Case report on the use of canakinumab for treatment of recurrent fevers and proteinuria in refractory systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease with a wide range of clinical manifestations and a characteristic renal involvement leading to proteinuria. There remains an unmet need in SLE disease management as standard treatments including anti-inflammatory drugs, corticosteroids, antimalarial agents, and immunosuppressant therapies are not always effective in moderating disease activity. We report a 41-year-old Caucasian female patient with a 12-year history of SLE complicated by debilitating nocturnal fevers and WHO Class IV lupus nephritis who for years was refractory to standard therapies but improved dramatically with canakinumab, an interleukin-1β (IL-1β)antagonist. This is the first case of the use of canakinumab in SLE. The standard interventions demonstrated no significant impact on her proteinuria (>3 g/24 h), joint complaints, and nocturnal fevers. Additionally, her anti-dsDNA levels remained elevated, and her kidney function did not improve significantly. In contrast, the introduction of canakinumab provided a rapid reduction in nocturnal fevers within 6 weeks (i.e. decreased in frequency by 90%). Her proteinuria has also dropped from 3.5 g/24 h to 0.274 g/24 h, and her prednisone has been tapered and discontinued. In addition, her renal function has improved with an average glomerular filtration rate (GFR) level of 84.14 ± 7.56. There has also been a significant decrease in both erythrocyte sedimentation rate (ESR) and anti-dsDNA levels compared with the previous treatments. We report that canakinumab could potentially represent the next step in SLE patients’ treatment who have failed conventional therapies or who are intolerant to them. In this case, the addition of canakinumab facilitated the tapering and ultimately discontinuing of corticosteroids. This case represents the first successful use of canakinumab in the treatment of refractory fevers and diffuse proliferative glomerulonephritis in SLE.

Plain language summary

Canakinumab in refractory systemic lupus erythematosus: A successful case report for managing recurrent fevers and kidney inflammation

Systemic lupus erythematosus (SLE) is a long-term autoimmune disease that affects multiple organs in the body, including the kidneys. Some patients with SLE do not respond well to standard treatments, such as anti-inflammatory drugs and immunosuppressants. This case report describes a 41-year-old woman with SLE and severe kidney inflammation who did not improve with conventional therapies. However, when she was given canakinumab, a medication that blocks a protein called IL-1β, her symptoms improved significantly. Within six weeks, her fevers decreased by 90%, her kidney function improved, and her protein levels in the urine dropped. This case suggests that canakinumab may be a promising treatment option for SLE patients who do not respond to or cannot tolerate traditional therapies. It also shows that canakinumab helped reduce the need for corticosteroids in this patient. This is the first successful use of canakinumab to treat refractory fevers and kidney inflammation in SLE patients.

Introduction

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. Common manifestations of systemic lupus include mucocutaneous involvement, joint pain and arthritis, hematologic abnormalities, and fatigue. Cardiac, pulmonary, or neurologic involvement can be life-threatening. Approximately 30–50% of subjects diagnosed with SLE will develop renal involvement leading to proteinuria. ¹ Laboratory abnormalities are common in SLE and include antibodies to nuclear antigens (ANA), antibodies to native DNA, among others, and hypocomplementemia. The spectrum of illness is wide and varied in SLE. Common treatments include anti-inflammatory drugs, corticosteroids, antimalarial agents, and immunosuppressant therapies. As standard treatments are not always effective in controlling symptoms of SLE disease, there is an unmet need in the management of this disease.

Here, we describe the first use of canakinumab in SLE. Canakinumab is an IL-1β blocker produced by macrophages and dendric cells, with similar regulation, expression, and secretion characteristics to its family (i.e. interleukin-1 (IL-1)) members such as the IL-1α and IL-18. Canakinumab has been used to treat autoinflammatory disorders including Familial Mediterranean Fever (FMF) and Adult-Onset Still’s Disease.

We report the first case of the use of canakinumab in SLE. The lack of response to traditional treatments for SLE coupled with debilitating daily fevers formed the rationale for use of Canakinumab in this patient.

Case

A 28-year-old Caucasian female with a SLE manifested by joint pain, WHO Class IV lupus nephritis, cutaneous disease, and intermittent fevers, was referred to our rheumatology clinic 12 years ago. In addition to fatigue and myalgias, debilitating nocturnal fevers (101–103°F) associated with arthralgias were her chief complaints. A thorough fever work-up identified no infectious explanation for her fever. Her family history was negative for lupus and other autoimmune diseases, as well as periodic fever syndromes. Pertinent laboratory findings include a positive antinuclear antibody (ANA), SLE-specific double-stranded DNA antibodies (Anti-dsDNA, titer 1:2560), hypocomplementemia, anti-Smith antibody (SM, >8.0 U/ml), and chromatin antibody (>8.0). Anti-cardiolipin antibodies, lupus anticoagulant, and rheumatoid factor were negative. Her average urine collection yielded 3.0 g of protein in a 24-h collection, eGFR (77 ml/min), and creatinine (0.97 mg/dl). She was treated with multiple regimes over the following 5 years that initially included high-dose corticosteroids (Prednisone 60 mg daily) in combination with mycophenolate (1.5 g twice daily). Her proteinuria, joint pain, and nocturnal fevers remained unchanged and IV Rituxan (1000 mg times two, 2 weeks apart) was added to the protocol. As her symptoms remained refractory, other medical strategies used to control lupus were pursued over the ensuing 5 years. Such treatment strategies including the use of monthly IV cyclophosphamide, azathioprine, methotrexate, tacrolimus, belimumab, and baricitinib in therapeutic doses demonstrated no significant impact on her condition. Additionally, her anti-dsDNA levels remained elevated, and her kidney function did not improve significantly (average GFR: 71.45 ± 12.05) with persistent proteinuria. To control her fevers, canakinumab, an IL-1β antagonist approved by the food and drug administration (FDA) for the treatment of FMF, was added to an experimental protocol composed of prednisone (5–20 mg daily), mycophenolic acid (1000 mg twice daily), and hydroxychloroquine (200 mg twice daily). Within 6 weeks, her nocturnal fevers decreased in frequency by 90%. Since canakinumab was instituted, her proteinuria has dropped from 3.5 g/24 h to 0.274 g/24 h, and her prednisone has been tapered and discontinued. Her renal function has improved with an average GFR level of 84.14 ± 7.56. There has also been a significant decrease in both ESR and anti-dsDNA levels compared with the previous treatments (Figure 1). Written informed patient’s consent was obtained for the treatment and publication. The case report publication guidelines were followed according to CARE (Case Report), ² and the checklist is available as supplemental material.

Figure 1.

The effects of the addition of canakinumab on anti-dsDNA and proteinuria (a) as well as number of fever episodes and ESR levels (b) in SLE patient with recurrent fever. Green box shows data after starting canakinumab.

Discussion

SLE is an autoimmune disease with approximately 30–50% renal involvement leading to proteinuriaf1. ¹ There is an unmet need in SLE disease management as standard treatments are not always effective in moderating disease activity.

In this report, we describe a patient with SLE complicated by debilitating nocturnal fevers and lupus nephritis who for years was refractory to standard therapies. The use of canakinumab was considered in this patient because of its known benefit in the management of other fever syndromes and the known association of IL-1activity in certain lupus patients. Recent reports have shown serum IL-1β levels correlate with SLE disease activity. ³

Canakinumab is a recombinant human monoclonal antibody that binds to IL-1β and neutralizes its activity. IL-1β belongs to the IL-1 family of cytokines produced by immune cells, with similar characteristics to IL-1α and IL-18. There are limited data on the use of IL-1 blocking agents to treat SLE. The fundamental role it plays in the inflammatory cascade provides a rationale for its use in some cases. For instance, the use of anakinra, an IL-1 receptor antagonist, has been reported as an alternative treatment for several cases of SLE refractory to conventional therapies. ⁴ There have been no reports of the use of canakinumab in the treatment of SLE.

Although anakinra and canakinumab are both Il-1 inhibitors, significant differences exist between these molecules. Anakinra blocks the interaction of both IL-1α and IL-1β on the IL-1 receptor, whereas canakinumab only binds to IL-1β. There are also significant differences in pharmacokinetics, half-lives, and binding affinity. ⁵

The introduction of canakinumab provided a rapid reduction in nocturnal fevers within weeks. There was also a dramatic improvement in proteinuria from 3.4 g/day before canakinumab use to 0.2 g/day observed within months of instituting this medication. There are few reports on the improvement of proteinuria after using canakinumab for Muckle–Wells syndrome ⁶ and FMF. ⁷ A recent study on FMF patients showed improvement in proteinuria was only found in patients with preserved renal function (GFR ⩾60 mL/min) ⁸ similar to our case. The mechanism by which proteinuria is reduced by inhibiting IL-1β deserves further investigation. By blocking IL-1β, glomerular filtration barrier components (i.e. podocytes ⁹ and glomerular endothelial cells ¹⁰ ) can be directly or indirectly (e.g. via mesangial cells ¹¹ ) affected. Canakinumab addition to our patient’s standard lupus therapies improved inflammation and fever reduction in this case, a patient previous with refractory disease.

Conclusion

We report that canakinumab could potentially represent the next step in SLE patient’s treatment who have failed conventional therapies or are intolerant to them. In this case, the addition of canakinumab facilitated the tapering and ultimately discontinuing of corticosteroids. This case represents the first successful use of canakinumab in the treatment of refractory fevers and diffuse proliferative glomerulonephritis in SLE.

Supplemental Material

sj-docx-1-trd-10.1177_26330040231191141 – Supplemental material for Case report on the use of canakinumab for treatment of recurrent fevers and proteinuria in refractory systemic lupus erythematosus

Supplemental material, sj-docx-1-trd-10.1177_26330040231191141 for Case report on the use of canakinumab for treatment of recurrent fevers and proteinuria in refractory systemic lupus erythematosus by Kimia Yavari and Joseph Grisanti in Therapeutic Advances in Rare Disease