2022 Volume 258 Issue 3 Pages 219-223
Telitacicept is a novel humanized, recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor and the Fc portion (TACI-Fc) fusion protein, designed to neutralize the activity of both B-cell lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). On March 9, 2021, telitacicept received its first approval in China for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE). Additionally, on April 15, 2020, the U.S. Food and Drug Administration (FDA) granted fast track designation to telitacicept for the treatment of SLE. Clinical studies of telitacicept in several other indications, including IgA nephropathy, multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, rheumatoid arthritis and Sjögren’s syndrome are underway in China. This is the first case that reports telitacicept successfully treated a SLE patient with refractory cutaneous involvement, which provides a potential therapeutic option for recalcitrant cutaneous manifestations of SLE. Furthermore, we review reported studies of BLyS targeted treatments for mucocutaneous lupus. Telitacicept appears to have activity in refractory cutaneous involvement of SLE and clinical trials are warranted to further assess this potential therapy.
Cutaneous manifestations are frequent, occurring in approximately 80% of patients with systemic lupus erythematosus (SLE) (Durcan et al. 2019). In some refractory cases, B cell targeted biologics, such as rituximab (RTX) and belimumab, have been reported to be efficacious (Fernández-Nebro et al. 2012; Torrente-Segarra et al. 2021).
Telitacicept (RC-18, RCT-18; RemeGen, Yantai, Shandong, China) is a novel humanized, recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor and the Fc portion (TACI-Fc) fusion protein, designed to neutralize the activity of both B-cell lymphocyte stimulator [BLyS, also known as the B-cell activation factor (BAFF)] and a proliferation-inducing ligand (APRIL) (Dhillon 2021). On March 9, 2021, telitacicept was granted conditional marketing approval by the Chinese National Medical Products Administration (NMPA) for the treatment of adult patients with active, autoantibody-positive SLE. On April 15, 2020, the U.S. Food and Drug Administration (FDA) granted fast track designation to telitacicept for the treatment of SLE.
We report a SLE patient with refractory cutaneous manifestations who was successfully treated with telitacicept.
A 39-year-old woman was admitted to Rheumatology and Immunology Department for recurrent erythema. Nine years ago, the patient who suffered from erythema and joint pain was diagnosed with SLE and was treated with prednisone, hydroxychloroquine sulfate and leflunomide. The erythema showed no improvement, so leflunomide was replaced by methotrexate. During the next one year, the symptoms recurrently attacked. Methotrexate was replaced by mycophenolate mofetil, and the symptoms finally achieved remission. Seven years ago, for economic reasons, mycophenolate mofetil was replaced by methotrexate.
Three years before this admission, the patient suffered from alopecia areata. One year ago, when prednisone was tapered to a dose of 7.5 mg once daily, the symptoms, including erythema, oral ulcers and joint swelling relapsed. The patient was admitted into our department. Laboratory examinations showed positive anti-dsDNA antibodies (1:32) and positive urine protein (4.7 g/L). The patient was treated with methylprednisolone (24 mg once daily), hydroxychloroquine and leflunomide. The erythema aggravated, so leflunomide was replaced by mycophenolate mofetil (750 mg once daily). Then methylprednisolone was gradually tapered to a dose of 12 mg once daily. One month before this admission, the erythema relapsed.
Physical examinations showed erythema spread over her face and hands. Laboratory examination showed positive antinuclear antibodies (1:320), positive anti-RNP antibodies, and positive anti-Ro-52 antibodies. Anti-dsDNA antibodies were negative. Complement 3 (C3) was 0.7 g/L, and complement 4 (C4) was 0.179 g/L. Urine protein was 0.09 g/24 h. Liver function, kidney function, blood count and urine test were normal. After considering the patient’s clinical manifestation and economic conditions, the patient was treated with telitacicept (160 mg once weekly) after being fully informed of the risks associated with it, combined with previous treatment.
The addition of belimumab improved the signs and symptoms of refractory cutaneous lupus. Impressive clinical improvement was seen as early as 4 weeks after initiation of therapy. We were able to document pictorial evidence of improvement as well demonstrating significant change in laboratory examinations result like C3 and C4 level (Fig. 1). Methylpredisolone was tapered to a dose of 10 mg once daily during the follow-up.
All experiments were performed in compliance with the relevant laws. This study was approved by the Biomedical Research Ethics Committee of our hospital and complied with the mandate of the Declaration of Helsinki (2013 edition). The reported patient provided her written informed consent.
Clinical profile of the patient.
(A) The photos of the hand before (A1) and 4 weeks after telitacicept (A2). (B) The changes of biomarkers; complement 3 (C3), complement 4 (C4) and IgG. Red arrows show the day of initial telitacicept. (C) The therapeutic timeline of the patient.
LEF, leflunomid; MTX, methotrexate; MMF, mycophenolate mofetil; HCQ, hydroxychloroquine sulfate; Pred, prednisone; MP, methylprednisolone.
We report a SLE patient who suffered from refractory cutaneous involvement and was effectively treated with telitacicept after failure to methotrexate, mycophenolate mofetil and anti-malarials. Rapid improvement was observed as early as two weeks after initiation of therapy. To our knowledge, this is the first case that reports telitacicept for refractory cutaneous manifestations of SLE.
For cutaneous involvement of SLE, topical or systemic glucocorticoids and anti-malarials (hydroxychloroquine) is the first-line treatment. For refractory cases, methotrexate, mycophenolate mofetil and azathioprine can be added (Fanouriakis et al. 2019). BLyS targeted biologics, such as belimumab, have been reported to be efficacious in refractory cutaneous lupus. We summarized the reported studies of BLyS targeted treatments for mucocutaneous involvement of lupus (Table 1).
According to the review, belimumab has positive effects on mucocutaneous involvement of SLE. In phase III clinical trials (BLISS-52 and BLISS-76), patients with mucocutaneous features from either 10 mg/kg group or 1 mg/kg group had obvious improvement at 52 weeks (Manzi et al. 2012). In another prospective observational study, 49% of patients had improved in mucocutaneous systemic lupus erythematosus disease activity Index 2000 (mcSLEDAI-2K) (Parodis et al. 2018). In a case series analysis involving 16 patients, cutaneous lupus erythematosus disease area and severity index-50 (CLASI-50) was observed in 8 patients (50%) and 3 (19%) had a complete response (Salle et al. 2020). Another case series study showed all of five enrolled patients experienced significant improvement in their skin rashes during an average of 16 weeks follow-up (Vashisht et al. 2017). However, in a RCT study on children with SLE, compared with placebo group, no observable difference was found in mucocutaneous British Isles lupus assessment group (BILAG) organ domain improvements at week 52 (Brunner et al. 2020).
The evidences of the efficacy of other BLyS antagonists are tenuous at best. In CHABLIS-SC1 study, the phase III clinical placebo-controlled trial of blisibimod, rapid improvements in mucocutaneous disease activity were observed in both blisibimod and placebo groups at week 4 (> 10%), week 8 (> 25%), week 12 (> 40%) and beyond (specific data were not shown) (Merrill et al. 2018). In ILLUMINATE-1 study of tabalumab, there were no differences in mucocutaneous improvement across subgroups (Isenberg et al. 2016).
As a novel recombinant TACI-Fc fusion protein, the efficacy of telitacicept for cutaneous impairment of SLE remains unclear. The phase I and IIb clinical trials of telitacicept did not provide enough data for the effects of telitacicept on mucocutaneous domain (Wu et al. 2019). In our case, the cutaneous improvement, in both face and upper extremities, was rapidly observed after initiation of therapy.
According to previous studies, BLyS and APRIL co-inhibitors are associated with increased severe toxicity. In a separate phase II/III trial of atacicept which can neutralize both BLyS and APRIL, two deaths were reported in higher dose group. Increased incidence of serious infections could be associated with rapid decline in IgG level during atacicept treatment. An approximately 30% reduction in serum IgG levels by as early as 4 weeks after initial atacicept treatment has been observed in phase I trial (Dall’Era et al. 2007). In our case, IgG level also decreased slightly, but the level was still within the normal range at 4 weeks.
In conclusion, this is the first case that reports telitacicept successfully treated a SLE patient with refractory cutaneous involvement, which provides a potential therapeutic option for recalcitrant cutaneous manifestations of SLE. Furthermore, we review reported studies of BLyS targeted treatments for mucocutaneous lupus. Further studies are warranted to assess the efficacy of BLyS antagonists for mucocutaneous involvement of SLE.
Review of reported studies of B-lymphocyte stimulator targeted treatments for mucocutaneous involvement of lupus.
SLE, systemic lupus erythematosus; CLE, cutaneous lupus erythematosus; RCT, randomized controlled trial; mcSLEDAI-2K, mucocutaneous systemic lupus erythematosus disease activity Index 2000; BILAG, British Isles lupus assessment group; CLASI-50, cutaneous lupus erythematosus disease area and severity index-50.
We thank the members of the National Natural Science Foundation of China (NSFC) and the Sichuan Science and Technology Program for their support. The work was supported by grant 81102274 from the National Natural Science Foundation of China (NSFC) (Hui Lin); grant 2017HH0110 supported by Sichuan Science and Technology Program (Hui Lin).
The authors declare no conflict of interest.
