This is the first study using items from the SF-36 to assess the ability of a type 2 score to categorize SLE patients according to the presence of symptoms of fatigue, widespread pain and depression. Using the SLEDAI score to define type 1 symptoms, SLE patients from the LUPUCE cohort were categorized into the four groups defined by Duke University, with a similar patient distribution. The differences between these groups were then explored and apart from clinical differences, no significant immunological or transcriptomic profiles associated with the categories were found.
The initial definition of type 2 symptoms relied on the ACR fibromyalgia criteria (12). Although these criteria are likely to reflect type 2 symptoms accurately, they are rarely available in clinical trials and in historical SLE cohorts. In contrast, SF-36 is widely used to assess HRQoL in SLE (3), as in many chronic diseases (18), and an item-level analysis has been shown to be useful to interpret HRQoL variations in SLE patients (17). We chose to select the most relevant items from the SF-36 questionnaire to define type 2 symptoms and build a score that was easy to use in other cohorts. The values of the type 2 score observed in the LUPUCE cohort were very similar to those from an independent cohort of SLE patients, the PSY-LUP cohort. In addition, the proportions of patients categorized into each of the four clinical groups using the SLEDAI and the type 2 score were almost the same in the LUPUCE cohort and in the cohort described by Duke University. This constitutes an external validation of the SF-36-derived type 2 score and could allow standardization of the clinical categorization of SLE patients into different cohorts. Until now, the clinical segregation of SLE patients was heterogeneous between different studies. Before the first description of type 1/type 2 symptoms by Duke University (10), some studies described SLE patients with active/inactive disease and high/low fatigue (7) and found quite similar proportions as with the type 1/type 2 categorization (19).
Interestingly, as in the cohort from Duke University, no significant difference was observed between the immunological profiles of the four clinical groups. This highlights the fact that categorization into these four clinical groups, instead of providing redundant information, is a complimentary tool for the care of SLE patients and for patient stratification in clinical trials. Patients with type 2 symptoms, regardless of clinical activity, are likely to report higher activity levels than that evaluated by physicians, which can result in discordant measures (10) challenging the interpretation of clinical trial results.
This is the first study to investigate the association between transcriptional signatures, particularly IFN signature, and clinical type 1/type 2 SLE categorization. We could have expected a higher IFN signature in patients with active SLE (type 1 and mixed groups). However, there was no significant difference in IFN signatures between patients with active SLE and patients with inactive SLE. Alternatively, we could also have expected higher IFN signatures in patients reporting fatigue (type 2 group). Indeed, IFN signature was elevated in patients with fibromyalgia (20, 21), and therapeutic IFN is associated with neuropsychiatric side-effects such as fatigue and depression (22). In contrast, we have previously shown a paradoxical association between HRQoL and IFN signatures, patients with higher IFN scores displaying better HRQoL in some SF-36 domains (mental health and vitality) (14). However here, although a majority of patients from the type 2 group had a moderate IFN score, no significant difference was observed with the other groups. This is consistent with the report of an absence of correlation between pro-inflammatory cytokines (including IFN) and HRQoL in SLE patients (23). The same has been observed in patients with primary Sjögren syndrome in whom there was no correlation between IFN signature and HRQoL/fatigue (24). Thus, the IFN signature, as an immunological marker, is not relevant to discriminate type 1 from type 2 profiles.
Our study has some limitations. First, we used items from the SF-36 questionnaire to assess fatigue and depression, and not more specific questionnaires dedicated to SLE patients (such as SLEQOL, LIT, L-QOL, LupusQOL, LupusPRO) (25). However, the SF-36 has been used for a long time and more widely than specific scales and it is well validated in SLE (26) and widely available, even retrospectively, in SLE cohorts. Second, the limited number of patients could lead to a loss of power after the division of the cohort into the four clinical groups. New studies with larger populations are therefore needed to confirm our results. Cohorts such as the LUPUCE cohort, providing well-characterized clinical, immunological, transcriptomic and HRQoL data, are very much needed.