International Behcet's Disease Care Day: Progress of New Behcet's Disease Drugs

Behçet's syndrome (BS), also known as Behçet's disease (BD), is a multisystem vasculitis characterized by oral and genital ulcers, papular and nodular skin lesions, arthritis, uveitis, venous And arterial thrombosis , aneurysm, central nervous system lesions and gastrointestinal ulcers, e.

At present, there is no unified treatment strategy for BS, and most national guidelines recommend treatment drugs according to the involvement of different syste.

Apst

In 2019, the.

A subgroup analysis of a phase III randomized, placebo-controlled, double-blind study of 39 patients with BS evaluated the effect of apremilast in Japanese patients [1], and confirmed that apremilast reduced the incidence of Japanese patients with .

Figure 1 Number of oral ulcers in the Japanese subgroup during the 12-week placebo-controlled period

Figure 2 Oral ulcer pain in the Japanese subgroup during the 12-week placebo-controlled period

(100-mm VAS) Variation

Another phase III, double-blind, placebo-controlled study [2] evaluated the efficacy and safety of apremilast in the treatment of BS-related oral ulcers for up to 64 wee.

JAK inhibitors

As a representative disease of variant vasculitis, BS is considered to be closely related to many inflammatory pathwa.

At present, there are few literatures on the treatment of BS with JAK inhibito.

Table 1 Clinical characteristics of patients with Behcet's disease with macrovascular/cardiac involvement

Another study [4] summarized the effects of tofacitinib in 13 patients with refractory BS and found that after an average follow-up of 8 months, the BS activity index was significantly improved, the inflammatory index was significantly reduced, and the amount of hormones used was significantly improv.

Figure 3 Efficacy of tofacitinib on BS patients

Notes: (A) Change from Baseline in Disease Activity Score (BDCAF 2006) (P=002); (B) Results of three clinical phenotypes of BS; (C) and (D) erythrocyte sedimentation rate during tofacitinib treatment (ESR) and C-reactive protein (CRP) changes

However, the treatment of BS with JAK inhibitors still lacks confirmation of large sample size, especially randomized controlled tria.

New Drugs of Biologics Emerge

In terms of high-profile biological agents, anti-TNF drugs currently occupy the main position in the treatment of BS, but considering that some patients may be ineffective or have contraindications to TNF-α inhibitors, finding new therapeutic targets is also a current rheumatology stu.

Therapeutic strategies targeting interleukin (IL)-17 are also considered to be potentially effective in .

A multicenter retrospective study [5] investigated 15 patients with BS who were refractory to treatment with colchicine, disease-modifying antirheumatic drugs (DMARDs), and at least one anti-TNF-α drug, with a minimum follow-up of 6 mon.

Notably, all patients who started on 300 mg/month achieved complete remission at 6 mont.

Figure 4 Schematic representation of patient response to treatment during follow-up

At present, there are no large-scale clinical studies and randomized controlled trials to confirm the efficacy of secukinumab, and from the existing studies, the current therapeutic doses are mostly 150mg and 300mg/month, which is similar to AS and psorias.

Ustekinumab, a humanized monoclonal antibody against IL-12 and IL-23, is a multicenter, prospective, clinical trial of 30 colchicine-resistant BS patients with active oral ulce.

Table 2 Efficacy of ustekinumab on BS-related oral ulcers

Another study that included 14 colchicine-resistant BS patients with active oral ulcers [7] also evaluated the efficacy of ustekinumab in BS patients, and the results showed that at 12 weeks, 64% of patients achieved complete remission, 21% achieved partial remission, and 14% had no response, with a significant reduction in the median number of oral ulcers and BS disease activity score from baseline (Figure

Figure 5 Mean number of oral ulcers in patients receiving ustekinumab (A) and

BS Activity Score (B) 

In general, new drugs continue to play an increasingly important role in the treatment of BS, giving patients more choices in the future, but high-quality evidence-based medicine is still lacking, and the optimal treatment population for these drugs is still uncle.

Not clear, I hope there will be more and better research results in the future to apply precision medicine to BS and benefit more patien.

references:

Takeno Mitsuhiro, Dobashi Hiroaki, Tanaka Yoshiya et .

Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled stu.

[J.

Mod Rheumatol, 2022, 32: 413-42

Hatemi Gülen, Mahr Alfred, Takeno Mitsuhiro et .

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical tri.

[J.

Clin Exp Rheumatol, 2021, null: 80-8

Liu Jinjing, Sun Luxi, Hou Yunxia, ​​Li Lu, Li Jing, Tian Xinping, Zheng Wenj.

Efficacy and safety of tofacitinib in the treatment of Behcet's disease with cardiac and large vessel involvement[.

Chinese Journal of Clinical Immunology and Allergy,2020 , 14(2):111-117

Jinjing, Liu, Yunxia, ​​Hou, Luxi, Sun et .

A pilot study of tofacitinib for refractory Behçet's syndro.

[.

Annals of the rheumatic diseases, 2020, 79(11): 1517-152

Fagni Filippo, Bettiol Alessandra, Talarico Rosaria et .

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre stu.

[J.

Ann Rheum Dis, 2020, 79: 1098-110

Mirouse Adrien, Barete Stéphane, Desbois Anne-Claire et .

Long-Term Outcome of Ustekinumab Therapy for Behçet's Disea.

[J.

Arthritis Rheumatol, 2019, 71: 1727-173

Mirouse Adrien, Barete Stéphane, Monfort Jean-Benoît et .

Ustekinumab for Behçet's disea.

[J.

J Autoimmun, 2017, 82: 41-4

Behçet's syndrome (BS), also known as Behçet's disease (BD), is a multisystem vasculitis characterized by oral and genital ulcers, papular and nodular skin lesions, arthritis, uveitis, venous And arterial thrombosis , aneurysm, central nervous system lesions and gastrointestinal ulcers, e.

, are mainly distributed in the ancient Silk Road, the exact pathogenesis is still uncle.

According to statistics , there are about 200,000 BS patients in China, and the ratio of male to female is close to 1:

At present, there is no unified treatment strategy for BS, and most national guidelines recommend treatment drugs according to the involvement of different syste.

The drugs currently used for the treatment of BS include glucocorticoids, thalidomide, azathioprine, tumor necrosis factor (TNF)-α antagonists, e.

, but these existing drugs still cannot meet all the needs of diagnosis and treatmen.

Today we will pay attention to the clinical research progress of new drugs for the treatment of .

Apst

In 2019, the.


Food and Drug Administration ( FDA ) approved the oral phosphodiesterase-4 selective inhibitor apremilast for the treatment of BS-related mouth ulcers, making it the first ever licensed in the.


The drug used for the treatment of oral ulcers in Behçet's disease, in recent years, more and more clinical studies have been conducted on this drug for the treatment of .

A subgroup analysis of a phase III randomized, placebo-controlled, double-blind study of 39 patients with BS evaluated the effect of apremilast in Japanese patients [1], and confirmed that apremilast reduced the incidence of Japanese patients with .

Number of mouth ulcers and overall disease activi.

Patients were randomly assigned to apremilast (30 mg twice daily; n=19) or placebo (n=20), and the primary endpoint was the area under the curve for the number of oral ulcers at 12 weeks (AUCWk0-12), Secondary endpoints were mouth ulcer pain, complete resolution of mouth ulcers, disease activity, and change from baseline in measures of disea.

At week 12, patients in the apremilast group had significantly fewer canker sores (Figure 1), significantly less pain (Figure 2), and more patients achieved complete healing of canker sores (59% .

20%), and the BS disease activity score was significantly lower than baseline (-15 vs 5), and quality of life was also improv.

Figure 1 Number of oral ulcers in the Japanese subgroup during the 12-week placebo-controlled period

Figure 2 Oral ulcer pain in the Japanese subgroup during the 12-week placebo-controlled period

(100-mm VAS) Variation

Another phase III, double-blind, placebo-controlled study [2] evaluated the efficacy and safety of apremilast in the treatment of BS-related oral ulcers for up to 64 wee.

Patients with BS were randomly assigned to placebo or apremilast 30 mg, and all patients received treatment until week 64 and were followed up 4 weeks after treatment was discontinu.

A total of 207 participants were included in the study, of whom 143 completed week 64 of treatme.

The results showed that AUCWk0-12 was significantly reduced (P<0001) with apremilast compared with placebo, and the number of oral ulcers, pain, complete/partial response, disease activity and quality of life showed improvement at week 12, and continued until week 6 During the study period, no new safety concerns were observed with Apremila.

The above data show that Apremilast is well tolerated and safe in the continuous treatment of BS-related oral ulce.

JAK inhibitors

As a representative disease of variant vasculitis, BS is considered to be closely related to many inflammatory pathwa.

In view of the fact that the JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in multiple links and processes of the immune system in the secretion and biological effects of various cytokines , it plays an important role in the occurrence and development of vasculitis, Therefore JAK inhibitors may play a role in .

At present, there are few literatures on the treatment of BS with JAK inhibito.

The Zheng Wenjie team of Peking Union Medical College Hospital published a literature in 2020 [3], which introduced the efficacy and safety of tofacitinib in the treatment of BS with heart and great vessel involveme.

A total of 5 patients who received 5-10 mg/day of tofacitinib after the combination of hormones combined with various immunosuppressants were not effective were included in the study (Table
The average follow-up was 16 mont.

The clinical symptoms were improved, and the inflammatory indicators were improv.

At the same time, the amount of hormones was also reduc.

It is believed that tofacitinib can help stabilize the condition of BS complicated with refractory large blood vessel involvement, and at the same time help reduce the amount of hormon.

Table 1 Clinical characteristics of patients with Behcet's disease with macrovascular/cardiac involvement

Another study [4] summarized the effects of tofacitinib in 13 patients with refractory BS and found that after an average follow-up of 8 months, the BS activity index was significantly improved, the inflammatory index was significantly reduced, and the amount of hormones used was significantly improv.

also decreas.

Figure 3 Efficacy of tofacitinib on BS patients

Notes: (A) Change from Baseline in Disease Activity Score (BDCAF 2006) (P=002); (B) Results of three clinical phenotypes of BS; (C) and (D) erythrocyte sedimentation rate during tofacitinib treatment (ESR) and C-reactive protein (CRP) changes

However, the treatment of BS with JAK inhibitors still lacks confirmation of large sample size, especially randomized controlled tria.

More case data are needed to confirm whether it is effective for all symptoms or only for a certain syst.

New Drugs of Biologics Emerge

In terms of high-profile biological agents, anti-TNF drugs currently occupy the main position in the treatment of BS, but considering that some patients may be ineffective or have contraindications to TNF-α inhibitors, finding new therapeutic targets is also a current rheumatology stu.

One of the tasks of an expe.

Therapeutic strategies targeting interleukin (IL)-17 are also considered to be potentially effective in .

IL-17 inhibitors are currently showing great success in ankylosing spondylitis (AS) and psorias.

A retrospective analysis in 2019 analyzed the treatment effect of 5 BS patients using secukinumab, and found that secukinumab 150mg/month and 300mg/month improved previously refractory mucocutaneous manifestations, while 300mg/month improved mucocutaneous manifestatio.

/month is more advantageo.

A multicenter retrospective study [5] investigated 15 patients with BS who were refractory to treatment with colchicine, disease-modifying antirheumatic drugs (DMARDs), and at least one anti-TNF-α drug, with a minimum follow-up of 6 mon.

Six patients with polyarticular involvement received 300 mg/month of secukinumab, while the others received 150 mg/month, and efficacy was assessed based on the number of oral ulcers in the past 28 days and a disease activity score for joint manifestations-2 At 3-month follow-up, 9 (67%) patients achieved remission (complete or partial), which further increased to 87% at 6 months, 79% at 12 months, and 18 months 90%, reaching 100% after 24 months (Figure

Notably, all patients who started on 300 mg/month achieved complete remission at 6 mont.

Seven (47%) patients achieved a response only after switching to a higher do.

This study shows that coukinumab is safe and effective for refractory BS patients with mucosal and joint phenotypes, and secukinumab can be considered for phenotype-tailored treatment in clinical practi.

Figure 4 Schematic representation of patient response to treatment during follow-up

At present, there are no large-scale clinical studies and randomized controlled trials to confirm the efficacy of secukinumab, and from the existing studies, the current therapeutic doses are mostly 150mg and 300mg/month, which is similar to AS and psorias.

There is a large gap in the usage in BS, and later clinical trials will further determine the optimal therapeutic dose for BS patien.

Ustekinumab, a humanized monoclonal antibody against IL-12 and IL-23, is a multicenter, prospective, clinical trial of 30 colchicine-resistant BS patients with active oral ulce.

An open-label study [6] evaluated the efficacy of ustekinumab in .

Enrolled patients received 90 mg of ustekinumab subcutaneously at weeks 0 and 4, and then every 12 wee.

The number of oral ulcers in each patient was assessed longitudinally, and the median [interquartile range (IQR)] of oral ulcers was calculat.

The primary efficacy endpoint was the proportion of patients achieving complete remission (defined as the absence of oral ulcers) at week 1 The results showed that after 12 weeks of ustekinumab treatment, the median number of oral ulcers per patient was significantly lower than baseline (P<0001), of which 18 (60%) patients achieved complete remission and 9 (30%) patients achieved complete remissi.

Patients achieved partial responses and 3 (10%) patients had no responses (Table
In addition, at 12 weeks, the BS disease activity score was significantly lower than baseline (P<000

Table 2 Efficacy of ustekinumab on BS-related oral ulcers

Another study that included 14 colchicine-resistant BS patients with active oral ulcers [7] also evaluated the efficacy of ustekinumab in BS patients, and the results showed that at 12 weeks, 64% of patients achieved complete remission, 21% achieved partial remission, and 14% had no response, with a significant reduction in the median number of oral ulcers and BS disease activity score from baseline (Figure
In conclusion, ustekinumab is effective in patients with refractory .

Figure 5 Mean number of oral ulcers in patients receiving ustekinumab (A) and

BS Activity Score (B) 

In general, new drugs continue to play an increasingly important role in the treatment of BS, giving patients more choices in the future, but high-quality evidence-based medicine is still lacking, and the optimal treatment population for these drugs is still uncle.

Not clear, I hope there will be more and better research results in the future to apply precision medicine to BS and benefit more patien.

references:

Takeno Mitsuhiro, Dobashi Hiroaki, Tanaka Yoshiya et .

Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled stu.

[J.

Mod Rheumatol, 2022, 32: 413-42

Hatemi Gülen, Mahr Alfred, Takeno Mitsuhiro et .

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical tri.

[J.

Clin Exp Rheumatol, 2021, null: 80-8

Liu Jinjing, Sun Luxi, Hou Yunxia, ​​Li Lu, Li Jing, Tian Xinping, Zheng Wenj.

Efficacy and safety of tofacitinib in the treatment of Behcet's disease with cardiac and large vessel involvement[.

Chinese Journal of Clinical Immunology and Allergy,2020 , 14(2):111-117

Jinjing, Liu, Yunxia, ​​Hou, Luxi, Sun et .

A pilot study of tofacitinib for refractory Behçet's syndro.

[.

Annals of the rheumatic diseases, 2020, 79(11): 1517-152

Fagni Filippo, Bettiol Alessandra, Talarico Rosaria et .

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre stu.

[J.

Ann Rheum Dis, 2020, 79: 1098-110

Mirouse Adrien, Barete Stéphane, Desbois Anne-Claire et .

Long-Term Outcome of Ustekinumab Therapy for Behçet's Disea.

[J.

Arthritis Rheumatol, 2019, 71: 1727-173

Mirouse Adrien, Barete Stéphane, Monfort Jean-Benoît et .

Ustekinumab for Behçet's disea.

[J.

J Autoimmun, 2017, 82: 41-4