Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial

Abstract

Background Primary hypertrophic osteoarthropathy (PHO) is a rare disease involving joint, bone and skin. Two underlying genes responsible for this disease—hydroxyprostaglandin dehydrogenase ( HPGD ) and solute carrier organic anion transporter family, member 2A1 ( SLCO2A1 )—are both associated with aberrant accumulation of prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is a key enzyme in PGE2 synthesis. This study was intended to evaluate the safety and efficacy of COX-2 inhibitor in the treatment of PHO. Methods We recruited patients presenting to Peking Union Medical Hospital between January 2009 and December 2016 who were diagnosed with PHO. Participants were given the COX-2 inhibitor etoricoxib (60 mg once daily) and followed up for 9 months. Gene analysis was performed at baseline. The following data were collected at baseline and during treatment: visual analogue score (VAS), volume of the distal middle finger (VDMF), knee joint circumference (KJC), serum and urinary levels of prostaglandin E2 (PGE2) and PGE metabolite (PGE-M) and serum levels of inflammatory markers. Results A total of 27 patients were recruited, including seven patients with PHO type I (PHOAR1) carrying HPGD gene mutations and 20 patients with PHO type II (PHOAR2) carrying SLCO2A1 gene mutations. After treatment with etoricoxib, the majority of patients experienced resolution of symptoms including pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%) and hyperhidrosis (55.0%). In both the PHO subtypes, serum and urinary levels of PGE2 were elevated at baseline and declined sharply upon treatment. For PHOAR1 patients, serum and urinary PGE-M levels were relatively low and demonstrated minimal response to COX-2 inhibition. Among PHOAR2 patients, mean serum and urinary levels of PGE-M presented at a high level at baseline and were normalized after 3 months of treatment. No severe adverse effects were reported during the study period. Conclusions We found COX-2 inhibitor to be safe and effective for the treatment of PHO in our cohort. The translational potential of this article The underlying genes responsible for PHO suggest COX inhibitor as potential therapy, and our study demonstrates the efficacy and safety of this treatment.

The first case of primary hypertrophic osteoarthropathy with soft tissue giant tumors caused by HPGD loss-of-function mutation

“…The PHO-related symptoms including joint swelling and hyperhidrosis, as well as the increased biochemical markers including ALP, β-CTX, hsCRP and IL-6 have also been markedly improved within 6 months. These findings were in agreement with the Li and Yuan’s study (21, 23). Interestingly, though the soft tissue tumor persisted, it has not grown since COX-2 inhibitor treatment, indicating the PGE 2 might play a central role in tumor progression of PHO patient.…”

“…We reviewed all 51 HPGD mutant patients (PHOAR1) reported before and found almost all of these PHOAR1 patients have digital clubbing (50/51, 98%) and periostosis (51/51, 100%). Besides, accompanying abnormalities such as hyperhidrosis (41/51, 80.4%), joint swelling (30/51, 58.8%), various forms of pachydermia (28/51, 54.9%) and arthralgia (22/51, 43.1%) have also been seen in a proportion of the PHOAR1 patients (1, 21, 22, 23, 25, 29, 34, 35, 36). Consistent with Hou’s study (27), gastrointestinal complications, peptic ulcer, chronic gastritis, anemia and myelofibrosis which were only presented in PHOAR2 patients, were absent in these PHOAR1 patients.…”

“…Currently, the most commonly used drugs were NSAIDS, since they were effective in alleviating arthritis and easing bone pain. Recently, the novel selective COX-2 inhibitors, etoricoxib, which not only suppress COX-2-derived PGE 2 synthesis and lower PGE 2 levels from upstream, but also improve biochemical selectivity over that of other selective COX-2 inhibitors (41, 42), has been shown to have a positive therapeutic effect on PHO patients in some clinical studies (21, 23). Indeed, the serum and urinary PGE 2 in our patient were decreased after 6-month etoricoxib treatment, confirming its efficacy to treat this disease based on pathogenic considerations.…”

“…Recently, COX-2 selective inhibitors, which inhibit the COX-2 enzyme and thereby suppress PGE 2 biosynthesis, represent promising treatment options for PHO. A few studies have shown that etoricoxib, a novel COX-2 selective inhibitor, has a positive therapeutic effect on PHO patients in terms of decreased urinary PGE 2 levels and improvement of clinical phenotypes including pachydermia, clubbing finger and joint swelling (21, 22, 23).…”

Klinische, diagnostische und therapeutische Aspekte der Pachydermoperiostose (PDP): Ein Fallbericht

“…Allgemeine Erwähnung in der Literatur findet die symptomatische Therapie mit Korticosteroiden und Colchicin [5], wobei entsprechende Studien unseres Wissens fehlen. Eine Studie von Yuan et al mit kleiner Fallzahl (n = 27) zeigte einen positiven Effekt von Etoricoxib auf Prostaglandin E2Spiegel, Arthralgie, Pachydermie und Trommelschlägelfinger [15]. In Einzelfällen ist ein positiver Effekt von oralem Aescin, Zoledronat sowie arthroskopischer Synovektomie beschrieben [16].…”