Research ArticleArticle

Anti-dsDNA and Antichromatin Antibody Isotypes in Serologically Active Clinically Quiescent Systemic Lupus Erythematosus

Amanda J. Steiman, Murray B. Urowitz, Dominique Ibañez, Timothy T. Li, Dafna D. Gladman and Joan Wither
The Journal of Rheumatology May 2015, 42 (5) 810-816; DOI: https://doi.org/10.3899/jrheum.140796

Abstract

Objective. Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) are clinically quiescent despite serologic activity. Since studies suggest that antichromatin antibodies are more sensitive than anti-dsDNA antibodies in detecting active SLE, and that immunoglobulin (Ig) G, in particular complement-fixing subclasses, may be more pathogenic than IgM, we investigated the levels of anti-dsDNA and antichromatin isotypes in SACQ patients as compared to non-SACQ patients with SLE.

Methods. Levels of IgM, IgA, IgG, and IgG1–4 antichromatin and anti-dsDNA were measured by ELISA. SACQ was defined as ≥ 2 years with the SLE Disease Activity Index 2000 (SLEDAI-2K) at 2 or 4 from serologic activity, during which patients could be taking antimalarials, but not corticosteroids or immunosuppressives. Unselected non-SACQ patients with SLE were used as comparators. SACQ patient serum samples were further stratified based on subsequent development of flare, defined as clinical SLEDAI-2K ≥ 1 and/or treatment initiation. Nonparametric statistics were used, and generalized estimating equations were applied to account for multiple samples in the same patient.

Results. SACQ patients’ complement-fixing antichromatin and anti–dsDNA IgG subclasses were significantly higher than those of non-SACQ patients. When the sample drawn latest in a SACQ period was analyzed, there was no difference between antichromatin or anti-dsDNA isotype or IgG subclass levels between patients who flared and those who remained SACQ, nor were consistent trends seen when samples were examined during SACQ and flare in the same patient.

Conclusion. The SACQ phenotype does not arise from a lack of pathogenic anti-dsDNA and/or antichromatin autoantibodies. Neither increases in antichromatin nor anti-dsDNA isotype or IgG subclass levels were predictive of or coincident with flare in SACQ patients.

Key Indexing Terms:

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by exacerbations and remissions in affected organ systems. In many patients with SLE, serum levels of anti-dsDNA antibodies and/or complement correlate with disease course, and can thus be of use in predicting disease flare; however, in other patients, clinical and serologic courses are discordant1. One such group of patients, termed serologically active clinically quiescent (SACQ), manifests persistent elevations in anti-dsDNA and/or hypocomplementemia in the absence of clinical manifestations of SLE over a protracted period of time2.

Currently, the mechanisms by which SACQ patients remain clinically inactive despite elevations of anti-dsDNA and/or hypocomplementemia remain unclear. It has been suggested that not all anti-dsDNA are equally pathogenic, with anti-dsDNA of high avidity, of immunoglobulin (Ig) G isotype, and complement-fixing IgG subclass best correlating with disease activity and renal involvement3,4,5,6,7,8,9,10,11. As a corollary, IgM isotype and non-complement-fixing IgG subclasses best correlate with disease quiescence. Further, antibodies to chromatin (antichromatin), the native nuclear form of DNA and histone proteins (or its repeating element, the nucleosome), have been shown by some to be of higher sensitivity and specificity than anti-dsDNA for SLE disease activity, especially when the latter is not present or proves discordant12,13,14,15,16,17,18,19,20. These findings raise the possibility that the anti-dsDNA and antichromatin Ig isotypes of SACQ patients are less pathogenic than those seen in the general SLE population.

In our study, we have examined anti-dsDNA and antichromatin Ig isotypes in SACQ and a cohort of unselected non-SACQ patients with SLE to address this possibility. We show that SACQ patients have at least equivalent levels of pathogenic Ig isotypes to other patients with SLE. We further demonstrate that there is no difference in Ig isotypes between SACQ patients who remain SACQ and those who ultimately flare, nor were consistent changes seen in the same patients assayed during the SACQ period and at flare. Thus, alternate immunologic mechanisms must be sought to explain SACQ patients’ clinical quiescence.

MATERIALS AND METHODS

Patient selection

The University of Toronto Lupus Clinic at the Centre for Prognosis Studies in the Rheumatic Diseases was established in 1970 to study clinical-laboratory correlations in SLE. All patients fulfilled 4 or more of the 1971 or 1982 American College of Rheumatology classification criteria, or 3 criteria together with a typical renal biopsy lesion of SLE. The clinic’s patients range from those with acutely active disease to patients in complete remission and not receiving any therapy21. All patients were followed with clinical and laboratory information collected using a standardized protocol at clinic visits, typically at 2-month to 6-month intervals that occur regardless of disease activity. For our study, patients registered in the Lupus Clinic database between July 1970 and April 2008 with visits no more than 18 months apart were identified.

SACQ was defined as at least a 2-year period without clinical activity but with persistent serologic activity [SLE Disease Activity Index 2000 (SLEDAI-2K) = 2 or 4, from positive anti-dsDNA antibody and/or hypocomplementemia only, at each clinic visit]. The patients could be taking antimalarials, but those treated with corticosteroids or immunosuppressive medications were excluded, ensuring the clinicians’ impression of clinical quiescence. Disease flare was defined by any increase in the SLEDAI-2K at a clinic visit not accounted for by either hypocomplementemia or anti-dsDNA, or by the initiation of corticosteroid or immunosuppressive treatment. Unselected patients with SLE were used as controls and consisted of non-SACQ clinic patients with variable clinical and serologic activity whose serum was archived within 1 year of a corresponding SACQ patient. Healthy controls were recruited from hospital and laboratory staff members who had no family history of autoimmune disease. The mean age of the controls was 34.8 years and 87.5% were women. All subjects signed informed consent forms and patients signed a consent form that allowed their clinical, serologic, and genetic material to be studied and reported.

Laboratory analyses

Archived serum samples of patients stored at −80°C that had not undergone a previous freeze-thaw cycle were retrieved. Serum levels of IgM, IgA, IgG, IgG1, IgG2, IgG3, and IgG4 anti-dsDNA and antichromatin antibodies were measured by ELISA using an approach adapted from our previous mouse and human SLE studies22,23. Briefly, H1-stripped chromatin (mainly mono- and dinucleosomes) was prepared from the human cell line, MOLT424. ELISA plates (Immunolon 2HB, VWR) were coated overnight with dsDNA (40 µg/ml) or chromatin (8 µg/ml) diluted in phosphate buffered saline at 4°C. Serum was diluted 1/100 for the measurement of IgM, IgA, and IgG, or 1/50 for IgG1–4. Bound antibodies were detected using alkaline-phosphatase conjugated goat anti-human IgM, IgA, or IgG antibodies (1:1000 dilution, all from Cedarlane), or biotin conjugated mouse anti-human IgG1–4 antibodies (1:500 dilution, all from Cedarlane except IgG2 from Caltag), followed by detection with alkaline-phosphatase conjugated streptavidin (1:1000 dilution). Absorbance was read at 405 nm. All assays were performed in triplicate. To control for interplate and interassay variability, the same positive control sera were on each plate. Although these sera were included to enable normalization of the sample values between plates if significant differences were noted, the values for these sera were very reproducible between assays and, therefore, no normalization was required between plates. To ensure that the antibodies being measured were specific for nucleosomes or dsDNA, plates with no antigen bound were included in every assay, and binding in the absence of antigen was subtracted.

Statistical analysis

Wilcoxon rank sum tests and generalized estimating equations (GEE) were used to report p values. The use of multiple samples from 1 patient was adjusted for through the use of a repeated measure model with an exchangeable correlation structure.

RESULTS

Thirty-eight serum samples from 23 patients, drawn during a prolonged SACQ period, were analyzed. Fifteen of the 38 samples (39%) corresponded to 9 patients whose SACQ period eventually ended in flare. Patient demographics did not differ between those who remained SACQ and those who ultimately flared (Table 1). Among those who flared, disease activity manifested mainly as arthritis or mucocutaneous involvement; 1 patient had serositis, another hemolytic anemia necessitating corticosteroid use, and none had major organ manifestations. Twenty-one unselected non-SACQ patients with SLE, whose serum was stored contemporaneously, were used as comparators. These patients had an age and disease duration similar to those of the SACQ patients, but were more likely to have received steroids and/or immunosuppressive medications than the SACQ patients. Similar proportions of SACQ patients and non-SACQ patients were treated with antimalarials at the time of study, but 71% of the non-SACQ patients were also receiving prednisone and 67% were taking immunosuppressive medications. The majority of patients were clinically active [17/21 (81%), clinical SLEDAI > 0] with a mean SLEDAI of 7.9 ± 5.9. All 23 SACQ patients and 20/21 of non-SACQ patients (95.2%) were anti-dsDNA–positive (by Farr assay, p = 0.48), with mean levels 25.0 ± 22.9 u/ml and 44.9 ± 33.0 u/ml, respectively (p = 0.03).

View this table:
Table 1.

Patient demographics divided by SACQ outcome. Values are mean ± SD or n (%) unless otherwise specified.

With the exception of IgM anti-dsDNA antibodies (which were lower in non-SACQ patients with SLE), antichromatin and anti-dsDNA IgG, IgM, IgG, or IgG/IgM levels among SACQ patients (using only the most recent sample when more than 1 sample was available) were not significantly different from those seen in the non-SACQ SLE cohort, and were significantly elevated as compared to healthy controls (Table 2). In general, the proportion of SACQ and non-SACQ patients with SLE who had elevated levels (> 2 SD above mean) of IgA, IgM, or IgG anti-dsDNA or antichromatin antibodies also did not differ, except that SACQ patients had an increased proportion of IgM anti-dsDNA antibodies [anti-dsDNA SACQ vs non-SACQ: IgA 13% vs 14%, IgM 35% vs 0% (p = 0.004), IgG 65% vs 38%. Antichromatin SACQ vs non-SACQ: IgA 43% vs 38%, IgM 48% vs 38%, IgG 91% vs 67%]. Further, when subdivided by IgG subclass (and after adjusting for multiple comparisons), SACQ patients’ levels of antichromatin IgG1 and 3, and anti-dsDNA IgG1 were significantly higher than those of the non-SACQ patients with SLE, with a trend toward higher levels of IgG2 in SACQ patients for both autoantibodies. IgG4 did not differ between groups (Figure 1).

Figure 1.
Figure 1.

Comparison of IgG subclass, measured by ELISA, between SACQ patients with SLE and unselected SLE controls. IgG: immunoglobulin G; SACQ: serologically active clinically quiescent; SLE: systemic lupus erythematosus.

View this table:
Table 2.

Antichromatin and anti-dsDNA levels in SACQ patients as compared to unselected non-SACQ patients and healthy controls. Values are mean ± SD (range) unless otherwise specified.

When a single sample drawn during a SACQ period per patient was analyzed, there was no difference between antichromatin or anti-dsDNA isotypes, or IgG subclass levels between SACQ patients who flared and those who remained SACQ (Table 3). When all samples were included using a GEE, antichromatin IgG2 and anti-dsDNA total IgG levels were significantly higher in SACQ patients who remained quiescent (p < 0.0001 for both, data not shown). There was no difference in antichromatin or anti-dsDNA IgG/IgM ratio in those SACQ patients who ultimately flared versus those who did not (Table 3). There was no correlation between the levels of anti-dsDNA or antichromatin Ig isotype or IgG subclass and time to flare. The mean time to flare (or most recent SACQ visit) from last sample analyzed was 2.1 years and 2.2 years in SACQ patients who remained SACQ and those who flared, respectively (ranges 1.0–3.8 yrs and 0.7–6.9 yrs, respectively). Following adjustment for the length of time between sample outcome dates, there was still no correlation between the levels of autoantibodies and flare (data not shown). A time-to-event analysis corroborated these negative findings.

View this table:
Table 3.

Mean antichromatin and anti-dsDNA levels in SACQ patients who subsequently flared versus those who remained SACQ (1 sample per patient). Values are mean ± SD unless otherwise specified.

There were only 5 patients in whom serologic samples were available both during SACQ periods and at the time of flare. Given the small sample size, these data were analyzed only qualitatively. (In the cases where > 1 sample was available for a disease state, the mean autoantibody level was recorded.) There did not appear to be any trend in fluctuations in autoantibody levels between SACQ and flare in any of these patients (Table 4).

View this table:
Table 4.

Comparison of autoantibody levels taken in the same patient during SACQ versus during flare*. Values are mean optical density as determined by ELISA.

DISCUSSION

SACQ patients with SLE represent a unique phenotype with clinical and serologic discordance. Previously, we have shown that among this unique patient subset, reflecting 6% of our SLE cohort, there are no clinical predictors of flare. Similarly, fluctuations in anti-dsDNA and/or complement levels in SACQ patients during a SACQ period were not predictive of disease flare25. The observation that SLE-related organ damage does not accrue subclinically during a prolonged SACQ period supports the practice of close clinical monitoring without the use of prophylactic corticosteroid or immunosuppressive medications26. However, damage does begin to accrue again once these patients flare, and thus a serologic marker of impending flare would permit early reintroduction of therapy. In our study, we examined autoantibody isotypes and IgG subclasses in SACQ patients to determine whether the lack of clinical symptoms in these patients arises from the presence of less pathogenic autoantibodies and to address whether changes in the level and types of autoantibodies predict or occur concurrently with subsequent flares.

Previously, increased levels of IgG as compared to IgM anti-dsDNA antibodies have been shown to be associated with active disease. For instance, Kessel, et al found that the SLEDAI was increased in patients whose anti-dsDNA IgG titers were higher than anti-dsDNA IgM titers9. Förger, et al also studied the anti-dsDNA IgG/IgM ratio in over 200 patients with SLE, and found that this ratio was a significant variable in distinguishing patients with and without nephritis7. Similar findings were observed by Villalta, et al, who also observed an association between anti-dsDNA IgA and IgA/IgM ratio with renal disease in SLE27. It has been theorized that IgM may be protective because of its ability to downregulate autoreactive B cells, resulting in decreased pathogenic IgG production9. Alternatively, IgM may act by binding circulating antigens, activating complement, and accelerating immune complex clearance. In support of this concept, administration of anti-dsDNA IgM to SLE-prone mice resulted in attenuated renal pathology and improved survival28. In contrast to these previous studies, we found no significant difference between the levels of IgG, IgM, or IgG/IgM ratio between SACQ and non-SACQ patients, and a trend toward somewhat higher IgG and lower IgM in SACQ patients who remained SACQ compared to those who flared (Table 2). While these later results did not achieve statistical significance (except for IgG anti-dsDNA using the GEE model), the consistency of this trend across both antichromatin and anti-dsDNA, regardless of whether 1 or multiple samples were analyzed, suggests that “protective” serology is not the driver of SACQ status.

Antinucleosome antibodies are among the first detected in the sera of patients with SLE. They are thought to be pathogenic, as evidenced by their presence in glomerular deposits and eluates of patients with SLE nephritis19,29,30. In fact, it is only through epitope spreading that nucleosome-specific T cells stimulate B cells to produce anti-dsDNA and antihistone antibodies19. In contrast, although anti-dsDNA is a hallmark of SLE, free dsDNA has been found to be poorly immunogenic. In their native state, strands of dsDNA are complex with histones in chromatin, and chromatin rather than free dsDNA is thought to be one of the main drivers of the immune response in SLE31. Consistent with this central role of chromatin, there is general consensus that antinucleosome antibodies are both sensitive and specific for SLE diagnosis and disease activity12,19,20,32, although the antinucleosome antibodies have also been reported in the antiphospholipid syndrome33. A metaanalysis by Bizzaro, et al determined that in selected studies, antinucleosome antibodies, but not anti-dsDNA, were associated with disease activity (p < 0.0001)19. This is further supported by a study by Suleiman, et al, who found that antinucleosome antibodies were 98% sensitive and 86% specific for detecting active SLE, versus 61% and 84% for anti-dsDNA sensitivity and specificity, respectively12. On the basis of these findings, we reasoned that the levels of antichromatin antibodies would correlate more closely than anti-dsDNA with the difference in disease activity between SACQ and non-SACQ patients, or with flares in disease activity within the SACQ population. However, our results for antichromatin antibodies were remarkably similar to those for anti-dsDNA, indicating that clinical quiescence in SACQ patients does not arise from less pathogenic antichromatin isotypes. Further, they do not predict or occur concurrently with flares in these patients. Our findings contrast with those of Ng, et al34, who investigated the levels of antinucleosome antibodies in “SACQ” patients and found that the presence and titer of these antibodies was significantly correlated with time to first flare after a SACQ period. However, it should be noted that in their study, “SACQ” status was defined quite differently from ours as a British Isles Lupus Assessment Group index score < 6 without any mention of a requirement of successful weaning from corticosteroids and/or immunosuppressive medications. Thus, our patients represent a subset different from those studied by Ng, et al, whose patients had low — but not absent — disease activity that may have merely been suppressed by ongoing treatment rather than reflecting a true SACQ remission, as we had defined it.

There are significant differences in the function of the different subclasses of IgG. IgG1 and IgG3 are excellent activators of complement and bind efficiently to Fc receptors on proinflammatory cells, whereas IgG2 and IgG4 do not. Thus, differences in the subclasses of autoantibodies produced could affect clinical disease activity and tissue damage. Consistent with this concept, several studies have found that higher levels of IgG (over IgM) autoantibodies, especially of the complement-fixing subclasses IgG1 and IgG3, are predictive of SLE disease activity5,9,28,35. These findings raised the possibility that SACQ patients might maintain clinical quiescence through the production of less pathogenic IgG subclasses. However, this was not the case. Indeed, the levels of SACQ patients’ complement-fixing antichromatin and anti-dsDNA IgG subclass autoantibodies were consistently significantly higher than those seen in the (generally clinically active) non-SACQ patients. Further, elevations in IgG1 or IgG3 were not seen in those SACQ patients who ultimately flared as compared to those who remained quiescent even when adjusted for time to event. While it could be argued that the significant latency between sample collection and time to flare in some patients prevented identification of trends that occurred immediately before the flare, the lack of consistent elevations in IgG1 and IgG3 autoantibodies in the 5 patients examined at the time of their flare argues against this point.

Our study suggests that SACQ patients remain clinically quiescent despite the presence of pathogenic autoantibodies. While the presence of relevant autoantigens is required for these antibodies to form immune complexes and mediate their damage, it appears that these autoantigens are not lacking in SACQ patients because the majority of SACQ patients are hypocomplementemic25. Thus, the findings in these patients diverge from the classic SLE paradigm that equates the presence of immune complexes with disease activity. Currently, the mechanism(s) that lead to this clinical quiescence remain to be fully determined. However, our ongoing studies suggest that proinflammatory factors are not produced in response to these complexes in SACQ patients.

In our small pilot study, we show that predicting clinical outcomes by serologic changes remains an elusive goal among SACQ patients. While our study was not powered to detect small differences between groups, the nature of the trends observed in our study suggest that even a sufficiently powered study would be unlikely to yield positive findings, and consequently, alternate biomarkers must be sought to aid in clinical decision making.

Footnotes

  • The University of Toronto Lupus Clinic is funded by the University Health Network, the Toronto General and Western Hospital Foundation, and the Arthritis Research Foundation. Dr. Steiman’s work has been supported by the 2011 Arthritis Centre of Excellence fellowship, 2011–2012 Geoff Carr Fellowship, and 2012–2014 UCB-CRA-TAS Postgraduate Rheumatology Fellowship. Dr. Wither is supported by the Arthritis Centre of Excellence and the Arthritis and Autoimmunity Research Centre.

  • Accepted for publication January 2, 2015.

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Keywords

DISEASE ACTIVITY
SEROLOGIC ACTIVITY
SYSTEMIC LUPUS ERYTHEMATOSUS
OUTCOME
ANTI-DNA ANTIBODIES
ANTICHROMATIN ANTIBODIES

Keywords