The novel immunomodulatory agent iguratimod, which interferes with B-cell differentiation, showed promise for refractory lupus nephritis in a small, preliminary study.
Among 13 patients who had failed or relapsed on at least two immunosuppressive therapies, the renal response rate was 92.3% at week 24, according to Qingran Yan, MD, and colleagues from Shanghai Jiaotong University in Shanghai.
That included a complete renal response in five patients (38.5%) and partial renal response in seven (53.8%), the researchers reported online in Arthritis Research & Therapy.
One of the most serious manifestations of systemic lupus erythematosus is lupus nephritis. Although there have been notable improvements in treatment of kidney involvement in recent decades, a substantial number of patients do not respond to currently available therapies and an estimated 10% of patients with lupus nephritis progress to end-stage renal disease.
The European League Against Rheumatism has recommended that patients with refractory lupus nephritis be switched from first-line therapy with cyclophosphamide to mycophenolate mofetil (Cellcept), or vice versa. Additional options include rituximab (Rituxan), which typically has been given along with cyclophosphamide, and calcineurin inhibitors given in combination with mycophenolate.
Iguratimod has been approved for the treatment of rheumatoid arthritis in China and Japan based on the results of randomized trials; one study that included almost 500 patients demonstrated noninferiority to methotrexate. In a murine model, iguratimod also prevented the development of nephritis, decreased the deposition of immune complexes, and reduced the severity of proteinuria.
The rationale for use of iguratimod for lupus nephritis includes its regulation of transcription factors involved in B-cell differentiation such as Blimp-1, its suppression of B-cell production of immunoglobulins, and its ability to decrease anti-double stranded DNA antibodies, the researchers explained.
Accordingly, from 2015 to 2018 they sequentially enrolled 14 patients whose proteinuria was at least 1 g/24 hours. Previous medications included cyclophosphamide, cyclosporine, azathioprine, rituximab, mycophenolate mofetil, and tacrolimus.
At the time of iguratimod initiation in oral dosages of 25 mg twice daily, all other immunosuppressants were withdrawn, while stable doses of prednisone, antimalarials, and angiotensin-converting enzyme/receptor inhibitors were permitted.
Complete response was defined as 24-hour urinary protein below 300 mg, normal blood cell counts or casts, and normal serum creatinine. Partial response required a 24-hour urinary protein between 300 and 2,000 mg and a decrease of at least 50% from baseline, serum albumin concentrations above 30 g/L, and an increase below 25% in serum creatinine.
Patients' median age was 30.5, and median proteinuria was 3.41 g/24 hours.
One patient was lost to follow-up, and one did not respond after 6 months of treatment.
The 12 responders continued treatment beyond the initial 24-week phase, with seven completing up to 144 weeks of treatment and maintaining stable urinary protein throughout. Three experienced renal relapses, at a median time of 80 weeks, and discontinued treatment.
Estimated glomerular filtration rate was stable in all patients, above 90 mL/min/1.73 m2 in the majority.
Most adverse events such as upper respiratory tract infections and slight decreases in white blood cell counts were mild.
However, one patient developed severe anemia after 12 weeks on iguratimod. The investigators were able to rule out potential causes such as hemolysis and occult bleeding. "Given that we were unable to identify a clear explanation for her anemia, drug-related reasons had to be considered," they stated. She was given a transfusion and treated with erythropoietin and the anemia resolved after 2 weeks.
Additional postmarketing surveillance assessing safety in 2,600 patients with rheumatoid arthritis has revealed that anemia is a common event, and if treatment in the affected patient had been quickly withdrawn, "this might not have been a serious adverse effect," they commented.
In previous studies, the most frequent adverse event associated with iguratimod was liver function impairment, but in this study, the only hepatic abnormality was a transient increase in alanine aminotransferase in one patient that resolved spontaneously.
The fact that the iguratimod treatment was not given in combination with other immunosuppressive agents implied that "the renal response observed in the study can validly be attributed to the treatment with iguratimod," the authors stated.
"It also made the results of the study compelling and reliable despite the absence of a control arm," they added.
The major limitation of the study was its small size, they acknowledged. Nonetheless, "more studies are warranted to verify the efficacy of iguratimod in the treatment of lupus nephritis as well as other manifestations of systemic lupus erythematosus," they concluded.
Disclosures
The study was funded by the National Key Research and Development program of China, the National Natural Science Foundation of China, Shanghai Municipal Science and Technology Fund, and Shanghai Jiaotong University.
Yan and co-authors disclosed no relevant relationships with industry.
Primary Source
Arthritis Research & Therapy
Source Reference: Kang Y, et al "Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study" Arthritis Res Ther 2020; DOI: 10.1186/s13075-020-02154-7.