Disease modification strategies in a patient with active SLE

History and presentation, treatment
The patient is a 39-year-old female who was diagnosed with systemic lupus erythematosus (SLE) in 2015 and initially presented with significant proteinuria (24-hour urine total protein, 6.6 g). Renal biopsy confirmed class II and V lupus nephritis (LN). Further laboratory investigations were consistent with SLE, including positive antinuclear antibodies (ANA), high anti-double stranded DNA (anti-dsDNA) level (>1000 IU/L), and positive lupus anticoagulant. Complement testing showed low levels of C3 and C4, suggestive of active disease.¹

In 2015, the patient was treated with moderate doses of prednisolone, hydroxychloroquine and angiotensin-converting enzyme (ACE) inhibitor, resulting in remission of proteinuria.

Past medical history revealed that the patient experienced one first trimester miscarriage in 2011. Her second pregnancy in 2014 was complicated by severe intrauterine growth retardation. These events were consistent with obstetric antiphospholipid syndrome (APS), but there were no reported episodes of symptomatic thromboembolism. The patient was put on aspirin (80 mg QD) for obstetric APS subsequently.

Since 2019, the patient developed recurrent and refractory vasculitis over her fingers, which impaired her activities of daily living, requiring prednisolone dose up to 30 mg QD for symptom control. These lesions became steroid-dependent and worsened whenever prednisone tapering was attempted.

Azathioprine was initially considered for immunosuppression. However, since the patient was an intermediate metabolizer for the nudix hydrolase 15 (NUDT15) enzyme, she was at increased risk of azathioprine myelotoxicity.² Instead, immunosuppressive therapy with mycophenolate mofetil (MMF) was started in July 2020, initially up to 1 g BID and gradually reduced to 250 mg BID due to persistent leucopenia (ie, white blood cell [WBC] count, 2.0 x 10⁹/L in September 2020).³

In February 2021, the patient was diagnosed with herpes zoster, which could be secondary to the immunosuppressive therapy for SLE. In July 2021, she experienced a rib fracture after a minor injury, which might indicate corticosteroid-induced osteoporosis.

Despite treatment, the patient’s disease activity remained high (ie, clinical SLE Disease Activity Index 2000 [SLEDAI-2K] score of 8 due to vasculitis rash; serological SLEDAI-2K score of 4 due to low complement and elevated anti-dsDNA; total SLEDAI-2K score of 12).⁴ Since MMF dose optimization was limited by leucopenia and steroid tapering resulted in worsening of vasculitis, the patient was started on add-on treatment with the immunoglobulin G1λ (Ig-G1λ) monoclonal antibody, belimumab (200 mg Q1W subcutaneous injections), in December 2021.⁵

The patient tolerated belimumab well and did not experience any adverse events (AEs). Improvements were seen in both clinical (ie, resolution of vasculitis after approximately 2 months of treatment initiation; improvement in clinical SLEDAI-2K score from 8 to 0) and serological parameters (ie, reduction in anti-dsDNA levels from 544 IU/L in September 2021 to 320 IU/L in March 2023; normalization of complement blood test results; serological SLEDAI-2K score of 2), while urine protein creatinine ratio (UPCR) remained normal.

Importantly, the addition of belimumab enabled successful tapering of prednisone to 7.5 mg QD in early 2022, without recurrence of vasculitis. Further steroid dose reduction was suggested, but the patient was reluctant due to concerns about vasculitis recurrence. MMF was switched to a weaker immunosuppressive agent, oral methotrexate (10 mg Q1W), in January 2023, which led to resolution of leucopenia.

The patient is currently well and has not experienced any disease flares since belimumab was initiated and after treatment adjustments were made.

Discussion
SLE is characterized by heterogeneous clinical presentation with unpredictable disease course and flares, making it difficult to diagnose and manage. Patients with this systemic disease may present with several common clinical abnormalities (eg, rash, photosensitivity, hair loss, arthritis) and organ involvement (eg, renal impairment) alongside serological abnormalities. Notably, SLE may also be organ-dominant and initial presentation may not include mucocutaneous or musculoskeletal complaints. The presentation may also mimic other illnesses, making it more challenging to diagnose.⁶ Therefore, a high index of initial suspicion of SLE is critical, especially among Asian patients, who are reported to have more severe disease and significant organ involvement vs other ethnicities.^7-10

Although advances in SLE management have resulted in improved 5-year survival rate from approximately 70 percent in the 1950s to >90 percent in the 2000s, the condition remains organ- and even life-threatening, especially in patients with uncontrolled disease.^11,12 Furthermore, its complications are associated with negative impacts on patients’ quality of life (QoL), high healthcare costs and significant productivity loss.¹³ As noted in our patient’s experience, important long-term side effects associated with some standard treatment options (eg, immunosuppressant-induced infectious complications, steroid-induced osteoporosis) are not uncommon and may limit their use in the SLE population.

As newer treatment options emerge, the concept of disease modification has become an important consideration in optimizing SLE management. Although there is currently no established definition for disease modification in SLE, minimization of disease activity, prevention of organ damage, and avoidance of treatment-associated toxicities are considered as core components of this concept.¹⁴

Our patient achieved disease modification across these key parameters after the addition of belimumab, which facilitated multidimensional improvements in terms of reduction in disease activity (ie, serological and symptomatic improvements), prevention of organ damage worsening (ie, vasculitis resolution and nephritis control), and optimization of treatment (ie, steroid tapering and switching of MMF to methotrexate to minimize treatment-related AEs).

Belimumab specifically inhibits binding of soluble B Lymphocyte Stimulator protein (BLyS), a B cell survival factor, to its receptors on B cells. BLyS levels are elevated in patients with SLE and are associated with increased SLE disease activity. In combination with other immunosuppressive agents, belimumab is currently indicated for treatment of adults with active SLE and/or LN and could be considered as a disease modifier in the SLE treatment paradigms, as demonstrated in our patient’s experience.^5,15

In summary, current SLE management goals should be geared towards long-term disease modification strategies (ie, preventing organ damage and achieving good symptom control by reducing disease activity while minimizing treatment-related toxicities to ensure improved QoL). In our patient’s case, this was achieved by the addition of belimumab to the conventional immunosuppressive therapies.