Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multisystem disease, characterized by wide heterogeneity in clinical presentation, course and responsiveness to therapy [1, 2]. Despite significant advances in the understanding of the pathophysiology and optimization of medical care [3, 4], patients with SLE have an age-standardized mortality rate of 3.2 per 1 million people [5] and carry a risk of progressive organ damage accrual and reduced health-related quality of life [6, 7].

The treat-to-target (T2T) approach, successfully applied in rheumatoid arthritis and other non-rheumatic conditions, is a therapeutic strategy aiming to improve disease outcomes through the achievement of a pre-specified goal [8]. An international task force has recently suggested applying the T2T strategy in SLE, recommending that the treatment target should be remission or, where this cannot be reached, the lowest possible disease activity [9]. Many different definitions of remission, none of them generally accepted, are currently available in the literature and many controversial issues have to be clarified, such as its real attainability as a treatment target in clinical practice [10‐12]. On the one hand, a framework for definition of remission in SLE (DORIS) has been recently set up by an international expert group [12]. On the other hand, a composite definition of minimal acceptable disease activity, the lupus low disease activity state (LLDAS), has been proposed by the Asia-Pacific Lupus Collaboration (APLC) [13]. LLDAS is based on the following criteria: (1) SLE Disease Activity Index 2000 (SLEDAI-2K) ≤4, with no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, gastrointestinal, haemolytic anaemia fever); (2) no new lupus disease activity compared with the previous assessment; (3) Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (PGA) ≤1; (4) current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well-tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents [13].

Early damage was demonstrated to be associated with lower 10-year survival, such that patients with initial damage have a fourfold higher mortality rate compared to those with no early damage [14]. In order to be considered a valid treatment target, LLDAS should be proved as being protective against damage accrual in the early SLE stages. However, LLDAS prevalence and its association with damage have been investigated in a few longstanding SLE cohorts with no homogeneous disease duration [13, 15, 16] and therefore no data are currently available on its potential role as an early treatment target.

This study primarily aimed to assess the frequency of LLDAS achievement and its association with early damage accrual in a homogeneous cohort of Caucasian patients with SLE prospectively assessed during the first 18 months of treatment after diagnosis. The secondary aim was to identify the main reasons for failure to achieve LLDAS.

In our study cohort 44% and 45% of patients were in LLDAS 6 and 18 months after treatment initiation, respectively. Despite a seemingly overall stable LLDAS rate, the dynamic nature of this condition was demonstrated. In fact, 14% of subjects first achieved LLDAS between the 6^th and 18^th month, whereas 13% of patients who were in LLDAS after 6 months of treatment lost LLDAS within the following 12 months. Golder et al. found that in a in a cross-sectional assessment, 44% of 1846 patients with SLE and a mean disease duration of 8.6 years did not achieve LLDAS [15]. Franklyn et al., in an SLE cohort with mean disease duration of 7.1 years, observed that 88% of patients achieved LLDAS at least once and that 38% of patients had this status for more than half of the follow-up duration [13]. These data suggest that the minimal disease activity, according to the LLDAS criteria, would be a more applicable goal in a T2T strategy than remission, according to the current definition [12, 25], especially in early disease stages [10]. Actually, Wilhem et al. observed that the median time to achieve durable remission, classified in four subtypes according to the principle proposed by the DORIS group, ranged between 1.8 and 11.0 years [10].

In this study, the most frequent reason for failure to achieve LLDAS 6 months after therapy initiation was daily prednisolone dosage >7.5 mg (83% of no LLDAS). In the study by Golder et al., prednisolone dosage was an unmet criterion in 57% of patients who did not achieve LLDAS [15]. In a study aiming to test the construct validity of LLDAS compared to expert opinion, disagreement was mainly due to low disease activity classification of patients with prednisolone daily dosage ≥7.5 mg (up to 10 mg/day), suggesting that such a higher dose was deemed acceptable by several experts who were interviewed [26]. Nevertheless, the lowest corticosteroid dose to be considered safe has not been definitely identified. Prednisolone >5 mg/day was reported to be associated with greater risk of osteoporosis, infections, cataracts and metabolic and cardiovascular disorders [27‐29]. Tharmer et al. observed that the risk of damage accrual in patients with SLE did not substantially increase with prednisolone cumulative doses <180 mg/month (equivalent to 6 mg/day) [30]. In our cohort, damage was definitely attributable to steroid use in 40% of cases. Gladman et al. reported that 58% and 80% of the damage accrued in the first year after diagnosis and in later disease, respectively, could be described as “possibly or definitely” steroid-related [23]. In contrast, a larger proportion of early damage was related to early inflammatory organ damage [24]. In our study we found that failure to achieve early LLDAS (at 6 months) and older age at diagnosis, but not corticosteroid daily dose, were independently associated with presence of damage after 18 months. Two further retrospective studies reported that patients with LLADS had a reduced risk of damage accrual in at least half of observations [13, 16]. Supported by our data and literature evidence on damage development, we consider 7.5 mg/day an acceptable cutoff to define low disease activity during initial treatment, but A lower cutoff should be targeted to minimize risk of steroid-related damage during maintenance therapy in patients with SLE.

Renal involvement and serological disorders, consisting of low complement and increased anti-dsDNA, had the lowest remission rate in our cohort. However, renal involvement at baseline was the most important factor associated with failure to achieve LLDAS at 6 months (OR 7.8, 95% CI 1.4–43.4; p = 0.019) and 18 months (OR 3.9, 95% CI 1.4–10.6; p = 0.008) from treatment initiation. In a cross-sectional study, increased anti-dsDNA (OR 0.65, 95% CI 0.53–0.81; p < 0.001), renal involvement (OR 0.60, 95% CI 0.48–0.75; p < 0.001), low complement (OR 0.52, 95% CI 0.40–0.67; p < 0.001) shorter disease duration (OR 0.31, 95% CI 0.19–0.49; p < 0.001) and history of discoid rash (OR 0.66, 95% CI 0.49–0.89; p = 0.006) were identified as negatively associated with LLDAS [15]. These findings suggest that renal involvement and serological abnormalities are associated with a lower likelihood of LLDAS achievement.

Whether or not serological disorders should be considered in the definition of minimal disease activity it is a matter of debate [26]. Persistently increased anti-dsDNA and low complement may be part of the serological active clinically quiescent (SACQ) disease pattern [31], with some evidence suggesting a proportion of patients with SACQ disease can spend years without flares [32] whilst other may relapse [33]. However, increasing-fluctuating anti-dsDNA level rather than absolute values can predict disease flares [34]. Thus, in order to enhance the association between minimal acceptable disease activity and long-term outcomes, it would be conceivable to consider rising levels of anti-dsDNA antibodies rather than their steady positivity in the LLDAS definition.

This study has some limitations. First, the relatively small sample size may have hampered the study results. Nevertheless, by enrolling consecutively diagnosed patients at the time of treatment initiation and following them up prospectively, we added some novel information on LLDAS as a potential treatment target. Second, the retrospective design of the study prevented us from testing LLDAS criterion validity by comparing it with other treatment targets such as the SLE Responder Index [35].

In conclusion, LLDAS is a promising treatment target in SLE, being attainable and negatively associated with damage accrual in the early stages of disease. However, it seems to poorly fit with the heterogeneity of clinical presentation in patients with SLE, mostly in those with renal involvement. On the one hand, the poor LLDAS attainability in patients with renal involvement could be due to greater severity and lasting disease activity in the renal domain. On the other hand, it could be due to the unsuitability of LLDAS in capturing the minimal disease activity in patients with renal involvement. Finally, greater consensus should be reached on the definition of serological disorders and prednisolone dose to be included in a unique definition of minimally acceptable disease activity.