Lori A. Love

A new approach to the classification of idiopathic inflammatory myopathy : myositis-specific autoantibodies define useful homogeneous patient groups

The IIM are a heterogeneous group of systemic rheumatic diseases which share the common features of chronic muscle weakness and mononuclear cell infiltrates in muscle. A number of classification schemes have been proposed for them, but none takes into consideration the marked immunologic, clinical, and genetic heterogeneity of the various clinical groups. We compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-SRP, anti-Mi-2 and anti-MAS) to the standard clinical categories (polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms, HLA types, and prognosis in 212 adult IIM patients. Although patients with inclusion body myositis (n = 26) differed in having significantly more asymmetric and distal weakness, falling, and atrophy than other patients, there were few other significant differences among the other clinical groups. In contrast, autoantibody status defined distinct sets of patients and each patient had only 1 myositis-specific autoantibody. Patients with anti-amino-acyl-tRNA synthetase autoantibodies (n = 47), compared to those without these antibodies, had significantly more frequent arthritis, fever, interstitial lung disease, and mechanics hands; HLA-DRw52; higher mean prednisone dose at survey, higher proportion of patients receiving cytotoxic drugs, and higher death rates. Those with anti-signal recognition particle antibodies (n = 7) had increased palpitations; myalgias; DR5, DRw52; severe, refractory disease; and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased V-sign and shawl-sign rashes, and cuticular overgrowth; DR7 and DRw53; and a good response to therapy. The 2 patients with anti-MAS antibodies were the only ones with alcoholic rhabdomyolysis preceding myositis; both had insulin-dependent diabetes mellitus, and both had HLA-B60, -C3, -DR4, and -DRw53. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis, and that specific associations of immunogenetics, immune responses, and clinical manifestations occur in IIM. Thus the myositis-specific autoantibodies aid in interpreting the diverse symptoms and signs of myositis patients and in predicting their clinical course and prognosis. We propose, therefore, that an adjunct classification of the IIM, based on the myositis-specific autoantibody status, be incorporated into future studies of their epidemiology, etiology, and therapy.

Current Concepts in the Idiopathic Inflammatory Myopathies: Polymyositis, Dermatomyositis, and Related Disorders

Idiopathic inflammatory myopathy, a category encompassing polymyositis, dermatomyositis, and a number of other disorders, is very uncommon, but has been the focus of intense study in the Arthritis and Rheumatism Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases for the past several years. We describe the clinical picture, stressing the need for biopsy to ensure correct diagnosis. It is especially important to recognize the treatment-resistant variant, inclusion body myositis. The extraskeletal manifestations, particularly the cardiopulmonary, oropharyngeal, gastrointestinal, and endocrine involvement, are described. The cardiopulmonary involvement, especially interstitial lung disease, arrhythmias, and cardiac failure, may dominate the clinical picture. The known causes are varied, and include drugs, toxins, and some infectious agents, however, in most cases a cause cannot yet be identified. Circumstantial evidence suggests that picornaviruses may initiate some cases in humans, and a very similar disease in mice caused by a picornavirus is actively under study. Studies of autoantibodies and cellular immune function support a central role for disordered immunity in the pathogenesis. The myositis-specific autoantibodies, especially those directed at certain enzymes important in protein synthesis (the aminoacyl-transfer RNA synthetases), are found in a clinically distinct subset of patients. Although most patients respond initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness develops. We describe several newer therapies under study for such cases and outline future directions in research.

Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy

PURPOSEnTo identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs.nnnPATIENTS AND METHODSnData were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria.nnnRESULTSnClinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patients response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone.nnnCONCLUSIONnDetermining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.

Severe Hepatotoxicity Associated with the Dietary Supplement LipoKinetix

Context Dietary supplements, unlike drugs, are not tightly controlled by the U.S. Food and Drug Administration (FDA) before marketing. Contribution LipoKinetix, a dietary supplement sold as an aid to promote weight loss, was associated with severe hepatotoxicity in seven previously healthy patients. None had evidence of viral infection or autoimmune disease or had ingested other hepatotoxic drugs. All patients recovered spontaneously after discontinuing use of LipoKinetix. Implications Although the FDA has issued warning letters to the manufacturer, physicians, and the public regarding LipoKinetix, federal oversight of dietary supplements remains problematic. Physicians should inquire about the use of dietary supplements when patients present with evidence of hepatotoxicity. The Editors Unlike licensed drugs, dietary supplements are not subject to review by the U.S. Food and Drug Administration (FDA) before marketing. Issues pertaining to the use of certain herbal products range from contamination with heavy metals (including lead, arsenic, and mercury) (1-3) to substitution of a product ingredient or misidentification of raw herbs that can result in toxicity (4). Hepatotoxicity has been associated with various herbal products (5, 6). LipoKinetix (Syntrax, Cape Girardeau, Missouri) capsules are sold as a dietary supplement for weight loss. In the United States,

Viruses in idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle

33 billion is spent yearly on weight-loss products and services (7), despite the absence of scientific evidence in humans to support such use (8). According to the manufacturer, the purported mechanism of action of LipoKinetix is modifying a process in the body called oxidative phosphorylation that thereby mimics exercise. LipoKinetix contains the following ingredients: norephedrine hydrochloride (25 mg), sodium usniate (100 mg), 3,5-diiodothyronine (100 g), yohimbine hydrochloride (3 mg), and caffeine (100 mg). We describe seven patients who between July and December 2000 developed acute hepatitis, including one patient who developed fulminant hepatic failure complicated by cerebral edema, after ingesting LipoKinetix. Case Series Five patients (four women and one man) were treated at Cedars-Sinai Medical Center, Los Angeles, California, and two patients (both men) were identified through the FDA MedWatch program. All seven patients had taken LipoKinetix according to the manufacturers recommendations, and none were taking prescription or over-the-counter medications (including acetaminophen). No patient had a medical history, and none were obese. Results of serologic testing for hepatitis A, B, and C were negative in all patients. Results of autoimmune serologic testing (for antinuclear antibodies and antismooth-muscle antibodies) and results of testing for cytomegalovirus and EpsteinBarr virus were also negative in five patients who were tested. The five patients from Cedars-Sinai Medical Center were Japanese nationals residing in the Los Angeles area. They had purchased different lot numbers of the product at the same health food store. Symptoms appeared within 4 weeks after initial ingestion of LipoKinetix. The other two patients, identified from the MedWatch program, were white bodybuilders who were acquaintances and had purchased the product through the Internet. They sought medical attention at 9 and 12 weeks, respectively, after first taking LipoKinetix. It is unclear whether the lot numbers of the product used by these two patients differed. The clinical summary is presented in Table 1. Three of the seven patients, including the patient who developed fulminant hepatic failure, were taking only LipoKinetix at the time symptoms occurred (Table 2). Two of the four patients taking multiple supplements subsequently resumed taking supplements other than LipoKinetix without incident. Table 1. Patient Characteristics Table 2. Supplements: Use and Duration Case Report A previously healthy, 20-year-old female Japanese exchange student began taking LipoKinetix for weight loss 2 weeks before presenting with a low-grade fever, malaise, and worsening epigastric pain. She had jaundice, was alert and oriented, and did not have hepatosplenomegaly. Laboratory studies revealed an aspartate aminotransferase level of 49.64 kat/L (2978 U/L), alanine aminotransferase level of 47 850 nkat/L (2871 U/L), total bilirubin level of 222 mol/L (13.0 mg/dL), and international normalized ratio of 2.8. Aminotransferase levels continued to increase and peaked 5 days after the patient discontinued taking LipoKinetix. The patient became increasingly coagulopathic and developed stage 2 hepatic encephalopathy. She was evaluated for liver transplantation. With the subsequent development of stage 3 encephalopathy, the patient was intubated. Intracranial pressure was 35 mm Hg, and mannitol was administered. The intracranial pressure decreased with supportive care, and liver function test results improved over the next 6 days. On discharge, she had no neurologic sequelae and the international normalized ratio was normal. Aminotransferase levels returned to normal within 12 weeks. Analysis Three different lot numbers of LipoKinetix capsules were obtained from three patients treated at Cedars-Sinai Medical Center. The FDA analyzed these samples at Pacific Regional Laboratory SW (Los Angeles, California) using liquid chromatographyelectrospray mass spectrometry and Fourier transform infrared spectroscopy. Analyses confirmed that the product samples contained norephedrine, yohimbine, 3,5-diiodothyronine, sodium usniate (analyzed as usnic acid), and caffeine, as listed on the product label. No contaminants (including heavy metals) were detected. Discussion Unlike with licensed drugs, the safety of herbal products has relied on their traditional use and formulations for appropriate dosage, administration, and avoidance of harmful interactions. The dietary supplement market is a multibillion-dollar industry; use of herbal products has increased an estimated 380% from 1990 to 1997 (9). Competition has driven dietary supplement manufacturers to seek obscure ingredients and to use them in nontraditional ways and combinations. We report on seven healthy people who were not taking any prescription drugs and developed severe hepatotoxicity while taking LipoKinetix. All patients had used the manufacturers recommended dosages. Five patients had taken the supplement for 1 month or less, and two patients had used the product for 2 to 3 months. All presented with symptoms characteristic of acute hepatitis, including fatigue and abdominal pain. In addition, results of biochemical testing were consistent with acute hepatitis. The peak aminotransferase levels and pattern of liver test results were compatible with drug-induced acute hepatocellular necrosis. There was no evidence of allergy, such as rash or eosinophilia. Three patients developed significant jaundice, and one developed fulminant hepatic failure. All recovered spontaneously after discontinuing use of LipoKinetix, and results of liver tests as well as symptoms normalized within 4 months in five patients (two patients declined to have further testing). No other hepatotoxic agent or other cause for hepatotoxicity could be identified. Of the four patients taking multiple supplements, only one had taken multiple Chinese herbal formulations; however, none of the ingredients were associated with hepatotoxicity according to the Chinese Materia Medica, the standard reference for Chinese herbs (10). LipoKinetix-induced hepatotoxicity appears to be idiosyncratic (5, 11, 12). No published reports have described hepatotoxicity associated with any of the other individual substances contained in LipoKinetix. Ephedra alkaloids have been associated with multiple adverse cardiovascular and central nervous system events (13). Only a single reported case of acute hepatitis has been associated with Ephedra; however, that patient had taken numerous other products (14). The FDA notes relatively few cases of hepatitis or elevated aminotransferase levels associated with dietary supplements containing ephedrine alkaloids (approximately 25 of 1400 cases). These adverse event reports are often complex, with patients concurrently using many other products (dietary supplements and drugs), some of which have known hepatotoxic effects. Although a direct hepatotoxic effect has not been reported for ephedrine or norephedrine (also a metabolite of ephedrine), phenylpropanolamine (racemic norephedrine) has been reported to potentiate the hepatotoxicity of carbon tetrachloride and acetaminophen in mice (6, 15). Sodium usniate, the salt form of usnic acid, is a secondary metabolite found in several genera of lichens, including Usnea, Letharia, and Parmelia. Toxic reactions, including ataxia leading to paralysis and death, have been reported in animals ingesting lichens containing usnic acid; data in humans, however, are limited. Usnic acid uncouples oxidative phosphorylation in murine liver mitochondria, resulting in inhibition of adenosine triphosphate synthesis and enhancement of Mg 2+-adenosine triphosphate activity, which may contribute to hepatic toxicity (16). None of the seven patients, however, exhibited lactic acidosis, a typical feature of drug-induced liver injury due to mitochondrial dysfunction. Yohimbine is an indole alkaloid from the bark of the African Pausinystalia yohimbe tree and is also found in Rauwolfia root (17). The FDA has not evaluated yohimbine for safety or efficacy for any indication. It is widely touted as a remedy for male impotence, but the mode of action is by selective blockade of the presynaptic 2-receptor (17). Yohimbine penetrates the central nervous system and can stimulate mood and motor activity (17). Nausea, vomiting, abdominal pain, dizziness, and headache have been reported when yohimbine is used at therapeutic doses (17). Unintentional thyrotoxicosis factitia, a condition related to ingestion of exogenous thyroid hormone from adulterat

Clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy

There is indirect evidence that various viruses have aetiological roles in the idiopathic inflammatory myopathies. By means of a sensitive and specific method based on the polymerase chain reaction (PCR), we sought direct evidence for the presence in affected muscle of nucleic acid sequences from Coxsackie virus, mumps virus, encephalomyocarditis virus, adenovirus, human T-lymphotropic virus types I and II, and human immunodeficiency virus. RNA was extracted from muscle biopsy samples obtained from 44 patients with idiopathic inflammatory myopathies a mean of 45 (range 0-216) months after disease onset. All the subjects were older than 16 years at disease onset. The integrity of the mRNA extracted was confirmed by the successful PCR amplification of insulin receptor mRNA in all samples. The PCR method was able to detect between 1 and 20 molecules of added viral nucleic acid for the picornaviruses sought. No detectable virus sequences were found, however, in any of the patients muscle samples or in samples from 13 controls. We tested for retroviral DNA in 22 samples (17 patients, 5 controls) that met our criterion for adequate DNA extraction (detectable beta-actin DNA by PCR); again no virus sequences were found. Persistence in muscle of these or closely related viruses is unlikely to be a continuing stimulus for disease in the idiopathic inflammatory myopathies.

Lymphocyte activation markers in idiopathic myositis: changes with disease activity and differences among clinical and autoantibody subgroups

OBJECTIVEnTo describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM.nnnMETHODSnClinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis.nnnRESULTSnThe clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002).nnnCONCLUSIONnThese findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM.

Noninfectious environmental agents associated with myopathies.

We studied the immunologic correlates of disease activity and differences among subgroups of patients with idiopathic inflammatory myopathy by analysing phenotypic and activation marker expression on peripheral blood mononuclear cells (PBMC). Compared with controls, myositis patients with clinically active disease (n = 51) had significantly lower proportions of CD8‐ cells and higher proportions of PBMC that expressed DR. CD3‐ DR, CD14‐ DR, interlcukin‐2 receptors. and the late T cell activation markers CD26 and TLiSA1. TLiSA1 expression, a marker for cytotoxic differentiation, correlated significantly with both clinical activity indices and serum levels of muscle‐associated enzymes. In serial studies of seven patients, the proportion of PBMC expressing MHC class II antigen and late T cell activation markers decreased as myositis disease activity decreased, independent of type of therapy. Among the clinical subgroups, polymyositis (n= 21) and inclusion body myositis (n=21) were virtually indistinguishable; dcrmatomyositis patients (n= 19) showed decreased proportions of CD3+DR+ and TLiSA1+ cells, and increased proportions of CD20+ and CD20+ DR+ cells compared with the other two groups. Patients with autoantibodies to histidyl‐tRNA synthctasc (Jo‐1 antigen. n= 11) had significantly lower proportions of CD3+ andCD4+ cells, lower CD4/CD8 ratios, and higher proportions of DR+ cells expressing CD20, compared with patients without anti‐Jo‐1 antibodies. These findings support the concept that activated lymphocytes, especially cells undergoing anamnestic responses and cytotoxic differentiation, are important in the pathogenesis of idiopathic myositis. Moreover, taken together with other studies, these data suggest that groups of patients segregated by clinical or autoantibody status have different mechanisms of systemic immune activation and immunopathology.

Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms.

Increasing attention is being focused on environmental agents as possible factors in the etiology of certain connective tissue disorders. As our awareness in this area increases, the number and diversity of these agents is expanding yearly and now includes, in addition to infectious agents, a variety of foods and dietary supplements, drugs, occupational and other toxic exposures, biologics, and medical devices. Some of these agents have been associated with the development of muscle disease through mechanisms that involve alterations in the vascular supply to muscle, depletion of electrolytes, direct toxic effects on mitochondria or other metabolic processes, or activation of the immune system. Individual host susceptibility factors, including preexisting organ dysfunction and particular metabolizer or immunogenetic phenotypes, also appear to be important for development of the clinical syndromes identified as environmentally associated myopathies. Although data in this area are limited, they suggest that when susceptible individuals are exposed to selected agents, physiologic alterations occur that lead to myopathy. Physician awareness of chemicals implicated with myopathy and dissection of their pathogenetic mechanisms through human and animal studies may aid in the identification of additional toxic agents, minimize new cases in the future, and lead to a better understanding of the idiopathic myopathies.

Pathologic changes in the cardiac interstitium of mice infected with encephalomyocarditis virus

OBJECTIVEnTo 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.nnnMETHODSnHLA-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).nnnRESULTSnConsidering 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.nnnCONCLUSIONnIn 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.