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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Specific events that occur during the development of systemic lupus erythematosus (SLE) can be quite variable among individual patients. The aim of this study was to identify patterns that distinguish early clinical events in SLE and to assess whether the presence of associated autoantibodies precedes the fulfillment of clinical criteria.

Methods

Through a retrospective chart review of military medical records, 130 patients who met the American College of Rheumatology (ACR) criteria for the classification of SLE were identified. The initial time at which each criterion was fulfilled was recorded. Autoantibody analysis was performed on serum samples, using enzyme-linked immunosorbent assays or immunofluorescence.

Results

The clinical features that were observed earliest were discoid rash and seizures, which developed a mean 1.74 and 1.70 years, respectively, before the diagnosis of SLE; however, arthritis was the criterion that was most commonly observed before diagnosis. The presence of IgG rheumatoid factor (IgG-RF) preceded the development of arthritis in 15 (94%) of the 16 patients who were positive for IgG-RF and in whom arthritis developed (Z = 10.2, P < 0.0001). Analogously, IgM-RF appeared before the development of arthritis in 13 (76%) of 17 patients. Anti–double-stranded DNA antibodies were associated with renal disease and appeared before evidence of nephritis in most patients (92%) (Z = 13.3, P < 0.0001). An analysis of the appearance of autoantibodies compared with the appearance of clinical criteria not associated with them revealed no significant temporal relationship.

Conclusion

Symptoms associated with the ACR criteria for classification of SLE are commonly present before the diagnosis of SLE, and development of organ-associated autoantibodies generally precedes the appearance of their associated clinical features.

Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by multisystem autoimmunity, leading to an array of different clinical presentations. This variability can add to the difficulty of timely diagnosis and intervention. The American College of Rheumatology (ACR) has developed criteria to classify patients with a diagnosis of SLE for research studies; 4 of the 11 criteria must be met (1, 2). Using the various permutations of these classification criteria, ∼330 clinical presentations are possible.

With so many different possible presentations, the clinical picture of SLE can be complex. Early prospective studies analyzed the accrual of SLE symptoms, based on repeated interviews of patients thought to be at high risk of SLE. Analyzing 150 patients defined by positive LE cell and multisystem disease, annual review of patient symptoms showed articular or cutaneous symptoms were the most common and were present in nearly 75% of patients (3). More recently, the initial clinical manifestations of SLE were analyzed by reviewing medical charts of identified patients with SLE (4, 5). The results of those studies showed some variance but in general demonstrated that arthralgias were the most common presenting symptom when analyzing previous medical records of SLE patients.

By studying patients with undifferentiated connective tissue disease (UCTD), several investigators have been able to identify clinical and serologic factors that are predictive of the development of SLE (6–9). In a large followup study of 665 patients with UCTD, SLE eventually developed in 28 patients (6). In those patients, the clinical symptoms that were the best predictors of an ultimate diagnosis of SLE were fever, photosensitivity, and serositis. Additionally, the development of antinuclear antibodies (ANAs) or anti–double-stranded DNA (anti-dsDNA) antibodies increased the risk of SLE. In another study in which 83 patients were followed up for at least 5 years, the most common symptom in patients in whom SLE eventually developed was arthralgia, which was present in 94% of patients in whom UCTD transitioned to SLE (8).

A unifying characteristic of patients with SLE is the presence of high titers of autoantibodies. Associations of several clinical symptoms and specific lupus autoantibodies have been noted; however, direct pathogenic mechanisms have been more difficult to establish. The presence of rheumatoid factor (RF) correlates with active inflammatory arthritis in SLE (10). Subacute cutaneous lupus erythematosus, photosensitivity, and leukopenia are all associated with anti-Ro antibodies (11–13), and anti-Ro has been observed in the affected skin of patients with SLE (14). Finally, lupus nephritis has been associated with several autoantibodies including anti-dsDNA, anti-C1q, and anti–ribosomal P antibodies (15, 16). Anti-dsDNA antibody titers have been shown to increase just prior to the diagnosis of SLE (17), and higher anti-dsDNA titers have been associated with nephritis (15). Furthermore, anti-dsDNA can be observed in affected kidneys of patients with SLE (18). Anti-C1q antibodies are also found in immune complex depositions in kidney samples from patients with SLE, and these autoantibodies contribute to tissue inflammation (16, 19).

Previous retrospective studies contributed to the knowledge about the order of onset of clinical criteria for SLE but have not correlated these findings with the development of autoantibodies. The current study has taken advantage of a large military serum repository providing access to both serum samples from and medical records for individuals in whom SLE later developed, in order to study relationships between the onset of ACR criteria and the appearance of select lupus-related autoantibodies.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Case identification.

Utilizing computer databases of military hospital records, military rheumatologists identified individuals with a potential diagnosis of SLE (based on International Classification of Diseases, Ninth Revision code 710.0). A total of 130 individuals were identified who met the following inclusion criteria: a diagnosis of SLE while serving in the military, availability of at least 1 retrievable serum sample prior to the diagnosis of SLE, and availability of sufficient sera for necessary testing. This study was in compliance with the Helsinki Declaration and had institutional review board approval from the Walter Reed Army Medical Center and the Oklahoma Medical Research Foundation.

A total of 633 serum samples from these 130 patients were retrieved (a mean ± SD of 4.9 ± 2.5 serum samples [range 1–12] per case). Although all patients were required to have at least 1 sample available prior to diagnosis, 59% of these individuals also had serum samples available after diagnosis. The timing of serum sample collection ranged from 9.4 years prior to the diagnosis of SLE to 6 years after diagnosis.

Clinical chart review.

Upon joining the US military, all recruits receive an evaluation at baseline that includes assessment of height, weight, temperature, pulse, and blood pressure, a “head-to-toe” history and physical examination, and a vision test, hearing test, complete blood cell count, urinalysis, and lipid profile. Female military personnel receive annual examinations thereafter, while male military personnel must have examinations at least every 5 years. In addition, soldiers have periodic physical examinations before and after deployment, which include the parameters evaluated in the baseline examination. Finally, all military personnel have additional symptom-directed examinations and laboratory evaluations as warranted. Periodic evaluations of military personnel may be influenced by the number of times they are deployed; however, specific types of service should not dramatically alter these evaluations for the majority of individuals.

Medical records were reviewed by a rheumatology-trained physician and/or nurse. Clinical and laboratory features for each case were obtained and collected in standardized data extraction forms. Stringent documentation requirements were used for review of the medical record. Various levels of evidence were graded as follows: 0 = no evidence, 1 = patient-reported evidence, 2 = physician-reported evidence not confirmed by physical examination findings, and 3 = physician-observed evidence documented in the medical record. All designations used in this study had level 3 evidence. Each ACR criterion was recorded as being either present or absent, in addition to the time when the criterion was first observed.

Information was also gathered on predefined aspects of the following symptoms or clinical features that are common in patients with SLE and SLE overlap syndromes: fever, fatigue, alopecia, rash, scleroderma, avascular necrosis, myositis, rheumatoid arthritis, Sjögren's syndrome, congestive heart failure, chronic obstructive pulmonary disease, myocardial infarction, asthma, pleural effusion, dialysis, renal insufficiency, renal transplant, headache, Raynaud's phenomenon, stroke, vasculitis, sicca complex, lymphoma, and inflammatory myopathy.

Demographic information obtained included ethnicity, sex, and age at disease onset (i.e., time at which the individual met at least 4 ACR criteria for the classification of SLE).

Autoantibody assays.

The presence of ANAs was determined using indirect immunofluorescence with HEp-2000 cells (Immunoconcepts, Sacramento, CA). The detection of antibodies at a 1:120 dilution was considered a positive result. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate sera for antibodies to common lupus autoantigens. One microgram of Sm, nuclear RNP (nRNP), Ro, or La (ImmunoVision, Springdale AR) per well was plated. These methods have been previously described in detail (20, 21). Anti-dsDNA antibodies were screened with a solid-phase assay (Varelisa; Pharmacia & Upjohn, Freiburg, Germany). All tests with equivocal results were repeated, and sera with persistently equivocal results for anti-dsDNA were tested by a Crithidia assay (Protrac Industries, Kerrville, TX), as previously described (17).

Anti-C1q antibody detection.

Antibodies to C1q were evaluated by ELISA. One microgram of antigen (C1q; Sigma, St. Louis, MO) was coated in each well of a 96-well polystyrene plate. Patient and control samples were titered to a dilution of 1:100 and incubated for 3 hours at room temperature. The secondary antibody anti-human conjugate (Jackson ImmunoResearch, West Grove, PA) was added at a 1:10,000 dilution and incubated overnight at 4°C. Paranitrophenyl phosphate disodium substrate was added, and development was read at 410 nm on the microplate reader. These results were standardized to the positive control at an optical density (OD) of 1.0.

RF assays.

A modified ELISA protocol was used to test for IgG-RF and IgM-RF. For the IgG-RF assay, 0.5 μg of human IgG Fc fragment (Sigma) was coated per well. For the IgM-RF assay, 0.5 μg of whole human IgG (Jackson ImmunoResearch) was coated per well. Plates were then incubated at room temperature for 2 hours, washed twice with wash solution (0.5% Tween in phosphate buffered saline [PBS]), then blocked with 100 μl/well 0.1% bovine serum albumin (BSA) and 3% milk in PBS and incubated at room temperature for 1.5 hours. Plates were washed twice with wash solution after the blocking step. Sera were diluted with 0.1% BSA and 0.5% Tween in PBS to dilutions of 1:100 and 1:1,000, and 2 replicates were plated for each sample dilution, using 50 μl/well. After 2 hours of incubation at room temperature, wells were washed 4 times and alkaline phosphatase–conjugated anti-human IgG or IgM (Sigma) was added at a final concentration of 1:5,000 and incubated overnight at 4°C. Wells were washed 4 times with wash solution, then 50 μl of a 1-mg/ml solution of paranitrophenyl phosphate was added to each well. ELISA results were read at 410 nm with a 490-nm reference, and each plate was read when the positive control had an OD of 1.0.

Statistical analysis.

For each criterion, the mean and median time periods from the first observed positive test result to diagnosis were calculated, using all individuals in whom symptoms ever developed as well as only those individuals in whom symptoms developed before the diagnosis of SLE (Table 1). Categorical variables (e.g., ethnicity and sex) were assessed by the chi-square statistic. Results of ELISAs that were ≥3 SD above normal background binding were considered positive. Z tests were used to test the significance of the proportion of patients in whom the development of antibodies preceded the presence of clinical criteria versus the proportion of patients in whom clinical criteria were present before the appearance of autoantibodies.

Table 1. Development of systemic lupus erythematosus symptoms*
SymptomPatients in whom symptom occurred before diagnosisAll patients in whom symptom developed
nMeanMediannMeanMedian
  • *

    Values are the number of years, with negative values indicating prediagnosis. NA = not applicable.

Malar rash13−0.99−0.58390.010
Discoid rash13−3.13−0.8323−1.74−0.42
Photosensitivity11−0.83−0.6747−0.080
Oral ulcers5−0.7−0.56510.320
Arthritis57−1.36−0.58112−0.68−0.17
Pericarditis3−0.42−0.42190.30
Pleuritis11−1.51−0.5461−0.120
Proteinuria11−1.6−0.5457−0.120
Renal casts4−0.58−0.4638−0.130
Seizures3−5.56−5.588−1.70−0.04
Psychosis1NANA6−0.33−0.04
Hemolytic anemia1NANA170.130
Leukopenia23−0.97−0.5879−0.080
Lymphopenia20−1.08−0.8385−0.010
Thrombocytopenia7−2.04−0.9215−0.96−0.08

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Gradual accrual of clinical criteria before diagnosis in most patients.

Among 130 patients with lupus, we identified 104 (80%) in whom at least 1 ACR-defined clinical criterion was present before the diagnosis of SLE was made. Among these 104 patients, 74 had a single clinical criterion appear before any other criteria were present, 26 patients had simultaneous development of 2 clinical criteria, and only 4 patients initially had 3 criteria, as recorded in the medical records.

The remaining 26 patients (20%) had no clinical criteria before the time at which SLE was classified but rather presented to the clinician with ≥4 diagnostic criteria. Of these 26 patients, 7 presented with 6 clinical criteria, 13 patients presented with 5 criteria, and 6 patients presented with 4 criteria. Interestingly, among the patients who presented with ≥4 criteria, half had renal disease and nearly half (12 of 26) had serositis. No statistically significant differences in sex, age at disease onset, or ethnicity were observed in these patients with sudden-onset SLE.

On average, the first clinical criterion was present 0.38 years prior to SLE classification according to the ACR criteria; however, the average length of time between development of each specific criterion and classification of ACR varied (Table 1). When all patients in whom the given criteria eventually developed were analyzed, discoid rash and seizures had the earliest mean onset times (1.74 and 1.70 years prior to diagnosis, respectively). Interestingly, central nervous system (CNS) disease, which was one of the earliest criteria to appear in patients in this study, did not commonly appear after diagnosis during the time these patients were monitored and documentation was available. In our patient population, CNS-related conditions developed in 10 patients; 6 of these patients had only seizures, 2 had only psychosis, and 2 patients had both seizures and psychosis. Nine of the 10 patients in whom CNS disease ever developed had this criterion prior to the diagnosis of SLE.

The initial clinical presentation varied widely from patient to patient, with each major classification criterion being present before diagnosis in at least 1 person (Figure 1). In the 105 individuals in whom ACR clinical criteria were present before SLE diagnosis, the most common symptom was arthritis, which was present in 57 (54%) of 105 individuals. When patients were analyzed according to ethnicity, the most common presenting criteria differed. Early evidence of malar rash and photosensitivity was significantly more common in European Americans than in African Americans (χ2 = 8.39, P = 0.003 and χ2 = 4.83, P = 0.03, respectively) (Figure 2a). Men were significantly more likely than women to present with renal disease as a first manifestation (χ2 = 9.24, P = 0.003), regardless of ethnicity (Figure 2b).

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Figure 1. Patients with systemic lupus erythematosus (SLE) who were positive for each American College of Rheumatology classification criterion, before the diagnosis of SLE and ever. Hemo. = hemolytic; CNS = central nervous system.

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Figure 2. Initial American College of Rheumatology criterion identified in 104 patients with SLE. a, Differences between European Americans and African Americans. b, Differences between men and women. ∗ = P = 0.003; ∧ = P = 0.03. See Figure 1 for definitions.

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Of the patients in whom clinical criteria developed before diagnosis and who ever were positive for ANAs (n = 97), 81 (84%) were positive for ANAs before the appearance of the first clinical criterion. Additionally, 5 patients (5%) had ANA positivity in their first available serum sample; however, they had a clinical criterion noted before this first sample was available. In the 11 patients in whom criteria were present before ANA positivity, the most common features were discoid rash (n = 4 patients [36%]) and arthritis (n = 3 patients [27%]).

In addition to the ACR clinical criteria, several symptoms that are common in patients with SLE and SLE overlap syndromes that are not considered SLE criteria were identified in our chart review. Several of these symptoms were common in our population, including fever in 34 patients, alopecia in 41 patients, headaches in 42 patients, Raynaud's phenomenon in 40 patients, and sicca complex in 12 patients.

Development and appearance of RF.

Because arthritis was the most common initial ACR criterion, all patient samples were analyzed for RF to determine whether the presence of this autoantibody preceded the onset of arthritis. In this study, 17 (13%) of 130 patients had IgG-RF, and clinically significant arthritis eventually developed in 16 of these IgG-RF–positive patients (94%) (Figure 3a). The presence of IgG-RF preceded the development of arthritis in 15 of the 16 patients (94%) who were positive for IgG-RF and in whom arthritis developed (Z = 10.2, P < 0.0001), and IgG-RF appeared within 3 months of arthritis onset in the 1 remaining patient (Figure 3c). In these cases, IgG-RF was present a mean 2.07 years prior to the first documented symptom of arthritis. IgM-RF was detected in 32 (25%) of 130 patients (Figure 3b) and appeared a mean 1.9 years prior to SLE diagnosis. Twenty-seven patients were positive for IgM-RF without IgG-RF. Arthritis developed in 17 (74%) of these patients, and IgM-RF preceded arthritis development in 13 of 17 patients (76%) (Figure 3d). Neither type of RF was associated with early onset or increased overall severity of SLE, and no sex or ethnicity differences were associated with RF.

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Figure 3. Relationship between autoantibodies and associated clinical symptoms in patients with systemic lupus erythematosus (SLE). a, Presence of rheumatoid factor (RF) autoantibodies before and after the diagnosis of SLE. b, The number of patients positive for RF (either IgG, IgM, or both) and the number of patients in whom arthritis eventually developed. c, In all but 1 patient, the presence of IgG-RF preceded the development of arthritis (P < 0.0001). d, In 13 of 17 patients in whom arthritis eventually developed, IgM-RF was present prior to arthritis. e and f, In the majority of patients with both renal disease and anti–double-stranded DNA (anti-dsDNA) (e) or renal disease and anti-C1q antibodies (f), the autoantibodies were detected before the onset of renal disease.

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Development of renal disease and the appearance of anti-dsDNA and anti-C1q antibodies.

Renal disease in SLE has previously been closely associated with the presence of anti-dsDNA. In this SLE cohort, 80 patients were positive for antibodies directed against dsDNA, and ACR-defined renal disease developed in 38 of these patients (P = 0.05) (17). In 35 (92%) of these 38 patients, anti-dsDNA antibodies were detectable before or concurrently with the onset of renal disease (Z = 13.3, P < 0.0001) (Figure 3e). In the remaining 3 patients, evidence of ACR-defined renal disorder appeared prior to the appearance of anti-dsDNA.

Thirty-five (27%) of the 130 patients in our cohort were positive for anti-C1q antibodies by screening ELISA. No significant difference in sex, ethnicity, or age at disease onset between the C1q-positive patients and the C1q-negative patients was demonstrated. Analysis of these 35 individuals revealed that 18 (51.4%) met the ACR criteria for renal disorder (either proteinuria or cellular casts); however, renal disorder was not statistically associated with the presence of antibodies directed against C1q, using this screening method. In the 18 patients with both anti-C1q antibodies and nephritis, the presence of autoantibodies to C1q preceded the onset of renal disorder in 13 patients (Z = 2.86, P = 0.0043) (Figure 3f). Furthermore, anti-C1q autoantibodies were detected a mean 1.4 years before the onset of renal disorder (median 1.56 years prior) in patients with both features.

Temporal relationship between autoantibodies and nonassociated clinical criteria.

To determine the importance of our findings that clinical symptoms develop after the appearance of associated autoantibodies, we also analyzed the appearance of autoantibodies compared with randomly chosen clinical criteria not associated with them. When comparing antibodies against Sm or nRNP with the appearance of photosensitivity, we observed that these antibodies did not appear before the onset of photosensitivity in a significant number of patients (Z = 1.64, P = 0.101 and Z = 1.70, P = 0.09, respectively). Similarly, anti-dsDNA antibodies did not appear before discoid rash in patients with both anti-dsDNA antibodies and discoid rash (Z = 0.57, P = 0.59), and IgG-RF did not appear before hematologic abnormalities (Z = 2.2, P = 0.03). The additional symptoms analyzed (Raynaud's phenomenon, sicca complex, headaches, alopecia, and fever) were not associated with any specific autoantibodies.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The initial presentation of SLE can be unpredictable, involving a myriad of manifestations that wax and wane over time, clouding the diagnosis and delaying prompt institution of therapy. In addition to the confusing clinical symptoms, a multitude of laboratory manifestations can appear that may or may not correlate with disease severity or progression. Some autoantibody profiles seem to correlate with specific clinical manifestations, but these relationships remain incompletely understood. In this study, the clinical records and sera of 130 patients with SLE were obtained from a military repository and evaluated to determine the associations between the time frame of autoantibody presentation and clinical manifestations.

In 104 patients in our study, clinical criteria appeared before SLE was diagnosed. The symptoms that appeared earliest were discoid rash and seizures, with a mean onset of 1.74 and 1.70 years, respectively, before diagnosis. CNS disease is a rare manifestation of SLE, and discoid rash more frequently occurs as a primary form of lupus. However, the relatively early appearance of both of these criteria in patients in whom SLE later developed should heighten suspicion for potential SLE among patients in whom these disorders develop along with other suggestive features. In this cohort, discoid rash and seizures did not generally occur after the diagnosis of lupus. On the contrary, oral ulcers frequently appeared after patients had met SLE criteria and are therefore less useful as an early diagnostic marker.

Arthritis is the most common ACR-defined clinical criterion for a diagnosis of SLE and tended to appear before fulfillment of disease classification in this patient group. Evaluation of SLE-specific manifestations and lupus-specific autoantibodies is clearly appropriate in patients presenting with primarily evidence of inflammatory arthritis, especially when treatment with biologic response modifiers is being considered; some of these agents are suitable for patients with rheumatoid arthritis but present concerns for certain patients with SLE. Because RF can be present in sera from patients with rheumatoid arthritis as well as sera from patients with SLE, additional clinical investigation seems to remain warranted in the presence of this autoantibody. However, in the majority of patients with arthritis in this study, RF did not develop during the course of the study.

Renal disease is considered one of the worst prognostic indicators in patients with SLE (22). The presence of autoantibodies has frequently been analyzed for clinical correlations and to evaluate potential pathogenic mechanisms. The most consistent association known is with high titers of anti-dsDNA autoantibodies. Previous work by our group has confirmed the association between anti-dsDNA and renal disease and has shown that the association exists even prior to the diagnosis of SLE; our group also has described increases in anti-dsDNA titers at the time of diagnosis (17). In the current study, anti-dsDNA autoantibodies appeared prior to or at the same time as ACR-defined renal disorder in the majority of patients who had both the autoantibodies and renal involvement (Figure 3e). Although the case for a pathogenic role for dsDNA antibodies continues to build, the exact initiation mechanisms remain uncertain.

Some studies have suggested a correlation between the presence of anti-C1q antibodies and renal disease, although such a correlation was not confirmed in this study while using ACR definitions of renal disorder. This lack of association may be influenced by unique aspects of the population studied or differences in technical approaches. However, in patients who were found to have antibodies to C1q as well as renal disorder criteria, the development of autoantibodies generally preceded the detection of renal abnormalities.

Based on the nature of the clinical documentation used in this study, several intrinsic limitations and potential biases are present. First, interpretation of the results of this study is limited by the clinical definitions and retrospective chart review methods used. Specifically, we used ACR-defined criteria to capture clinical symptoms. The criterion for renal disease may not be met by some lupus patients with class IIb and/or class III renal disease without documentation of proteinuria or cellular casts. Second, although at least 1 prediagnosis serum sample was available for each patient (and more than 1 sample was available for most patients), the specific time points that could be analyzed were limited to what was available from the repository. Third, clinical information is dictated by what can be obtained through retrospective chart review and the frequency of physician visits by each patient. These health care provider interactions are potentially different between individuals, based upon frequency of deployment, sex, and age. In addition, physical examinations were not performed specifically to identify ACR-defined criteria for the classification of SLE; therefore, some criteria, such as oral ulcers, may have been less likely to be identified. The timing of evaluations could also be influenced by the likelihood of a particular individual's seeking health care for a specific symptom or problem, which could potentially skew the results based on a quicker presentation of patients with severe clinical symptoms, such as seizures or serositis. Finally, we were concerned that our data could be biased by the early appearance of autoantibodies in general. Therefore, we analyzed the relationship between several autoantibodies and nonassociated clinical criteria and found that there was no significant relationship, thus further supporting the associations that were observed.

Despite these limitations, results of the current study strongly support a defined temporal relationship between the accrual of autoantibodies and fulfillment of associated clinical criteria. This study also suggests an important role for the early detection of autoantibodies in the clinical management of SLE.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Dr. James had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Heinlen, Harley, James.

Acquisition of data. Heinlen, Akbarali, James.

Analysis and interpretation of data. Heinlen, McClain, Merrill, Harley, James.

Manuscript preparation. Heinlen, McClain, Merrill, Edgerton, Harley, James.

Statistical analysis. Heinlen, Harley, James.

Acquisition of samples. Harley.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We thank Donny Wynn, MD, Melissa Arbuckle, MD, PhD, Valerie Skaggs, PhD, and the referring military rheumatologists.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  • 1
    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 12717.
  • 2
    Hochberg MC, for the Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997; 40: 1725.
  • 3
    Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971; 50: 8595.
  • 4
    Jacobsen S, Petersen J, Ullman S, Junker P, Voss A, Rasmussen JM, et al. A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets. Clin Rheumatol 1998; 17: 46877.
  • 5
    Font J, Cervera R, Ramos-Casals M, Garcia-Carrasco M, Sents J, Herrero C, et al. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. Semin Arthritis Rheum 2004; 33: 21730.
  • 6
    Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol 2003; 21: 31320.
  • 7
    Danieli MG, Fraticelli P, Salvi A, Gabrielli A, Danieli G. Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin Rheumatol 1998; 17: 195201.
  • 8
    Mosca M, Neri R, Bencivelli W, Tavoni A, Bombardieri S. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years. J Rheumatol 2002; 29: 23459.
  • 9
    Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria [review]. Clin Exp Rheumatol 1999; 17: 61520.
  • 10
    Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Kalden JR, et al, for the SLE Study Group. Rheumatoid factors in systemic lupus erythematosus: association with clinical and laboratory parameters. Rheumatol Int 2000; 19: 10711.
  • 11
    Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev 2005; 4: 25363.
  • 12
    Dillon CF, Jones JV, Reichlin M. Antibody to Ro in a population of patients with systemic lupus erythematosus: distribution, clinical and serological associations. J Rheumatol 1983; 10: 3806.
  • 13
    Kurien BT, Newland J, Paczkowski C, Moore KL, Scofield RH. Association of neutropenia in systemic lupus erythematosus (SLE) with anti-Ro and binding of an immunologically cross-reactive neutrophil membrane antigen. Clin Exp Immunol 2000; 120: 20917.
  • 14
    Maddison PJ, Reichlin M. Deposition of antibodies to a soluble cytoplasmic antigen in the kidneys of patients with systemic lupus erythematosus. Arthritis Rheum 1979; 22: 85863.
  • 15
    Reichlin M, Wolfson-Reichlin M. Correlations of anti-dsDNA and anti-ribosomal P autoantibodies with lupus nephritis. Clin Immunol 2003; 108: 6972.
  • 16
    Trouw LA, Groeneveld TW, Seelen MA, Duijs JM, Bajema IM, Prins FA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 2004; 114: 67988.
  • 17
    Arbuckle MR, James JA, Kohlhase KF, Rubertone MV, Dennis GJ, Harley JB. Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol 2001; 54: 2119.
  • 18
    Winfield JB, Faiferman I, Koffler D. Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus: association of high avidity antinative DNA antibody with glomerulonephritis. J Clin Invest 1977; 59: 906.
  • 19
    Mannik M, Merrill CE, Stamps LD, Wener MH. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus. J Rheumatol 2003; 30: 1495504.
  • 20
    McClain MT, Ramsland PA, Kaufman KM, James JA. Anti-sm autoantibodies in systemic lupus target highly basic surface structures of complexed spliceosomal autoantigens. J Immunol 2002; 168: 205462.
  • 21
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 152633.
  • 22
    McLaughlin J, Gladman DD, Urowitz MB, Bombardier C, Farewell VT, Cole E. Kidney biopsy in systemic lupus erythematosus. II. Survival analyses according to biopsy results. Arthritis Rheum 1991; 34: 126873.