Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study

Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems [1‐3]. Lupus nephritis (LN) is associated with high mortality and morbidity rates. Over recent decades, substantial progress has been made in developing immunosuppressant agents and biologic therapies [4]. However, a significant proportion of patients either do not respond to first-line immunosuppressive drugs or quickly relapse after initial remission. Approximately 10% of patients with LN will experience continued worsening of renal function and go on to develop end-stage renal disease [5].

To treat refractory LN, the European League Against Rheumatism (EULAR) recommendations suggest a switch of either cyclophosphamide (CYC) to mycophenolate mofetil (MMF) or vice versa. In addition, a switch to B cell depletion therapy with rituximab may be considered [4]. In previous studies of refractory LN, an add-on strategy has usually been adopted; for example, rituximab has been added to another immunosuppressant, typically CYC [6‐8], or a calcineurin inhibitor combined with MMF [9, 10]. These strategies may help to ensure efficacy but could mask the role of the newly added drug.

In recent decades, a new immunomodulatory drug, iguratimod, has emerged as a potential candidate for the treatment of autoimmune diseases. It has been approved for treating rheumatoid arthritis (RA) in northeast Asia. According to data from RA clinical trials in Japan and China, iguratimod is superior to a placebo and non-inferior to methotrexate and sulfasalazine [11‐14]. In our preclinical study on lupus, iguratimod prevented autoimmune nephritis in MRL/lpr mice, decreased the amount of proteinuria, and reduced immune complex deposition [15].

Previous studies on possible mechanisms have provided compelling evidence supporting the rationale for using iguratimod to treat lupus. Iguratimod, an immunomodulatory agent, interferes with B cell differentiation. It was found to suppress B cell production of immunoglobulins over a decade ago [16]. In a phase III clinical trial on RA, iguratimod reduced serum immunoglobulin concentrations [12, 14]. In RA and lupus animal models, iguratimod has decreased autoantibody titers, including anti-collagen antibody [17, 18] and anti-double strand (dsDNA) antibody [15]. Interestingly, iguratimod reportedly decreases peripheral plasma cell counts without affecting the total B cell population in MRL/lpr mice [15] and patients with RA who are receiving iguratimod monotherapy [19]. Further investigation has shown that iguratimod regulates the key transcription factors affecting plasma cell differentiation, especially Blimp-1, through the PKC/Egr1 axis [19]. In this study, we aimed to explore the efficacy and safety of iguratimod in patients with refractory LN.

CYC, MMF, and rituximab are the agents recommended for the treatment of refractory LN by the EULAR guidelines [4]. However, this regimen does not guarantee a treatment response. In our study, six patients had had inadequate responses to both CYC and MMF before enrollment and another patient had failed on rituximab. Thus, there is a significant unmet need for new agents and strategies for treating refractory LN.

In this study, we showed for the first time the feasibility and potential efficacy of iguratimod in LN management, with a 92.3% response rate at week 24. This response rate is comparable to that reportedly achieved by other therapies that have been investigated for treating refractory LN, including calcineurin inhibitors [9, 10], rituximab [6‐8], and stem cell transplantation [25].

Of note, unlike in most other studies, we did not combine iguratimod with other immunosuppressive agents in this study. Moreover, we did not increase the study patients’ steroid dosages. Fortunately, we enrolled 13/14 patients before their steroids had been increased, the one exception being a patient whose prednisone dosage had been increased to 35 mg/day in other hospitals. Therefore, the renal response observed in the study can validly be attributed to the treatment with iguratimod. It also made the results of the study compelling and reliable despite the absence of a control arm.

We found that patients with baseline active urine sediments tended to be more likely to achieve CR later (4/9 in sediment positive patients vs. 1/4 in sediment negative patients), implying that patients with a more active phenotype may be more likely to respond fully to iguratimod treatment. However, the tendency to an association between baseline kidney damage and treatment outcome was not statistically significant, likely because of our small sample size. With only two non-responders, there was not a significant difference in the positive sediment rate between the responders and non-responders.

During the extended follow-up period, three (25%) of the responding patients had renal relapses. None of them had responded to the medication they had received before iguratimod and none of them achieved CR on iguratimod. Given that the achievement of CR is a critical predictor of relapse-free remission, our findings are consistent with those reported by other researchers in similar settings. The flare rate in our study was comparable to that previously reported, namely 12–64%, the rate varying according to race, pathological distribution, and duration of follow-up [26]. Thus, iguratimod could have a role in the maintenance therapy of LN.

Targeting B cell/plasma cells is a promising and attractive strategy for treating refractory LN. Notable B cell depletion by rituximab has been reported [6], and this agent has been recommended despite failing in the initial randomized controlled study [27]. In addition, the proteasome inhibitor bortezomib, which targets plasma cells, has been shown to be effective for treating refractory LN in the short term [28]. These results support the rationale of using iguratimod, which is a B cell terminal differentiation inhibitor, to treat refractory LN.

In addition, iguratimod has been shown to inhibit multiple inflammatory cytokines and chemokines that are involved in LN, such as interleukin (IL)-17, macrophage migration inhibitory factor, IL-6 and IL-1β, and NF-κB activation [18, 29‐31]. The suppression of both autoreactive B cells and inflammation suggest that iguratimod may be an effective treatment for LN.

One of the concerns raised by our findings is the severe anemia that one patient developed during treatment (the only serious adverse effect reported). Routine clinical tests, including a bone marrow smear, failed to reveal the exact mechanism of the anemia, probably because of our preemptive use of erythropoietin. In fact, post-market surveillance has shown that anemia is a common AE [24]. If our patient had stopped the treatment promptly, this might not have been a serious adverse effect.

The major limitation of the current study is the small sample size, which was mainly attributable to our stringent inclusion criteria and the study design. We carefully controlled every confounding factor that might have interfered with interpretation of the results. We chose patients with active renal manifestations only, stopped their immunosuppressants to rule out any residual effects from them, and maintained low dose steroids and other treatments to exclude the confounding effect of steroids. We believe the results of the current study clearly show the value of iguratimod in treating LN. On the basis of the current findings, we are performing a randomized controlled clinical trial to compare the efficacy of iguratimod with that of CYC-azathioprine sequential therapy in the induction therapy of active LN (NCT02936375).

Another limitation of this study is that in most patients, renal biopsies were performed at the time of onset of proteinuria. After several treatment regimens and with time, the pathology may have changed, influencing the effects of treatment. A low rate of repeat biopsy is a common problem [32]; only three of our patients agreed to repeat biopsies.

Our findings suggest that the novel immunomodulatory drug iguratimod may be a new candidate for the treatment of LN. More studies are warranted to verify the efficacy of iguratimod in the treatment of LN as well as other manifestations of SLE.