STUDY PROTOCOL
A multicenter, randomised, double-blind trial was performed from September 2017 to February 2020 at 15 centres in the USA. This trial investigated the efficacy and safety of filgotinib and lanraplenib in LN patients that had histopathologically confirmed (biopsy performed within 18 months prior to screening) Class V LN (with or without accompanying Class II LN), with a urine protein excretion ≥ 1.5 g/day and an estimated glomerular filtration rate (eGFR_MDRD ≥ 60 mg/min/1.73m²) based on the Modification of Diet in Renal Disease (MDRD) formulation. Membranous lupus nephritis was treated with at least one immunosuppressive therapy (mycophenolate mofetil, azathioprine, tacrolimus, cyclosporine, cyclophosphamide or chlorambucil) for at least 6 consecutive months within 1 year before screening. Oral glucocorticoids were allowed at doses that were ≤ 20 mg/day of prednisone or equivalent and remained stable through week 16 of the study. Patients were also permitted to continue hydroxychloroquine at a stable dose. Treatment with an ACE inhibitor or angiotensin II receptor blocker, or documented intolerance to these agents was required. Patients were excluded if they had received previous treatment with a JAK inhibitor within 3 months of day 1 or rituximab or other B cell depleting agent within 6 months of day 1.

In order to increase recruitment in March 2018, the protocol was changed:

• • Window for kidney biopsy was extended to 36 months prior to screening

• • eGFR criteria was changed to include patients with eGFR ≥ 40 mg/min/1.73m²

• • Duration of prior immunosuppressive treatment was changed to the discretion of the investigator

• • Additional treatments such as methotrexate, leflunomide and moderate- to high-dose glucocorticoids were allowed.

Patients were randomised in a 1:1 ratio to 200 mg filgotinib or 30 mg lanraplenib. Randomisation was stratified by prior cyclophosphamide treatment. Patients who had ≥ 35% reduction in proteinuria at 16 weeks continued to receive their assigned blinded study treatment for 16 more weeks. For patients who did not have a ≥ 35% reduction in proteinuria, their study treatment was switched for the next 16 weeks in a blinded fashion.

After 32 weeks of blinded treatment, patients who had a ≥ 35% reduction in urinary protein excretion from day 1 or from week 16 continued their assigned blinded treatment for 20 more weeks in the Extended Blinded Treatment Phase. Subjects who did not achieve a ≥ 35% reduction in urinary protein excretion at week 32 compared with baseline were allowed to continue whichever study treatment led to the greatest reduction in proteinuria at the subject’s and investigator’s discretion. The use of a new, or increased dose of an existing, immunosuppressant agent, including glucocorticoids required discontinuation of the study treatment.A total of nine patients were recruited who were randomised to receive filgotinib (n=5) or lanraplenib (n=4). Three subjects completed the study, 6 patients discontinued the study (3 due to adverse effects .

Systemic lupus erythematosus disease activity index from the Safety of Estrogens in Lupus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) total score remained stable for three of the four patients in the filgotinib group from baseline to week 16. No improvement in anti-dsDNA or complement levels was observed in either group.

SAFETY

Majority of patients in both treatment periods reported at least one adverse event (AE). The most common adverse events during the study were neutropenia and bronchitis (two patients each). Up to week 16, grade ≥3 adverse events were reported in one subject (20%) in the filgotinib group and in three subjects (75%) in the lanraplenib group. After week 16, only one subject reported an AE of grade ≥3 (filgotinib to lanraplenib group). Most adverse events were not considered related to the study drug.

One subject in the lanraplenib arm reported two treatment-emergent serious adverse events (SAEs) and both were not considered to be related to the study drug.

The following grade ≥3 treatment emergent AEs (TEAEs) were reported: neutropenia, lymphopenia, hypercholesterolemia, hypoalbuminemia, worsening of SLE, and acute kidney injury (one subject each). From baseline to week 16, one subject (20%) in the filgotinib group and two subjects (50%) in the lanraplenib group prematurely discontinued study drug due to TEAEs. No TEAE causing study drug discontinuation was reported after week 16. There were no reports of venous thromboembolism, herpes zoster, malignancy or death during the study.

Although the number of patients included were very limited, this study may support future studies using filgotinib or other JAK inhibitors in (especially Class V) LN patients.

Deucravacitinib (NCT03943147 – Terminated)

Deucravacitinib is an allosteric TYK2 inhibitor with a high specificity to TYK2 pseudokinase domain. TYK2 is a member of the JAK family but TYK2 inhibitors have a different profile than that of other JAK inhibitors. Receptors of cytokines such as interleukin-12, interleukin-23 and type I interferons are TYK2-dependent, which differ from JAK1- or JAK3-dependent cytokine receptors (such as interleukin-2, interleukin-15 and interleukin-6 receptors) or JAK2-dependent receptors (such as the receptors of erythropoietin, thrombopoietin and granulocyte-macrophage colony stimulating factor.(NCT03943147 was a phase 2, randomized, double-blinded, placebo-controlled clinical trial aimed to evaluate the safety and effectiveness of BMS-986165 (deucravacitinib) with background treatment in participants with LN.

This study was terminated due to insufficient enrollment. Inclusion criteria were 18–75 year-old patients that met Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria for SLE, that have renal biopsy compatible with International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III, Class IV (segmental or global) LN with or without Class V LN and that have a urine protein:creatinine ratio (UPCR) ≥1.5 mg/mg or UPCR ≥1 mg/mg assessed with a 24-hour urine specimen. Exclusion criteria were pure Class V LN or screening estimated glomerular filtration rate ≤30 mL/min/1.73 m² or dialysis within 12 months before screening or plans for dialysis. within 6 months after enrollment in the study or presence of end-stage renal disease.

In part A, all study participants would receive mycophenolate mofetil (MMF) at a dose of 1.5 to 3.0 g/day for 12 weeks. Participants who meet the criteria to continue in Part B but do not meet the randomization criteria could continue on open label MMF with or without corticosteroids. In Part B, participants with an inadequate renal response to MMF would be randomized to blinded study treatment deucravacitinib 3 mg BID, deucravacitinib 6 mg BID, or placebo BID, as add-on therapy to MMF. No participants were randomized to receive deucravacitinib 3 mg BID or placebo BID due to low enrollment. This study was terminated due to insufficient enrollment; only 16 patients were enrolled.

Six patients completed part A and 10 patients did not complete part A (4 due to other reasons, 1 due to adverse event, 1 due to non-compliance with study drug, 1 due to protocol specified withdrawal criterion being met and 3 due to termination of the study by sponsor). A total of 6 patients started Part B. Three patients completed Part B whereas the remaining 3 were unable to complete the study due to sponsor terminating the study. Only one patient received deucravacitinib in Part B. UPCR decreased 34.9 percent in week 24 in that patient. That patient failed to achieve partial renal response (≥ 50% reduction from baseline in 24-hour UPCR) and complete renal response (UPCR ≤ 0.5 mg/mg and an estimated glomerular filtration rate ≥ 60 mL/min or ≤ 20% decrease from baseline) in 24 weeks or 52 weeks.

Among the sixteen patients that participated in Part A, 1 patient had serious adverse event (COVID-19 pneumonia) and 7 patients had other adverse events (1 patient had sensorineural deafness, 1 patient had abdominal discomfort, 1 patient had abdominal distension and 1 patient had hematochezia, 1 patient had pyrexia, 1 patient had gallbladder polyp, 1 patient had nasopharyngitis, 1 patient had upper respiratory tract infection, 1 patient had urinary tract infection, 1 patient had blood pressure increase, 1 patient had weight increase, 1 patient had arthralgia, 1 patient had muscle spasms and 1 patient had dizziness). The only patient that completed Part B had COVID-19 as a serious adverse event. As other adverse events, he had flank pain, prolonged prothrombin time, prolonged activated partial thromboplastin time, increased international normalized ratio. Most adverse effects do not seem to be related to the study drug.

Baricitinib (NCT05432531 – Ongoing)

A phase 3 trial of selective JAK1 and JAK2 inhibitor baricitinib in patients with lupus nephritis is currently ongoing [NCT05432531]. Eligibility criteria include 18–60 years old LN patients. Patients with a history of cardiac disease and thrombosis will be excluded. Patients will be randomized to receive monthly IV cyclophosphamide (0.7 g/m²/month) or baricitinib (4 mg/day po). Primary outcome measure will be the quantity of protein in 24-hour urine. Secondary outcomes will be serum complement 3 level, serum anti dsDNA titers and SLEDAI-2K at the third and sixth months.

Case Reports

Case reports that describe the use of JAK inhibitors are listed in Table 2.

Table 2: Case reports that describe the use of JAK inhibitors in patients with lupus nephritis

Garufi et al report the successful use of JAK inhibitors in 2 rhupus patients (19). One of these patients is a 52 year old Caucasian male patient diagnosed with Class V LN who later developed symmetric polyarthritis, anti cyclic citrullinated peptide antibodies and rheumatoid factor positivity. He previously received glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine A, cyclophosphamide, rituximab. Abatacept temporarily controlled renal disease and the articular flares during the following years. Then tacrolimus was added to abatacept for a renal flare. Since arthritis and residual proteinuria persisted, abatacept was stopped and baricitinib 4 mg/day was added to tacrolimus and hydroxychloroquine. After 6 months the patient achieved a stable improvement in the joint involvement and complete renal remission with a reduction of proteinuria from 750 mg/day to 230 mg/day in 6th month.

Peng et al identified a novel DExD/H-box helicase 58 (DDX58) pathogenic variant R109C in 5 untreated families with lupus nephritis. This variant is a gain of function mutation, elevating type I interferon signaling due to reduced autoinhibition which leads to retinoic acid inducible gene I (RIG-I) hyperactivation, increased RIG-I K63 ubiquitination and mitochondrial antiviral-signaling protein (MAVS) aggregation. Transcriptome analysis revealed an increased interferon signature in patients’ monocytes. One of these patients was diagnosed with class IV+V LN when she was 12 years old. She received intravenous methylprednisolone and cyclophosphamide for induction therapy, which was followed by a maintenance regimen of oral glucocorticoids and azathioprine. When she was 28 years old, her disease relapsed and she was given intravenous glucocorticoid and cyclophosphamide. After a partial remission with this reinduction regimen, she received a maintenance regimen of methylprednisolone, MMF and hydroxychloroquine for 6 years. Despite this treatment her titer of autoantibodies remained high and complement levels were low. Mycophenolate mofetil was stopped for 5 weeks and then she received oral baricitinib for 6 months. Baricitinib enabled decrease of antinuclear antibody titer, elevated complement levels and stabilized disease activity. Renal disorder was not alleviated (no details concerning the serum creatinine level or proteinuria were provided in the text). No adverse effects or serious adverse events were present. Baricitinib effectively suppressed proinflammatory cytokines and expression of interferon stimulated genes especially in CD14 positive peripheral blood mononuclear cells. The authors claimed that suppression of type 1 interferon signature in this patient with baricitinib provided clinical implication that JAK inhibitors may be a potential treatment strategy in LN patients with DDX58 R109C variant.

Conclusion

Heterogeneity of organ involvement and the highly variable clinical course of SLE makes designing clinical trials in SLE challenging. There are many clinical trials that aim to assess the efficacy and safety of JAK inhibitors in SLE. However very few studies so far have focused on the efficacy and safety of JAK inhibitors in LN.

Unfortunately, very few Class V LN patients joined filgotinib trial and deucravacitinib trial was terminated due to insufficient enrollment. In filgotinib study, 4 patients on this drug achieved a reduction in median proteinuria of 50.7 percent compared to baseline. SELENA-SLEDAI score stabilized in 3 of these 4 patients at week 16. Two patients remained on filgotinib for 52 weeks and they achieved a median reduction in 24-hour urine protein of 78.3% at week 52. Only 1 deucravacitinib patient completed part B and that patient failed to achieve partial renal response. The case report of the rhupus patient with Class V LN and residual proteinuria described significant reduction in proteinuria when baricitinib was added to tacrolimus and hydroxychloroquine. In the other case report, baricitinib helped reduction of ANA titer and increased complement levels but renal disorder was not alleviated. The authors did not state the proteinuria levels before and after baricitinib treatment. When the issue of safety is concerned, no patients had major adverse events.