Background Hydroxychloroquine (HCQ) is a mainstay of the initial and long-term treatment of systemic lupus erythematosus (SLE). HCQ blood levels can reflect adherence to the medication and have been correlated with SLE outcomes. However, little is known about the relationship between HCQ levels and SLE disease activity according to the Type 1 & 2 SLE Model, in which Type 1 activity is thought to be mediated by inflammation, e.g., arthritis, rash, nephritis, and Type 2 manifestations have uncertain relationship to inflammation, e.g., fatigue, myalgias, mood disturbance, and cognitive dysfunction.

Method Patients meeting the 1997 American College of Rheumatology or 2012 Systemic Lupus International Collaborating Clinics classification criteria for SLE were recruited from an academic lupus clinic. Whole blood HCQ levels were measured in Exagen’s clinical laboratory using liquid chromatography coupled to mass spectrometry and were categorized as under-exposure (HCQ <200 ng/ml), subtherapeutic (HCQ between 200-1000 ng/ml), or therapeutic HCQ Levels (HCQ >1000 ng/ml). Type 1 SLE activity was measured by Type 1 Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Type 2 SLE activity measures included Type 2 PGA and patient-reported Polysymptomatic Distress (PSD) score (sum of widespread pain index and symptom severity score). Type 1 and 2 SLE Model classifications are defined in table 1. Self-reported adherence to HCQ was measured using the visual analog scale of the Medication Adherence Self-Report Inventory.

We examined demographic and clinical differences among patients with different HCQ blood levels using the Chi-squared and Kruskal-Wallis tests. We also examined the distribution of HCQ levels across different types of lupus activities.

Results This cross-sectional analysis included 156 patients (median age 42, 91% female, 61% black, 43% married or cohabiting, 60% with annual household income ≤$50,000, and 47% with Medicaid/Medicare insurance). In this cohort, 32% were classified to have Minimal SLE (low Type 1 & 2 activity), 12% had active Type 1 with low Type 2 SLE activity, 24% had active Type 2 with low Type 1 SLE activity, and 32% had Mixed SLE (high Type 1 & 2 activity).

Of the 127 patients who provided adherence data, 70% reported ≥90% adherence to the prescribed dose. HCQ whole blood levels were in the under-exposure range in 19%, subtherapeutic in 35%, and therapeutic in 46% of patients (table 2).

No significant differences in sociodemographics, dosing parameters, HCQ dose, and self-reported adherence were found among patients with under-exposed, subtherapeutic, and therapeutic HCQ levels.

Lower HCQ levels were significantly associated with both higher Type 1 and Type 2 SLE activities. Patients with lower HCQ levels self-reported more polysymptomatic distress, widespread pain, and symptoms severity, as well as a trend for more cognitive dysfunction and depression (table 3). There is a trend that patients with Mixed SLE activity were more likely to have under-exposed HCQ levels (table 4).

Conclusion More than half of the patients had lower than therapeutic HCQ blood levels, but self- reported adherence was similarly high across the groups, highlighting the importance of using objective adherence assessments. Surprisingly, lower HCQ levels were associated with both higher Type 1 and Type 2 SLE activity. Although Type 2 SLE manifestations have unclear relationship to inflammation, their inverse association with HCQ blood levels, particularly among patients with concurrent Type 1 SLE activity, suggest that in some SLE patients, immunologic activity may play a role in these chronic debilitating symptoms. Our data also suggests that perhaps low HCQ blood levels allow inflammatory Type 2 SLE symptoms to be active. Future study should explore the longitudinal relationship between HCQ levels and Type 1 and 2 SLE activities.

Lay summary A novel model classifies different lupus symptoms into Type 1 & 2 lupus activity. In this model, symptoms that are known to be mediated by inflammation, such as arthritis, rash, and kidney involvement by lupus are classified as Type 1 lupus activity; symptoms that have unclear relationship to inflammation, such as fatigue, brain fog, and widespread pain are classified as Type 2 lupus activity.

Hydroxychloroquine (HCQ) is one of the most important lupus medications, and we know that taking HCQ consistently is important to control inflammation (Type 1 lupus activity), but we have limited information on how HCQ may help with type 2 lupus activity.

In this study, we tested HCQ blood levels in patients with lupus taking this medication and found that levels were low in more than half of the patients, suggesting that these patients were not taking the medication consistently. Patients with low HCQ levels had higher Type 1 and Type 2 lupus activities compared to patients with higher HCQ levels. Our findings suggest that in some patients, Type 2 lupus activity is related to inflammation, and having low HCQ levels is allowing the inflammatory Type 2 lupus symptoms to be active.