Acetaminophen as a possible safer alternative for reducing prostaglandin E2-major urinary metabolites concentrations and alleviating joint pain in pachydermoperiostosis

Pachydermoperiostosis (PDP) is an autosomal recessive hereditary disease that predominantly affects males, characterized by three distinctive diagnostic features: digital clubbing, periostosis, and pachydermia of the face.¹ Severe pachydermia can lead to ridges and furrows of the scalp, giving rise to a cerebriform appearance termed cutis verticis gyrata (CVG).¹ PDP is classified into three subcategories: a complete form presenting the full-blown phenotype, including CVG; an incomplete form with three diagnostic features without CVG; and a forme fruste with pachydermia without or with minimal periostosis.¹ PDP arises from prostaglandin E2 (PGE2) excess due to variations in two genes: HPGD and SLCO2A1.^{2, 3} The concentration of PGE2-major urinary metabolites (PGE-MUM) reflects that of serum PGE2 and is positively correlated with the severity of SLCO2A1-mutated PDP.⁴ PDP patients can be complicated by hyperhidrosis, arthralgia, or chronic enteropathy associated with SLCO2A1 (CEAS).⁴

Etoricoxib, a selective cyclooxygenase-2 inhibitor (COX-2i), decreases serum PGE2 levels and alleviates pachydermia and arthralgia in PDP patients.^{5, 6} However, COX-2i has been found to induce mucosal injuries in the small intestine of 33% of healthy volunteers, suggesting potential hazards for individuals with SLCO2A1 mutations at risk for CEAS.^{7, 8} Here, we report a complete form PDP patient with a history of total colectomy who experienced benefits from acetaminophen.

Our patient, previously reported,^{4, 9} presented with hyperostosis, digital clubbing, and pachydermia accompanied by CVG (Figure 1). The patient carried compound heterozygous mutations c.940+1 G > A (p.R288Gfs*7) and c.1807C > T (p.R603*) in SLCO2A1. He developed severe gastrointestinal bleeding and underwent total colectomy at the age of 19. Since the age of 28, he had been suffering from chronic arthralgia. The arthralgia was relieved with oral celecoxib at 400 mg/day, but it was terminated because of stomachache. Alternatively, acetaminophen was initiated at varying dosages ranging from 0 to 2000 mg/day, depending on the severity of arthralgia. Three years later, capsule endoscopy was performed due to stomachache and found obliquely to annular ulcers in the ileum. Possible diagnoses included intestinal tuberculosis, Crohn's disease, intestinal Behcet's disease, drug-induced enteritis, and CEAS. The absence of caseating granuloma, cobblestone appearances, or repeated genital ulcerations suggests less likely the former three diseases, respectively. Drug-induced enteritis was unlikely because resuming the acetaminophen did not reproduce the abdominal pain. Diagnosis of CEAS was suggestive but inconclusive because the colon mucosa was inaccessible due to the total colectomy performed in the past. Without treatment, the mean concentration of PGE-MUM was 236.0 µg/g creatinine (n = 5; mean 236.0 [range 134.0–307.0]) (Figure 2). PGE-MUM decreased to 59.8 µg/g creatinine during celecoxib treatment. Subsequently, after the initiation of acetaminophen, the mean concentration of PGE-MUM decreased to 89.7 µg/g creatinine (n = 17; mean 89.7 [range 43.5–139.0]). Acetaminophen also ameliorated arthralgia.

COX-2i causes fewer gastrointestinal injuries compared to traditional nonsteroidal anti-inflammatory drug but this does not apply to long-term use.⁸ Therefore, it is advisable to conduct capsule endoscopy and schedule blood tests when administering COX-2i to PDP patients.⁸ Acetaminophen has similar spectrum of actions to COX-2i, with weaker analgesia but superior tolerability. The effectiveness of acetaminophen varies depending on the levels of arachidonic acid and peroxides.¹⁰ At high peroxide levels, acetaminophen has no anti-inflammatory activity as observed in rheumatoid arthritis or acute gout.¹⁰ Herein, we observed the efficacy of acetaminophen against arthralgia of PDP. As limitations, we monitored a single patient and did not conduct a statistical assessment to validate the safety of acetaminophen.

In summary, instead of a COX-2i, acetaminophen can be a favorable option for safely diminishing PGE-MUM levels and improving arthralgia in PDP patients with a higher risk of peptic ulcers, including CEAS. Further investigations are required to identify an optimal PGE-MUM concentration cut-off, which achieves improved clinical symptoms.

Takegami, Nomura, Niizeki, and Kabashima had complete access to all the study data, and they bear full responsibility for the data's integrity and the accuracy of the data analysis. Acquisition, analysis, or interpretation of data: Takegami, Nomura, Yoshikawa, Niizeki, and Kabashima. Manuscript drafting: Takegami, Nomura, Yonekura, Senda, Niizeki, and Kabashima. Critical revision of the manuscript for significant intellectual content: Takegami, Nomura, Niizeki, and Kabashima. Pachydermoperiostosis diagnosis: Niizeki, Yoshida, Seki, Nakabayashi.Guidance on digestive symptoms: Hisamatsu, Kitamoto, Yamamoto, Honzawa, Seno. Administrative, technical, or material support: Nomura, Niizeki, and Kabashima. Supervision: Nomura, Niizeki, and Kabashima.

The authors declare no conflict of interest.

The ethical committee approval is not required because this study is a single case report. All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication.