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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.

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OBJECTIVE: To assess L-tryptophan (LT) dose, age, sex, and immunogenetic markers as possible risk or protective factors for the development of LT-associated eosinophilia-myalgia syndrome (EMS) and related clinical findings. METHODS: HLA-DRB1 and DQA1 allele typing and Gm/Km phenotyping were performed on a cohort of 94 white subjects with documented LT ingestion and standardized evaluations. Multivariate analyses compared LT dose, age, sex, and alleles among groups of subjects who ingested LT and subsequently developed surveillance criteria for EMS, developed EMS or characteristic features of EMS (EMS spectrum disorder), or developed no features of EMS (unaffected). RESULTS: Considering all sources of LT, higher LT dose (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8), age >45 years (OR 3.0, 95% CI 1.0-8.8), and HLA-DRB1*03 (OR 3.9, 95% CI 1.2-15.2), DRB1*04 (OR 3.9, 95% CI 1.1-16.4), and DQA1*0601 (OR 13.7, 95% CI 1.3-1.8) were risk factors for the development of EMS, whereas DRB1*07 (OR 0.12, 95% CI 0.02-0.48) and DQA1*0501 (OR 0.23, 95% CI 0.05-0.85) were protective. Similar risk and protective factors were seen for developing EMS following ingestion of implicated LT, except that DRB1*03 was not a risk factor and DQA1*0201 was an additional protective factor. EMS spectrum disorder also showed similar findings, but with DRB1*04 being a risk factor and DRB1*07 and DQA1*0201 being protective. There were no differences in sex distribution, Gm/Km allotypes, or Gm/Km phenotypes among any groups. CONCLUSION: In addition to the xenobiotic dose and subject age, polymorphisms in immune response genes may underlie the development of certain xenobiotic-induced immune-mediated disorders, and these findings may have implications for future related epidemics.

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5-Hydroxy-L-tryptophan (5-HTP) is the immediate precursor in the biosynthesis of 5-hydroxy-tryptamine (5-HT; serotonin) from the essential amino acid L-tryptophan (L-Trp). The use of L-Trp as a dietary supplement was discontinued in 1989 due to an outbreak of eosinophilia-myalgia syndrome (EMS) that was traced to a contaminated synthetic L-Trp from a single manufacturer. 5-HTP has since become a popular dietary supplement in lieu of the removal of L-Trp from the market. Because of its chemical and biochemical relationship to L-Trp, 5-HTP has been under vigilance by consumers, industry, academia and government for its safety. However, no definitive cases of toxicity have emerged despite the worldwide usage of 5-HTP for last 20 years, with the possible exception of one unresolved case of a Canadian woman. Extensive analyses of several sources of 5-HTP have shown no toxic contaminants similar to those associated with L-Trp, nor the presence of any other significant impurities. A minor chromatographic peak (peak X) reported in some 5-HTP samples lacks credibility due to chromatographic artifacts and infinitesimal concentrations, and has raised undue speculations concerning its chemistry and toxicity.

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With hindsight, it is easy to criticise the standards of food regulation of two decades ago. Nevertheless, when the Spanish toxic oil syndrome (TOS) appeared in 1981, there were many who asked why aniline was permitted as an official adulterant for imported French rape seed oil, and why such adulterated oils were often illegally refined in Spain and marketed without difficulty. This review brings up to date a comprehensive survey of the ensuing research published in 1995 and concentrates on recent significant findings. These include the identification of the refinery that produced the toxic oil, and the detection of oil contaminants with possible aetiological significance. Possible chemical links have been found between oil contaminants and those detected in L-tryptophan implicated in the eosinophilia-myalgia syndrome (EMS). There is good evidence that the initial pathogenetic mechanism is immunological. On metabolic evidence, it is suggested that not one, but a group of, toxic agents was responsible for TOS.

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Contaminants in biotechnologically manufactured L-Tryptophan (Trp) are suspected to be responsible for the outbreak of an unknown autoimmune disease in 1989. The contaminants, found in Trp-lots of a Japanese manufacturer, are classified in EMS-correlated and non EMS-correlated substances. Up to now six EMS-correlated substances are known. One of these compounds is 2-(3'-indolylmethyl)-indole (IMT). IMT was detected as a major contaminant in two investigated EMS-associated trp-samples. In a seven step chemical synthesis IMT was obtained for use as a reference substance. A model system to investigate the formation of IMT was created using Trp and 3-indolylmethanol (IM). IMT formation was observed at acidic and alkaline pH-values and the optimal molar ratio of Trp to IM is 100:1. In addition an IMT formation was observed from indole, formaldehyde and Trp as well as from Trp and 3-indolylacetaldehyde.

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On-line HPLC/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) in conjunction with NMR has been successfully employed to identify and structurally characterize seven contaminants found in three different commercial preparations of melatonin. Six of these contaminants were identified as analogues of impurities found in contaminated L-tryptophan (an over-the-counter dietary supplement) associated with the eosinophilia-myalgia syndrome (EMS) epidemic that occurred in the United States during 1989. In particular, our studies identified two compounds with MH+ = 249 to be hydroxymelatonin isomers. Four other compounds with MH+ = 477 were identified as melatonin-formaldehyde condensation products. These compounds are structural analogues of L-tryptophan contaminants, namely, 'peak C' and 'peak E' that were previously implicated as etiological agents causing EMS. It has been reported that melatonin consumption has resulted in eosinophilia in some humans taking high doses of this supplement. Although there has not been a major outbreak of EMS-like symptoms from consumption of melatonin, this study clearly suggests that tighter control and regulation of nutritional supplements sold and used as drugs is necessary.

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OBJECTIVE: To test whether individuals can be identified in a geographically defined population who would meet criteria for the eosinophilia-myalgia syndrome (EMS) established by the US Centers for Disease Control and Prevention (CDC), i.e, (1) eosinophil count > 1 x 10(9)/l, (2) myalgia severe enough to limit usual activities of daily living, and (3) no evidence of infection or neoplasm that could explain the first 2 findings. METHODS: To discover the number of individuals who would meet CDC criteria, the population was exhaustively searched using methods adapted from active pharmacoepidemiologic surveillance. Medical consultants and primary care practitioners were questioned as many as 5 times in a search for patients with severe myalgia. A predetermined protocol was used to screen those patients who appeared to meet CDC criteria for EMS using active surveillance methods. The study population was limited to Québec and Ontario (combined population 18,980,000) with special attention to the period July 1, 1992, to June 30, 1993. RESULTS: The prevalence of severe incapacitating myalgia was 43 per 100,000 persons, including 19 individuals with eosinophilia > 1 x 10(9)/l, who met CDC criteria for EMS. None of these individuals were reported to have taken L-tryptophan (LT). CONCLUSION: The CDC criteria for EMS are met by individuals in the general population who have never been exposed to LT.

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Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.

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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.

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This article examines the methodology of the epidemiological studies of the association between L-tryptophan and eosinophilia-myalgia syndrome (EMS) and evaluates the validity of the conclusions from these studies. In the initial case-control studies of L-tryptophantryptophan and EMS there were a variety of methodological problems, including different sources and different exclusion criteria for cases and controls, which could have resulted in selection bias, as well as problems with information bias and confounding. The studies of manufacturer and brand also had similar potential for bias. The L-tryptophan-EMS association is based on two small studies that had important methodological inadequacies. Subsequent studies of brand of L-tryptophan also contained errors in design, which may have produced biased results and call the conclusions into question. The cause of eosinophilia-myalgia syndrome remains unknown.

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Eosinophilia myalgia syndrome (EMS), was defined by the Centers for Disease Control (CDC) as eosinophilia > 1000 mm3 and incapacitating myalgia without infection or neoplasm. Studies suggested that use of L-tryptophan (L-T), was a risk factor. We conducted a pharmacoepidemiological survey in Canada where access to L-T is limited. Using the active surveillance method, a 100% sample of potentially involved specialists and a 15% sample of family physicians from Ontario and Quebec were surveyed regarding treatment of patients with severe myalgia within the past year. Follow-up amplified clinical and laboratory information. Overall response rates were 61.4%. Thirty-eight per cent of respondents reported at least one patient. Of 6423 patients assessed, 19 'definite' and 25 'possible' EMS cases were identified. Information from physicians did not suggest use of L-T in patients with definite or possible EMS. It was considered that the cases found an underestimate of the incidence of EMS. Its continuing occurrence in Canada brings causal interpretations of earlier studies into question.

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Almost any rheumatic disorder can occasionally be characterized by the presence of eosinophilia, but there are only a few in which eosinophilia is a defining characteristic. These include eosinophilic fasciitis as well as toxin-induced disorders such as eosinophilia-myalgia syndrome and toxic oil syndrome. The epidemiology, clinical features, and pathogenesis of these conditions are reviewed in this article, and a rational approach to management of these entities is discussed.

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Consumption of certain product lots of L-tryptophan (LT) has been reported to be epidemiologically associated with an outbreak of eosinophilia-myalgia syndrome (EMS) in the United States. Since the production lots were found to contain 3-phenylamino alanine (PAA) as an impurity, its effects were studied by administering the substance orally by gavage to 5-week-old Sprague-Dawley rats. Groups of animals were given PAA for 13 consecutive weeks at dose levels of 1, 10 and 100 mg/kg per day. The animals were killed at 4 or 8 weeks. Hematological and blood biochemical tests were performed and detailed histopathological observations were made. No significant abnormalities were observed in the test animals and in particular no EMS-like conditions. A brief summary of other animal studies using several species of rats and mice performed in our laboratory since 1989 on various LT related substances is also presented. No EMS-like effects were observed in these studies.

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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.

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An epidemic of a new disease, termed eosinophilia-myalgia syndrome, occurred in the USA in 1989. This syndrome was linked to the consumption of L-tryptophan manufactured by a single company utilizing a fermentation process. All the findings indicate that the illness was probably triggered by an impurity formed when the manufacturing conditions were modified. This outbreak highlights the need for close monitoring of the chemical purity of biotechnology-derived products, and for rigorous testing of such products following any significant changes to the manufacturing process.

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OBJECTIVE: To review the epidemiologic features of eosinophilia-myalgia syndrome (EMS) in Germany. DESIGN: We determined the incidence of EMS in Germany through May 1992 and analyzed the dose of L-tryptophan used, the duration of intake, and the concurrent medications. MATERIAL AND METHODS: All patients receiving L-tryptophan preparations in Germany were already under medical supervision before the onset of the disease; thus, information on patient history and other potential risk factors was readily available. Because of the drug status of L-tryptophan preparations, brands could be accurately traced back to suppliers of raw materials. Statistical differences in age and gender of patients, dose of L-tryptophan, eosinophil count, and skin involvement were sought between patients with and those without concurrent medications. RESULTS: On the basis of guidelines established by the Centers for Disease Control and Prevention, 105 patients fulfilled the criteria for EMS. No apparent correlation was found between the incidence of EMS and the dose of L-tryptophan or the duration of intake before onset of EMS. Assessment of the study group showed that 45% were taking various other medications, whereas 55% were taking L-tryptophan only. Analysis by type of pharmaceutical agent showed no preponderance of a specific concurrent drug (in particular, psychotropic drugs). Thus, concurrently used medications did not seem to be an important variable. All cases of EMS were associated with L-tryptophan from formulators that had used raw materials from the previously implicated source. CONCLUSION: This study supports the pathophysiologic role of a contaminant in L-tryptophan in the occurrence of cases of EMS in Germany.

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