Positioning of apremilast in treatment of Behçet’s disease

Abstract

Behçet’s disease is a chronic relapsing inflammatory disorder characterized by oral and genital ulcers, skin lesions, and uveitis. Although the involvement of the gastrointestinal, large vascular, and central nervous systems is less common, it can be fatal at times. To suppress inflammatory exacerbations and recurrences which can cause irreversible organ damage, treatment should be individualized according to the disease phenotype and severity. Apremilast, an oral phosphodiesterase 4 inhibitor, is used to treat psoriasis. The enzyme specific inhibitor increases intracellular cAMP levels, which modulate multiple signaling pathways in both innate and adaptive immunocompetent cells, leading to attenuation of inflammatory responses through the suppression of the functions of various types of immunocompetent cells including Th1 cells, Th17 cells and M1 macrophages. Current evidence shows that apremilast is effective for oral ulcer, the most common symptom of Behçet’s disease. An oral ulcer is considered to represent the basic immunopathology of Behçet’s disease, because the disease susceptibility genes are shared between Behçet’s disease and recurrent aphthous stomatitis. The favorable effects have been documented in other inflammatory diseases with symptoms similar to those of Behçet’s disease. The further studies would shed the light on the potential of apremilast for the treatment of Behçet’s disease.

Keywords:

• Behçet’s disease
• apremilast
• recurrent apthous stomatitis
• genome-wide association study

Background

Behçet’s disease (BD) is a chronic relapsing inflammatory disorder characterized by oral and genital ulcers, papulopustular and nodular lesions, and uveitis [1–3]. These common symptoms are usually self-limiting except ocular involvement which potentially causes blindness without appropriate treatment. In contrast, the involvement of the gastrointestinal, large vascular, and central nervous systems is less frequent but often serious, leading to irreversible damages and even fatal events [1–3]. The goal of the treatment is to promptly suppress inflammatory exacerbations and prevent recurrences which potentially leave irreversible damages [4]. Because of heterogeneous clinical presentations and various grades of severity, the treatment is not consistent for all patients and needs to be personalized [4]. Mild mucocutaneous lesions are treated with topical corticosteroids and colchicine, while serious organ involvement including ocular lesions requires potent immunosuppressive therapies including corticosteroids, immunosuppressants, and TNF inhibitors (Table 1) [1–4].

Table 1. Standard and optional therapies for individual symptoms in Behçet’s disease.

	Mucocutaneous lesions	Ocular lesion		Arthritis	Intestinal lesion	Vascular lesion	Neurological lesion
		Anterior uveitis	Posterior uveitis				Acute type	Chronic progressive type
Topical corticosteroid	〇	〇	〇	△
Colchicine	〇	〇	〇	〇			〇*
Systemic corticosteroid	△		△	〇	〇	〇	〇	E
Azathioprine	△		〇	〇	〇	〇		E
Methotrexate				〇	△	△		〇
Cyclophosphamide						〇		E
Cyclosporine			〇				X	X
5-aminosalicylic acid					〇
TNF inhibitor	△	E	〇	△	〇	〇	△	〇

〇：Standard therapy, △：Optional therapy, 　X: Contraindication, 〇*：Prophylaxis of recurrence.

E: Recommended by the 2018 update of the European League Against Rheumatism (EULAR) recommendations for the management of Behçet’s syndrome (4) but not the 2019 guidelines of the management of Behçet’s disease by Behçet’s Disease Research Committee, Ministry of Health, Labour and Welfare, Japan.

A recurrent oral ulcer is the most common and usually the first presentation in most of BD patients [1,5]. Painful oral ulcers, which appear in almost all patients, cause difficulty in eating and drinking, and impair their quality of life. Standard therapies for oral ulcers include topical steroids and oral agents such as colchicine [4,6], although these therapies are not very effective in some patients. Recently, an oral anti-inflammatory agent, apremilast (specific phosphodiesterase (PDE) 4 inhibitor), has been approved for treatment of recurrent oral ulcers in BD patients in Japan after successful global clinical trials [7,8]. A couple of papers have reported that apremilast is beneficial for refractory oral ulcers to conventional clinical therapies [9,10]. This article presents a review of the pharmacological action and clinical efficacy of apremilast for oral ulcer and a discussion about its positioning in the treatment of BD.

Mechanism of action of apremilast

PDE consists of 11 families (PDE 1-11) and catalyzes the breakdown of 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP), which function as second messengers in the regulation of multiple cellular signaling pathways [11,12]. Of the 11 families, PDE4 is expressed in the brain, cardiovascular tissues, smooth muscles, keratinocytes, and inflammatory cells including T cells, monocytes, macrophages, neutrophils, dendritic cells, and eosinophils [12,13]. All of the four subtypes of PDE4, PDE4A-D, are specific for cAMP but not for cGMP. PDE4 dependent cAMP degradation increases the production of proinflammatory mediators and suppresses that of anti-inflammatory mediators [12,13]. Indeed, PDE4 expression is upregulated in inflammatory lesions in various diseases [14]. Targeting PDE4 is expected to be a promising therapeutic approach in the treatment of inflammatory diseases [11–13]. In the last two decades, besides BD, PDE4 inhibitors have been proposed and tried as an effective therapeutic strategy for inflammatory conditions, including asthma, chronic obstructive pulmonary disease, psoriasis, psoriatic arthritis, atopic dermatitis, inflammatory bowel diseases, rheumatoid arthritis, systemic lupus erythematosus, and neuroinflammation besides BD [12,13,15]. However, the development of most of the PDE 4 inhibitors has been discontinued because of their narrow therapeutic windows, which results in dosing limitations and causes adverse events such as nausea and emesis. Exceptionally, apremilast is now widely used for psoriasis [13,16]. Subsequently, the agent has been currently approved in Japan for BD.

Pharmacological actions of PDE4 inhibitors are mediated by an increased level of intracellular cAMP, which modulates multiple signaling pathways through the activation of phosphokinase A (PKA) and the exchange protein 1/2 activated by cAMP (Epac1/2) (Figure 1) [13]. On one hand, activated PKA phosphorylates cAMP responsive element binding protein (CREB), activating transcription factor 1 (ATF-1), and cAMP responsive element modulator (CREM), leading to an increase in anti-inflammatory cytokines. On the other hand, activated PKA modulates the transcriptional activity of NF-κB through competitive recruitment of CREB binding protein (CBP) or the homologous protein p300, as a transcriptional coactivator of NF-κB, resulting in the reduction of proinflammatory cytokines [12,13]. Additionally, PKA activation also interferes with Bcl-6 mediated synthesis of proinflammatory cytokines and the proliferation of immune cells [12,13]. The alternative pathway is mediated by Epac1/2, which is activated in the wake of cAMP elevation and interacts with a small GTPase protein, Rap, resulting in suppression of proinflammatory cytokine synthesis and cell proliferation [13,17]. Because PDE4 is expressed in various types of immunocompetent cells, the inhibitors can modulate both the innate and adaptive immune systems (Figure 1). Immunopharmacological effects of apremilast have been studied mainly in patients with psoriasis [12]. Accumulated evidence has shown that PDE4 inhibition suppresses the functions of Th1,Th17, and production of proinflammatory cytokines by M1 macrophages, whereas the agent enhances the regulatory functions of IL-10 producing B cells and anti-inflammatory M2 macrophages [12,13,18,19]. These effects are considered to contribute to the clinical efficacy of apremilast for psoriasis.

Figure 1. G-protein coupled receptor (GPCR) stimulates adenyl cyclase (AC) which converts ATP into cAMP. PDE4 inhibitors accumulate intracellular cAMP, which subsequently activates phosphokinase A (PKA) and the exchange protein 1/2 activated by cAMP (Epac1/2). Activated PKA phosphorylates cAMP responsive element binding protein (CREB), activating transcription factor 1 (ATF-1), and cAMP responsive element modulator (CREM), leading to an increase in anti-inflammatory cytokines. On the other hand, activated PKA suppresses the functions of NF-κB through competitive recruitment of CREB binding protein (CBP) or the homologous protein p300, resulting in the reduction of proinflammatory cytokines. PKA activation also interferes with Bcl-6 mediated synthesis of proinflammatory cytokines and proliferation of immune cells. Activated Epac1/2 interacts with a small GTPase protein, Rap, resulting in the suppression of proinflammatory cytokine synthesis and cell proliferation. As a result, PDE4 inhibitors exhibit anti-inflammatory effects by modulating the functions of various immunocompetent cells, as shown.

The pharmacologic profile of apremilast seems reasonable as a therapeutic strategy for BD. A recently proposed concept, MHC-I-opathy suggests clinical and pathophysiological similarities between psoriasis and BD [20–22]. Both the diseases have similar distribution of lesions in the skin, eye, joint, and intestine, though individual features are different between them.

BD and psoriasis is strongly associated with HLA-B*51 and HLA-Cw*6, respectively [21,23]. ERAP1, encoding endoplasmic reticulum aminopeptidase 1 (ERAP-1), which trims peptides in the ER before loading them onto MHC class I molecules, was identified as a susceptible gene only in psoriasis patients with HLA-Cw*6 but not the others [24]. Likewise, a similar genetic interaction was found between ERAP1 and HLA-B*51 in BD [25], though susceptible ERAP1 allele in psoriasis is protective for BD. These findings suggest pathogenic roles of particular antigens, which have not been determined, in the both diseases. The disease susceptible genes suggest the involvement of Th1 and Th17 cells, and NF-kB signaling pathways in the inflammatory processes of both the diseases [20,23,25–32] (Table 2). In addition, we and others have shown polarized M1 macrophages with defective M2 functions as represented by reduced expression of IL-10 and heme-oxygenase (HO)-1 in BD [23,28,33].

Table 2. Susceptibility genes of psoriasis and psoriatic arthritis, and recurrent aphthous stomatitis in disease associated genes with Behçet’s disease.

Adaptive immunity
HLA
susceptible	B*51	B*15	B*27	B*57	A*26
protective	B*49	A*3
Antigen presentation	ERAP1
Cytokine receptors	IL23-IL12RB	IL23R	EGR2(ADO-EGR2)
Intracellular signaling  pathways	STAT4	PTPN1(CEBP-PTPN1)
Apoptosis	GIMAP
Innate immunity
cytokine related	IL10	IL12A	IL1A-IL1B	LACC1
chemokine receptors	CCR1	CCR1/CCR3
DAMPS/PAMPS sensor	MEFV	TLR4	NOD2	RIPK2
intracellular signaling  pathways	TNFAIP3	IRF8	CEBP(CEBP-PTPN1)
NK cell receptor	KLRC4
Others	FUT2

Bolds indicate susceptibility genes in psoriasis and psoriatic arthritis.

Underlines indicate susceptibility genes identified in patients with recurrent oral ulcers.

* Susceptible ERAP1 allele in Behçet’s disease is protective for psoriasis.

It seems reasonable that some of therapeutic agents including TNF inhibitors are used for both psoriasis and BD, which shared some of the genetic, pathophysiological, and clinical features. Thus, PDE4 can be also a promising target for BD as well as psoriasis [12,34].

Clinical trials of apremilast in BD patients

Treatment of BD should be personalized according to the disease phenotype and severity (Table 1) [4]. Colchicine, owing to its safety and tolerability profile, recommended as the first-line treatment in BD patients who only have skin and mucosa involvement [4,6]. However, two of three randomized, controlled studies on colchicine failed to show efficacy against oral ulcers [4,6]. Another standard therapy is application of topical corticosteroids, which may reduce the pain and duration of oral ulcers without preventing recurrences [6]. There is an unmet need for safe, and effective treatments for oral ulcers in patients with BD, especially in those having refractory oral ulcers which impair quality of life.

Apremilast is one of the candidates that satisfy these unmet needs. Recent clinical studies have shown the efficacy and safety of apremilast against oral ulcers in BD patients [7–9]. A phase 2 clinical trial, which was conducted in Turkey and the USA, showed that apremilast was effective in reducing the number and pain of oral ulcers and overall disease activity while improving the quality of life in BD patients with mucocutaneous involvement [7]. Subsequently, a global, phase III, multicenter, randomized, double-blind, placebo-controlled study, RELIEF enrolled a total of 207 BD patients having active oral ulcers despite at least one previous medication from 10 countries including Japan [8]. This trial evaluated the efficacy, safety, and tolerability of apremilast. In the trial, the primary endpoint was the area under the curve (AUC) for the number of oral ulcers through 12 weeks (AUC_0-12wk), which was significantly lower in the apremilast group than control. Reduction of the number and pain in the visual analogue scale (VAS) of oral ulcers were observed as early as 1st week and the efficacy continued during the administration. Although beneficial effects on the other BD related individual symptoms were not statistically proven, overall disease activity assessed by Behçet’s Syndrome Activity Score (BSAS) and Behçet’s Disease Current Activity Form (BDCAF) were significantly more improved in the apremilast group than in the control group. This was the case for Behçet’s Disease Quality of life (BDQoL) as well.

Nausea, diarrhea, upper respiratory tract infection, upper abdominal pain, and vomiting occurred in a higher percentage of patients receiving apremilast. These adverse events were generally mild and consistent with the previously known safety profiles of apremilast. No serious infection was documented. While 7 out of 104 patients receiving apremilast were dropped out from the trial during the 12 weeks of the placebo-controlled phase, 21 of 103 patients discontinued the trial in the placebo control group, indicating that the therapy was well tolerated. These results were consistent for subgroups analyzed according to baseline characteristics such as disease duration, previous treatment, and geographic regions. Similar results were confirmed in a prespecified subgroup analysis of 39 Japanese patients.

Recently, De Luca et al evaluated the efficacy and safety of apremilast in BD patients with mucocutaneous involvement resistant and/or intolerant in comparison with conventional therapies including colchicine and corticosteroids [9]. The case series did not include patients with uveitis and serious organ involvement. In consistence with the RELIEF study, the report demonstrated favorable effects of apremilast on oral ulcers and overall disease activity as assessed by BSAS, BDCAF, and BDQoL scores. It is of note that the efficacy is associated with robust sparing effects of corticosteroid and colchicine. On the other hand, the agent was discontinued because of adverse events such as diarrhea in 3 patients and suicidal ideation in one. Of 3 patients having diarrhea, 2 concomitantly received colchicine, while the other had a history of gastrointestinal involvement. Another retrospective study from Italy also showed similar clinical outcomes in 13 BD patients with oral and genital ulcers refractory to multiple therapeutic agents including TNF inhibitors [10].

Efficacy for the other manifestations of BD

It is interesting whether apremilast has favorable effects on the other BD related manifestations, because apremilast treatment was associated with improvement of overall disease activity and BDQoL scores [7,8]. However, both the phase II and phase III studies were not designed to determine whether apremilast improves BD related manifestations other than the oral ulcer.

In RELIEF, active skin symptoms were found in 56% of the patients at the baseline and were evaluated by physician’s global assessment. However, the instrument was not sensitive enough to detect the change during the studies. No significant efficacy for genital ulcers was found in RELIEF, although a positive trend was noted in a phase II trial and another study [7,8,10].

Because no previous studies included BD patients having serious manifestations such as active uveitis and the involvement of the large vascular, gastrointestinal, and central nervous systems, the efficacy of apremilast is undetermined for these serious forms of manifestations [7–10]. The phase III trial showed no evidence of worsening of uveitis in the apremilast group, while two patients had a flare of preexisting ocular involvement in the control group during the 12 weeks of the placebo-controlled period [8]. No major organ involvement appeared in either groups during the period, which was too short to assess prophylactic effects on de novo diseases with uveitis or major organ involvement [8]. Thus, neither positive nor negative signals of apremilast were available for the other BD-related symptoms from previous studies, mainly because the study designs were not appropriate.

At this moment, the author does not recommend using apremilast for BD related manifestations except for oral ulcers as a primary target. However, because BD patients must have other symptoms in addition to recurrent oral ulcers, information about efficacy for other BD-related symptoms should be accumulated in real-world settings.

Potential of apremilast for treatment of the other BD-related manifestations

Because recurrent oral ulcer is not only the most common but also the first presentation of BD in most patients [1,5], it is often considered as a constitutional condition in BD. Moreover, it is listed as an essential symptom in the diagnostic criteria of the International Study Group for Behçet’s Disease [35]. Recent genetic studies have suggested that oral ulcers represent the immnopathophysiolgy of BD [23,25,28–30,32,36]. During the last decade, genome-wide association study (GWAS) and subsequent detail genetic studies have identified several BD susceptibility genes, most of which are involved in both the innate and acquired immunity systems [23,25,28–30,32] (Table 2). These studies have contributed to clarification of the immunopathophysioloy of BD. Interestingly, a GWAS in patients with recurrent aphthous stomatitis (RAS) has demonstrated that several susceptibility genes are shared between BD and RAS except HLA(36) (Table 2). An association of BD with HLA-B*51 is well established, whereas that of ROS with HLA-DRB1*0103 has been only found in the UK populations [36]. Otherwise, common disease susceptibility genes are found in both the innate and adaptive immune systems (Table 2). These findings raise the possibility of similar immunopathological mechanisms leading to clinical presentation with oral ulcers in the two conditions. Otherwise, based on genetic backgrounds which are responsible for oral ulcers, additional genetic factors such as the HLA and environmental elements might contribute to the development of BD. Thus, it is plausible that effective strategies for oral ulcers also attenuate the other manifestations of BD.

Apremilast is widely used medication in patients with psoriasis and psoriatic arthritis [12,13,16], which have some clinical and immunopathological similarities with BD [20]. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) strongly recommends apremilast for patients with peripheral arthritis who have an inadequate response to csDMARD(37) . It is also recommended conditionally for csDMARD naïve patients and those with an inadequate response to bDMARD [37]. Previous studies including RELIEF showed a trend of the improvement of peripheral arthritis in BD patients [10].

Clinical efficacy of apremilast for skin manifestations in psoriasis is not a referral for those in BD because the skin lesions are quite different between the two diseases. Rather, favorable outcomes in other skin diseases such as hidradenitis suppurativa and chronic recalcitrant erythema nodosum leprosum may encourage the use for cutaneous lesions in BD [38,39].

Of the serious organ manifestations, the gastrointestinal involvement might be a possible target of apremilast becasue PDE4 inhibitors have shown beneficial effects in experimental models of murine colitis [13,15]. The clinical trials of tetomilast, a PDE4 inhibitor, failed to show significant efficacy for ulcerative colitis, though a trend toward decreasing the severity of bleeding was noted in the tetomilast group [15]. A phase II clinical trial of apremilast is ongoing in ulcerative colitis. Although mild diarrhea and nausea are common as adverse events of apremilast, at least the agent does not appear to be a contraindication for BD patients with the gastrointestinal involvement.

In the central nervous system (CNS), microglia play an important role in maintaining immunohomeostasis and can be a target of PDE4 inhibition in neuroinflammation [40]. However, apremilast does not penetrate the blood-brain barrier. Both favorable and unfavorable effects of apremilast on CNS are considered few in BD patients.

Conclusion

Current evidence shows that the therapeutic target of apremilast is only recurrent oral ulcers, but not the other symptoms in BD patients. However, as recent genetic studies have suggested that oral ulcer is a constitutional condition in BD, the agent has more diverse potential in treating various symptoms of BD as discussed here. Further studies in the real world would be helpful to answer this issue.

Conflict of interest

The author has served as a consultant for Celgene Corporation and as a speaker for AbbVie, Eisai, and Tanabe-Mitsubishi.

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Additional information

Funding

This work is partly supported by grants from Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research [#17K0990], and the Behçet’s Disease Research Committee, Research on Specific Disease of the Health Science Research, the Ministry of Health, Labor, and Welfare.