Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus
Melissa R. Arbuckle, M.D., Ph.D., Micah T. McClain, Ph.D., Mark V. Rubertone, M.D., R. Hal Scofield, M.D., Gregory J. Dennis, M.D., Judith A. James, M.D., Ph.D., and John B. Harley, M.D., Ph.D.
Background Although much is known about the natural historyof systemic lupus erythematosus (SLE), the development of SLEautoantibodies before the diagnosis of the disease has not beenextensively explored. We investigated the onset and progressionof autoantibody development before the clinical diagnosis.
Methods The Department of Defense Serum Repository containsapproximately 30 million specimens prospectively collected frommore than 5 million U.S. Armed Forces personnel. We evaluatedserum samples obtained from 130 persons before they receiveda diagnosis of SLE, along with samples from matched controls.
Results In 115 of the 130 patients with SLE (88 percent), atleast one SLE autoantibody tested was present before the diagnosis(up to 9.4 years earlier; mean, 3.3 years). Antinuclear antibodieswere present in 78 percent (at a dilution of 1:120 or more),anti–double-stranded DNA antibodies in 55 percent, anti-Roantibodies in 47 percent, anti-La antibodies in 34 percent,anti-Sm antibodies in 32 percent, anti–nuclear ribonucleoproteinantibodies in 26 percent, and antiphospholipid antibodies in18 percent. Antinuclear, antiphospholipid antibodies, anti-Ro,and anti-La antibodies were present earlier than anti-Sm andanti–nuclear ribonucleoprotein antibodies (a mean of 3.4years before the diagnosis vs. 1.2 years, P=0.005). Anti–double-strandedDNA antibodies, with a mean onset 2.2 years before the diagnosis,were found later than antinuclear antibodies (P=0.06) and earlierthan anti–nuclear ribonucleoprotein antibodies (P=0.005).For many patients, the earliest available serum sample was positive;therefore, these measures of the average time from the firstpositive antibody test to the diagnosis are underestimates ofthe time from the development of antibodies to the diagnosis.Of the 130 initial matched controls, 3.8 percent were positivefor one or more autoantibodies.
Conclusions Autoantibodies are typically present many yearsbefore the diagnosis of SLE. Furthermore, the appearance ofautoantibodies in patients with SLE tends to follow a predictablecourse, with a progressive accumulation of specific autoantibodiesbefore the onset of SLE, while patients are still asymptomatic.
Systemic lupus erythematosus (SLE) is an autoimmune diseasethat is virtually always accompanied by the production of autoantibodies.In fact, it has been demonstrated that autoantibodies contributedirectly to the pathologic changes of SLE.1 Since autoantibodiesare central to the pathogenesis of the disorder, their developmentmust coincide with or precede clinical disease. Although theprevalence of SLE autoantibodies among patients with confirmedSLE has been established, we know little about the autoimmunehistory of patients before SLE is diagnosed.
We evaluated a prospectively assembled collection of frozenserum samples to test the hypothesis that the appearance ofautoantibodies precedes the diagnosis of SLE. The U.S. Departmentof Defense Serum Repository contains more than 30 million serumsamples. The stringent physical requirements of the U.S. militaryensure that subjects are healthy on induction for active duty.A review of military medical records identified 130 persons,some formerly and some currently on active duty, who met thecriteria for SLE and for whom stored serum samples obtainedbefore diagnosis were available.
Methods
Serum Samples
Since 1985, the Department of Defense Serum Repository has storedserum samples obtained from U.S. Armed Forces personnel on enlistmentand, on average, every other year thereafter. The samples arestored at –30°C. Military data bases were searchedfor records containing the International Classification of Diseases,9th Revision, Clinical Modification (ICD-9-CM) code for SLE(710.0). Records containing this code from 336 persons withserum in the repository were reviewed. Patients were excludedbecause of inadequate data, insufficient evidence of a diagnosisof SLE,2 or the absence of prediagnosis serum samples. For eachpatient with SLE, four controls were randomly selected fromamong people on active military duty, matched for sex, ethnicgroup, age (within one year), length of military service, sampleavailability, and enlistment date (to control for the durationof sample storage).
Review of Medical Records
Data on clinical and laboratory findings and on sex, ethnicgroup, date of birth, and date and age at diagnosis were obtainedby review of medical records.2 The presence of each criterionfor SLE was determined from the medical records, with many ofthe diagnostic criteria being documented by military rheumatologyreferral centers.
The protocol was reviewed and approved by the institutionalreview board of the Oklahoma Medical Research Foundation andthe Human Use Committee of the Walter Reed Army Medical Center.Informed consent for the testing of coded, stored serum samplesand the review of records by appropriate military personnelwas waived by both institutions. To protect the privacy of thepatients, their names and unique personal information were notrecorded or released. The dates of the sampling and the analysesranged from 1992 to 1999.
Autoantibody Assays
Assays for antinuclear antibodies were performed by indirectimmunofluorescence with HEp-2000 cells (Immuno Concepts). Detectionof antinuclear antibodies at a dilution of 1:120 was considereda positive result. Enzyme-linked immunosorbent assays were usedto evaluate serum for antibodies to Sm, nuclear ribonucleoprotein,Ro, La, and phospholipids (IgG and IgM).3,4 Values that were3 SD or more above normal values for background binding wereconsidered positive results. Anti–double-stranded DNAantibodies were screened with a solid-phase assay (Varelisa,Pharmacia Upjohn Diagnostics). All tests yielding equivocalresults were repeated, and samples with persistently equivocalresults for anti–double-stranded DNA were tested witha crithidia immunofluorescence assay (Protrac Industries).5
Statistical Analysis
Categorical variables (such as ethnic group and sex) were assessedby the chi-square statistic. For each type of autoantibody,the time from autoantibody positivity to the diagnosis of SLEwas calculated on the basis of the date of the first positiveantibody test and the date of diagnosis. Patients in whom antibodiesdeveloped before diagnosis were assigned negative values forthe time between antibody development and diagnosis, and patientsin whom antibodies developed after diagnosis were assigned positivevalues for the time between antibody development and diagnosis.For patients whose first available serum sample yielded a positiveantibody-test result, this time represents a lower boundaryfor the duration of positivity before the diagnosis of SLE.
For each antibody, the mean time from the first recorded positivetest to the diagnosis of SLE was calculated on the basis ofdata from all patients in whom that antibody had developed atany time. Student's t-test was used to test for differencesbetween antibodies with respect to the mean time from the firstpositive test to the diagnosis. The antibodies were sorted intothree groups: early-, intermediate-, and late-appearing antibodies.Within each group, the mean time from the development of antibodiesto the diagnosis of SLE did not differ significantly among antibodies(P>0.05). The mean time from antibody development to diagnosisfor each of the three groups of antibodies was determined bycomputing averages weighted according to the number of personswith each antibody.
The time between antibody development and the appearance ofthe first American College of Rheumatology clinical criterionfor SLE was also calculated and analyzed. The mean and medianvalues for the time from the appearance of the first clinicalcriterion to the diagnosis of SLE were not similar to each other,unlike the other values analyzed. Means are therefore presentedfor all values, except for the time from the appearance of thefirst clinical criterion to the diagnosis of SLE, for whichmean and median values are presented.
Kaplan–Meier product–limit survival curves6,7 wereconstructed for the time from the initial positive serum sampleto the time of diagnosis and to the appearance of the firstAmerican College of Rheumatology clinical criterion. Data frompatients with a positive autoantibody test for the earliestserum sample available for testing were treated as censoredobservations at the time of the first serum sample. The differencesbetween autoantibodies in the time from the first positive testto the appearance of the first clinical criterion for SLE werethen evaluated with the use of Gehan's generalized Wilcoxontest.7,8,9
Results
Patient Population
A diagnosis of SLE was established in 130 military personnel,some formerly and some currently on active duty, for whom serumsamples obtained before diagnosis were available. Of these 130patients, 36 percent were men, 62 percent were black, 26 percentwere of European ethnic background, 10 percent were Hispanic,and 2 percent were Asian. The mean (±SD) age at diagnosiswas 30.4±6.8 years (range, 18.5 to 46.9). A mean of 4.9±2.5serum samples were available for each patient (range, 1 to 12).The earliest available serum sample for each patient was obtaineda mean of 4.4±2.5 years before the diagnosis (with amaximal interval of 9.4 years). Serum samples obtained afterthe diagnosis (up to six years afterward) were also availablefrom 77 patients (59 percent). For the analysis of autoantibodiesdetected after the diagnosis, the data were censored to reflectthe loss to follow-up of persons after the time of collectionof the last available serum sample.
Autoantibody Prevalence
A total of 633 serum samples from patients and 390 samples fromcontrols were evaluated for autoantibody binding with the useof assays for antinuclear antibodies or specific antigens. Antinuclearantibodies were the most prevalent autoantibodies in serum samplesobtained before the diagnosis, occurring in 78 percent of thepatients, but other autoantibodies were also frequently foundbefore the diagnosis (Table 1). In fact, most of the patientswith a specific type of autoantibody had a positive test forthat autoantibody before the diagnosis (Table 1).
Table 1. Detection of Autoantibodies before Diagnosis and before the Onset of Symptoms in 130 Patients with Systemic Lupus Erythematosus.
Of the 130 initial matched controls, 3.8 percent were positivefor one or more autoantibodies (3 percent for anti–double-strandedDNA, 3 percent for anti-Ro, 2 percent for antiphospholipid,and 2 percent for anti–nuclear ribonucleoprotein antibodies).These results are similar to those previously published.10,11,12,13Antinuclear antibodies were detected in 9.2 percent of samplesfrom the matched controls at a dilution of 1:40, but in noneof the control samples at a dilution of 1:120, the criterionused in this study. No control samples were positive for anti-Smor anti-La antibodies.
Samples from an additional 130 matched controls were also testedfor antibodies at two separate times, a mean of 4.69 years apart.None of these control samples had antinuclear antibodies (ata 1:120 dilution), anti-Sm antibodies, or anti-La antibodies.One control had anti-Ro antibodies. Anti–nuclear ribonucleoproteinor antiphospholipid antibodies developed in two other controls,and two controls with initially positive tests subsequentlyhad negative tests.
Time from the Development of Autoantibodies to the Diagnosis of SLE
For each subject, the first positive test was identified foreach autoantibody. In a substantial number of patients withSLE (90 of 130, or 69 percent), antibodies were detected inthe first available serum sample, and therefore the time fromthe development of autoantibodies to the diagnosis of SLE waslonger than our estimate. At least one SLE autoantibody waspresent before diagnosis (up to 9.4 years earlier; mean, 3.3)in 115 patients (88 percent). The mean interval between theearliest autoantibody detection and diagnosis ranged from 3.68years for anti-Ro antibodies to 0.88 year for anti–nuclearribonucleoprotein antibodies (Table 1). The antibodies couldbe clearly separated into three groups according to the lengthof this interval. The intervals between the first detectionof antibodies and the diagnosis of SLE for antinuclear, antiphospholipid,anti-Ro, and anti-La antibodies were statistically indistinguishablefrom one another (Table 2) and were longer than those for anti-Smand anti–nuclear ribonucleoprotein antibodies (mean, 3.4vs. 1.2 years; P=0.005). Anti–double-stranded DNA antibodieswere first detected a mean of 2.2 years before diagnosis, whichwas later than the first detection of antinuclear antibodies(P=0.06) and earlier than that of anti–nuclear ribonucleoproteinantibodies (P=0.005).
Table 2. Relative Timing of the Development of Autoantibodies in Patients with Systemic Lupus Erythematosus.
In a substantial proportion of cases, autoantibodies were presentin the earliest available serum sample and were therefore neverdocumented as having been undetectable (Table 1). To allow forpatients with positive results in the first sample who may actuallyhave had autoantibodies much earlier, we used Kaplan–Meierproduct–limit curves (Figure 1) to evaluate the changein the proportion of patients with positive results over time.
Figure 1. Kaplan–Meier Product–Limit Curves for the Proportion of Patients with Positive Antibody Tests Relative to the Time of Diagnosis or Appearance of the First Clinical Manifestation of Systemic Lupus Erythematosus (SLE).
For each autoantibody, the proportion of patients testing positive relative to the time of diagnosis or to the time of appearance of the first clinical criterion was assessed. In the analyses of the time from antibody development to the diagnosis of SLE (Panel A), antinuclear antibodies (ANA) appeared significantly earlier than anti-Sm antibodies (Z=3.22, P<0.001) and anti–nuclear ribonucleoprotein antibodies (anti-nRNP) (Z=4.18, P<0.001) but not significantly earlier than anti-Ro, anti-La, antiphospholipid (APL), or anti–double-stranded DNA antibodies (anti-dsDNA). In the analyses of the time from antibody development to the first clinical manifestation (Panel B), antinuclear antibodies appeared significantly earlier than anti-Sm antibodies (Z=2.98, P=0.003) and anti–nuclear ribonucleoprotein antibodies (Z=4.34, P<0.001) but not significantly earlier than the other autoantibodies, with anti–double-stranded DNA antibodies being intermediate (P=0.06).
The proportion of patients with SLE who had anti-Sm or anti–nuclearribonucleoprotein antibodies increased dramatically in the yearbefore the diagnosis. Among patients who ever had a positiveautoantibody result, the rate of seroconversion was approximately20 percent during the year before diagnosis for antinuclear,anti-Ro, or anti-La antibodies and 30 percent for anti–double-strandedDNA antibodies. In contrast, the rate of initial detection inthe year before the diagnosis was 82 percent for anti-Sm antibodiesand 75 percent for anti–nuclear ribonucleoprotein antibodies.These findings reflect the close temporal relation between thedevelopment of these autoantibodies and clinical disease.
Time from the Development of Autoantibodies to the Appearance of the First Clinical Criterion
In 27 patients, the first documented appearance of one of theclinical criteria of SLE occurred in the same month as the diagnosisof SLE. Most patients had a more insidious onset of disease;21 of 130 (16 percent) presented with a clinical symptom morethan three years before the diagnosis, and a few presented witha clinical symptom as much as a decade before the diagnosis.These data are somewhat skewed, and, on average, the patientspresented with the first clinical symptom 1.5 years before thediagnosis (median, 0.42 year).
Since nearly all patients also acquired autoantibodies beforethe diagnosis of SLE, we calculated the time from the appearanceof individual autoantibodies to the appearance of any clinicalmanifestation of SLE. Serum samples obtained before the appearanceof any clinical manifestation of SLE were available for 115of the 130 patients. In most of the antibody-positive patients(90 percent), antibodies developed before the appearance ofthe first clinical manifestation. Indeed, analysis of the dataaccording to the time from the first detection of each antibodyto the onset of the first clinical (nonantibody) criterion forSLE showed the progressive nature of this disorder (Table 1and Figure 1 and Figure 2). Over 90 percent of patients whowere ever positive for antinuclear, anti-Ro, anti-La, antiphospholipid,or anti–double-stranded DNA antibodies had a positivetest long before the first clinical manifestation of SLE. However,the initial detection of anti–nuclear ribonucleoproteinand anti-Sm antibodies (mean interval before diagnosis, 1.2years) tended to coincide with the onset of clinical manifestationsof SLE (mean interval, 1.5 years).
Figure 2. Accumulation of Systemic Lupus Erythematosus Autoantibodies.
The curve shows the average number of types of autoantibody in relation to the time of diagnosis of systemic lupus erythematosus. Seven autoantibodies were evaluated, which bind cellular constituents (antinuclear antibodies), Ro, La, double-stranded DNA, Sm, phospholipid, and nuclear ribonucleoprotein. The time of diagnosis and the median time of the first appearance of any clinical criterion useful for the classification of systemic lupus erythematosus (clinical onset) are indicated by arrows.
Accrual of Autoantibodies
The rate of appearance of new types of autoantibodies graduallyincreased up to the diagnosis of SLE. This accrual of antibodiesin the year before diagnosis virtually stopped at diagnosis(Figure 2). Six years before the diagnosis, patients had, onaverage, 1.47 of the 7 types of antibodies measured in thisstudy. This number increased to 2.58 with the appearance ofthe first clinical criterion and then to 3.01 at diagnosis.This process of accrual of autoantibody specificities haltedat diagnosis, with only 3.07 specificities present as late asfive years after diagnosis.
Discussion
The prospectively assembled Department of Defense Serum Repositoryis a large, unique resource that has provided an opportunityto examine the development of autoimmunity before the onsetof clinical illness in patients with SLE. A number of importantlessons are clear from these observations. Some autoantibodies(antinuclear, anti-Ro, anti-La, and antiphospholipid antibodies)usually precede the onset of SLE by many years. Others (anti-Smand anti–nuclear ribonucleoprotein antibodies) typicallyappear only months before diagnosis, during the time when characteristicclinical manifestations appear. Anti–double-stranded DNAantibodies are intermediate between these two groups of antibodies.This pattern is consistent with the known reports of positivetests for antinuclear, anti-Ro, anti-La, and antiphospholipidantibodies before the diagnosis of SLE,14,15,16,17,18,19 andwith the virtual absence of reports of positive tests for anti-Smand anti–double-stranded DNA antibodies before the clinicaldiagnosis.
Our findings also correlate with the observed frequency of theseautoantibodies in the normal population and their known associationwith disease activity.20,21 Anti-Ro, anti-La, antiphospholipid,and antinuclear antibodies are in fact relatively common innormal persons who never have clinical symptoms of rheumaticdisease. In contrast, anti–double-stranded DNA, anti-Sm,and anti–nuclear ribonucleoprotein antibodies are veryrare in normal persons.13,22 We found that the interval betweenthe first positive test for each of these three autoantibodiesand the initial clinical manifestation of disease was shorterthan that for anti-Ro, anti-La, antiphospholipid, and antinuclearantibodies.
A half-century ago, when the diagnosis was first made with confidence,the five-year mortality among patients with SLE was 50 percent.23Dubois argued that corticotropin and corticosteroids were responsiblefor the dramatic improvement in survival between the 1950s andthe 1970s.24 Our results show that new autoantibodies steadilyaccumulate before the diagnosis and cease to accumulate thereafter(Figure 2), perhaps as a result of unknown aspects of the naturalhistory of the disease or of the modern treatments typicallyused when SLE is diagnosed.
SLE tends to arise in asymptomatic persons with positive serologictests for SLE-associated autoantibodies. The extent to whichthe risk among those with positive serologic tests exceeds theoverall rate of 5.6 per 100,000 per year25 can be only crudelyestimated from our data. The presence of antinuclear antibodies(at a dilution of 1:120 or more) or anti-Ro, anti-La, or antiphospholipidantibodies appears to increase the risk by a factor of at least40 (according to their relative frequency in the normal controlsin our study); however, their presence does not suggest thatthe onset of clinical illness is imminent. Our findings do notaddress the question of whether asymptomatic persons incidentallydiscovered to have SLE-specific autoantibodies (anti-Sm or anti–double-strandedDNA antibodies) should be monitored or treated.
Our results are consistent with data from prospective studiesof asymptomatic women with positive tests for anti-Ro antibodieswho gave birth to babies with neonatal SLE manifested as completecongenital heart block. After 5 to 10 years of follow-up, eitherSjögren's syndrome or SLE developed in many of these women.26In a 10-year follow-up of healthy subjects with a positive testfor rheumatoid factor, rheumatoid arthritis developed in only9 of 129, but this rate was 40 times as high as that among subjectswithout rheumatoid factor.27 There are also prospective datafrom persons with positive tests for diabetes-associated autoantibodiesshowing that 70 to 80 percent of those in whom type 1 diabeteslater developed could be identified by using a panel of autoantibodies.28In all of these diseases, as in SLE, there is a tendency forthe appearance of autoantibodies to precede the clinical onsetof disease, a finding that underscores the potential importanceof autoantibodies in the pathogenesis of these diseases.
Even though our study suggests that immune events occur yearsbefore the diagnosis of SLE, our findings should be interpretedin the context of the limitations of the data. The estimatesof time provided by this study are biased by the substantialproportion of patients (69 percent) whose data were censoredbecause autoantibodies were present in the first available serumsample (obtained a mean of four years before the diagnosis).If serum samples obtained before the development of autoantibodieshad been available for all patients, our estimates of the meantime from autoantibody development to the diagnosis would havebeen longer. Consequently, this study provides a lower-boundaryestimate of the time before the diagnosis at which particularautoantibodies develop.
Our serologic and clinical findings, along with those of previousstudies,29 suggest that there are at least three phases in thedevelopment of SLE autoantibodies (Figure 3). In the first,or normal, phase, are asymptomatic persons with no SLE autoantibodies.Only 32 of the 130 patients in whom SLE developed (25 percent)were found to be in this phase at the time of the first serumsample. In the second phase, benign autoimmunity, there is alaboratory finding but without immediate clinical manifestations.Antinuclear, anti-Ro, anti-La, or antiphospholipid antibodiesare most likely to be present during this phase. The third phase,pathogenic autoimmunity, is marked by the presence of the moreominous autoantibodies — namely, anti–double-strandedDNA, anti-Sm, and anti–nuclear ribonucleoprotein antibodies— and by the onset of signs and symptoms leading to clinicalpresentation and diagnosis.
Figure 3. Phases in the Development of Pathogenic Autoimmunity.
Normal immunity progresses to benign autoimmunity through the influence of genetic composition and environment. Later, benign autoimmunity progresses to pathogenic autoimmunity. Symptoms of clinical illness appear soon after pathogenic autoimmunity develops.
This concept of a crescendo of autoimmunity culminating in clinicalillness is also supported by data showing increased concentrationsof autoantibodies before diagnosis30 and progressive accrualof autoantibody specificities at the epitope level. The anti-Smresponse, for example, appears to be elicited first by a singleantigenic structure. The responses to the first few additionalepitopes follow a specific sequence of immune structural recognition.These responses eventually mature (over a period of approximatelytwo years) into a more idiosyncratically complex reaction thatbinds an average of eight epitopes of Sm B.31,32
Our results show that clinical SLE is preceded by complicatedautoimmune changes that are usually under way for many yearsbefore diagnosis. Antinuclear, anti-Ro, anti-La, and antiphospholipidantibodies appear first, followed by anti–double-strandedDNA antibodies, and then by anti-Sm and anti–nuclear ribonucleoproteinantibodies. The number of autoantibody types continues to increaseuntil the time of diagnosis and therapeutic intervention. SLE,then, is the culmination of compound autoimmune abnormalitiesthat begin simply, perhaps even as isolated immunologic events,and that spread and multiply until they are manifested as apotentially devastating clinical disease.
Supported by grants from the National Institutes of Health (AI31584,RR15577, AR4904, AR48940, AR01981, AR45084, AR45231, AR42460,AI24717, and RR14467 [for biostatistical support]) and the Departmentof Veterans Affairs.
The opinions and assertions contained herein are the privateviews of the authors and are not to be construed as officialor as reflecting the views of the Departments of the Army, Navy,or Defense.
We are indebted to Ben Bruner, Tara Bruner, Roy Rindler, andXana Kim for their technical assistance; to Drs. Christie Burgin,Don Parker, and Chris Aston for statistical assistance; andto Kimmie Kohlhase and the cooperating military rheumatologistsand rheumatology clinics for case identification.
Source Information
From the Arthritis and Immunology Program, Oklahoma Medical Research Foundation (M.R.A., M.T.M., R.H.S., J.A.J., J.B.H.), the Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center (M.T.M., R.H.S., J.A.J., J.B.H.), and the Department of Veterans Affairs (R.H.S., J.B.H.) — all in Oklahoma City; the Department of Rheumatology, Walter Reed Army Medical Center (M.R.A., G.J.D.), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (G.J.D.) — both in Bethesda, Md.; and the U.S. Army Center for Health Promotion and Preventive Medicine, Washington, D.C. (M.V.R.).
Address reprint requests to Dr. James at the Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, or at jamesj{at}omrf.ouhsc.edu.
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(2009). Cigarette Smoking, STAT4 and TNFRSF1B Polymorphisms, and Systemic Lupus Erythematosus in a Japanese Population. The Journal of Rheumatology
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(2009). Reproductive Factors and Risk of Systemic Lupus Erythematosus: Nationwide Cohort Study in Denmark. The Journal of Rheumatology
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Kono, D. H., Haraldsson, M. K., Lawson, B. R., Pollard, K. M., Koh, Y. T., Du, X., Arnold, C. N., Baccala, R., Silverman, G. J., Beutler, B. A., Theofilopoulos, A. N.
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(2009). Human Idiopathic Membranous Nephropathy -- A Mystery Solved?. NEJM
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Martin, D. A., Zhang, K., Kenkel, J., Hughes, G., Clark, E., Davidson, A., Elkon, K. B.
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Grus, F. H., Joachim, S. C., Bruns, K., Lackner, K. J., Pfeiffer, N., Wax, M. B.
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Rai, G., Ray, S., Shaw, R. E., DeGrange, P. F., Mage, R. G., Newman, B. A.
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