Trial of Apremilast for Oral Ulcers in Behçet’s Syndrome

Hatemi, Gülen; Mahr, Alfred; Ishigatsubo, Yoshiaki; Song, Yeong Wook; Takeno, Mitsuhiro; Kim, Doyoung; Melikoğlu, Melike; Cheng, Sunfa; McCue, Shannon; Paris, Maria; Chen, Mindy; Yazıcı, Yusuf

doi:10.1056/nejmoa1816594

Cited by 139 publications

(120 citation statements)

References 15 publications

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“…However, this trial did not provide enough information on previous therapies and extra-mucocutaneous manifestations. A recent phase III trial has shown signi cant improvement of pain and number of oral ulcers in 104 patients treated with APR, resolution maintained over 12 weeks and in many cases also resolution of genital ulcers [16]. Because of that, the U.S. FDA has recently approved APR for BD ulcers (www.fda.gov).…”

Section: Discussionmentioning

confidence: 99%

“…Also, the time of follow-up was not very long. Moreover, to the best of our knowledge, both trials used APR in monotherapy and they did not assess the effect of APR on extra-mucocutaneous manifestations of BD [15,16]. Thus, the strict criteria required for inclusion may constitute a limitation at the time of considering APR in real-life patients.…”

Section: Discussionmentioning

confidence: 99%

“…Because of that, features of RCTs may differ from those of clinical practice, which could in uence the results of the treatment [14]. Two randomized double-blinded phase II and III clinical trials have shown e cacy and safety of APR for oral ulcers of BD [15,16]. Based on these trials, the U. S. Food and Drug Administration (FDA) has recently approved APR for the treatment of oral ulcers associated with BD (www.fda.gov).…”

Section: Introductionmentioning

confidence: 99%

“…addition, all patients had received csDMARDs, and in many cases bDMARDs. The csDMARDs and dosages were the following: methotrexate (MTX) (n = 27, median dose [IQR] 15[15][16][17][18][19][20] mg s.c. or p.o./week), azathioprine (AZA) (n = 24, median dose [IQR] 100 [100-150] mg p.o./day), cyclosporine A (n = 9, median dose [IQR] 200 [175-225] mg p.o./day), dapsone (n = 6, median dose [IQR] 100 [100-175] mg p.o./day), cyclophosphamide (n = 3, i.v. pulses of 500 mg every 15 days for 3 months), sulfasalazine (SSZ) (n = 3, 2 g p.o./day), hydroxychloroquine (HCQ) (n = 2, 200 mg p.o.…”

mentioning

confidence: 99%

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Apremilast in refractory orogenital ulcers and other manifestations of Behçet's disease. National multicenter study of 51 cases in clinical practice.

Atienza‐Mateo

Martín-Varillas

Gil

et al. 2020

Preprint

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Background Oral and/or genital aphthous ulcers are the most common symptoms of Behçet´s disease (BD), and are often refractory to conventional treatment. The inhibitor of phosphodiesterase-4 apremilast (APR) has demonstrated efficacy in the treatment of this manifestations. The objective of the present study was to assess the efficacy of APR in the management of refractory oral and/or genital ulcers in patients with BD. Methods National multicenter open-label observational study on BD patients with recurrent oral and/or genital ulcers. In all cases orogenital ulcers were refractory to conventional therapy. APR was given and maintained at standard dose of 30 mg twice daily. The main outcome was the achievement of oral and/or genital ulcers remission. Efficacy of APR for other clinical manifestations was also evaluated. Results We included 51 patients (35 women/16 men; mean age 44.7 ± 13.2 years). Before APR, all patients had received several systemic conventional and/or biologic drugs. APR was initiated because of refractory oral (n = 19) or genital (n = 2) aphthous ulcers or both (n = 30). Other manifestations found at APR onset were arthralgia/arthritis (n = 16), folliculitis/pseudofolliculitis (n = 14), erythema nodosum (n = 3), furunculosis (n = 2), paradoxical psoriasis induced by TNFα-inhibitors (n = 2), ileitis (n = 2), deep venous thrombosis (n = 2), leg ulcers (n = 1), erythematosus and scaly skin lesions (n = 1), fever (n = 1), unilateral anterior uveitis (n = 1) and neurobehçet (n = 1). After a mean follow-up of 8.5 ± 6.9 months, most patients had experienced improvement of orogenital ulcers and prednisone dose had been successfully reduced or discontinued. APR also yielded improvement of some non-aphthous manifestations such as the cutaneous follicular and intestinal manifestations. However, the effect on musculoskeletal manifestations was variable. Conclusion APR yielded a rapid and maintained improvement of refractory mucocutaneous ulcers of BD, even in patients refractory to several systemic drugs including biologic therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Apremilast in refractory orogenital ulcers and other manifestations of Behçet's disease. National multicenter study of 51 cases in clinical practice.

Atienza‐Mateo

Martín-Varillas

Gil

et al. 2020

Preprint

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“…14 In a double-blind, randomized, phase 3, controlled study, the area under the curve of the total number of oral ulcers was significantly decreased after 12 weeks of apremilast (n = 104) compared with placebo (n = 103) (P < 0.0001). 15 In addition, the reduction in pain from the baseline and the complete remission rate were larger with apremilast (both P < 0.0001). Based on these findings, apremilast is recommended for oral aphthous ulcers in Behc ßet's disease.…”

Section: Cq7 Is Apremilast Effective For Oral Aphthous Ulcers In Behmentioning

confidence: 88%

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication

Nakamura

Iwata

Asai

et al. 2020

The Journal of Dermatology

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In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long‐term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.

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Common Oral Conditions

Stoopler,

Villa,

Bindakhil

et al. 2024

JAMA

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ImportanceDry mouth, oral candidiasis, and recurrent aphthous ulcers are 3 of the most common oral conditions that may be associated with patient discomfort, decreased quality of life, and morbidity.ObservationsIn a meta-analysis of 26 population-based cohort and cross-sectional studies, the global prevalence of dry mouth symptoms was 23% (95% CI, 18% to 28%), placing individuals at risk of oral candidiasis, dental caries, dysgeusia, masticatory/speech impairment, and oropharyngeal dysphagia. Dry mouth is associated with using more than 3 oral medications per day (odds ratio [OR], 2.9 [95% CI, 1.4 to 6.2]), head and neck radiation, and Sjögren disease. Symptoms may include difficulty swallowing and speaking, thirst, and halitosis. Dry mouth is associated with an 11.5% (95% CI, 3.6% to 27%) higher risk of oral candidiasis, based on a meta-analysis of 6 observational cohorts. Management of dry mouth includes mechanical salivary stimulants, oral moisturizers, and/or systemic sialagogues. Oral candidiasis is an opportunistic fungal infection caused by overgrowth of the Candida genus with C albicans, which accounts for 76.8% of infections. The prevalence of oral candidiasis is higher in patients who are immunosuppressed, for example, those with HIV (35% [95% CI, 28% to 42%]) and those with salivary gland hypofunction (OR, 3.02 [95% CI, 1.73 to 5.28]). Common risk factors associated with oral candidiasis include use of antibiotics (P = .04) and oral mucosal disorders such as lichen planus. Oral burning and dysgeusia are common symptoms of oral candidiasis. Treatment includes addressing risk factors and use of topical and/or systemic antifungal medications. Recurrent aphthous stomatitis is characterized by symptomatic round or oval oral ulcers, which are covered by a gray-white fibrin layer and encircled by an erythematous ring. A meta-analysis of 10 case-controlled studies revealed an increased risk of recurrent aphthous stomatitis associated with polymorphism of IL-1β (+3954C/T) (OR, 1.52 [95% CI, 1.07 to 2.17]) and IL-1β (−511C/T) (OR, 1.35 [95% CI, 1.09 to 1.67]). Another meta-analysis of 9 case-control studies reported that patients with recurrent aphthous stomatitis had a higher frequency of nutritional deficiencies, including vitamin B12 (OR, 3.75 [95% CI, 2.38 to 5.94]), folic acid (OR, 7.55 [95% CI, 3.91 to 14.60]), and ferritin (OR, 2.62 [95% CI, 1.69 to 4.06]). Recurrent aphthous stomatitis can be associated with systemic diseases. A meta-analysis of 21 case-control studies revealed that celiac disease is associated with a higher incidence of recurrent aphthous stomatitis (25% vs 11%; OR, 3.79 [95% CI, 2.67 to 5.39]; P &lt;.001). Topical corticosteroids are first-line agents to manage recurrent aphthous stomatitis; however, systemic medications may be necessary in more severe cases.Conclusions and RelevanceDry mouth, oral candidiasis, and recurrent aphthous ulcers are common oral conditions that may be associated with patient discomfort, decreased quality of life, and morbidity. First-line treatment includes over-the-counter sialagogues for dry mouth, topical antifungals for oral candidiasis, and topical corticosteroids for aphthous ulcers. Oral conditions that do not improve with first-line treatment may require treatment with systemic medications.

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Trial of Apremilast for Oral Ulcers in Behçet’s Syndrome

Cited by 139 publications

References 15 publications

Apremilast in refractory orogenital ulcers and other manifestations of Behçet's disease. National multicenter study of 51 cases in clinical practice.

Apremilast in refractory orogenital ulcers and other manifestations of Behçet's disease. National multicenter study of 51 cases in clinical practice.

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication

Common Oral Conditions

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