Introduction
Despite systemic lupus erythematosus (SLE) clinical trials being conducted for over half a century, there are only two biologic therapies that are approved by the FDA to treat SLE: belimumab and anifrolumab. The heterogeneity of SLE patients—in both clinical manifestation and underlying biology and pathogenesis—is part of what has made it difficult to achieve sufficient drug efficacy. This heterogeneity can make it difficult for a single drug to be effective in a diverse clinical trial population.
Luckily, there are now quantitative systems pharmacology (QSP) models that can support researchers to more efficiently analyze SLE drug efficacy by simulating treatments within specific and customizable subgroups of SLE patients.
In this blog post, you’ll learn more about SLE symptoms that make drug development so challenging for this disease.
Heterogeneity of SLE Clinical Manifestations
SLE clinical manifestations can involve many different organs and can differ greatly in severity. Examples of the wide variety of symptoms that can manifest as part of SLE include:
- Cutaneous: Mild rashes to severe skin lesions
- Photosensitivity: Sensitivity to ultraviolet radiation
- Non-specific or general symptoms, such as fever, fatigue, weight loss, oral or nasal ulcers
- Raynaud’s phenomenon: Reduced blood flow in extremities such as the fingers and toes
- Musculoskeletal problems: Characterized by joint pain, swelling, and arthritis
- Renal involvement: Lupus nephritis, resulting in inflammation of kidneys
- Neuropsychiatric lupus: Affecting the nervous system, can manifest as many different neurological and psychiatric symptoms including headaches, seizures, psychosis, cognitive impairment
- Cardiopulmonary complications: Such as pericarditis and pleuritis
- Flares: Flare are worsening of SLE symptoms and can range from mild to severe. Flares can also manifest as many different symptoms including skin rashes, joint paint, fatigue, and headaches. Severe flares occur in 20-30% of people with SLE (PMID: 33631651).
SLE patients display significant biological heterogeneity that goes beyond clinical symptoms. Differences in autoantibody types—ranging from anti-dsDNA, which fluctuates with disease activity, to more stable markers like anti-Sm—and complement protein levels (such as varying C3 and C4 levels) highlight distinct immunologic processes (PMIDs: 26581343, 28281463, 36830735). Additionally, SLE patients may exhibit abnormal blood cell counts and shifts in immune cell populations, including B cells and innate immune cells, underscoring diverse underlying pathologies (PMIDs: 31795353, 35298669).
Furthermore, variations in cytokine profiles and type I interferon gene signatures contribute to disease complexity and influence treatment responses. For example, high interferon signatures correlate with increased disease activity and may predict better responses to therapies like anifrolumab, while elevated BAFF levels can indicate a switch to belimumab (PMIDs: 31190735, 32366280). Advances in transcriptome technology now enable more precise analysis of these molecular differences, paving the way toward personalized treatment regimens tailored to each patient’s unique biology.
How QSP Modeling Can Help
Quantitative systems pharmacology (QSP) makes it easier to test different drug therapies and regimens in a heterogeneous population. Different characteristics of SLE patients, such as immune cell levels, C3 and C4 complement levels, and interferon gene signature can be captured in the SLE QSP model. Specific drug regimens can then be tested in different subgroups of patients to assess how patients with different characteristics respond. The SLE QSP model can also be used to test the number of patients needed in those chosen subgroups to get the desired clinical effect.
Our SLE QSP model captures single-organ effects, such as cutaneous lupus erythematosus disease area and severity index (CLASI) and swollen joint count (SJC), and multi-organ effects, such as British Isles lupus assessment (BICLA) and systemic lupus erythematosus responder index (SRI). Clinical efficacy can be explored in patient sub-populations. For example, in patients with more lesion and rash manifestations, there may be more interest in assessing CLASI scores rather than clinical output scores that consider other organs and therefore may be less sensitive to specifically cutaneous responses.
In addition to clinical responses, the SLE QSP model can assess the effects of specific drug therapies and regimens on the underlying biology affecting the clinical outputs. Examples include time course measurements of changes in immune cell, cytokine, and complement levels.
Efficiency and Cost Effectiveness of QSP Modeling
Assessing subgroups of SLE patients in real-world clinical trials has several challenges, including lengthy recruitment periods and extended timelines for observing clinical improvements, particularly survival endpoints, which can take years. QSP modeling enables rapid assessment of SLE efficacy, providing useful insights for development of real-world clinical trials, such as identifying patient characteristics that predict optimal treatment responses. QSP models also expedite clinical trial design elements by simulating efficacy predictions in novel trial parameters such as inclusion/exclusion criteria, dosing, and therapy combinations.
By identifying the specific SLE population that is most likely to benefit from the specified SLE regimen, these analyses significantly improve cost-effectiveness as well. Moreover, QSP modeling can help in determining the most effective dosing regimen or combination of doses for specific SLE populations, limiting the number of treatment arms that would need to be tested in real-world clinical trials.
Conclusion
The heterogeneity of SLE patients can make clinical trial assessments complicated. QSP modeling enables efficient, cost-effective trial planning by predicting outcomes for different dosing strategies and inclusion criteria, while offering insights into underlying disease biology. By tailoring clinical trial design and focusing on the most responsive patient populations, QSP supports the advancement of precision medicine in SLE.
If you have an SLE drug in development and would like to discuss using our QSP model, schedule a time to connect.