderma-like conditions remains to be systematically addressed. Because of the relative rarity of these conditions, few well-controlled clinical treatment trials have been performed. In addition, there is no consensus on optimal management. Much anecdotal information and small clinical series indicate that phototherapy may have a role in the treatment of scleroderma-like conditions.

We describe a case of acute acalculous cholecystitis occurring in a 43-year-old woman with a history of the eosinophilia-myalgia syndrome, associated with the ingestion of 1-tryptophan. The patient underwent a laparoscopic cholecystectomy and subsequent histological examination of the gallbladder revealed an infiltrate predominantly of eosinophils, suggesting a possible relationship to the underlying condition. This may represent a late complication of the eosinophilia-myalgia syndrome--such an association has not previously been reported in the literature. The gastrointestinal and hepatic complications of this syndrome are discussed.

The clinical status of patients with the eosinophilia-myalgia syndrome (EMS) was studied 2-4 years after its description in 2 databases: (1) a structured review of 205 patients with EMS completed by 15 physicians 18-24 months after onset, which included symptoms, physical findings, laboratory data, and responses to treatments; (2) a self-report questionnaire completed by 344 patients with EMS 42-48 months after onset. Most patients continued to experience symptoms, but almost none experienced new signs of acute inflammation more than one year after onset of EMS. These databases, while presenting information concerning longterm outcomes of more patients with EMS than other reported sources, remain limited by patient selection and the absence of information concerning clinical symptoms before development of EMS.

EMS, EF, and TOS are all relatively rare disorders. There are considerable data to suggest that most (if not all) of these cases may be due to toxin exposure, although the precise etiologic agent(s) has yet to be identified. It is likely that the pathogenic mechanisms responsible for disease are similar in these entities, and thus the distinctions between these illnesses may be largely semantic. Rational therapy includes the removal of an inciting agent if identified, and the application of symptom-based treatment based on the organ or tissue involved, and whether there is evidence of active inflammation is present.

Eosinophilia-myalgia syndrome, a recently described illness, reached epidemic proportions in 1989 and was linked to the ingestion of L-tryptophan containing trace amounts of several contaminants. Eosinophilia-myalgia syndrome shares many clinical and pathologic similarities with toxic-oil syndrome, an epidemic linked to the ingestion of adulterated cooking oil that occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, a condition first described in 1974. Over the past year, much work has been done in understanding the etiology and pathogenesis of eosinophilia-myalgia syndrome and toxic-oil syndrome. Follow-up data detailing the long-term sequelae and mortality rates for these two conditions are becoming available. The results from these studies are reviewed in this paper.

The eosinophilia-myalgia syndrome associated with L-tryptophan-containing products is highlighted by eosinophilia, incapacitating myalgias, and diverse multisystemic manifestations. In addition to involvement of the skin, skeletal muscle, and peripheral nerves, visceral damage has been quite prominent, particularly affecting the lungs, the heart, and the liver. Hepatic involvement has been manifested by altered liver tests but is clinically silent. We report the unique case of a woman with this syndrome who developed abdominal pain, a clinical picture of hepatitis and chronically abnormal liver tests. Histologic examination of the liver disclosed eosinophilic hepatitis with piecemeal necrosis. The occurrence of clinically overt hepatic involvement has not been reported previously. Potential mechanisms of liver damage in eosinophilia-myalgia syndromes are discussed.

Eosinophilia-myalgia syndrome (EMS) is a multisystem illness of uncertain pathogenesis that occurred in an epidemic related to the ingestion of contaminated L-tryptophan. To investigate the role of immune dysfunction in EMS we prospectively measured a serologic index of T-cell activation, the soluble interleukin-2 receptor (sIL-2R), in 7 patients followed into the late stages of the illness. As a group, EMS patients had significantly elevated sIL-2R levels throughout the study. Five patients suffered chronic symptoms of myalgia, arthralgia, muscle cramps, fatigue, or subjective memory impairment and all had persistently elevated sIL-2R levels. Two patients had near-resolution of EMS and normal sIL-2R levels. We conclude that chronic symptoms are common in EMS and are associated with persistent T-cell activation as measured by serum sIL-2R levels. These findings suggest that immunosuppressive treatment may be beneficial in EMS.

The eosinophilia-myalgia syndrome (EMS) is a recently described systemic disorder distinguished by the development of characteristic muscle spasm, myalgia, neuropathy, and scleroderma-like cutaneous induration. Life-threatening manifestations have included cardiopulmonary and acute ascending neuropathic syndromes. Current evidence indicates that this is a severe illness with the potential for long-term disability. Careful follow-up studies will help to better define new features of this disease, such as the recent awareness of severe neurocognitive abnormalities in some patients. The association of EMS with the ingestion of L-tryptophan may provide important clues toward the understanding of idiopathic fibrosing syndromes, as well as toxin-induced autoimmune phenomena. Rational therapy will be dependent upon a more complete understanding of the pathogenesis of this and related diseases.

Eosinophilia-myalgia syndrome is a recently described clinical syndrome caused by a suspected contaminant of L-tryptophan, an essential amino acid that was manufactured and sold as a nutritional supplement. This study reports the clinical and pathological findings of 22 cases of eosinophilia-myalgia syndrome evaluated at the Cleveland Clinic and includes data for up to 1 year of follow-up (for the epidemic cases). Nineteen of the 22 cases were evaluated and followed prospectively in the time period from November 1989 to November 1990. Two of the 22 represented nonepidemic forms of the syndrome which occurred prior to the 1989 epidemic. During a review of all cases of biopsy-proven diffuse fasciitis with eosinophilia at the Cleveland Clinic since 1978, one of the 22 was retrospectively identified as having an epidemic form of the syndrome, with onset in July 1989. In this study, adverse prognosticating factors in eosinophilia-myalgia syndrome included nerve and muscle involvement, fasciitis, and weight loss. Eosinophilia-myalgia syndrome is striking in its severity and diversity, and its features are similar to those of two other unusual illnesses--toxic oil syndrome and diffuse fasciitis with eosinophilia. With the recent purification of the suspected contaminant, it is hoped that further clues to the etiology of this syndrome and similar syndromes will be uncovered.