Effects of apremilast on pustulotic arthro‐osteitis in a real‐world setting: Report of five cases

Dear Editor, Pustulotic arthro-osteitis (PAO) is a chronic refractory arthritis which is observed in 10–30% of patients with palmoplantar pustulosis (PPP) (Yamamoto, 2019). Although guselkumab is recently approved for PPP/PAO, its effects on the joint manifestation in a real-world setting is not yet unknown, and because of the high cost of guselkumab, there are many patients with PAO who cannot benefit from biologic therapy. In this study, we report on five patients with PAO/PPP who were treated with apremilast. All of the patients were female, and age ranged between 42 and 70 years, with a mean age of 53.4. Two patients developed PPP lesions prior to the onset of arthralgia, and three patients developed PAO almost simultaneously with PPP. The number of current, previous, and never smokers was 2, 1, and 2, respectively. One patient suffered from Grave's disease. One patient underwent tonsillectomy and one patient had odontogenic infection and underwent dental treatment; however, joint manifestation persisted. Bone scintigraphy revealed increased uptake in the sternocostoclavicular (n = 4), temporomandibular (1), and sacroiliac (1) joints, as well as peripheral joints such as wrist and ankle (1) and finger (2). Four patients were treated with apremilast monotherapy (30 mg twice a day) after initial titration, whereas in the remaining one patient, oral prednisolone was administered in the rheumatology department. Effect of apremilast on the joint pain was assessed by visual analogue scale (VAS) before and after apremilast treatment. The observed period was between 2 and 6 months. Dramatic effect was observed in two patients, whose pain VAS score was reduced to 0 and 10% of the pretreatment scores. Moderate effect was obtained in one patient, whose pain VAS was reduced to 30% of the previous scores. Mild effect was observed in one patient, which reduced to 80%; however, her joint pain worsened after discontinuation of apremilast. In the remaining case, apremilast resulted in no effects on severe joint pain. In one patient, the dose of apremilast was reduced to 30 mg per day due to diarrhea. The results are shown in Table 1. Joint manifestation known as PAO is a major comorbidity of PPP. The clavicles, sternum, and sternoclavicular joints are mostly affected, but peripheral joints are also involved. Although oral medicine such as retinoid, cyclosporine, methotrexate, colchicine, and antibiotics, as well as apheresis therapy, have been used, treatment for PAO is not easy. A recent Phase 3 trial demonstrated that guselkumab (both 100 and 200 mg) treatment for PAO resulted in a significant improvement in EQ-5D VAS score (Terui et al., 2019); however, not all patients agree with biologic therapy due to high cost. PAO is also often triggered by focal infections, and mitigated by systemic administration of antibiotics or the surgical treatment of focal infections, such as tonsillectomy (Yamamoto, 2019). By contrast, our patients suffered from joint pain even after tonsillectomy (n = 2) and dental treatment (n = 1). Apremilast blocks phosphodiesterase-4, which regulates immune and inflammatory process through modification of the levels of intracellular cyclic adenosine monophosphate, protein kinase A, and various inflammatory cytokine production. To date, only a few cases have been reported on apremilast therapy for PAO or SAPHO syndrome (Adamo et al., 2018; Eto, Nakao, & Furue, 2019; Takama et al., 2019). Recently, Eto et al. (2019) reported that apremilast was effective for PPP in three patients, in one of whom apremilast was also effective for PAO. By contrast, in our cases, the effects of apremilast were not parallel in the skin and joint manifestations. Apremilast showed favorable effects on arthralgia in four cases, whereas none of their palmoplantar or nail lesions showed much improvement, although two of whom had slight skin lesions only before apremilast administration. The reason why the effects of apremilast were not parallel in the skin and joint lesions is currently unknown, but apremilast may be one of the effective new therapies for PAO, which severely impairs patients' quality of life.