Unmet Needs in the Pathogenesis, Treatment of Systemic Lupus Erythematosus

A multi-system disease with diverse clinical presentations, systemic lupus erythematosus (SLE) is a complex entity with a treatment outcome unique to each patient. While efforts have been made to improve the understanding of the various mechanisms involved in SLE pathogenesis to advance the development of targeted therapies, progress has been slow. Belimumab (Benlysta^®) remains the only new treatment approved by the US Food and Drug Administration (FDA) for SLE in almost 60 years,¹ highlighting the challenges of developing new treatments for this disease. Despite the slow progress, better treatment options and strategy have resulted in significant improvements in quality of life and survival rates. The reported current 5-year survival rate for patients with SLE is 95%, almost double the rate reported in the 1950s.²

However, improved survival has ushered in new challenges that inadvertently increase the risk of death in this patient population. The unmet needs of patients with SLE have changed over the decades. Addressing these needs requires improved understanding of the disease pathophysiology, better treatment options, and improved disease assessment and management strategy.

Several studies have explored these needs, and all have consistently identified challenges in several domains that collectively result in poor patient outcomes, including translational science, clinical trials, and disease management.^2-4 A comprehensive review by Anisur Rahman, PhD, from University College London Institutional Research Information System (UCL IRIS), United Kingdom, and colleagues identified 3 key domains of unmet need in patients with SLE: management of cardiovascular disease risk, fatigue, and refractory SLE.²

Elevated risk for cardiovascular disease (CVD) is now a leading cause of morbidity and mortality in patients with SLE. The underlying etiology and pathophysiology remain poorly understood.^5,6 Various theories have been offered, however, including the role of immune complexes, dysfunctional inflammatory mechanisms, and elevation of specific inflammatory proteins, such as anti-apolipoprotein A-I antibodies, anti-HDL antibody, C-reactive protein, and various autoantibodies including oxidized low-density lipoprotein/beta2 glycoprotein 1 complexes.^2,7,8

Given that traditional CVD risk factors do not fully explain the elevated risks in patients with SLE,^5,6 current recommendations for the management of CVD risk is not specific to this patient population, and focus on the management of traditional CVD risk factors including smoking cessation and the management of blood pressure and lipids.² The American College of Rheumatology recommends a tight blood pressure control target of <130/80 mmHg, statin therapy for low-density lipoprotein (>100 mg/dL), and treatment to control SLE disease.⁹ Defining the etiology of elevated CVD risk, the underlying pathophysiology and specific recommendations for SLE management remain an unmet need.

In addition to elevated CVD risks, frequently reported unmet needs are related to physical symptoms including fatigue, pain, poor sleep patterns, cognitive dysfunction, challenges with activities of daily living, and psychological well-being.^3,4 These unmet needs were found to correlate with diagnostic delay, delay in optimal treatment, and poor monitoring of disease activity and treatment effectiveness due to a paucity of sensitive biomarkers. Treatment discontinuation due to side effects remains problematic.⁴ Fatigue is universal in patients with SLE, and its disabling symptoms are one of the major contributors to poor quality of life.

The causes of fatigue are complex and heterogeneous, and appear to be influenced by the underlying disease pathology, comorbid presentations, and treatment side effects.² Recommendations for the management of fatigue are empirical, adopting a common sense approach, including ensuring adequate sleep, adequate pain control, treating coexisting metabolic disorders, and engaging in regular paced activity.²

In view of the debilitating symptoms of fatigue, there is a recent increased effort to identify a surrogate biomarker for fatigue. To date, several potential biomarker candidates have been investigated, including various pro-inflammatory serum cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-2 [IL-2], IL-6, IL-10, interferon-alpha [IFN- α] and transforming growth factor beta [TGFβ]), and F₂-isoprostane (a marker of oxidative stress). However, these candidates have not yet advanced to clinical evaluation.²

Treatment of refractory lupus, such as nephritis, recalcitrant cutaneous lesions, and neurological involvement, continues to challenge medical management, and remains an area of unmet medical need.^2,4 Efficacy and safety are key challenges in the development of new treatment options for SLE, and while several agents are currently in clinical development, success of these trials has been modest, and several have failed to reach their primary end point in phase 3 studies.

The challenges of developing new treatment and managing SLE were discussed at the 18th Annual International Targeted Therapies meeting, which brought together more than 100 leading scientists and clinicians in the field of rheumatology from around the world.¹⁰ Several primary and secondary unmet needs were discussed in the areas of translational science, clinical science and therapeutic trials, and clinical care.¹⁰ The unmet needs included: better understanding of the disease pathophysiology and its heterogeneity to enable development of predictive tools for therapeutic response, the need to prevent disease progression in patients at risk, and the ability to cure disease when diagnosed.

Unmet needs in clinical trial design included a standardized definition of disease remission, choice of end points, patient selection, sample size, and treatment of comparative groups.

Other unmet needs included improved identification and targeting of the innate immune response, improved understanding of targeting specific therapies to specific disease manifestations,¹⁰ and improved management of comorbidity and patient-centered care, together with the development of a scientific infrastructure to support data-sharing.

Until new treatment options are approved to address the unmet needs for SLE, Dr Rahman and colleagues recommend that physicians should focus on optimal management of standard CVD risk factors, and minimize fatigue by asking patients about their sleep patterns, optimizing pain relief, and identifying and managing other causes of fatigue such as anemia and metabolic disturbances.²

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References

1. BENLYSTA^® (belimumab) for injection. Highlights of Prescribing Information. Accessed October 25, 2017.
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9. Pons-Estel GJ, González LA, Zhang J, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology (Oxford). 2009;48(7):817-822.
10. Winthrop KL, Strand V, van der Heijde DM, et al. The unmet need in rheumatology: reports from the Targeted Therapies meeting 2016. Clin Exp Rheumatol. 2016;34(4 Suppl 98):69-76.