Effect of omalizumab on symptoms of seasonal allergic rhinitis: a randomized controlled trial.

CONTEXT: Seasonal allergic rhinitis is a common IgE-mediated disorder that produces troublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody (omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. OBJECTIVE: To assess the efficacy and safety of omalizumab for prophylaxis of symptoms in patients with seasonal allergic rhinitis. DESIGN: Randomized, double-blind, dose-ranging, placebo-controlled trial conducted from July 25 through November 21, 1997. SETTING: Twenty-five outpatient centers throughout the United States. PATIENTS: Five hundred thirty-six patients aged 12 to 75 years with at least a 2-year history of moderate to severe ragweed-induced seasonal allergic rhinitis and a baseline IgE level between 30 and 700 IU/mL. INTERVENTIONS: Patients were randomly assigned to receive omalizumab, 50 mg (n = 137), 150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneously just prior to ragweed season and repeated during the pollen season every 3 weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments) and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL (3 total treatments). MAIN OUTCOME MEASURES: Self-assessed daily nasal symptom severity scores (range, 0-3), rescue antihistamine use, and rhinitis-specific quality of life during the 12 weeks from the start of treatment. RESULTS: Nasal symptom severity scores were significantly lower in patients who received 300 mg of omalizumab than in those who received placebo (least squares means, 0.75 vs 0.98, respectively; P =.002). A significant association was observed between IgE reduction and nasal symptoms and rescue antihistamine use. Rhinitis-specific quality of life scores were consistently better in patients who received 300 mg of omalizumab than in those who received lower dosages or placebo and did not decline during peak season. The frequency of adverse events was not significantly different among the omalizumab and placebo groups. CONCLUSION: Omalizumab decreased serum free IgE levels and provided clinical benefit in a dose-dependent fashion in patients with seasonal allergic rhinitis.

Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial.

BACKGROUND: Beta2-adrenergic agonists are frequently used for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease. Formoterol and salmeterol are long-acting beta2-agonists. In addition to its long duration of action, formoterol has been reported to have an onset of action similar to that of albuterol. OBJECTIVE: This study compared the effects on lung function of regular twice-daily inhalation of formoterol or salmeterol in adults with moderate to moderately severe persistent asthma who were receiving daily inhaled corticosteroids. METHODS: In this 6-month, multicenter, open-label, parallel-group study, patients with moderate or moderately severe asthma were randomized to receive either formoterol 12 microg BID or salmeterol 50 microg BID. The primary end point was mean morning peak expiratory flow (PEF) measured 5 minutes after dosing and entered in a patient diary each day during the first 4 weeks of treatment. Secondary end points included mean morning and evening predose PEF and number of episode-free days recorded in the patient diaries during the first 4 weeks of treatment, use and time of rescue medication, symptom scores, and overall mean morning predose PEF (spirometric measurements made by the physician during scheduled visits) for the entire treatment period. Safety assessments included spontaneously reported adverse events and vital signs. RESULTS: A total of 528 patients were randomized to study treatment, 262 to formoterol and 266 to salmeterol. There were no significant differences in demographic or baseline characteristics between treatment groups, except in the proportion of current smokers in the formoterol group (4.6%) compared with the salmeterol group (1.5%; P = 0.039). Based on the information recorded in patients' diaries, those receiving formoterol showed significant improvement in mean morning PEF measured 5 minutes after dosing (P < 0.001), reduced use of rescue medication (P < 0.03), and an increased number of episode-free days (P < 0.04) compared with patients receiving salmeterol. Mean predose morning and evening PEF and symptom scores based on diary data and mean morning predose PEF based on measurements obtained during office visits were comparable between the 2 treatment groups throughout the study. CONCLUSIONS: In this open-label trial, patients randomized to formoterol treatment had greater improvement in mean PEF 5 minutes after dosing, required significantly less rescue medication (fewer actuations of albuterol), and experienced more episode-free days compared with patients receiving salmeterol. Thus, although both formoterol and salmeterol are long-acting beta2-agonists, formoterol had a more rapid onset of action.

Triamcinolone acetonide aqueous nasal spray versus loratadine in seasonal allergic rhinitis: efficacy and quality of life.

BACKGROUND: The new aqueous formulation of triamcinolone acetonide (TAA) was compared with loratadine in patients with seasonal allergic rhinitis. OBJECTIVE: The primary objective of the study was to compare the safety and efficacy of TAA aqueous with loratadine in relieving the symptoms of seasonal allergic rhinitis. METHODS: A total of 351 patients were enrolled into this 4-week, double-blind, double-dummy, randomized, parallel group study. Patients received either TAA aqueous nasal spray (220 microg) or loratadine (10 mg) once daily. Efficacy variables were rhinitis symptom changes from baseline, physician global evaluations, and the patient dropout rate due to insufficient treatment effect. Safety and quality of life also was evaluated. RESULTS: Both TAA aqueous-treated and loratadine-treated patients had improvement in symptoms as early as day 1. Overall, TAA aqueous was significantly (P < .05) more effective than loratadine in reducing total nasal symptoms and individual symptoms of nasal congestion, nasal itch, and sneezing. Ocular symptoms improved from baseline in both groups. There was no statistically significant difference between groups based on physician global evaluation. A similar number of patients in each group discontinued the study due to ineffective treatment. Triamcinolone acetonide aqueous patients maintained a significantly (P < .05) better quality of life in three of the dimensions (activity, nasal symptoms, and practical problems) and for overall quality of life. There were no differences between the two treatment groups in the incidence of adverse events, none of which were clinically significant. CONCLUSIONS: Both TAA aqueous and loratadine were effective and well-tolerated in the treatment of patients with seasonal allergic rhinitis. Triamcinolone acetonide aqueous was significantly (P < .05) more effective than loratadine in controlling nasal symptoms of seasonal allergic rhinitis and maintaining a better quality of life for the patients.

Seven cases of complete and incomplete forms of Churg-Strauss syndrome not related to leukotriene receptor antagonists.

BACKGROUND: Various forms of Churg-Strauss syndrome have been reported in association with the use of leukotriene receptor antagonists in asthmatic patients. OBJECTIVE: Our purpose was to increase awareness that different forms of the Churg-Strauss syndrome occur in patients not receiving leukotriene modifiers. METHODS: We searched for all the cases of Churg-Strauss syndrome that were seen in the University of Rochester Medical Center, New York, in the past 4 years. RESULTS: We identified 7 patients, 6 of whom fulfilled the American College of Rheumatology criteria for the classification of Churg-Strauss syndrome. None of them used leukotriene receptor antagonists. All had asthma and sinus disease. The duration and severity of their asthma varied considerably. In the majority of the patients the features of Churg-Strauss syndrome became obvious as the systemic corticosteroid dose was being tapered or discontinued, although 3 patients had not been receiving maintenance oral corticosteroids at disease onset. Three patients had positive antineutrophil cytoplasmic antibodies test result (perinuclear pattern). There was histologic documentation of vasculitis in 4 patients. Five of 7 patients responded to high-dose corticosteroid treatment. CONCLUSION: Our 7 cases are similar to the various forms of Churg-Strauss syndrome that have been reported in association with the leukotriene receptor antagonists. Complete or incomplete forms of this syndrome can become apparent in asthmatic patients as systemic corticosteroids are being tapered but can also occur in patients with mild asthma of short duration who use only inhaled corticosteroids.

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group.

BACKGROUND: Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE: The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS: In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS: The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS: The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.

Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma.

BACKGROUND: Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent. OBJECTIVES: The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma. METHODS: In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test. RESULTS: The mean baseline FEV1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo (p < 0.001). The mean changes in morning peak expiratory flow were 12, 22, 27, and 30 L/min in the 200, 400, 800, and 1600 microg budesonide total daily dose groups, respectively, and -27 L/min for the placebo group. A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1. Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo. There were no clinically significant differences in treatment-related adverse experiences among groups. CONCLUSIONS: Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses. It was well tolerated and significantly more effective than placebo.

Fluticasone propionate powder administered through Diskhaler versus triamcinolone acetonide aerosol administered through metered-dose inhaler in patients with persistent asthma.

BACKGROUND: Attempts to delineate efficacy and safety differences among inhaled corticosteroids have been difficult because of the lack of well-controlled, comparative studies reported in the medical literature. METHODS: A randomized, double-blind, double-dummy study was conducted in 24 outpatient centers. A total of 291 male and female patients at least 12 years of age with asthma (FEV1 between 50% and 80% of predicted value), who had previously received maintenance therapy with beclomethasone dipropionate or triamcinolone acetonide, were switched to treatment with fluticasone propionate powder (250 microg twice daily), triamcinolone acetonide aerosol (200 microg four times daily), or placebo for 24 weeks. RESULTS: Mean increase in FEV1 from baseline to end point was significantly (p = 0.009) greater in patients switched to treatment with fluticasone compared with patients switched to treatment with triamcinolone (0.27 L and 0.07 L, respectively). At end point, mean increase in morning peak expiratory flow from baseline was 21 L/min with fluticasone compared with mean decreases of 6 L/min and 28 L/min with triamcinolone and placebo, respectively (p < 0.001 vs triamcinolone and placebo). Supplemental rescue albuterol use decreased by 30% from baseline with fluticasone (p < 0.05 vs triamcinolone and placebo) compared with triamcinolone (6%) or placebo (increased by 50%). The percentage of patients withdrawn from the study because they met predefined lack-of-efficacy criteria was higher with placebo (60%) and triamcinolone (27%) than with fluticasone (17%). Incidence of adverse events and low morning plasma cortisol concentrations were similar across treatment groups except for oral candidiasis (p = 0.035, fluticasone vs placebo). CONCLUSION: Fluticasone propionate powder twice daily (500 microg/day) was superior in efficacy to triamcinolone acetonide aerosol four times daily (800 microg/day) in patients with persistent asthma.

Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients.

BACKGROUND: Cyclophosphamide (CP) is one of the relatively few drugs implicated in systemic allergic reactions for which the metabolites are well known. Formation of CP metabolites is a multistep, time-dependent process (hours) with significant interindividual differences. Although allergic reactions to CP have been recorded in 17 previous reports, skin testing with CP or its metabolites has been included in only five. We now describe five patients receiving monthly cycles of intravenous CP whose allergic reactions included clinical features of type I hypersensitivity but were atypical in their markedly delayed onset (i.e., 8 to 16 hours in patients 1 to 4 and 10 days in patient 5). OBJECTIVE: The objective was to investigate these late-developing clinical reactions by skin testing with CP and two of its major metabolites. METHODS: The five patients and a control group receiving intravenous CP uneventfully were studied by the same skin test protocol. RESULTS: The four individuals in the control group were unreactive to CP or its metabolites. All five patients with late-onset allergic reactions had positive immediate skin test results to CP metabolites but not to CP itself. We propose that the allergic reactions in patients 1 to 4 were mediated, wholly or in major part, by IgE antibodies reactive with allergens derived from time-dependent drug metabolites. The 10-day lag time in patient 5 is unexplained. Immunomodulation by the underlying malignancies or by the immunosuppressive drugs could have contributed. CONCLUSION: IgE-mediated allergic drug reactions may have a delayed onset if the allergen is a time-dependent drug metabolite, illustrated in this study by CP.

Sulfuric acid aerosol followed by ozone exposure in healthy and asthmatic subjects.

These studies evaluated symptom and pulmonary function responses of humans sequentially exposed to sulfuric acid aerosol and ozone. Thirty healthy subjects and 30 allergic asthmatic subjects underwent 3-hr exposures in an environmental chamber to 100 micrograms/m3 sulfuric acid and sodium chloride (control) aerosols (in random order), followed 24 hr later by 3-hr exposures to ozone (0.08, 0.12, or 0.18 ppm). Each subject was studied four times, receiving each aerosol preexposure followed by two of the three ozone concentrations. For the healthy group, no convincing symptomatic or physiologic effects of exposure to either the aerosol or ozone on lung function were found. For the asthmatic group, preexposure to sulfuric acid altered the pattern of response to ozone in comparison with sodium chloride preexposure and appeared to enhance the small mean decrements in FVC that occurred in response to 0.18 ppm ozone (means +/- SE: -3.6 +/- 1.5% with sodium chloride preexposure, -6.8 +/- 1.7% with sulfuric acid preexposure). Individual responses among asthmatic subjects were quite variable, some demonstrating reductions in FEV1 of more than 35% following ozone exposure. Analysis of variance of changes in FVC revealed evidence for interactions between aerosol and ozone exposure both immediately after (P = 0.005) and 4 hr after (P = 0.030) exposure. Similar effects were seen for FEV1. When normal and asthmatic subjects were combined, four-way analysis of variance revealed an interaction between ozone and aerosol for the entire group (P = 0.0022) and a difference between normal and asthmatic subjects (P = 0.0048). There was no significant effect of exposures on symptoms for either normal or asthmatic subjects. Asthmatic subjects differ from healthy volunteers in their functional responses following sequential exposures to aerosols and ozone and appear to represent a susceptible population.

Mononeuritis multiplex and vasculitis. Association with anti-neutrophil cytoplasmic autoantibody.

Mononeuritis multiplex is known to occur in many illnesses including certain types of systemic vasculitis. Anti-neutrophil cytoplasmic autoantibody (ANCA) has been described in association with Wegener's granulomatosis, polyarteritis nodosa, pauci-immune necrotizing crescentic glomerulonephritis, and so-called ANCA-associated vasculitis. We describe three patients who presented with mononeuritis multiplex and positive tests for ANCA. A careful search revealed underlying vasculitis in two of the three patients. Whereas both respiratory and renal involvement are well known in ANCA-associated vasculitis, to our knowledge the relationship of mononeuritis multiplex and ANCA positivity has not previously been described. The three patients were treated with steroids and oral cyclophosphamide. All demonstrated marked clinical improvement, as well as a decrease or disappearance of the ANCA. Since mononeuritis multiplex may be a presenting symptom of many illnesses, a serological marker may be helpful for early diagnosis and prompt treatment.

Position dependent livedo reticularis in cholesterol emboli syndrome.

We describe a case of a 64-year-old Filipino man who presented with cholesterol emboli syndrome manifesting as worsening hypertension, renal failure and livedo reticularis involving the upper legs and lower abdomen. The livedo reticularis became very prominent with the patient standing, but completely vanished after several minutes of lying supine. Deep cutaneous biopsy of an area of skin that was found to be consistently involved with livedo reticularis demonstrated cholesterol clefts in several vessels, thus establishing the diagnosis in this patient, and avoiding the more problematic option of biopsying an involved visceral organ.

Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults.

BACKGROUND: A history (or lack thereof) of penicillin allergy is known to be unreliable in predicting reactions on subsequent administration of the drug. This study tests the usefulness of four penicillin allergen skin tests in the prediction of IgE-mediated reactions subsequent to administration of penicillin. METHODS: Eight centers cooperated in the National Institute of Allergy and Infectious Diseases trial of the predictive value of skin testing with major and minor penicillin derivatives. Hospitalized adults were tested with a major determinant (octa-benzylpenicilloyl-ocytalysine) and a minor determinant mixture and its components (potassium benzylpenicillin, benzylpenicilloate, and benzylpenicilloyl-N-propylamine). Patients then received a therapeutic course of penicillin and were observed, for 48 hours, for adverse reactions compatible with an IgE-mediated immediate or accelerated allergy. RESULTS: Among 726 history-positive patients, 566 with negative skin tests received penicillin and only seven (1.2%) had possibly IgE-mediated reactions. Among 600 history-negative patients, 568 with negative skin tests received penicillin and none had a reaction. Only nine of the 167 positive skin test reactors received a penicillin agent and then usually by cautious incremental dosing. Two (22%) of these nine patients had reactions compatible with IgE-mediated immediate or accelerated penicillin allergy; both were positive to the two determinants. CONCLUSIONS: These data corroborate previous data about the negative predictive value of negative skin tests to these materials. The reaction rate in skin test-positive patients was significantly higher than in those with negative skin tests, demonstrating the positive predictive value of positive tests to both major and minor determinants. The number of patients positive only to the major determinant or only to the minor determinant mix was too small to draw conclusions about the positive predictive value of either reagent alone.

Vascular disease in the antiphospholipid syndrome: a comparison with the patient population with atherosclerosis.

The antiphospholipid syndrome was diagnosed in 19 of 1078 patients treated between 1987 and 1991. All patients with antiphospholipid syndrome had either anticardiolipin antibody (16/19) or lupus anticoagulant (10/19); three patients had thrombocytopenia, eight patients had a prolonged partial thromboplastin time, and 10 patients had an elevated erythrocyte sedimentation rate. The most common site of involvement was the cerebral circulation (nine patients), manifested by transient ischemic attacks or stroke. Eight patients had upper extremity disease, characterized by symptoms of Raynaud's phenomenon, with angiographic lesions involving the brachial, radial, ulnar, and/or digital arteries. Lower extremity disease occurred in seven patients, with clinical presentations similar to those of atherosclerosis and varying angiographic patterns. In comparison with the population having atherosclerosis, patients with arterial manifestations of antiphospholipid syndrome were more likely to be women (13 of 19 versus 411 of 1078, p less than 0.02), were significantly younger (46.2 years versus 63.6 years, p less than 0.0001), did not smoke (1 of 19 patients versus 700 of 1078, p less than 0.0001), had a higher percentage of upper extremity involvement (8 of 18 versus 13 of 1078, p less than 0.0001), and had a higher incidence of early graft failure (9 of 12 grafts versus 13 of 371 grafts, p less than 0.0001). The syndrome is associated with the repetitive failure of vascular reconstructions and occlusion of native vessels. Antiphospholipid syndrome should therefore be suspected in young, female, nonsmokers with vascular disease, especially those with involvement of the upper extremity, cerebrovascular disease with normal findings on extracranial carotid angiography, and premature graft failure.

Antibodies to retroviral proteins and reverse transcriptase activity in patients with essential cryoglobulinemia.

Human T cell lymphotropic virus type I (HTLV-I) gag and env protein-specific antibodies were identified in 6 of 13 patients with essential cryoglobulinemia (EC), by Western blot and radioimmunoprecipitation analysis. Supernatants of cells from 2 of the 5 EC patients tested showed reverse transcriptase activity. DNA sequences homologous to HTLV-I could not be detected by polymerase chain reaction, thus excluding the presence of prototype HTLV-I in each patient with EC. The data suggest that retroviral proteins distinct from but related to HTLV-I may be involved in the pathogenesis of EC in some patients.

Penicillin resensitization among hospitalized patients.

The purpose of this study was to determine the frequency of resensitization to penicillin after oral or intravenous treatment with beta-lactam antibiotics in hospitalized patients with histories of penicillin allergy. Seventeen adults (aged 24 to 76 years) and one child (aged 10 years) were treated intravenously and/or orally with beta-lactam antibiotics after negative skin tests were obtained with benzylpenicilloyl polylysine, potassium penicillin G, and alkaline hydrolysis products of penicillin G as minor determinant mixture. Repeat skin testing was performed 1 to 12 months after the therapy. Three patients (16%) became skin test positive after the treatment. Two patients reacted to potassium penicillin G alone, and the other patient reacted to benzylpenicilloyl polylysine and minor determinant mixture. These three patients were among the 15 patients who were treated with intravenous antibiotics. This study reveals a high percentage of skin test conversion after intravenously administered penicillin therapy and confirms the present practice of advising patients with a history of penicillin allergy who have successfully completed penicillin treatment to have a repeat skin test before future exposure to beta-lactam antibiotics.

Detection and mapping of polymorphic KpnI alleles in the human T-cell receptor constant beta-2 locus.

Southern blot analysis with human T-cell receptor (TcR) beta-chain specific cDNA probes revealed two novel allelic forms of the TcR beta-2 gene locus. Three different genotypes were noted based on the presence of polymorphic KpnI restriction fragments: I, 5.7 kb fragment only; II, 3.9 kb and 1.8 kb fragments only; III, all three polymorphic fragments. This hybridization pattern suggested that the presence or absence of a polymorphic KpnI site within the 5.7 kb fragment defines the two different allelic forms of the TcR beta chain locus. By Southern blot analysis of genomic DNA from T-cell lines with deleted C-beta-1 regions and computer-assisted restriction site mapping of germline and cDNA sequences of the C-beta-2 locus, the polymorphic KpnI site was localized at 24 bp 5' to the third exon of the C-beta-2 gene. It was determined that the polymorphic KpnI site and the earlier described polymorphic BglII site located 5' to the C-beta-2 gene are not co-inherited. No difference was noted in distribution of the KpnI genotypes and allelic frequencies between 26 normal individuals and 22 patients with systemic lupus erythematosus. However, this newly characterized polymorphism of the TcR locus should provide a useful tool to analyse the role of inherited genetic variations in the function of T lymphocytes under normal and pathological conditions.

Clonal B cell expansions in patients with essential mixed cryoglobulinaemia.

In essential mixed, type II, cryoglobulinaemia (EMC) monoclonal autoantibodies with rheumatoid factor activity are synthesized at an accelerated rate by non-malignant B lymphocytes. In order to determine if the high cryoglobulin production rate is related to a clonal B cell expansion, cell surface markers of peripheral blood lymphocytes (PBL) were analysed by flow cytometry and the rearrangement of immunoglobulin (Ig) genes was investigated by Southern blot analysis of DNA extracted from the PBL of 12 EMC patients. Clonal expansion of B cells could be detected using DNA probes specific for the c kappa, c-mu, and JH genes in four out of 12 patients, two of whom also showed specific expansions of mu heavy and kappa light chain bearing cells using flow cytometry. The rearrangement of the c-myc locus was also noted in one of the patients with detectable Ig gene rearrangements. Demonstration of clonal B cell expansions in EMC patients shows that the clonal type of Ig gene rearrangements are not unique markers of malignant lymphomas but may also occur in autoimmune lymphoproliferative disorders. Since malignant B cell lymphomas can develop in a small number of EMC cases, the follow-up of these patients should be pursued indefinitely.