The pachydermoperiostosis prostaglandin paradigm
By Warren R. Heymann, MD
Prostaglandins were the rage when I started medical school in 1975; their role in inflammatory dermatoses was considered of paramount importance throughout my residency in the early 1980s. Hours were spent studying the transformation of arachidoinic acid to prostaglandins and leukotrienes, via the respective cyclo-oxygenase and lipoxygenase pathways. In his 1982 Ingram Lecture, Malcom Greaves stated: “The story of prostaglandins (PGs) is in itself a remarkable one, beginning in 1935 with semen and arriving in 1982 in the skin, with a long way to go yet.” (1)
This commentary was inspired by a case report with an impressive result, based on understanding molecular mechanisms, leading to treatment modifying of an “old” pathway — the rapid improvement of pachydermoperiostosis (PDP) with etoricoxib (a COX-2 inhibitor). (2)
PDP (aka primary hypertrophic osteoarthropathy or Touraine‐Solente‐Gole syndrome) is a rare genetic disease, with a reported prevalence of 0.16%. Primary clinical features include pachydermia (thickening of skin), clubbing of the digits, and periostosis (new bone formation). In 1935, three French dermatologists, Touraine et al, classified the entity as a familial disorder with three forms: complete (periostosis and pachyderma), incomplete (without pachyderma), and the forme fruste (pachydermia with minimal skeletal changes). Primary PDP usually manifests in adolescence, occurring almost exclusively in males, with a male: female ratio of 7:1. Other features that may accompany PDP are considered minor criteria: cutis verticis gyrata, hyperhidrosis, seborrhea, acne, flushing, arthralgia, joint effusion, and column-like legs. (3,4)
Secondary PDP is far more common that the familial disorder; it occurs as a secondary manifestation of pulmonary or extrapulmonary (cardiac, gastrointestinal, hepatobiliary, hematological) chronic diseases and malignancies. Hypertrophic osteoarthropathy associated with pulmonary pathology is also known as hypertrophic pulmonary osteoarthropathy (HPOA). The common age of presentation is 55 to 75 years, without racial or gender predominance. Ninety percent of reported HPOA is associated with malignancy. Non-small cell lung cancer is the most common cause of secondary hypertrophic osteoarthropathy. (5)
Primary PDP is inherited as an autosomal recessive disorder, although autosomal dominant transmission has been described in some families with incomplete penetrance. Recent molecular studies identified a mutation in the hydroxyl‐prostaglandin dehydrogenase (HPGD) gene, encoding a prostaglandin E2 (PGE2) catabolizing enzyme. Another mutation has been found in the SLCO2A1 gene (solute carrier organic anion transporter family member 2A1), which encodes a prostaglandin transporter responsible for uptake of PGE2. Mutations in these two genes result in higher levels of PGE2 when compared to healthy controls. (6) Pachydermia severity and the associated histological changes are correlated with serum PGE2 levels. Elevated PGE2 levels are hypothesized to induce cytokine-mediated tissue remodeling and vascular stimulation, by platelet-derived growth factor (PDGF) and vascular endothelial growth factor, respectively. (2,4)
Despite stabilizing over time, PDP’s effect on quality of life may be profound. Unfortunately, no specific therapies for primary PDP exist. Therapeutic options have included NSAIDs, systemic corticosteroids, colchicine, isotretinoin, botulinum toxin, and plastic surgery. (3,7) The main thrust of managing secondary PDP is treating the primary disease process, such as associated malignancies, which, if successful, improve the appearance of PDP. (5)
As stated earlier, the impetus for this commentary was the report of dramatic improvement of PDP in a 26-year-old Chinese man due to a mutation in the SLCO2A1 gene, treated with the COX-2 inhibitor etoricoxib. Improvement started within a week of treatment. (2) This drug is not available in the United States, however, should I see such a patient, or even with a forme fruste of the disorder such as cutis verticis gyrata, I will strongly consider the use of celecoxib. Alesandrella et al reported the case of a 17-year-old man with PDP due to a novel mutation of the SLCO2A1 gene, who demonstrated striking improvement with hydroxychloroquine over 18 months. (6) Hydorxychloroquine has only a mild inhibitory effect on cyclo-oxygenases (8); presumably other anti-inflammatory mechanisms may be responsible for its efficacy.
Prostaglandins may no longer be in vogue, but their biologic effects are vital nevertheless. Although two case reports may not change the therapeutic paradigm for primary or secondary PDP, they open new vistas for therapy and research for these significant disorders.
Point to remember: Inhibiting prostaglandin E2 (PGE2), either by COX-2 inhibition, or possibly by hydroxychloroquine, may be a valuable therapeutic option for patients with pachydermoperiostosis.
Our expert’s viewpoint
By Ian Coulson, BSc, MBBS, FRCP
Being of the same vintage as Dr. Heymann, prostaglandins and leukotrienes were the source of considerable research. Indeed, I recall having an intradermal infusion of 5 HETE and a skin biopsy taken 24 hours later — the histologic picture showed features of acute psoriasis. The research was headed by Malcolm Greaves, one of my first teachers in dermatology, who had the enviable talent for seeing the implications of basic science advances in dermatology. It is nice to see further fruits of basic research to the unusual condition of pachydermoperiostosis. For sufferers developing clubbing, hand hyperhidrosis, swollen wrists, etc., hitherto there has been little to offer by way of therapy. A simple safe therapy as discussed will be welcomed if confirmed by other studies.