Eosinophilia in Rheumatologic/Vascular Disorders.

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.

[Diagnostic problems in eosinophilic fasciitis]. / Problemy diagnostyczne zwiazane z eozynofilowym zapaleniem powiezi.

We presented two cases with symptoms of diffuse swelling of subcutaneous tissue, stiffness and tenderness of involved areas, fever, eosinophilia and hypergammaglobulinemia. The inflammatory infiltrates consisting of lymphocytes, plasma cells and eosinophils were yielded in fascia. The difficulties in differentition of the symptoms between eosinophilic fasciitis and "eosinophilia-myalgia syndrome" are discussed.

Eosinophilic perimyositis as the presenting feature of a monoclonal T-cell expansion.

A 51-year-old physically active man was investigated for exertional myalgias and muscle stiffness. On examination he had mild proximal muscle weakness of the upper extremities and retraction of the digit flexors. Blood eosinophilia was present, but serum creatine kinase (CK) levels and an electromyographic study were normal. A skin-fascia-muscle biopsy of the calf revealed a macrophagic and CD4+ T-cell infiltration of the perimysium, and a T-cell expansion was observed in blood, bone marrow, and muscle. A diagnosis of eosinophilic perimyositis was made, and prednisone and azathioprine were administrated with a good clinical response. This case highlights the differential diagnosis of blood eosinophilia with muscle disorders, and underscores that eosinophilic perimyositis may be the expression of a T-cell monoclonal expansion. Although the pathogenesis behind the T-cell expansion is unclear but probably inflammatory, we suggest regular follow-up to allow early treatment of any T-cell lymphoproliferative malignancy that may develop.

Persistent microvasculopathy in chronic eosinophilia-myalgia syndrome.

Acute eosinophilia-myalgia syndrome (EMS) due to contaminated L-tryptophan (LT) exposure is an inflammatory microangiopathy of the dermis, fascia, and muscle. Select individuals evolve from acute EMS to have persistence of myalgia, fatigue, cramps, and skin changes for years. Many develop memory dysfunction and confusion. The objective of this study is to delineate the pathology in individuals with chronic EMS. Seventeen patients with ongoing symptoms representing chronic EMS are studied by skin, fascia, and muscle biopsies four to five years after exposure to contaminated LT and initial onset of EMS. All have microvascular disease. Most have lymphocytic inflammatory infiltrates. Several have dermal sclerosis. The findings indicate that persistent microvascular disease is present in chronic EMS. The pathologic changes are similar to those of acute EMS but with notable differences. Tissue eosinophil infiltration is rare in the chronic state as compared to acute EMS. The persistence of endothelial pathology indicates continuing microvascular dysfunction.

1,1'-Ethylidenebis[tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome.

1,1'-Ethylidenebis[tryptophan] (EBT), a derivative of L-tryptophan (LT), is a trace contaminant in batches of LT implicated by epidemiologic evidence in the pathogenesis of the eosinophilia-myalgia syndrome (EMS). We treated female Lewis rats with EBT or unimplicated LT (4 mg per 100 grams daily) by intraperitoneal injection. No rash or weakness occurred in either group. All three EBT rats had a few necrotic muscle fibers. In two rats, perimysium and fascia were abnormally thickened and infiltrated with lymphocytes, macrophages, and sparse eosinophils; two rats had sparse perineurial inflammatory cells. Rats treated with unimplicated LT showed no abnormality. These findings replicate an important feature of human EMS and support the epidemiologic evidence linking EBT to the pathogenesis of the human disease.

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

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.

Immunohistochemical analysis of lymphocytes in postmortem study of the heart from fatal cases of the eosinophilia myalgia syndrome and of the toxic oil syndrome.

Inflammatory lesions of coronary arteries and cardiac neural structures are postmortem histopathologic features of both the eosinophilia-myalgia syndrome (EMS) and the toxic oil syndrome (TOS). The inflammation is primarily lymphocytic. For further definition of the lymphocytes, immunohistochemical analysis was carried out in the hearts of three victims of EMS and four victims of TOS. Many CD45RO+ T cells, OPD4+ helper/inducer T (Th) cells, and CD20+ B cells were observed in these neurovascular lesions, notably in the conduction system and the coronary chemoreceptor. T cells were prominent in EMS around nerves, ganglia, and sometimes around arteries. B cells and Th cells, however, were more prominent in TOS around arteries. The percentage of T cells in EMS (59.6 +/- 2.4%) was significantly higher than in TOS (45.0 +/- 4.2%), whereas that of B cells was significantly higher in TOS (27.7 +/- 4.4%) than in EMS (17.5 +/- 1.3%) (p < 0.01, respectively). There was no significant difference between the syndromes in the percentages of Th cells. Therefore cytotoxic/suppressor T cells are more prominent in EMS than in TOS. These findings suggest that (1) cellular immune mechanisms are involved in cardioneuropathy in victims of both EMS and TOS; (2) cell-mediated cytotoxicity directed against chemoreceptor neural structures and sinus nodal myocytes is prominent in EMS; and (3) some humoral factors may also be involved in the pathogenesis of TOS.

Axonal neuropathy in eosinophilia-myalgia syndrome.

Three patients with eosinophilia-myalgia syndrome linked to consumption of L-tryptophan supplement developed a severe sensorimotor axonal neuropathy. All three had myalgia, elevated eosinophil count, and later developed fasciitis. Neuropathy was found at all stages of the illness and resulted in disability which was irreversible despite cessation of L-tryptophan. Nerve conduction studies showed reduced motor and sensory evoked response amplitudes with select sparing of some nerves and the arms were more involved than the legs. Cerebrospinal fluid protein content was increased in one of two patients so tested. Creatine kinase was normal and muscle biopsy showed perimysial inflammation. Sural nerve biopsy in one case showed epineural perivascular inflammation. Our data showed that a severe sensorimotor axonal neuropathy occurs in eosinophilia-myalgia syndrome, suggestive of mononeuritis multiplex.

Restrictive cardiomyopathy associated with the eosinophilia-myalgia syndrome.

OBJECTIVE: We report the first case of restrictive cardiomyopathy occurring in a patient with the eosinophilia-myalgia syndrome. DESIGN: In this article, we discuss the various clinical manifestations of the eosinophilia-myalgia syndrome. MATERIAL AND METHODS: In a 46-year-old woman with the eosinophilia-myalgia syndrome, orthopnea, chronic persistent edema, and severe dyspnea on exertion developed 2 years after she had discontinued use of L-tryptophan. Doppler echocardiography showed ventricular filling confined to early diastole and no atrial filling during ventricular systole--the Doppler hallmarks of restrictive disease. Right-sided cardiac catheterization revealed that the pulmonary wedge pressure equaled the pulmonary artery diastolic pressure and the mean right atrial pressure. A myocardial biopsy specimen showed dense endocardial fibrosis. Special immunofluorescent stains for eosinophilic granule major basic protein showed substantial deposition along the endocardial myocardial interface, an indication that eosinophils were present some time in the past. RESULTS: A follow-up telephone call 14 months after the patient's initial assessment at the Mayo Clinic revealed that she had class III symptoms of congestive heart failure. She was receiving high doses of three diuretics daily, and her condition had improved considerably since her first examination at our institution. CONCLUSION: Restrictive cardiomyopathy may occur in the setting of the eosinophilia-myalgia syndrome and should be considered in patients with this disease in whom exertional dyspnea and peripheral edema occur.

Fibrogenic growth factors in the eosinophilia-myalgia syndrome and the toxic oil syndrome.

BACKGROUND AND DESIGN: We sought to determine if growth factors of potential pathogenetic significance are deposited in the skin, muscle, and peripheral nerve lesions of eosinophilia-myalgia (EMS) and toxic oil syndrome. Immunohistochemical studies using affinity-purified peroxidase-conjugated antibodies to detect transforming growth factor-beta, platelet-derived growth factorAA and growth factorBB, fibroblast growth factor, epidermal growth factor, and interleukin 4 were performed on formalin-fixed, paraffin-embedded specimens. Seven skin biopsy specimens from EMS, six skin biopsy specimens from toxic oil syndrome, nine muscle biopsy specimens from EMS, and one sural nerve biopsy specimen from EMS were studied. RESULTS: Growth factor staining was noted primarily in the epidermis and periappendageal locations of the dermis. The presence of TGF-beta and platelet-derived growth factorAA in the periappendageal dermis was significantly more prevalent in EMS than toxic oil syndrome (57% vs 0%). Prominent staining of transforming growth factor-beta was also present in the perimysial connective tissue of five (63%) of eight EMS muscle biopsy specimens and one sural nerve biopsy specimen. CONCLUSIONS: These studies implicate transforming growth factor-beta and platelet-derived growth factorAA as potentially important cytokines in EMS and suggest that the pathogenesis of tissue fibrosis in EMS and toxic oil syndrome may be dependent on different growth factors.

Eosinophilia-myalgia syndrome: a clinicopathological study of four patients.

Eosinophilia-myalgia syndrome is an idiopathic disorder characterized by myalgia, especially of the extremities and peripheral eosinophilia. It is found in some patients as a result of tryptophan ingestion. We examined four patients showing clinical features and muscle biopsy changes consistent with eosinophilia-myalgia syndrome. The results of conventional histology were compared with immunohistochemical studies using monoclonal antibodies to human T lymphocytes, macrophages, HLA-DR antigen. Our findings confirm the potential importance of lymphocytes and macrophages in this syndrome. In particular, new observations are presented concerning the immunoreactivity of HLA-DR antigen.

Immune-mediated mechanisms and immune activation of fibroblasts in the pathogenesis of eosinophilia-myalgia syndrome induced by L-tryptophan.

To determine the immunopathogenesis of the persistent symptoms of patients with eosinophilia-myalgia syndrome (EMS) induced by L-tryptophan, we performed immunocytochemical studies on 10 muscle and fascia biopsy specimens obtained during the acute disease and the chronic persistent connective tissue sclerosis. A series of monoclonal antibodies was used in a single- or double-immunostaining technique to detect and quantify T-cell subsets, macrophages, major histocompatibility complex antigens, eosinophilic basic protein-positive cells, and resting fibroblasts expressing Thy-I antigen or activated fibroblasts expressing the activation marker F-19. We found inflammatory cells consisting of CD8+ cells (45% +/- 8.9%), T4 cells (36% +/- 10.1%), and macrophages (19% +/- 12%), scattered or perivascularly in the fascia, the perimysium, and the endomysial septae. Only rare granulated or degranulating eosinophils were noted. Many muscle fibers around fascicles or near blood vessels expressed major histocompatibility complex-I antigens. The mean number of fibroblasts in the fascia, the perimysial connective tissue, and the spindle capsule was increased in the EMS patients' specimens compared with the endomysial cells seen in six disease-control muscle biopsy specimens from patients with chronic inflammatory myopathies or dystrophies (P < .01). Up to 70% of the fibroblasts in EMS were activated and up to 30% of them expressed HLA-DR antigen. In the disease controls up to 29% of the fibroblasts were activated but none expressed DR. Repeat muscle biopsy a year later in a patient whose symptoms persisted showed reduced inflammation but an increased number of activated fibroblasts and enhanced DR expression. We conclude that in EMS there is a T-cell-mediated process against components of the extracellular matrix, including fibroblasts, in the fascia and the perimysium that persists even years after the drug is discontinued. Because the fibroblasts are activated and aberrantly express DR antigen, they may be the target cells playing a role in the continuing clinical and histologic signs of tissue sclerosis.

Fatal eosinophilia myalgia syndrome in a marrow transplant patient attributed to total parenteral nutrition with a solution containing tryptophan.

A 16-year-old white male with acute biphenotypic leukemia developed evidence of the eosinophilia myalgia syndrome associated with total parenteral nutritional support with solutions containing tryptophan, which were given during his initial induction chemotherapy and also after autologous marrow transplantation. He developed pronounced eosinophilia and a vasculitic skin rash, myalgias of the abdomen, upper trunk, and neck, and died of respiratory distress with no evidence of an infectious etiology. Autopsy revealed diffuse vasculitis involving the heart, lungs, kidneys, testes, spleen, liver, skin, gut wall and marrow with neuritis of gut wall nerves and ganglia. Thus, the eosinophilia myalgia syndrome can be associated with parenteral tryptophan administration.

Comparison of the pathology of fascia in eosinophilic myalgia syndrome patients and idiopathic eosinophilic fasciitis.

The L-tryptophan eosinophilic myalgia syndrome (EMS) clinically has some similarities with idiopathic eosinophilic fasciitis (EF). In order to study the pathology of both syndromes, we analyzed 21 biopsies of patients with EMS and 8 with idiopathic EF. In both diseases there is dermal and fascial mucin and dermal edema, but this was more common in EMS. EMS is also characterized by dilated lymphatics, dermal and septal sclerosis and macrophage-rich inflammation. Neural inflammation was seen in 4 of the cases with EMS and in none with idiopathic EF. In both syndromes, there are many histopathological similarities. The differences may be due to sampling and to sample size. The nerve lesions of EMS may result from the nature of lymphocyte-macrophage inflammation, or the effect of the eosinophil neurotoxin and may not be a primary event.

[Eosinophilia-myalgia syndrome. Clinical aspects and follow-up of 10 patients]. / Das Eosinophilie-Myalgie-Syndrom. Klinik und Verlauf bei 10 Patienten.

A retrospective study (1985-1989) of patients suffering from diffuse fasciitis with eosinophilia revealed that five of eight patients had taken L-tryptophan-containing drugs before the onset of the disease. In addition, since this drug-disease association was first described five patients have been diagnosed during the year 1990. All ten patients developed peripheral eosinophilia, myalgia and deep skin involvement indistinguishable from eosinophilic fasciitis. Corticosteroids were able to reduce the pain and inflammatory parameters, but did not prophylactically improve the long-standing sclerodermalike skin thickening. In 2/5 patients with symptoms longer than 1 year, low-dose corticosteroid maintenance therapy has been continuously required to control joint and muscle pain.

[L-tryptophan-associated chronic eosinophilia-myalgia syndrome treated with cyclosporin]. / L-Tryptophan-assoziiertes chronisches Eosinophilie-Myalgie-Syndrom behandelt mit Ciclosporin.

After 2 weeks of ingestion of 130 g L-Tryptophan a 52 year old female develops an Eosinophilia Myalgia Syndrome with acute onset of deep venous thrombosis of forearm and possible initial cardiac manifestation featuring intermittent sinustachykardia. This is followed by a severe chronic disease (follow-up 15 months) with diffuse scleroderma and sensomotoric polyneuropathia. The deep muscle biopsy-specimen shows mononuclear infiltration of fascia and interstitial myositis with rare eosinophils. A blood eosinophilia (900/ul) occurs only in the initial acute onset of the illness. Plasma level of Kynurenine is significantly high (4000 pmol/ml), collagenneosynthesis is activated (Procollagen type III peptid 0.927 U/ml). No significant clinical improvement was seen with Acathioprine (100 mg/d) and Prednisolon (40-60 mg/d), after treatment with Ciclosporin scleroderma regresses completely, polyneuropathy is persisting.

L-tryptophan syndrome: histologic features of scleroderma-like skin changes.

The eosinophilia-myalgia syndrome (EMS) associated with the ingestion of L-tryptophan (LT) containing products has recently been recognized in the United States. We report the histologic features of the cutaneous scleroderma-like changes in four patients. All of the patients met the Center for Disease Control criteria for EMS and had a history of LT ingestion. Skin biopsies showed increased dermal mucin and dermal sclerosis, with trapping of adnexal structures. There are clinical and histologic similarities between EMS, scleroderma, the toxic oil syndrome, and fasciitis with eosinophils.

Gastrointestinal involvement in L-tryptophan (L-Trp) associated eosinophilia-myalgia syndrome (EMS).

We report a 45-year-old female who had symptomatic gastrointestinal involvement, eosinophils in the cellular infiltrate, and who proved to have L-tryptophan-associated eosinophilia-myalgia syndrome. This case illustrates that gastrointestinal disease can be a major, seemingly primary clinical presentation in this syndrome, and that a drug history, specifically L-tryptophan, needs to be included in the differential diagnosis of "eosinophilic gastroenteritis."