- Email: [email protected]
The eosinophilia-myalgia syndrome
The Eosinophilia Myalgia Syndrome RICHARD
M. SILVER,
MD
A
seemingly new illness was first described in the United States in late 1989, when physicians in New Mexico reported the occurrence #of generalized myalgia and eosinophilia in three women, each of whom had a prior history of ingesting the amino acid, L-tryptophan.’ The illness, which has been linked to the ingestion of L-tryptophan containing trace amounts of chemical contaminants reached epidemic proportions in late 1989, and it quickly subsided when L-tryptophan - containing products were recalled. This illness, now known as the eosinophilia -myalgia syndrome (EMS), was frequently complicated by the occurrence of sclerodermalike hardening of the skin and subcutaneous tissues and, thus, may be added to a growing list of environmental or toxin exposures implicated in the pathogenesis of sclerodermatous disorders. EMS shares many features with diffuse fasciitis with eosinophilia (DFE or Shulman’s disease),2 as well as with the toxic oil syndrome (TOS), another sclerodermalike disease which occurred as an epidemic in 1981, affecting nearly 20,000 individuals in Spain.3 The study of EMS and related conditions is important, not only for the sake of public health, but also for the insight which may be gained for better understanding of systemic sclerosis (SSc) and other fibrosing cutaneous processes.
L-Tryptophan Metabolism in Health and Disease L-tryptophan is the scarcest of the essential amino acids. During the 198Os, L-tryptophan was widely advocated and used for a number of conditions such as depression, From the Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina. Address correspondence to Richard M. Silver, MD, Professor of Medicine and Pediatrics, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425-2229.
0 1994 by Elsevier Science Inc.
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insomnia, obesity, and premenstrual syndrome. The use of L-tryptophan for these conditions was based on its metabolic role as a precursor for the synthesis of the neurotransmitter serotonin (5-hydroxytryptamine) (Figure 1). In addition to its role in the synthesis of serotonin, L-tryptophan is also metabolized by kynurenine to nicotinamide dinucleotide (NAD) and nicotinic acid, or niacin (see Figure 1). In fact, the vast majority of ingested L-tryptophan is metabolized via the kynurenine pathway, and only a fraction is metabolized to serotonin. The ratelimiting enzyme in the metabolism of L-tryptophan under normal circumstances is the hepatic enzyme tryptophan dioxygenase (TDO). The metabolism of L-tryptophan is altered during certain inflammatory conditions, including EMS, in which the extrahepatic enzyme indoleamine 2,3dioxygenase (IDO) is induced, becoming the rate-limiting enzyme in the metabolism of L-tryptophan.4 L-tryptophan metabolism is shunted along this pathway, and large amounts of kynurenine and its breakdown products may be formed in extrahepatic sites such as the lungs and the central nervous system. Interferon-y is the most potent inducer of ID0,4 and interleukin-2 and tumor necrosis factor-a! may also upregulate ID0 .5,6Glucocorticoids act to downregulate the expression of IDO while upregulating TDO. Altered L-tryptophan metabolism was described in a number of inflammatory and rheumatic conditions, including SSc, long before the discovery of ID0.7 Of interest was the observation in 1981, by Sternberg et al., of altered metabolism of L-tryptophan in a patient with a sclerodermalike illness associated with the ingestion of 5-hydroxy-L-tryptophan .* Although this patient’s elevated level of kynurenine was initially attributed to a possible inborn error of metabolism, subsequent studies suggest that it was due to the induction of IDO, with shunting of L-tryptophan via the kynurenine pathway. Similarly, Jablonska and her colleagues described elevated kynurenine levels in patients with SSc and in pa-
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Figure 1. Metabolism of L-typtophan via the serotonin and the kynurenine pathways. tients with DFE,9,10 also likely to have been due to induction of IDO. L-tryptophan metabolism was also shunted via the kynurenine pathway in EMS patients.” During the active, eosinophilic phase of the illness, untreated EMS patients had low plasma levels of L-tryptophan and high plasma levels of kynurenine and its breakdown product, quinolinic acid. I1 Plasma neopterin, a marker of interferon-y, was elevated and correlated with quinolinic acid.12 When given a loading dose of L-tryptophan, such patients demonstrated enhanced kynurenine and quinolinic acid synthesis13 (Figure 2). Corticosteroid-treated EMS patients metabolized L-tryptophan in a manner similar to age- and sex-matched healthy controls (see Figure 2). Thus, the handling of L-tryptophan in EMS is the result of cytokine induction of ID0 and not related to an inborn error of metabolism. Identical findings have been reported in patients with TOS12 and DFE.*O It remains to be determined what role, if any, the enhanced kynurenine pathway of L-tryptophan metabolism plays in the pathogenesis of these similar conditions.
Epidemiology of EMS Federal and state health agencies in the United States acted swiftly to detine the syndrome and investigate its etiology.14 The Centers for Disease Control (CDC) established the following case definition for surveillance purposes: (1) eosinophil count > 1 X 109/L; (2) generalized myalgia of sufficient severity to limit activity; and (3) exclusion of neoplasm or infection to account for the syndrome.15 As of August 1, 1992, the CDC reported 1,511
cases of EMS and 38 deaths from neurologic, cardiac, and pulmonary complications. Cases have also been reported from Europe and Japan. In view of the passive surveillance system in the United States and the rigid case definition, it is estimated that only one-half of those patients meeting the surveillance case definition have been reported and that there may be another 3,000 individuals who consumed L-tryptophan and are now exhibiting symptoms consistent with EMS but do not meet the full surveillance criteria. Higher prevalence rates were reported from states where more active surveillance was conducted, including Minnesota,16 Oregon,l’ New Mexico,ls and South Carolina.19 Thus, the true prevalence of EMS is not known but is likely to be greater than CDC reports suggest. A number of case-control studies showed a very strong association of EMS with the ingestion of L-tryptophan,16-lS leading to its recall from the retail market by the Food and Drug Administration. A study from Minnesota found that 29 of 30 (97%) EMS patients and 21 of 35 controls (60%) had consumed L-tryptophan manufactured by a single manufacturer (odds ratio, 19.3, 95% confidence interval, 2.5 to 844.9, p < 0.001).16 A traceback study in Oregon yielded similar results, with 98% of EMS cases having consumed L-tryptophan from a single manufacturer; retail lots of L-tryptophan produced by this manufacturer between January and June 1989 were implicated in the syndrome.” Study of a cohort of 418 L-tryptophan users from a single psychiatry practice showed that the risk of developing EMS was related to increasing dose of L-tryptophan, as well as increased age of the user.19 These and other studies suggested that con-
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C tamination during the manufacture of L-tryptophan was related to, if not responsible for, the epidemic and that the attack rate might have been influenced by cofactors such as age. The manufacturing process employed by the implicated company involved a bacterial fermentation process with subsequent filtration and purification. Late in 1988, a genetically modified strain (V) of Bacillus amyloliquefuciens that yielded increased amounts of L-tryptophan was introduced. At about the same time, the filtration process was modified to reduce the amount of activated carbon and to bypass a reverse osmosis membrane filter. In a case-control study, significant associations between lots used by case patients and changes in the manufacturing process were confirmed (p < 0.05).16 High-performance liquid chromatography of the company’s L-tryptophan demonstrated several peaks, one (peak E) strongly associated with the syndrome.16 The structure of peak E was soon defined and continned to be l,l’-ethylidenebis(L-tryptophan) (EBT).20 A
recent case-control study of over 500 patients attending a single medical clinic, where they purchased L-tryptophan between July and December 1989, revealed an attack rate of 2.2% and a significant association between EMS and ingestion of L-tryptophan containing a high concentration of EBT (70 pg/g).21 UV-5, a second trace contaminant of L-tryptophan, was subsequently identified as 3-(phenylamino)alanine (PAA), and it, too, has been linked epidemiologically to the EMS epidemic.22 Four other trace contaminants present in implicated batches of L-tryptophan have been associated with the EMS epidemic (peak AAA, peak C, peak FF, and peak 200). These elegant epidemiologic studies showing an association between several trace contaminants and the EMS epidemic cannot address the issue of causation. The latter can only be addressed by animal studies in which purified chemical constituents of implicated batches of L-tryptophan are administered, alone or in combination, to animals presumed to be susceptible to inflammation and fibrosis in a fashion analogous to that of man. Several
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such studies have been reported and others are now underway. Implicated L-tryptophan and synthesized EBT have been shown to induce fibrosis, with or without inflammation, in the fascia and perimysium of female Lewis rats.23,24The Lewis rat is susceptible to a number of inflammatory diseases, presumably related to impairment of the hypothalamic-pituitary-adrenal axis; no such impairment has been demonstrated in patients with EMS. Recently, a second model has been proposed employing C57/BL6 mice. 25In this model, daily intraperitoneal administration of EBT yields significant inflammation and fibrosis of the dermis, fascia, and perimysium consistent with changes observed in subjects with EMS. Mast cells, also seen in EMS lesions, have been observed in each of these proposed models. In neither model has tissue or blood eosinophilia been observed. These and perhaps other models require further study to elucidate the etiology and the pathogenesis of EMS. Such studies may provide information relevant to other conditions, such as TOS, DFE, and SSc.
Clinical Features of EMS EMS is a multisystem disease that in its acute phase often had a flulike onset with fever, rash, arthralgia, and dyspnea, as well as the characteristic myalgia and eosinophilia. Nearly one-third of all patients required hospitalization. The majority of patients were Caucasian females, a reflection of the ingestion patterns of L-tryptophan rather than race or gender susceptibility. The median daily dose of L-tryptophan ingested was 1.5 g. Myalgia was nearly universal and often was diffuse and debilitating. 26*27Serum levels of creatine kinase were usually normal, but aldolase was elevated in many untreated patients. 26 Electromyography was sometimes abnormal but nonspecific. Severe muscle cramps occurred, and for many patients this has been a persistent and debilitating feature of the chronic phase of EMS. The pathogenesis of the myalgia and cramps is not known. Ischemia and neuropathic changes may underlie their pathogenesis, but myonecrosis was not seen on muscle biopsy. An acquired metabolic abnormality is also possible, given the recent observation of abnormal P-31 magnetic resonance spectroscopy of skeletal muscle.28 Eosinophilia is one of the criteria for the case definition of EMS and was present in most but probably not all patients. Overall, the median percentage of eosinophils was 39% and the median eosinophil count was over 5 X 109/L.29 Serum and urine levels of two eosinophil granule products, major basic protein and eosinophil-derived neurotoxin, were elevated in some patients, signifying
Clinics in Dermatology 2994;22:457-465 eosinophil activation, and degranulation.30 Similarly, tissue levels of eosinophil granule proteins also appeared to have been accentuated.30 Interleukin-5, a cytokine that stimulates eosinophil production and enhances eosinophi1 survival, was detectable in the serum of some EMS patients and may have played a role in the eosinophilia and activation seen in EMS.31 Eosinophilia resolved promptly after the administration of glucocorticoids. Skin rash or induration was present in the majority of patients with EMS. 11,26,27Erythematous macules, sometimes pruritic, were often present on the trunk and the extremities during the acute phase. Papular eruptions (papular mucinosis) occurred in some patients.32 Subcutaneous edema, sometimes massive, occurred acutely in many patients, affecting the upper and lower extremities and sometimes producing nerve entrapment such as carpal tunnel syndrome. Edema often evolved to a tense, woody induration with a peau &orange quality similar to that seen in patients with DFE. Unlike SSc, the face and the acral portions of the body were usually spared by the indurative process. Also, EMS patients generally did not have Raynaud’s phenomenon, nor did they have abnormal nailfold capillaries. l* Alopecia affecting the scalp and the body was sometimes present in the early phase of EMS, apparently the result of telogen effluvium with complete resolution.33 Peripheral neuropathy occurred in many EMS patients.27,34-37 Diffuse and localized paresthesia or hyperesthesia were frequent. An ascending polyneuropathy occurred rarely. Many of the known deaths from EMS were related to complications secondary to severe neuropathy, such as respiratory failure or pneumonia. Central nervous system involvement has also been described.38-31 Acute encephalopathy has been reported in a few patients. Magnetic resonance imaging has revealed multiple white-matter lesions in a number of such cases, and one autopsy showed a perivascular lymphocytic infiltrate and a lymphocytic meningitis.41 In several cases central nervous system signs and symptoms appeared long after the eosinophilia had resolved. A major concern of patients and physicians is the possible occurrence of neurocognitive dysfunction. AIthough a thorough, controlled study has yet to be performed, a number of investigators have reported the presence of neurocognitive dysfunction such as memory impairment, difficulty concentrating, difficulty remembering words or names of persons, and so on, in as many as 60% of EMS patients. 42,43Neither the actual prevalence nor the pathogenesis of this aspect of EMS is known at this time. Potential neurotoxic mediators in EMS include eosinophil- derived neurotoxin and the kynurenine metabolite quinolinic acid. Significant elevations of quino-
Clinics in Dermatology 1994;12:457-465 linic acid were detected not only in the plasma,l’ but also in the cerebrospinal fluid of EMS patients.13,35 Elevated levels of quinolinic acid in cerebrospinal fluid have been reported in other inflammatory conditions, including AIDS-related dementia where the levels correlate with the degree of neurocognitive dysfunction.44 Many EMS patients had dyspnea and cough during the early phase of the illness,45-47 but respiratory complaints were less frequent and severe than in TOS, where noncardiogenic pulmonary edema was severe and sometimes fatal. Nevertheless, one carefully conducted study found a high incidence of pulmonary symptoms in EMS patients.48 The study found frequent abnormalities in diffusing capacity and maximal static respiratory pressures, suggesting the presence of parenchymal lung involvement and respiratory muscle weakness.48 Linear opacities, with or without pleural effusions, were frequently seen on chest radiographs and usually resolved with corticosteroid therapy. Interstitial pneumonitis with eosinophilia and perivascular inflammation was evident on lung biopsy. Bronchoalveolar lavage (BAL) fluid contained eosinophils and fibroblast proliferation stimulating activity. 49 In some patients, pulmonary vascular disease was present and sometimes fatal. Unlike in TOS, few cases of late-onset pulmonary hypertension have been reported during the first 4 years of follow-up of EMS patients. Cardiac involvement has been reported and was implicated in the death of some EMS patients, but overall cardiac disease has not been a major feature of the illness. Pathologic lesions in the coronary arteries, neural structures and conducting system in three patients provided a basis for significant cardiac electrical instability and sudden death.50 Similar lesions were observed in cardiac tissue of patients with TOS5* Repeated episodes of coronary artery spasm were observed in one patient with EMS whose endomyocardial biopsy showed focal deposits of eosinophil major basic protein.52 This patient responded to intravenous magnesium infusion (I’. Hertzman, personal communication), suggesting a depletion of magnesium as the cause of the coronary vasospasm, similar to what has been observed in subjects with idiopathic variant angina pectoris. 53 Magnesium deficiency might also underlie the myalgia and cramps that complicate chronic EMS; in fact, preliminary studies suggest that magnesium repletion ameliorates some of these symptoms (D. Clauw, personal communication). Gastrointestinal involvement in EMS has been reported but was apparently uncommon. Malabsorption with steatorrhea, hypoalbuminemia, and weight loss was described, with eosinophilic infiltration of the stomach, small bowel, and colon.54
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Figure 3. Skin biopsy specimenfrom EMS patient (hematoxylin and eosin, X40). The epidermis (top) is normal, whereas the dermis shows a mononuclear cell infiltrate and extensive collagen deposition.
Histopathology of EMS Full-thickness biopsies of skin lesions show an inflammatory and fibrosing process affecting the dermis and subcutaneous tissue including the fascia and extending to the perimysium (Figures 3 and 4). A perivascular mononuclear cell infiltrate is seen, with or without eosinophils. Endothelial cells appear swollen, but true vasculitis is rare. Similar lesions were seen in patients with TOS, although results of full-thickness biopsies were seldom reported. Inflammation and fibrosis affecting the subcutaneous fat, septa, and fascia are also seen in the lesion of DFE, but cutaneous changes appear to be more prominent in EMS.55~56One problem encountered in comparing EMS to DFE is the fact that many reported cases of DFE during the late 1980s were shown retrospectively to represent patients who ingested L-tryptophan. In one study, nearly 65% of patients initially diagnosed between 1986 and 1990 as having DFE actually had a history of L-tryptophan ingestion prior to the onset of their illness.57 Mast cells and Factor XIIIa -positive (dermal dendritic) cells are present in the infiltrates of EMS and DFES5 as well in the dermal lesions of TOS and SSc. Papular mucinosis is another dermatologic feature common to these conditions. In general, such histopathologic features occur as a pancutaneous - subcutaneous process in EMS, whereas they tend to involve the subcutis alone in DFE. Inflammation of cutaneous nerves may also distinguish EMS from DFE.56 Reactive mesenchymal cells sharing features of histiocytes and fibroblasts are present in the deep fascia.58 Ex-
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and fibrosis have been described, accompanied by vasculopathy and angioneogenesis.34 Type II muscle fiber atrophy occurred, perhaps secondary to disuse or glucocorticoid therapy; myonecrosis was rare.
Treatment and Course of EMS
Figure 4. Fascia and musclefrom EMS patient (hemafoxylin and eosin, X50). The fascia (top) is thickened and contains an inflammatory cell infiltrate composed of lymphocytes, macrophages,and plasma cells. The injlammafory cell infiltrate extends to the perimysium of the underlying skeletal muscle. pression of mRNA for types I and VI collagen, as well as transforming growth factor-p, (TFG-P), is increased in affected fascia1,59*60supporting a role for cytokine-driven fibrosis. In addition to the increased expression of TGF-P is evidence of increased production of other cytokines, including interferon-y, l2 IL-4,61 and IL-5.31 The nature of the dermal lymphocytic infiltrate has not been well characterized. Fascial and muscle specimens contain predom(most are CDS-I-) and macroinantly T-lymphocytes phages; B-lymphocytes and eosinophils are present but make up only a fraction of the cellular infiltrate.63 BAL fluid analysis has also revealed an increased proportion of CDS+ lymphocytes, and lung biopsies have shown a predominance of CDS-I- lymphocytes in the interstitial and perivascular infiltrate.63 Peripheral nervous system lesions have been characterized by axonal degeneration or, less commonly, by demyelination. In some cases, epineural inflammation
Optimal treatment of EMS, as well as its natural history, remain to be determined. As was the case in TOS, EMS has become a chronic disease for many patients. In one population-based cohort the course during the initial 4 to 6 months was severe, followed by a decrease in myalgia, pulmonary complications, skin rash, and edema.64 Another study confirmed that despite the early improvement, many patients remained symptomatic 12 months after onset of disease. 65 Myalgia and fatigue persisted in the majority of cases, and only 26% reported that they were able to perform all normal daily activities. An 18 to 24-month follow-up of 210 EMS patients revealed that fever, edema, weight loss, fatigue, and rash were improved or resolved in more than 75% of patients; other symptoms except cognitive complaints improved to a lesser extent.66 Cognitive difficulties appear to have developed later in the course of the disease, and significant improvement in such symptoms has not been observed. Further analysis of neurocognitive function and followup of this cohort is planned. Treatment has generally been empiric and uncontrolled. Eosinophilia, edema, and pneumonitis usually resolved promptly after the initiation of glucocorticoid therapy, but disease duration does not appear to have been affected, and symptoms often returned after withdrawal of glucocorticoids. A variety of other agents including nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, cyclosporin A, methotrexate, plasmapheresis, d-penicillamine, antimalarials, and octreotide have been employed, but none has shown consistent beneficial effects. Except for anecdotal reports, no therapy has been shown conclusively to be effective in the treatment of EMS. The same can be said for therapy of DFE and TOS.
Conclusions EMS is a multisystem disease whose cutaneous manifestations resemble certain other sclerodennalike conditions, such as TOS and DFE. Its association with the ingestion of L-tryptophan containing trace chemical contaminants adds to a growing list of environmental and toxin exposures capable of producing sclerodermalike illnesses. Elucidation of the precise toxin(s) in implicated
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batches of L-tryptophan, host factors conferring susceptibility, and the cellular and molecular basis of pathogenesis should lead to better understanding and treatment of this and related conditions. Heightened awareness of toxic epidemics such as EMS may also lead to regulatory changes designed to ensure greater safety of drugs and food supplements.
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S, Kencka D. Tryptophan metaboeosinophilic fasciitis. In: Black CM, Topics in Rheumatology: Systemic New York: Gower Medical, 1985;
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eosinophilia-myalgia 1097-105.
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30. Martin RW, Duffy J, Engel AG, et al. The clinical spectrum of the eosinophiia-myalgia syndrome associated with L-tryptophan ingestion. Clinical features in 20 patients and aspects of pathophysiology. Ann Intern Med 1990; 113:124-34. 31. Owen WF Jr, Petersen J, Sheff DM, et al. Hypodense eosinophils and interleukin 5 activity in the blood of patients with the eosinophilia-myalgia syndrome. Proc Nat1 Acad Sci USA 1990;87:8647-51. 32. Kaufman L, Seidman R, Phillips M, et al. Cutaneous manifestations of the L-tryptophan-associated eosinophiliamyalgia syndrome: A spectrum of sclerodermatous skin disease. J Am Acad Derm 1990;23:1063-69. 33. Benedict LM, Abel1 E, Jegasothy B. Telogen effluvium associated with eosinophilia-myalgia syndrome. J Am Acad Dermatol 1991;25:112. 34. Smith BE, Dyck PJ. Peripheral neuropathy in the eosinophilia-myalgia syndrome associated with t-tryptophan ingestion. Neurology 1990;40:1035-40. 35. Heiman-Patterson TD, Bird SJ, Parry GJ, et al. Peripheral neuropathy associated with eosinophilia - myalgia syndrome. Ann Neural 1990;28:522-28. 36. Donofrio PD, Stanton C, Miller VS, et al. Demyelinating polyneuropathy in eosinophilia-myalgia syndrome. Muscle & Nerve 1992;15:796-805. 37. Tolander LM, Bamford CR, Yoshino MT, et al. Neurologic complications of the tryptophan-associated eosinophiliamyalgia syndrome. Arch Neurol1991;48:436-38. 38. Adair JC, Rose JW, Digre KB, et al. Acute encephalopathy associated with the eosinophilia-myalgia syndrome. Neurology 1992;42:461-62. 39. Greenfield BM, Mayer JW, Sibbitt RR. The eosinophiliamyalgia syndrome and the brain. Ann Intern Med 1991;115:159-60. 40. Lynn J, Rammohan KW, Bomstein RA, et al. Central nervous system involvement in the eosinophilia-myalgia syndrome. Arch Neurol 1992;49:1082-85. 41. Pixley JS, Eaton JM, Zweig RM. Central nervous system inflammation in the eosinophilia-myalgia syndrome. Br J Rheumatol 1992;32:174. 42. Anonymous. Eosinophilia-myalgia syndrome: Follow-up survey of patients-New York, 1990-1991. MMWR 1991;40:401-03. 43. Krupp LB, Masur DM, Kaufman LD. Neurocognitive dysfunction in the eosinophilia-myalgia syndrome. Neurology 1993;43:931-36. 44. Heyes MP, Brew BJ, Martin A, et al. Quinolinic acid in cerebrospinal fluid and serum in HIV-l infection: Relationship to clinical and neurologic status. Ann Neurol 1991;29:202-09. 45. Tazelaar HD, Myers JL, Drage CW, et al. Pulmonary disease associated with L-tryptophan-induced eosinophilic myalgia syndrome. Clinical and pathologic features. Chest 1990;97:1032-36.
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46. Strumpf IJ, Drucker RD, Anders KH, et al. Acute eosinophilic pulmonary disease associated with the ingestion of L-tryptophan-containing products. Chest 1991;99: 8-13. 47. Banner A, Borochovitz D. Acute respiratory by pulmonary vasculitis after L-tryptophan Rev Respir Dis 1991;143:661-64.
failure caused ingestion. Am
48. Read CA, Clauw D, Weir C, et al. Dyspnea and pulmonary function in the L-tryptophan-associated eosinophiliamyalgia syndrome. Chest 1992;101:1282-68. 49. Campagna AC, Blanc PD, &swell LA, et al. Pulmonary manifestations of the eosinophilia-myalgia syndrome associated with tryptophan ingestion. Chest 1992;lOl: 1274-81. 50. James TN, Kamb ML, Sandberg GA, et al. Postmortem studies of the heart in three fatal cases of the eosinophilia myalgia syndrome. Ann Intern Med 1991;115:102-10. 51. James TN, Gomez-Sanchez MA, Martinez-Tello FJ, et al. Cardiac abnormalities in the toxic oil syndrome, with comparative observations on the eosinophilia-myalgia syndrome. J Am Co11 Cardiol 1991;18:1367-79. 52. Hertzman PA, Maddoux GL, Stemberg EM, et al. Repeated coronary artery spasm in a young woman with the eosinophilia-myalgia syndrome. JAMA 1992;267: 2932-34. 53. Goto K, Yasue H, Okumura K, et al. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 1990;65:709 - 12. 54. de Schryver-Kecskemieti K, Bennert KW, Cooper GS, et al. Gastrointestinal involvement in L-tryptophan (L-Trp) associated eosinophilia-myalgia syndrome (EMS). Dig Dis Sci 1992;37:697701. 55. Feldman SR, Silver RM, Maize JC. A histopathologic comparison of Shulman’s syndrome (diffuse fasciitis with eosinophilia) and the fasciitis associated with the eosinophilia-myalgia syndrome. J Am Acad Dermatol 1992;26:95-100. 56. Umbert I, Winkelmann RK, Wegener L. Comparison of the pathology of fascia in eosinophilic myalgia syndrome patients and idiopathic eosinophilic fasciitis. Dermatol 1993;186:18-22. 57. Blauvelt A, Falanga V. Idiopathic and L-tryptophan-associated eosinophilic fasciitis before and after L-tryptophan contamination. Arch Dermatol 1991;127:1159-66. 58. Lin JD, Phelps RG, Gordon ML, et al. Pathologic manifestations of the eosinophilia myalgia syndrome: Analysis of 11 cases. Hum Path01 1992;23:429-37. 59. Varga J, Peltonen J, Uitto JM, et al. Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: Demonstration of elevated type I collagen gene expression in affected tissues. A clinicopathologic study of four patients. Ann Intern Med 1990;112:344-51. 60. Peltonen J, Varga J, Sollberg S, et al. Elevated expression of the genes for transforming growth factor-l and type VI
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collagen in diffuse fasciitis associated with the eosinophilia-myalgia syndrome. J Invest Derm 1991;96: 20-25. 61. Kaufman LD, Gruber BL, Needleman BW. Interleukin-4 levels in the eosinophilia-myalgia syndrome. Am J Med 1991;91:664-65. 62. Emslie-Smith AM, Engel AG, Duffy J, et al. Eosinophilia myalgia syndrome: I. Immunocytochemical evidence for a T-cell-mediated immune effector response. Ann Neurol 1991;29:524-28. 63. Tazelaar HD, Myers JL, Strickler JG, et al. Tryptophaninduced lung disease: An immunophenotypic, immunoflu-
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orescent, and electron microscopic study. Mod Path01 1993;6:56-60. 64. Culpepper RC, Williams RG, Mease PJ, et al. Natural history of the eosinophilia-myalgia syndrome. Ann Intern Med 1991;115:437-42. 65. Hedberg K, Urbach D, Slutsker L, et al. Eosinophiliamyalgia syndrome. Natural history in a population-based cohort. Arch Intern Med 1992;152:1889-92. 66. Hertzman P, Clauw D, Kaufman L, et al. 18 -24 month structured follow-up of 210 patients with eosinophiliamyalgia syndrome (EMS) in 12 states. Arthritis Rheum 1993;36(suppl):R26.
M. SILVER,
MD
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seemingly new illness was first described in the United States in late 1989, when physicians in New Mexico reported the occurrence #of generalized myalgia and eosinophilia in three women, each of whom had a prior history of ingesting the amino acid, L-tryptophan.’ The illness, which has been linked to the ingestion of L-tryptophan containing trace amounts of chemical contaminants reached epidemic proportions in late 1989, and it quickly subsided when L-tryptophan - containing products were recalled. This illness, now known as the eosinophilia -myalgia syndrome (EMS), was frequently complicated by the occurrence of sclerodermalike hardening of the skin and subcutaneous tissues and, thus, may be added to a growing list of environmental or toxin exposures implicated in the pathogenesis of sclerodermatous disorders. EMS shares many features with diffuse fasciitis with eosinophilia (DFE or Shulman’s disease),2 as well as with the toxic oil syndrome (TOS), another sclerodermalike disease which occurred as an epidemic in 1981, affecting nearly 20,000 individuals in Spain.3 The study of EMS and related conditions is important, not only for the sake of public health, but also for the insight which may be gained for better understanding of systemic sclerosis (SSc) and other fibrosing cutaneous processes.
L-Tryptophan Metabolism in Health and Disease L-tryptophan is the scarcest of the essential amino acids. During the 198Os, L-tryptophan was widely advocated and used for a number of conditions such as depression, From the Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina. Address correspondence to Richard M. Silver, MD, Professor of Medicine and Pediatrics, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425-2229.
0 1994 by Elsevier Science Inc.
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insomnia, obesity, and premenstrual syndrome. The use of L-tryptophan for these conditions was based on its metabolic role as a precursor for the synthesis of the neurotransmitter serotonin (5-hydroxytryptamine) (Figure 1). In addition to its role in the synthesis of serotonin, L-tryptophan is also metabolized by kynurenine to nicotinamide dinucleotide (NAD) and nicotinic acid, or niacin (see Figure 1). In fact, the vast majority of ingested L-tryptophan is metabolized via the kynurenine pathway, and only a fraction is metabolized to serotonin. The ratelimiting enzyme in the metabolism of L-tryptophan under normal circumstances is the hepatic enzyme tryptophan dioxygenase (TDO). The metabolism of L-tryptophan is altered during certain inflammatory conditions, including EMS, in which the extrahepatic enzyme indoleamine 2,3dioxygenase (IDO) is induced, becoming the rate-limiting enzyme in the metabolism of L-tryptophan.4 L-tryptophan metabolism is shunted along this pathway, and large amounts of kynurenine and its breakdown products may be formed in extrahepatic sites such as the lungs and the central nervous system. Interferon-y is the most potent inducer of ID0,4 and interleukin-2 and tumor necrosis factor-a! may also upregulate ID0 .5,6Glucocorticoids act to downregulate the expression of IDO while upregulating TDO. Altered L-tryptophan metabolism was described in a number of inflammatory and rheumatic conditions, including SSc, long before the discovery of ID0.7 Of interest was the observation in 1981, by Sternberg et al., of altered metabolism of L-tryptophan in a patient with a sclerodermalike illness associated with the ingestion of 5-hydroxy-L-tryptophan .* Although this patient’s elevated level of kynurenine was initially attributed to a possible inborn error of metabolism, subsequent studies suggest that it was due to the induction of IDO, with shunting of L-tryptophan via the kynurenine pathway. Similarly, Jablonska and her colleagues described elevated kynurenine levels in patients with SSc and in pa-
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Epidemiology of EMS Federal and state health agencies in the United States acted swiftly to detine the syndrome and investigate its etiology.14 The Centers for Disease Control (CDC) established the following case definition for surveillance purposes: (1) eosinophil count > 1 X 109/L; (2) generalized myalgia of sufficient severity to limit activity; and (3) exclusion of neoplasm or infection to account for the syndrome.15 As of August 1, 1992, the CDC reported 1,511
cases of EMS and 38 deaths from neurologic, cardiac, and pulmonary complications. Cases have also been reported from Europe and Japan. In view of the passive surveillance system in the United States and the rigid case definition, it is estimated that only one-half of those patients meeting the surveillance case definition have been reported and that there may be another 3,000 individuals who consumed L-tryptophan and are now exhibiting symptoms consistent with EMS but do not meet the full surveillance criteria. Higher prevalence rates were reported from states where more active surveillance was conducted, including Minnesota,16 Oregon,l’ New Mexico,ls and South Carolina.19 Thus, the true prevalence of EMS is not known but is likely to be greater than CDC reports suggest. A number of case-control studies showed a very strong association of EMS with the ingestion of L-tryptophan,16-lS leading to its recall from the retail market by the Food and Drug Administration. A study from Minnesota found that 29 of 30 (97%) EMS patients and 21 of 35 controls (60%) had consumed L-tryptophan manufactured by a single manufacturer (odds ratio, 19.3, 95% confidence interval, 2.5 to 844.9, p < 0.001).16 A traceback study in Oregon yielded similar results, with 98% of EMS cases having consumed L-tryptophan from a single manufacturer; retail lots of L-tryptophan produced by this manufacturer between January and June 1989 were implicated in the syndrome.” Study of a cohort of 418 L-tryptophan users from a single psychiatry practice showed that the risk of developing EMS was related to increasing dose of L-tryptophan, as well as increased age of the user.19 These and other studies suggested that con-
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C tamination during the manufacture of L-tryptophan was related to, if not responsible for, the epidemic and that the attack rate might have been influenced by cofactors such as age. The manufacturing process employed by the implicated company involved a bacterial fermentation process with subsequent filtration and purification. Late in 1988, a genetically modified strain (V) of Bacillus amyloliquefuciens that yielded increased amounts of L-tryptophan was introduced. At about the same time, the filtration process was modified to reduce the amount of activated carbon and to bypass a reverse osmosis membrane filter. In a case-control study, significant associations between lots used by case patients and changes in the manufacturing process were confirmed (p < 0.05).16 High-performance liquid chromatography of the company’s L-tryptophan demonstrated several peaks, one (peak E) strongly associated with the syndrome.16 The structure of peak E was soon defined and continned to be l,l’-ethylidenebis(L-tryptophan) (EBT).20 A
recent case-control study of over 500 patients attending a single medical clinic, where they purchased L-tryptophan between July and December 1989, revealed an attack rate of 2.2% and a significant association between EMS and ingestion of L-tryptophan containing a high concentration of EBT (70 pg/g).21 UV-5, a second trace contaminant of L-tryptophan, was subsequently identified as 3-(phenylamino)alanine (PAA), and it, too, has been linked epidemiologically to the EMS epidemic.22 Four other trace contaminants present in implicated batches of L-tryptophan have been associated with the EMS epidemic (peak AAA, peak C, peak FF, and peak 200). These elegant epidemiologic studies showing an association between several trace contaminants and the EMS epidemic cannot address the issue of causation. The latter can only be addressed by animal studies in which purified chemical constituents of implicated batches of L-tryptophan are administered, alone or in combination, to animals presumed to be susceptible to inflammation and fibrosis in a fashion analogous to that of man. Several
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such studies have been reported and others are now underway. Implicated L-tryptophan and synthesized EBT have been shown to induce fibrosis, with or without inflammation, in the fascia and perimysium of female Lewis rats.23,24The Lewis rat is susceptible to a number of inflammatory diseases, presumably related to impairment of the hypothalamic-pituitary-adrenal axis; no such impairment has been demonstrated in patients with EMS. Recently, a second model has been proposed employing C57/BL6 mice. 25In this model, daily intraperitoneal administration of EBT yields significant inflammation and fibrosis of the dermis, fascia, and perimysium consistent with changes observed in subjects with EMS. Mast cells, also seen in EMS lesions, have been observed in each of these proposed models. In neither model has tissue or blood eosinophilia been observed. These and perhaps other models require further study to elucidate the etiology and the pathogenesis of EMS. Such studies may provide information relevant to other conditions, such as TOS, DFE, and SSc.
Clinical Features of EMS EMS is a multisystem disease that in its acute phase often had a flulike onset with fever, rash, arthralgia, and dyspnea, as well as the characteristic myalgia and eosinophilia. Nearly one-third of all patients required hospitalization. The majority of patients were Caucasian females, a reflection of the ingestion patterns of L-tryptophan rather than race or gender susceptibility. The median daily dose of L-tryptophan ingested was 1.5 g. Myalgia was nearly universal and often was diffuse and debilitating. 26*27Serum levels of creatine kinase were usually normal, but aldolase was elevated in many untreated patients. 26 Electromyography was sometimes abnormal but nonspecific. Severe muscle cramps occurred, and for many patients this has been a persistent and debilitating feature of the chronic phase of EMS. The pathogenesis of the myalgia and cramps is not known. Ischemia and neuropathic changes may underlie their pathogenesis, but myonecrosis was not seen on muscle biopsy. An acquired metabolic abnormality is also possible, given the recent observation of abnormal P-31 magnetic resonance spectroscopy of skeletal muscle.28 Eosinophilia is one of the criteria for the case definition of EMS and was present in most but probably not all patients. Overall, the median percentage of eosinophils was 39% and the median eosinophil count was over 5 X 109/L.29 Serum and urine levels of two eosinophil granule products, major basic protein and eosinophil-derived neurotoxin, were elevated in some patients, signifying
Clinics in Dermatology 2994;22:457-465 eosinophil activation, and degranulation.30 Similarly, tissue levels of eosinophil granule proteins also appeared to have been accentuated.30 Interleukin-5, a cytokine that stimulates eosinophil production and enhances eosinophi1 survival, was detectable in the serum of some EMS patients and may have played a role in the eosinophilia and activation seen in EMS.31 Eosinophilia resolved promptly after the administration of glucocorticoids. Skin rash or induration was present in the majority of patients with EMS. 11,26,27Erythematous macules, sometimes pruritic, were often present on the trunk and the extremities during the acute phase. Papular eruptions (papular mucinosis) occurred in some patients.32 Subcutaneous edema, sometimes massive, occurred acutely in many patients, affecting the upper and lower extremities and sometimes producing nerve entrapment such as carpal tunnel syndrome. Edema often evolved to a tense, woody induration with a peau &orange quality similar to that seen in patients with DFE. Unlike SSc, the face and the acral portions of the body were usually spared by the indurative process. Also, EMS patients generally did not have Raynaud’s phenomenon, nor did they have abnormal nailfold capillaries. l* Alopecia affecting the scalp and the body was sometimes present in the early phase of EMS, apparently the result of telogen effluvium with complete resolution.33 Peripheral neuropathy occurred in many EMS patients.27,34-37 Diffuse and localized paresthesia or hyperesthesia were frequent. An ascending polyneuropathy occurred rarely. Many of the known deaths from EMS were related to complications secondary to severe neuropathy, such as respiratory failure or pneumonia. Central nervous system involvement has also been described.38-31 Acute encephalopathy has been reported in a few patients. Magnetic resonance imaging has revealed multiple white-matter lesions in a number of such cases, and one autopsy showed a perivascular lymphocytic infiltrate and a lymphocytic meningitis.41 In several cases central nervous system signs and symptoms appeared long after the eosinophilia had resolved. A major concern of patients and physicians is the possible occurrence of neurocognitive dysfunction. AIthough a thorough, controlled study has yet to be performed, a number of investigators have reported the presence of neurocognitive dysfunction such as memory impairment, difficulty concentrating, difficulty remembering words or names of persons, and so on, in as many as 60% of EMS patients. 42,43Neither the actual prevalence nor the pathogenesis of this aspect of EMS is known at this time. Potential neurotoxic mediators in EMS include eosinophil- derived neurotoxin and the kynurenine metabolite quinolinic acid. Significant elevations of quino-
Clinics in Dermatology 1994;12:457-465 linic acid were detected not only in the plasma,l’ but also in the cerebrospinal fluid of EMS patients.13,35 Elevated levels of quinolinic acid in cerebrospinal fluid have been reported in other inflammatory conditions, including AIDS-related dementia where the levels correlate with the degree of neurocognitive dysfunction.44 Many EMS patients had dyspnea and cough during the early phase of the illness,45-47 but respiratory complaints were less frequent and severe than in TOS, where noncardiogenic pulmonary edema was severe and sometimes fatal. Nevertheless, one carefully conducted study found a high incidence of pulmonary symptoms in EMS patients.48 The study found frequent abnormalities in diffusing capacity and maximal static respiratory pressures, suggesting the presence of parenchymal lung involvement and respiratory muscle weakness.48 Linear opacities, with or without pleural effusions, were frequently seen on chest radiographs and usually resolved with corticosteroid therapy. Interstitial pneumonitis with eosinophilia and perivascular inflammation was evident on lung biopsy. Bronchoalveolar lavage (BAL) fluid contained eosinophils and fibroblast proliferation stimulating activity. 49 In some patients, pulmonary vascular disease was present and sometimes fatal. Unlike in TOS, few cases of late-onset pulmonary hypertension have been reported during the first 4 years of follow-up of EMS patients. Cardiac involvement has been reported and was implicated in the death of some EMS patients, but overall cardiac disease has not been a major feature of the illness. Pathologic lesions in the coronary arteries, neural structures and conducting system in three patients provided a basis for significant cardiac electrical instability and sudden death.50 Similar lesions were observed in cardiac tissue of patients with TOS5* Repeated episodes of coronary artery spasm were observed in one patient with EMS whose endomyocardial biopsy showed focal deposits of eosinophil major basic protein.52 This patient responded to intravenous magnesium infusion (I’. Hertzman, personal communication), suggesting a depletion of magnesium as the cause of the coronary vasospasm, similar to what has been observed in subjects with idiopathic variant angina pectoris. 53 Magnesium deficiency might also underlie the myalgia and cramps that complicate chronic EMS; in fact, preliminary studies suggest that magnesium repletion ameliorates some of these symptoms (D. Clauw, personal communication). Gastrointestinal involvement in EMS has been reported but was apparently uncommon. Malabsorption with steatorrhea, hypoalbuminemia, and weight loss was described, with eosinophilic infiltration of the stomach, small bowel, and colon.54
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Figure 3. Skin biopsy specimenfrom EMS patient (hematoxylin and eosin, X40). The epidermis (top) is normal, whereas the dermis shows a mononuclear cell infiltrate and extensive collagen deposition.
Histopathology of EMS Full-thickness biopsies of skin lesions show an inflammatory and fibrosing process affecting the dermis and subcutaneous tissue including the fascia and extending to the perimysium (Figures 3 and 4). A perivascular mononuclear cell infiltrate is seen, with or without eosinophils. Endothelial cells appear swollen, but true vasculitis is rare. Similar lesions were seen in patients with TOS, although results of full-thickness biopsies were seldom reported. Inflammation and fibrosis affecting the subcutaneous fat, septa, and fascia are also seen in the lesion of DFE, but cutaneous changes appear to be more prominent in EMS.55~56One problem encountered in comparing EMS to DFE is the fact that many reported cases of DFE during the late 1980s were shown retrospectively to represent patients who ingested L-tryptophan. In one study, nearly 65% of patients initially diagnosed between 1986 and 1990 as having DFE actually had a history of L-tryptophan ingestion prior to the onset of their illness.57 Mast cells and Factor XIIIa -positive (dermal dendritic) cells are present in the infiltrates of EMS and DFES5 as well in the dermal lesions of TOS and SSc. Papular mucinosis is another dermatologic feature common to these conditions. In general, such histopathologic features occur as a pancutaneous - subcutaneous process in EMS, whereas they tend to involve the subcutis alone in DFE. Inflammation of cutaneous nerves may also distinguish EMS from DFE.56 Reactive mesenchymal cells sharing features of histiocytes and fibroblasts are present in the deep fascia.58 Ex-
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and fibrosis have been described, accompanied by vasculopathy and angioneogenesis.34 Type II muscle fiber atrophy occurred, perhaps secondary to disuse or glucocorticoid therapy; myonecrosis was rare.
Treatment and Course of EMS
Figure 4. Fascia and musclefrom EMS patient (hemafoxylin and eosin, X50). The fascia (top) is thickened and contains an inflammatory cell infiltrate composed of lymphocytes, macrophages,and plasma cells. The injlammafory cell infiltrate extends to the perimysium of the underlying skeletal muscle. pression of mRNA for types I and VI collagen, as well as transforming growth factor-p, (TFG-P), is increased in affected fascia1,59*60supporting a role for cytokine-driven fibrosis. In addition to the increased expression of TGF-P is evidence of increased production of other cytokines, including interferon-y, l2 IL-4,61 and IL-5.31 The nature of the dermal lymphocytic infiltrate has not been well characterized. Fascial and muscle specimens contain predom(most are CDS-I-) and macroinantly T-lymphocytes phages; B-lymphocytes and eosinophils are present but make up only a fraction of the cellular infiltrate.63 BAL fluid analysis has also revealed an increased proportion of CDS+ lymphocytes, and lung biopsies have shown a predominance of CDS-I- lymphocytes in the interstitial and perivascular infiltrate.63 Peripheral nervous system lesions have been characterized by axonal degeneration or, less commonly, by demyelination. In some cases, epineural inflammation
Optimal treatment of EMS, as well as its natural history, remain to be determined. As was the case in TOS, EMS has become a chronic disease for many patients. In one population-based cohort the course during the initial 4 to 6 months was severe, followed by a decrease in myalgia, pulmonary complications, skin rash, and edema.64 Another study confirmed that despite the early improvement, many patients remained symptomatic 12 months after onset of disease. 65 Myalgia and fatigue persisted in the majority of cases, and only 26% reported that they were able to perform all normal daily activities. An 18 to 24-month follow-up of 210 EMS patients revealed that fever, edema, weight loss, fatigue, and rash were improved or resolved in more than 75% of patients; other symptoms except cognitive complaints improved to a lesser extent.66 Cognitive difficulties appear to have developed later in the course of the disease, and significant improvement in such symptoms has not been observed. Further analysis of neurocognitive function and followup of this cohort is planned. Treatment has generally been empiric and uncontrolled. Eosinophilia, edema, and pneumonitis usually resolved promptly after the initiation of glucocorticoid therapy, but disease duration does not appear to have been affected, and symptoms often returned after withdrawal of glucocorticoids. A variety of other agents including nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, cyclosporin A, methotrexate, plasmapheresis, d-penicillamine, antimalarials, and octreotide have been employed, but none has shown consistent beneficial effects. Except for anecdotal reports, no therapy has been shown conclusively to be effective in the treatment of EMS. The same can be said for therapy of DFE and TOS.
Conclusions EMS is a multisystem disease whose cutaneous manifestations resemble certain other sclerodennalike conditions, such as TOS and DFE. Its association with the ingestion of L-tryptophan containing trace chemical contaminants adds to a growing list of environmental and toxin exposures capable of producing sclerodermalike illnesses. Elucidation of the precise toxin(s) in implicated
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batches of L-tryptophan, host factors conferring susceptibility, and the cellular and molecular basis of pathogenesis should lead to better understanding and treatment of this and related conditions. Heightened awareness of toxic epidemics such as EMS may also lead to regulatory changes designed to ensure greater safety of drugs and food supplements.
References 1. Hertzman PA, Blevins WL, Mayer J, et al. Association of the eosinophilia-myalgia syndrome with the ingestion of L-tryptophan. N Engl J Med 1990;332:869 - 73. A new syn2. Shulman LE. Diffuse fasciitis with eosinophilia: drome? Trans Assoc Am Phys 1975;88:70-86. 3. Toxic Epidemic Syndrome Study Group. Toxic epidemic syndrome, Spain, 1981. Lancet 1982;ii~697-702. 4. Ozaki Y, Edelstein Ml’, Duch DS. The actions of interferon and antiinflammatory agents on induction of indoleamine 2,3dioxygenase in human peripheral blood monocytes. Biochem Biophys Res Commun 1987;144:1147-53. 5. Brown RR, Lee CM, Kohler PC, et al. Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2. Cancer Res 1989;49:4941-44 6. Schiller JH, Witt PL, Storer B, et al. Clinical and biologic effects of combination therapy with gamma-interferon and tumor necrosis factor. Cancer 1992;69:562-71. 7. Houpt JB, Ogryzlo MA, Hunt M. Tryptophan metabolism in man (with special reference to rheumatoid arthritis and scleroderma). Sem Arthritis Rheum 1973;2:333-53. 8. Sternberg EM, van Woert MH, Young SN, et al. Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa. N Engl J Med 1980;303:782 - 87. 9. Stachow A, Jablonska A, Skiendzielewska A. Biogenic amines derived from tryptophan in systemic and cutaneous scleroderma. Acta Derma Venereol (Stockholm) 1979;59: 1-5. 10. Stachow A, Jablonska lism in scleroderma and Myers AR, eds. Current sclerosis (scleroderma). 130-34.
S, Kencka D. Tryptophan metaboeosinophilic fasciitis. In: Black CM, Topics in Rheumatology: Systemic New York: Gower Medical, 1985;
11. Silver RM, Heyes MI’, Maize JC, et al. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 1990;322:874-81. 12. Silver RM, Sutherland SE, Carreira I’, et al. Alterations in tryptophan metabolism in the toxic oil syndrome and in the eosinophilia-myalgia syndrome. J Rheumatol 1992;19: 69-73. 13. Silver RM, McKinley K, Smith EA, et al. Tryptophan metabolism via the kynurenine pathway in patients with the
eosinophilia-myalgia 1097-105.
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